Title of Invention

PROCESS FOR MAKING OPHTHALMIC LENSES

Abstract The present invention relates to aqueous processes for the production of silicone hydrogel contact lenses.
Full Text PROCESS FOR MAKING OPHTHALMIC LENSES
FIELD OF THE INVENTION
This invention relates to aqueous processes for making silicone
hydrogel contact lenses that do not cause ocular discomfort.
BACKGROUND OF THE INVENTION
It is well known that contact lenses can be used to improve
vision. Various contact lenses have been commercially produced for many
years. Hydrogel contact lenses are very popular today. These lenses are
often more comfortable to wear than contact lenses made of hard materials.
Malleable soft contact lenses can be manufactured by forming a lens in a
multi-part mold where the combined parts form a topography consistent with
the desired final lens. Contact lenses made from silicone hydrogels have
been disclosed. However, many of the raw materials which are used to
make silicone hydrogel contact lenses have impurities which cannot be
efficiently removed using the conventional water and saline based leaching
steps.
Some early disclosed methods used only water. However, these
early processes used extremely long water leaching and/or high
temperatures to extract undesirable components. No clinical data on the
resulting lenses is available to confirm removal of undesirable impurities.
Processes for removing undesired impurities from silicone hydrogel
lenses via leaching steps using alcohols have been disclosed. The alcohols
can sting the eye and must be completely removed from the contact lens.
Special handling steps must be taken to dispose of the alcohols making the
manufacturing process more expensive. Moreover; the use of organic
solutions can present drawbacks, including, for example: safety hazards;
increased risk of down time to a manufacturing line; high cost of release
solution; and the health hazards associated with organic solvents.

While modifying the leaching process is possible, it would be
desirable to find silicone hydrogel materials which are free of impurities
which cause undesirable ocular reactions, such as stinging.
SUMMARY OF THE INVENTION
The present invention relates to a process comprising
(a) curing in a mold a reaction mixture comprising at least one silicone
containing component wherein said reaction mixture is substantially free
from sparingly water soluble components or impurities having a retention
time, relative to TRIS of less than about 0.9 to form a lens;
(b) contacting said lens and mold with an aqueous solution at a
temperature less than 99°C for less than about 1 hour, to release said lens
from the mold and
(c) optionally post processing the lens, wherein said post processing,
if conducted, is conducted with aqueous solutions for a time less than 6
hours.
DETAILED DESCRIPTION OF THE INVENTION
It has been found that silicone hydrogels can be made via an
aqueous hydration process so long as certain impurities are kept below an
amount which causes ocular discomfort. Specifically, it has been found that
compounds in silicone hydrogel contact lenses which can cause ocular
discomfort are sparingly soluble in water, but have sufficient mobility in tears
or tear components to move from the lens into ocular tissue. Compounds
and impurities which are sparingly soluble in water and are able to move
directly to the ocular tissue when in direct contact with ocular tissue may also
contribute to ocular discomfort. As used herein "sparingly water soluble"
means that less than about 2000 ppm of the compound is soluble in water at
25ºC. These components and impurities are hereinafter referred to as
"sparingly water soluble" or "SWS" components and impurities. When


present as teachable compounds, these SWS compounds are not
completely removed using aqueous solutions in the extraction and hydration
steps of the contact lens manufacturing process. However, SWS
compounds may leach from the contact lens during wear, causing ocular
discomfort to the wearer. Thus it is imperative to insure that no SWS
compounds and impurities remain in the contact lens.
Unfortunately attempts to identify all of the chemical moieties which
cause ocular discomfort have been unsuccessful. However, applicants have
found that the SWS compounds and impurities may be characterized using
liquid chromatography as described herein, and have a retention time
relative to 3-metrmeryloxypropyltris(trirnethylslfoxy)silane ("TRIS"). measured
in an HPLC using mixtures of acetonitrile, water, isopropanol and formate
buffer as the solvent of less than about 0.9. Thus,, applicants have found
that silicone hydrogel contact lenses may be made using aqueous
processing so long as sparingly water soluble compounds or impurities
having relative retention times of less than about 0.9 are substantially
excluded from the reactive mixture or are bound to the lens polymer during
curing.
As used herein retention time means the time from injection of the
sample into an HPLC to the time of the peak of edition. The retention times
used in the present invention are relative retention times measured against
3-methacryloxypropyltris(trimethylsiboxy)silane ("TRIS") using the same
conditions, column and equipment for both TRIS and the sample to be
measured. The use of a relative retention time instead of an absolute
retention time allows for more consistent retention time values regardless of
the specific HPLC system selected.
In the examples, the Applicants used an Agilent 1100 HPLC with a
Thermo ODS Hyperslf column of dimensions 150 x 4.6 mm x 5 Μ, with
attached Finnigan LCQ Classic mass spectrometer with electrospray
ionization in tandem with UV and ELSO (Sedex). While applicants have


used the specifically disclosed equipment, any C18 column and equivalent
equipment will provide results consistent with those claimed herein. The
solvent gradient profile specified in Table 6 should be used to determine the
relative retention times specified herein. The chromatographic analysis is
performed at about 25°C.
Other chromatographic conditions are well known in the art, and will
not affect the results of this test so long as they are within the conditions
commonly used in the art, such as but not limited to tubing volumes.
Samples are prepared by making 2% (wt/wt) solutions of each test
material in isopropyl alcohol. 3 μL of sample solution is injected into the
HPLC, using a flow rate of 1 ml/minute. The eluting solvent for each sample
was varied using the gradient program shown in Table 6 of the Examples.
The contact lenses of the present invention are formed by combining
the desired lens forming components into a reactive mixture. The reactive
mixture comprises the reactive components, initiators, and other desired
components described below. The reactive mixture used to form contact
tenses is substantially free from SWS components and impurities having a
retention time, relative to TRIS of less than about 0.9 and in another
embodiments less than about 0.8.
As used herein "substantially free from SWS compounds and
impurities" means the lens has a concentration of SWS compounds and
impurities insufficient to cause ocular discomfort. Ocular discomfort may be
measured by putting contact lenses on the eyes of at least 10 patients, and
collecting subjective information at initial insertion and after 30 minutes of
wear. As used herein ocular discomfort is a score of leas than about 20%,
preferably less than about 10% and preferably less than about 5% of the
subjects noting discomfort at 30 minutes of wear.
As used herein, "ocular discomfort" means a subjective rating of at
least moderate stinging or burning within 30 minutes of insertion of the
contact lens on the eye.


In one embodiment the reactive mixture comprises SWS compounds
and impurities having a retention time, relative to TRIS specified herein in an
amount of less than about 3000, in another embodiment less than about
1000 ppm, in another embodiment less than about 200 ppm, and in another
embodiment less than about 100 ppm.
In another embodiment the amount in the reactive mixture of SWS
compounds and impurities having the retention time, relative to TRIS
specified herein is not controlled, but the curing conditions are selected to
produce a cured contact lens having less than an ocular discomfort causing
amount of said component or impurity. In one embodiment the less than an
ocular discomfort causing amount of said component or impurity comprises
an amount less than about 2000 ppm based upon the weight of the lens in a
fulty hydrated state.
The reactive mixtures comprise at least one silicone containing
component.
The term components includes monomers macromers and
prepolymers. "Monomer" refers to lower molecular weight compounds that
can be polymerized to higher molecular weight compounds, polymers,
macromers, or prepolymers. The term "macromer" as used herein refers to
a high molecular weight polymerizable compound. Prepolymers are partially
polymerized monomers or monomers which are capable of further
polymerization.
A "silicone-contalning component" is one that contains at least one [-
Si-O-] unit in a monomer, macromer or prepolymer. Preferably, the total Si
and attached O are present in the silicone-containing component in an
amount greater than about 20 weight percent and more preferably greater
than 30 weight percent of the total molecular weight of the silicone-
containing component. Useful silicone-containing components preferably
comprise polymerizable. functional groups such as acrylate, methacryiate,
acrylamide, methacrylamide, vinyl, N-vinyl lactam, N-vinylamide, and styryl


functional groups. Examples of silicone-containing components which are
useful in this invention may be found in U.S. Pat. Nos. 3,808,178; 4,120,570;
4,136,250; 4,153.641; 4,740.533; 5,034,461 and 5.070.215, and EP080639.
These references disclose many examples of olefinic: silicone-containing
components.
While almost any silicone containing component may be included, in
order to provide the lenses of the present invention with the desired
modulus, the majority of the mass fraction of the silicone components used
in the lens formulation should contain only one polymerizable functional
group ("monofunctional silicone containing component"). In silicone
containing lenses, to insure the desired balance of oxygen transmissibility
and modulus it is preferred that all components having more than one
polymerizable functional groups ("multifunctional components") make up no
more than 10 mmol/100 g of the reactive components, and preferably no
more than 7 mmol/100 g of the reactive components. Suitable
monofunctional silicone containing components include
polysiloxanylalkyl(meth)acrylic monomers of Formula I

wherein: R denotes H or lower alky I; X denotes O or NR4; each R4
independently denotes hydrogen or methyl,
each R1-R3 independently denotes a lower alkyl radical or a phenyl radical
and
n is 1 or 3 to 10.
Mono-functional polydimethylsiloxanes (mPDMS) may also be used.
Suitable mPDMS compounds include Structure II:



where b = 0 to 100, where it is understood that b is a distribution having a
mode equal to a stated value, preferably 2 to 16, more preferably 3 to 10;
R56 is a monovalent group containing at least one ethylenically unsaturated
moiety, preferably a monovalent group containing a styryf, vinyl, or
methacrylate moiety, more preferably a methacrylate moiety; each R56 is
independently a monovalent alkyl, or aryl group, which may be further
substituted with alcohol, amine, ketone, carboxylic acid or ether groups,
preferably unsubstituted monovalent alkyl or aryl groups, more preferably
methyl; Rao is a monovalent alkyl, or aryl group, which may be further
substituted with alcohol, amine, ketone, carboxylic acid or ether groups,
preferably unsubstituted monovalent alkyl or aryl groups, preferably a C1-10
aliphatic or aromatic group which may include hetero atoms, more preferably
C3-8 alkyl groups, most preferably butyl; and R61 is independently alkyl or
aromatic, preferably ethyl, methyl, benzyl, phenyl, or a monovalent siloxane
chain comprising from 1 to 100 repeating Si-O units. Examples of suitable
mPDMS compounds include 3-methacryloxy-2-
hydroxypropyloxy)propylbis(trimethylsitoxy)methy(silane,
monomethacryloxypropyl terminated mono-n-butyl terminated
polydimethylsiloxane, methacryloxypropylpentarnethyt dislloxane,
combinations thereof and the like.
Examples of polysiloxanylalkyl (meth)acrylic monomers include
methacryloxypropyl tris(trimethysiloxy) silane, pentamethyldisiloxanyl

methylmethacrylate, and methyldi(trimethyisiloxy)methacryloxymethyl silane.
Methacryloxypropyl tris(trimethylslioxy)silane is the most preferred.
In some embodiments monofunctional poiydimethylsiloxanes may be
preferred, as they lower not only modulus, but also tan 6, white bulky
silicones, such as those containing at least one branching trimethytslioxy
group will increase tan 6. Accordingly, at least about 30 and preferably at
least about 60 weight% of all the silicone components should be non-bulky
silicone containing compounds such as polydimethyisiloxanes.
In one embodiment, where a silicone hydrogel lens is desired, the
lens of the present invention will be made from a reactive mixture comprising
at least about 20 and preferably between about 20 and 70%wt silicone
containing components based on total weight of reactive-monomer
components from which the polymer is made.
In addition to the monofunctional silicone containing components,
multifunctional silicone containing components and/or bulky silicone
containing compounds may also be included in amounts which do not impart
an undesirably high modulus and/or tan 6.
One class of silicone-containing components is a .
poly(organosiloxane) prepolymer represented by formula III:
Formula III
wherein each A independently denotes an activated unsaturated group, such
as an ester or amide of an acrylic or a methacrytic acid or an alkyl or aryl
group (providing that at least one A comprises an activated unsaturated
group capable of undergoing radical polymerization); each of R5, R6, R7 and
R8 are independently selected from the group consisting of a monovalent
hydrocarbon radical or a halogen substituted monovalent hydrocarbon


radical having 1 to 18 carbon atoms which may have ether linkages between
carbon atoms;
R9 denotes a divalent hydrocarbon radical having from 1 to 22 carbon
atoms, and
m is 0 or an integer greater than or equal to 1, and preferable 5 to
400, and more preferably 10 to 300. One specific example is a, ω-
bismethacryloxypropyl polydimethylsiloxane.
Another useful class of silicone containing components includes
silicone containing vinyl carbonate or vinyl carbamate monomers of the following formula:
Formula III

wherein: Y denotes O, S or NH; Rsi denotes a silicone-containing organic
radical; R denotes
hydrogen or methyl; d is 1, 2, 3 or 4; and q is 0 or 1. Suitable silicone-
containing organic radicals Rsi include the following:
(CH2)q•Si[(CH2)8.CH3]b
(CH2)qSI[OSi((CH2)8CH3)3]3


Wherein p is 1 to 6; R10 denotes an alkyl radical or a fluoroalkyl
radical having 1 to 6 carbon atoms; e is 0 to 200; q' is 1, 2, 3 or 4; and s is 0,
1.2, 3,4 or 5.
The silicone-containing vinyl carbonate or vinyl carbamate monomers
specifically include: 1,3-bis[4-(vinyloxycarbonyloxy)but-1-yl]tetramethyl-
disiloxane; 3-(vinyloxycarbonylthk>) propyl-[tris (trimethylsiloxy)silane]; 3-
[tris(trimethylsiloxy)silyl] propyl allyl carbamate; 3-[tris(trimethylsiloxy)silyl]
propyl vinyl carbamate; trimethylsilylethyl vinyl carbonate;
trimethylsliylmethyl vinyl carbonate, and

Another class of silicone-containing components includes
polyurethane macromers of the following formulae:
Formulae IV-VI
(*D*A*D*G). *D*D*E1;
E(*D*G*D*A), *D*G*D#E1 or;
E(*D*A*D*G). *D*A*D*E1
wherein:
D denotes an alkyl diradical, an alkyl cycloalkyl diradical, a cycloalkyl
diradical, an aryl diradical or an alkylaryl diradical having 6 to 30 carbon
atoms,
G denotes an alkyl diradical, a cycloalkyl diradical, an alkyl cycloalkyl
diradical, an aryl diradical or an alkylaryl diradical having 1 to 40 carbon
atoms and which may contain ether, thio or amine linkages in the main
chain;
* denotes a urethane or ureido linkage;


• is at least 1;
A denotes a divalent polymeric radical of formula:
Formula VII

R11 independently denotes an alkyl or fluoro-substituted alkyl group having 1
to 10 carbon atoms which may contain ether linkages between carbon atoms;
y is at least 1; and p provides a moiety weight of 400 to 10,000; each of E
and E1 independently denotes a polymerizable unsaturated organic radical
represented by formula:
Formula VIII

wherein: R12 is hydrogen or methyl; R13 is hydrogen, an alkyl radical having
1 to 6 carbon atoms, or a —CO—Y—R18 radical wherein Y is —O—,Y—S—
or —NH—; R14 is a divalent radical having 1 to 12 carbon atoms; X denotes
—CO— or —OCO—; Z denotes —O— or —NH—; Ar denotes an aromatic
radical having 6 to 30 carbon atoms; w is 0 to 6; x is 0 or 1; y is 0 or 1; and z
is 0 or 1.
A preferred sliicone-containing component is a polyurethane
macromer represented by the following formula:
Formula IX


wherein R16 is a diradical of a diisocyanate after removal of the isocyanate
group, such as the diradical of isophorone diisocyanate. Another suitable
silicone containing macromer is compound of formula X (in which x + y is a
number in the range of 10 to 30) formed by the reaction of fluoroether,
hydroxy-terminated polydimethylsiloxane, isophorone diisocyanate and
isocyanatoethylmethacrylate.

Other silicone containing components suitable for use in mis invention
include those described is WO 96/31792 such as macromers containing
potysiloxane. polyalkylene ether, diisocyanate, polyfluorinated hydrocarbon,
polyfluorinated ether and polysaccharide groups. U.S. Pat. Nos. 5,321,108;
5,387,662 and 5,539.016 describe polysiloxanes with a polar fluorinated
graft or side group having a hydrogen atom attached to a terminal difluoro-
substituted carbon atom. US 2002/0016383 describe hydrophilic siloxanyl
methacrylates containing ether and siloxanyl linkanges and crosslinkable
monomers containing polyether and polysiloxanyl groups. Any of the
foregoing polysiloxanes can also be used as the silicone containing
component in this invention.

The reactive mixture may also comprise at least one hydrophilic
component. Hydrophilic monomers can be any of the hydrophilic monomers
known to be useful to make hydrogels.
One class of suitable hydrophilic monomers include acrylic- or vinyl-
containing monomers. Such hydrophilic monomers may themselves be
used as crosslinking agents, however, where hydrophilic monomers having
more than one polymerizable functional group are used, their concentration
should be limited as discussed above to provide a contact lens having the
desired modulus. The term "vinyl-type" or "vinyl-containing" monomers refer
to monomers containing the vinyl grouping (-CH=CH2) and are generally
highly reactive. Such hydrophilic vinyl-containing monomers are known to
polymerize relatively easily.
"Acrylic-type" or "acrylic-containing" monomers are those monomers
containing the acrylic group: (CH2=RCOX) wherein R is H or CH3. and X is
O or N. which are also known to polymerize readily, such as N.N-dimethyl
acrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), glycerol
methacrylate, 2-hydroxyethyl methacrylamide, polyethyleneglycol
monomethacrylate, methacrylic acid and acrylic acid.
Hydrophilic vinyl-containing monomers which may be incorporated
into the silicone hydrogels of the present invention include monomers such
as N-vinyl amides, N-vinyl lactams (e.g. NVP), N-vinyl-N-methyl acetamjde,
N-vinyl-N-ethyl acetamide, N-vinyl-N-ethyl formamide, N-vinyl formamide,
with NVP being preferred.
Other hydrophilic monomers that can be employed in the invention
include polyoxyethylene polyols having one or more of the terminal hydroxyl
groups replaced with a functional group containing a polymerizable double
bond. Examples include polyethylene glycol, ethoxylated alkyl glucoside,
and ethoxylated bisphenol A reacted with one or more molar equivalents of
an end-capping group such as isocyanatoethyl methacrylate OEM"),
methacrylic anhydride, methacryloyl chloride, vinylbenzoyl chloride, or the


like, to produce a polyethylene polyol having one or more terminal
polymerizable olefinic groups bonded to the polyethylene* polyol through
linking moieties such as carbamate or ester groups.
Still further examples are the hydrophilic vinyl carbonate or vinyl
carbamate monomers disclosed in U.S. Patents No. 5,070,215, and the
hydrophilic oxazolone monomers disclosed in U.S. Patents No. 4,910,277.
Other suitable hydrophilic monomers will be apparent to one skilled in the
art
In one embodiment the hydrophilic comprises at least one hydrophilic
monomer such as DMA, HEMA, glycerol methacrytate,. 2-hydroxyethyl
methacrylamide, NVP, N-vinyl-N-methyl acrylamide, polyethylenegfycol
monomethacrylate, methacrylic acid and acrylic acid with DMA being the
most preferred.
The hydrophilic monomers may be present in a wide range of
amounts, depending upon the specific balance of properties desired.
Amounts of hydrophilic monomer up to about 50 and preferably between
about 5 and about 50 weight %. based upon all components in the reactive
components are acceptable. For example, in one embodiment lenses of the
present invention comprise a water content of at least about 25%, and in
another embodiment between about 30 and about 70%. For these
embodiments, the hydrophilic monomer may be included in amounts
between about 20 and about 50 weight %.
Other components that can be present in the reaction mixture used to
form the contact lenses of this invention include wetting agents, such as
those disclosed in US 6,367,929, WO03/22321, WO03/22322,
compatibiHzing components, such as those disclosed in US2003/162,862
and US2003/2003/125,498, ultra-violet absorbing compounds, medicinal
agents, antimicrobial compounds, copolymerizable and nonpolymerizable
dyes, release agents, reactive tints, pigments, combinations thereof and the
like:


A polymerization catalyst may be included in the reaction mixture.
The polymerization initiators includes compounds such as lauryl peroxide,
benzoyl peroxide, isopropyl percarbonate, azobisisobutyronitrile. and the
like, that generate free radicals at moderately elevated temperatures, and
photoinitiator systems such as aromatic alpha-hydroxy ketones,
alkoxyoxybenzoins, acetophenones. acylphosphine oxides,
bisacylphosphine oxides, and a tertiary amine plus a diketone, mixtures
thereof and the like. Illustrative examples of photoinitiators are 1-
hydroxycyclohexyl phenyl ketone, 2-hydroxy-2-methyl-1-phenyl-propan-1-
one, bis(2,6-dimethoxybenzoyl)-2,4-4-trimethylpentyl phosphine oxide
(DMBAPO), bis(2,4,6-trimethylbenzoyl)-phenyl phospNneoxide (Irgacure
819), 2,4,6-trimethylbenzyldiphenyl phosphine oxide and 2,4,6-
trimethylbenzoyl diphenylphosphine oxide, benzoin methyl ester and a
combination of camphorquinone and ethyl 4-(N,N-dirnethytarnino)benzoate.
Commercially available visible light initiator systems include Irgacure 819,
Irgacure 1700, Irgacure 1800, Irgacure 819, Irgacure 1850 (all from Ciba
Specialty Chemicals) and Lucirin TPO initiator (available from BASF).
Commercially available UV photoinitiators include Darocur 1173 and Darocur
2959 (Ciba Specialty Chemicals). These and other photoinitators which may
be used are disclosed in Volume III, Photoinitiators for Free Radical Cattonic
& Anionic Photopolymerization, 2nd Edition by J.V. Crivello& K. Dietliken
edited by G. Bradley; John Wiley and Sons; New York; 1998. The initiator is
used in the reaction mixture in effective amounts to initiate
photopolymerization of the reaction mixture, e.g., from about 0.1 to about 2
parts by weight per 100 parts of reactive monomer. Polymerization of the
reaction mixture can be initiated using the appropriate choice of heat or
visible or ultraviolet light or other means depending on the polymerization
initiator used. Alternatively, initiation can be conducted without a
photoinitiator using, for example, e-beam. However, when a photoinitiator is
used, the preferred initiators are bisacylphosphine oxides, such as bis(2,4,6-


trimethylbenzoyl)-phenyl phosphine oxide (Irgacure 819®) or a combination
of 1-hydroxycyclohexyl phenyl ketone and bis(2,6-dimethoxybenzoyl)-2,4-4-
trimethylpentyl phosphine oxide (DMBAPO). and in another embodiment the
method of polymerization initiation is via visible light activation. A preferred
initiator is bis(2,4,6-trimethylbenzoyl)-phenyl phosphine oxide (Irgacure
819®).
The reactive components (silicone containing component, hydropnilic
monomers, lubricious polymers, and other components which are reacted to
form the lens) are mixed together either with or without a diluent to form the
reaction mixture.
In one embodiment a diluent is used having a polarity sufficiently low to
solubilize the non-polar components in the reactive mixture at reaction
conditions. One way to characterize the polarity of the diluents of the
present invention is via the Hansen solubility parameter, 6p. In certain
embodiments, the Sp is less than about 10, and preferably less than about 6.
Suitable diluents are further disclosed in US Ser. No 60/452898 and US
6,020,445.
Classes of suitable diluents include, without limitation, alcohols having 2 to
20 carbons, amides having 10 to 20 carbon atoms derived from primary
amines, ethers, polyetners, ketones having 3 to 10 carbon atoms, and
carboxylic acids having 8 to 20 carbon atoms. For all solvents, as the
number of carbons increase, the number of polar moieties may also be
increased to provide the desired level of water misdbility. In some
embodiments, primary and tertiary alcohols are preferred. Preferred classes
include alcohols having 4 to 20 carbons and carboxylic acids having 10 to 20
carbon atoms.
Preferred diluents include diluents that have some degree of solubility in
water. In some embodiments at least five percent of the diluent is misdble
water. Examples of water soluble diluents include 1-decanol, 1-octanol, 1-


pentanol, 1-hexanol, 2-hexanol, 2-octanol, 3-methyl-3-pentanol, 2-pentanol,
t-amyl alcohol, tert-butanol, 2-butanol, 1-butanol, 2-methyl-2-pentanol, 2-
ethyl-1-butanol. ethanol, 3,3-dimethyl-2-butanol, decanoic acid, octanoic
acid, dodecanotc acid, 1-ethoxy-2- propanol, 1-tert-butoxy-2-propanol, EH-5
(commercially available from Ethox Chemicals), 2,3,6.7-tetrahydroxy-2,3,6,7-
tetramethyl octane, 9-(1-methylethyl)-.2,58,10,13,16-hexaoxaheptadecane,
3,5,7,9,11,13-hexamethoxy-1-tetradecano), mixtures thereof and the like.
The reactive mixture of the present invention may be cured via any
known process for molding the reaction mixture in the production of contact
lenses, including spincasting and static casting. Spincasting methods are
disclosed in U.S. Patents Nos. 3,408,429 and 3,660,545, and static casting
methods are disclosed in U.S. Patents Nos. 4,113,224 and 4,197,266. In
one embodiment the contact lenses of this invention are formed by the
direct molding of the silicone hydrogels, which is economical, and enables
precise control over the final shape of the hydrated lens. For this method,
the reaction mixture is placed in a mold having the shape of the final desired
silicone hydrogel, i.e. water-swollen polymer, and the reaction mixture is
subjected to conditions whereby the monomers polymerize, to thereby
produce a polymer in the approximate shape of the final desired product.
After curing the tens is treated to remove unreacted components and
release the lens from the lens mold.
As used herein, the term 'treat" means to expose a cured lens to an
aqueous solution, but excludes equilibration, sterilization and storage of the
lens. Aqueous solutions are solutions which primarily comprise water. In
one embodiment the aqueous solutions of the present invention comprise at
least about 70 % water and in others at least about 90 weight% water.
Aqueous solutions may also include additional water soluble components
such as release agents, wetting agents, slip agents, pharmaceutical and
nutraceutical components, combinations thereof and the like. Release
agents are compounds or mixtures of compounds which, when combined


with water, decrease the time required to release a contact lens from a mold,
as compared to the time required to release such a lens using an aqueous
solution that does not comprise the release agent. In one embodiment the
aqueous solutions comprise less than about 10 weight %, and in others less
than about 5 weight % organic solvents such as isopropyl alcohol, and in
another embodiment are free from organic solvents, in these embodiments
the aqueous solutions do not require special handling, such as purification,
recycling or special disposal procedures.
In various embodiments, treatment can be accomplished, for
example, via immersion of the lens in an aqueous solution or exposing the
lens to a flow of an aqueous solution. In various embodiments, treatment
can also include, for example, one or more of heating the aqueous solution;
stirring the aqueous solution; increasing the level of release aid in the
aqueous solution to a level sufficient to cause release of the lens;
mechanical agitation of the tens; and incorporating at least one leach aid in
the aqueous solution to a level sufficient to facilitate adequate removal of
unreacted components from the lens.
Treatment may be conducted by various implementations, such as
but not limited to a batch process wherein lenses are submerged in a
solution contained in a fixed tank for a specified period of time or in a vertical
process where lenses are exposed to a continuous flow of an aqueous
solution.
In some embodiments the aqueous solution can be heated with a
heat exchanger or other heating apparatus to further facilitate leaching of the
lens and release of the lens from a mold part For example, heating can
include raising the temperature of an aqueous solution to the boiling point
while a hydrogel lens and mold part to which the lens is adhered are
submerged in the heated aqueous solution. Other embodiments can include
controlled cycling of the temperature of the aqueous solution.

Sonne embodiments can also include the application of physical
agitation to facilitate leach and release. For example, the lens mold part to
which a lens is adhered, can be vibrated or caused to move back and forth
within an aqueous solution. Other embodiments may include ultrasonic
waves through the aqueous solution.
These and other similar processes can provide an acceptable means
of releasing the lens.
As used herein, "released from a mold" means that a lens is either
completely separated from the mold, or is only loosely attached so that it can
be removed with mild agitation or pushed off with a swab. In the process of
the present invention the conditions used include temperature less than
99ºC for less than about 1 hour.
The lenses of the present invention require minimal treatment. The
treatment is conducted with aqueous solutions for times less than about 6
hours, in some embodiments less than about 4 hours, less than about 2
hours and sometimes less than about 1 hour.
The lenses of the present invention require minimal post treatment
Post treatment is an optional part of treatment and includes solution
exchange and extraction but not sterilization, storage and equilibration. In
embodiments where post treatment is included, the post treatment is
conducted with aqueous solutions for times less than about 6 hours, in some
embodiments less than about 4 hours, less than about 2 hours and
sometimes less than about 1 hour.
The treated lenses may be sterilized by known means such as, but
not limited to autoclaving.
It will be appreciated that all of the tests specified herein have a
certain amount of inherent test error. Accordingly, results reported herein
are not to be taken as absolute numbers, but numerical ranges based upon
the precision of the particular test.


In order to illustrate the invention the following examples are included.
These examples do not limit the invention. They are meant only to suggest
a method of practicing the invention. Those knowledgeable in contact
lenses as well as other specialties may find other methods of practicing the
invention. However, those methods are deemed to be within the scope of
this invention.
EXAMPLES
The following abbreviations are used in the examples below:
SIGMA 2-propenoic acid. 2-methyl-,2-hydroxy-3-[3-[1,3,3,3-
tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propoxy]propyl
ester
SiNAA N-(2-hydroxy-3-(3-(bis(trimethylsilyloxy)methylsilyl)
propyloxy)propyl)-2-methyl acrylamide
DMA N,N-dimethylacrylamide
HEMA 2-hydroxyethyl methacrylate
mPDMS 800-1000 MW (Mn) monomethacryloxypropyl terminated mono-
n-butyl terminated polydimethylsiloxane
Norbloc 2-(2'-hydroxy-5-methacrylyloxyetriylphenyl)-2H-benzotriazole
CG11850 1:1 (wgt) blend of 1-hydroxycyclohexyl phenyl ketone and
bis(2,6-dimethoxybenzoyl)-2,4-4-trimethylpentylphosphine
oxide
PVP poly(N-vinyl pyrrolidone) (K values noted)
Blue HEMA the reaction product of Reactive Blue 4 and HEMA, as
described in Example 4 of U.S. Pat no. 5,944,853
IPA isopropyl alcohol
D3O 3,7-dimethyl-3-octanol
mPDMS-OH mono-[3-methacryloxy-2-hydroxypropyloxy)-propyl terminated,
mono-butyl terminated polydimethylsiloxane
TEGDMA tetraethyleneglycoldimethacrylate


TrEGDMA triethyleneglyco) dimethacrylate
TRIS 3-methacryloxypropyltris(trimethylsiloxy)silane
acPDMS bis-3-acryloxy-2-hydroxypropyloxypropyl polydimethylsiloxane
(MW 1000 and 2000. acrylated polydimethylsiloxane)
fromGelest and Degussa, respectively
maPDMS methacryloxypropyl terminated polydimethylsHoxane (MW 550-
700) from Gelest
CGI 819 bis(2,4,6-trimethylbenzoyl)-phenylphosphineoxide
M2D10 1000-1100 MW (Mn) monomethacryloxybutyl terminated
mono-n-butyl terminated polydimethylsiloxane
OH-TRIS 3-methacryloxy-2-hydroxypropyltris(trimethylsiloxy)silane
SiNAA dimer N,N-bis[2-hydroxy-3-(3-(bis(trimethylsilyloxy)methyisilyl)
propyloxy)propyl]-2-methyl acrylamide
Throughout the Examples intensity is measured using an IL1400A
radiometer, using an XRL 140A sensor.
Examples 1-5
The reaction components and diluent (t-amyl alcohol) listed in Table 2
were mixed together with stirring or rolling for at least about 3 hours at about
23°C, until all components were dissolved. The reactive components are
reported as weight percent of all reactive components and the diluent is
weight percent of final reaction mixture. The reaction mixture was placed
into thermoplastic contact lens molds (frontcurves made from Zeonor®
obtained from Zeon, Corp. and back curves made from' polypropylene) and
irradiated using Philips TL 20W/03T fluorescent bulbs at 45°C for about 15
minutes in N2. The molds were opened and lenses were released in H2O at
95°C for twenty minutes, then hydrated in water at 70°C for about 3.5 hours,
then placed in packing solution for about 30 minutes at ambient temperature.


The lenses were packaged in borate buffered saline solution in glass vials
and sterilized for 20 minutes at 121°C.
Leachables were measured as follows
Sample Preparation — Lens Extraction
Using a lens swab, hydrated lenses were placed on blotting paper
and then blotted with a second piece of blotting paper to remove any excess
water from the lens surface. For each leachable component tested, ten
lenses were weighed into a tared scintillation vial and the weight was
recorded. 5 mLs of solvent listed in Table 1 was added to the lens vial and
the mixture was sonicated for a period of 1 hour.

Sample Preparation - Lens Extraction for SiGMA Glycol
The lenses were prepared as above, except the lenses were briefly
rinsed in Dl water, and dried overnight both at room temperature. 5 mLs of
acetonitrile (CH3CN, ACN) was added to the lens vial and the mixture was
sonicated for a period of 1 hour. 500 μL of the supernatant, 50 μL of a
dodecane/ACN (0.05 g dodecane/100 mL ACN) solution, and 100 μL of
Regisil RC-2 reagent (N,O-bis(trimethylsilyl)trifluoroacetamide with 1%
trichlorosilane) were added to the GC vial.
Leachable SIGMA Analysis
Leachable SiGMA analysis was performed via C18 RP-HPLC with UV
detection. A Phenomenex ODS-3 column of dimensions 150 mm x 4.5 mm
was used. The mobile phase employed was 20/80 water (99.95% with


0.05% H3PO4)/ACN (99.95% with 0.05% H3PO4) for a period of 17 minutes
using a flow of 1 mL/min. The injection volume was 50 μL. SiMAA2 was
detected using a UV absorbance detector at 210 nm. Results are shown in
Table 3. below.
Leachable SiGMA Glycol Analysis
Leachable SiGMA glycol analysis was performed via GC/FIO. A
Restek RTX-5 column of dimensions 30 m x 0.25 mm with a film thickness of
0.5 μm. the carrier gas used helium at 100°C with 2 min hold. The oven
ramp conditions included 8°C/min to 325°C, followed by a 5 min hold. The
injection and detection temperatures were 250°C and 280°C, respectively.
The oxidizer and fuel flow were 440 mL/min and 40 m/min, respectively.
Make up was 20mL/min. The injection volume was 1 μL Results are shown
in Table 3, below.
Leachable SiGMA Epoxide Analysis
Leachable SiGMA epoxide analysis was performed via GC/FIO. A
DB-5 column of dimensions 30 m x 0.25 mm with a film thickness of 0.5 turn.
The carrier gas used helium at 50°C with 5 min hold. The oven ramp
conditions included 25°C/min to 175°C, followed by a hold for 6 min,
followed by 25°C/min to 325°C, followed by a 5 min hold. The injection and
detection temperatures were 220°C and 280°C, respectively. The injection
volume was 1 μL. Results are shown in Table 3, below.
Leachable BHT Analysis
Leachable BHT analysis was performed via HPLC with UV detection.
A Zorbax Eclipse column of dimensions 75 mm x 4.6 mm with a mean
particle size of 3.5 μm was used. The mobile phase employed was a linear
gradient of 30/70 water (99.95% with 0.05% H3PO4)/ACN (99.95% with


0.05% H3PO4) to 100 % IPA over a period of 20.10 minutes using a flow of 1
rnL/rnin. The injection volume was 50 μL. BHT was detected using a UV
absorbance detector at 210 nm. Results are shown in Table 3, below.
The lenses made in Examples 1 through 5 were evaluated
clinically on human eyes. Initially lenses from each example were fit on five
subjects in a randomized, bilateral study. The lenses were worn for a 30
minute (maximum) open eye period. If the initial 5 subjects reported
equivalent physiological performance of the test lenses compared to the
control lens, an additional 10 subjects were evaluated (a maximum of 15
patients for 30 minutes of exposure). If the initial study subjects reported
ocular discomfort with the test lens, no additional subject were enrolled. The
percentage of patients reporting ocular discomfort is listed below in Table 3.





Examples 6-8
ACUVUE ADVANCE* with HYDRACLEAR™ brand contact lenses
were removed from their packages, and equilibrated in 70/30 IPA/water
mixture by rolling in jars of 70/30 IPA/water mixture (1 lens/4 mLs) for 30(±5)
minutes. All liquid was drained and replaced with a SiGMA spiked solution (1
lens/4 mLs) as shown in Table 4and the lenses rolled. After 60(±10) minutes,
the spaced solution was drained and Dl water was added to the lenses. The
lenses were rolled in Dl water for 30(±5) minutes. Lenses were then
inspected in Dl water, packaged in vials of borate buffered saljne, and
sterilized at 120°C for about 20 minutes. The lenses were analyzed for
teachable SiGMA and SiGMA glycol and clinically evaluated for ocular
discomfort (OD). The results are shown in Table 4, below. Standard
deviations are shown in parenthesis.

Examples 9-11
Examples 6-8 were repeated, except that the ACUVUE ADVANCE*
with HYDRACLEAR™ brand contact lenses were treated with SiGMA glycol
solutions of the concentrations shown in Table 5, below. The lenses were
analyzed for teachable SiGMA and SiGMA glycol and clinically evaluated for
ocular discomfort (OD). The results are shown in Table 5, below.


Examples 12-14
Examples 6-8 were repeated, except that the ACUVUE ADVANCE*
with HYDRACLEAR™ brand contact lenses were treated with BHT solutions
of the concentrations shown in Table 6. below.. The lenses were analyzed for
teachable BHT, SiGMA and SiGMA glycol and clinically evaluated for ocular
discomfort (OD). The results are shown in Table 6, below.

Examples 13-35
HPLC retention times were measured for the compounds shown in
Table 8 as follows. An Agilent 1100 HPLC with a Thermo ODS Hypersil
column of dimensions 150 x 4.6 mm x 5 μ, with attached Finnigan LCQ
Classic mass spectrometer with eiectrospray ionization in tandem with UV
and ELSD (Sedex) was used. Samples were prepared by making 2% (wt/wt)
solutions of each test material in IPA. A 3 μL of sample solution was injected,
using a flow rate of 1 ml/minute. The eluting solvent for each sample was
varied using the gradient program shown in Table 7. The retention time is the
time from injection to the time of the peak of elution of each sample as
determined by UV absorption or electron spectrometry.



What is claimed is
1. A process comprising
(a) curing in a mold a reaction mixture comprising at least one silicone
containing component wherein said reaction mixture is substantially free from
sparingly water soluble components or impurities having a retention time,
relative to TRIS of less than about 0.9 to form a lens;
(b) contacting said lens and mold with an aqueous solution at a
temperature less than 99°C for less than about 1 hour; to release said lens
from the mold and
(c) optionally post processing the lens, wherein said post processing, if
conducted, is conducted with aqueous solutions for a time less than 6 hours.

2. The process of claim 1 wherein said reaction mixture further comprises at
least one hydrophilic component
3. The process of claim 2 wherein said hydrophilic component comprises at
least one acrylic- or vinyl-containing monomer.
4. The process of claim 2 wherein said hydrophilic component comprises
at least one monomer selected from the group consisting of DMA, 2-
hydroxyethyl methacrylate, glycerol methacrylate, 2-hydroxyethyl
methacrylamide, N-vinyl pyrrolidone, N-vinyl-N-rnethyl acrylamide,
polyethyleneglycol monomethacrylate, methacrylic acid, acrylic add and
combinations thereof.
5. The process of claim 1 wherein said aqueous processing time is less than
about 4 hours.
6. The process of claim 1 wherein said aqueous processing time is less than
about 2 hours.

7. The process of claim 1 wherein said aqueous processing time is less than
about one hour.
8. The process of claim 1 wherein said component or impurity is present in an
amount of less than about 3000 ppm in the reaction mixture.
9. The process of claim 1 wherein said component or impurity is present in an
amount of less than about 1000 ppm in the reaction mixture.

10. The process of claim 1 wherein said component or impurity is present in
an amount of less than about 200 ppm based upon all components in the
reaction mixture.
11. The process of claim 1 wherein said component or impurity is present in
an amount of less than about 100 ppm based upon all components in the
reaction mixture.
12. The process of claim 1 wherein said component or impurity has a
retention time relative to TRIS of less than about 0.8.
13. The process of claim 1 wherein said at least one silicone component is
selected from the group consisting of silicone containing monomers,
prepolymers, macromers and mixtures thereof.
14. The process of claim 1 wherein said at least one silicone component
comprises at least one silicone monomer.
15. The process of claim 1 wherein said reactive mixture is a substantially
homogeneous mixture.
16. The process of claim 1 wherein said silicone component is present in
said reactive mixture in an amount between about 20 and 70 weight %.

17. The process of claim 2 wherein said hydrophilic component is present
in said reactive mixture in an amount up to about 50 weight %.
18. The process of claim 2 wherein said hydrophilic component is present
in said reactive mixture in an amount between about 5 and about 50 weight
%.
19. The process of claim 1 wherein said silicone component comprises at
least ore polymerizable functional group selected from the group consisting of
acrylate, methacrylate, acrylamide, methacrylamide, N-vinyl lactam, N-
vinylamide, and styryl functional groups.
20. The process of claim 1 wherein said silicone component comprises at
least one monpfunctional silicone containing component.
21. The process of claim 1 wherein said reaction mixture is free from
measurable amounts of sparing water soluble components or impurities
having a retention time, relative to TRIS of less than about 0.9.
22. The process of claim 1 wherein said aqueous solution further comprises
at least one release aid.
23. A contact lens made by the process of claim 1.
24. A process for producing an ophthalmic lens which does not cause ocular
discomfort when worn by a human comprising the steps of .
(a) curing in a mold a silicone containing reaction mixture comprising less
than about 3000 ppm of any sparingly water soluble component or impurity
having a retention time, relative to TRIS of less than about 0.9 minutes to form
said ophthalmic lens;
b) contacting said lens and mold with an aqueous solution at a temperature
less than 99°C for less than about 1 hour; to release said lens from the mold
and

(c) optionally post processing the lens, wherein said post processing, if
conducted, is conducted with aqueous solutions for a time jess than 6 hours.
25. A process comprising
(a) curing in a mold a reaction mixture comprising at least one silicone
containing component, and at least one sparingly water soluble component or
impurity having a retention time, relative to TRIS of less than about 0.9 to
produce a cured contact lens having less than an ocular discomfort causing
amount of said component or impurity,
(b) contacting said lens and mold with an aqueous solution at a
temperature less than 99°C for less than about 1 hour; to release said lens
from the mold and
(c) optionally post processing the lens, wherein said post processing, if
conducted, is conducted with aqueous solutions for a time less than 6 hours.

26. The process of claim 25 wherein said reaction mixture further comprises
at least one hydrophilic component.
27. The process of claim 26 wherein said hydrophilic component comprises
at least one acrylic- or vinyl-containing monomer.
28. The process of claim 26 wherein said hydrophilic component
comprises at least one monomer selected from the group consisting of DMA,
2-hydroxyethyl methacrylate, glycerol methacrylate, 2-hydroxyethyl
methacrylamide. N-vinyl pyrrolidone, N-vinyl-N-methyt acrylamide,
polyethyleneglycol monomethacrylate, methacrylic acid, acrylic acid and
combinations thereof.
29. The process of claim 25 wherein said aqueous processing time is less
than about 4 hours.
30. The process of claim 25 wherein said aqueous processing time is less
than about 2 hours.

31. The process of claim 25 wherein said aqueous processing time is less
than about one hour.
32. The process of claim 25 wherein said at least one sparingly water soluble
component or impurity is present in said lens after step b, in an amount less
than about 2000 ppm based upon weight of said lens in a fully, hydrated state.
33. The process of claim 25 wherein said aqueous solution further comprises
at least one release aid.
34. The process of claim 25 wherein said sparingly water soluble component
or impurity is present in said lens after step b, in an amount of less than about
1000 ppm based upon weight of said lens in a fully hydrated state.
35. The process of claim 25 wherein said sparingly water soluble component
or impurity is present in said tens after step b, in an amount of less than about
200 ppm based upon weight of said lens in a fully hydrated state.
36. The process of claim 25 wherein said sparingly water soluble component
or impurity is present in said lens after step b in an amount of less than about
100 ppm based upon weight of said lens in a fully hydrated state.
37. The process of claim 25 wherein said component or impurity has a
retention time relative to TRIS of less than about 0.8.
38. The process of claim 25 wherein said at least one silicone component is
selected from the group consisting of silicone containing monomers,
preporymers, macromers and mixtures thereof.
39. The process of claim 25 wherein said at least one silicone component
comprises at least one silicone monomer.

40. The process of claim 25 wherein said reactive mixture is a substantially
homogeneous mixture.
41. The process of claim 25 wherein said silicone component is present in
said reactive mixture in an amount between about 20 and 70 weight %.
42. The process of claim 26 wherein said hydrophilic component is present
in said reactive mixture in an amount up to about 50 weight %.
43. The process of claim 26 wherein said hydrophilic component is present
in said reactive mixture in an amount between about 5 and about 50 weight
%.
44. The process of claim 25 wherein said silicone component comprises at
least one polymerizable functional group selected from the group consisting of
acrylate, methacrylate, acrylamide, methacrylamide, N-vinyl lactam, N-
vinylamide, and styryl functional groups.
45. The process of claim 25 wherein said silicone component comprises at
least one monofunctional silicone containing component.
46. A contact lens made by the process of claim 25.
47. A process comprising
(a) curing in a mold a silicone containing reaction mixture wherein ail
reaction mixture components and impurities which are sparingly water soluble
have a retention time, relative to TRIS of at least about 1 to form a lens;
(b) contacting said lens and mold with an aqueous solution at a
temperature less than 99°C for less than about 1 hour, to release said lens
from the. moid and
(c) optionally post processing the lens, wherein said post processing, if
conducted, is conducted with aqueous solutions for a time less than 6
hours.

The present invention relates to aqueous
processes for the production of silicone hydrogel
contact lenses.

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=FBxVB990XAJjxyvCfIJpsg==&loc=wDBSZCsAt7zoiVrqcFJsRw==


Patent Number 268580
Indian Patent Application Number 3880/KOLNP/2008
PG Journal Number 36/2015
Publication Date 04-Sep-2015
Grant Date 04-Sep-2015
Date of Filing 23-Sep-2008
Name of Patentee JOHNSON & JOHNSON VISION CARE, INC.
Applicant Address 7500 CENTURION PARKWAY, SUITE 100 JACKSONVILLE, FLORIDA
Inventors:
# Inventor's Name Inventor's Address
1 DIANA ZANINI 3652 FALLON OAK DRIVE, JACKSONVILLE, FLORIDA 32277
2 AZAAM ALLI 3489 ADVANTAGE LANE, JACKSONVILLE, FLORIDA 32277
3 JAMES D. FORD 515 NASSAU COURT, ORANGE PARK, FLORIDA 32003
4 SHIVKUMAR MAHADEVAN 1905 WHITE DOGWOOD LANE, ORANGE PARK, FLORIDA 32003
5 KRISTY CANAVAN 2326 COMPANION CIRCLE WEST, JACKSONVILLE, FLORIDA 32224
6 DAVID C. TURNER 12159 TRAVERTINE TRAIL, JACKSONVILLE, FLORIDA 32223
PCT International Classification Number B29D 11/00,G02B 1/04
PCT International Application Number PCT/US2007/007196
PCT International Filing date 2007-03-23
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 11/387,250 2006-03-23 U.S.A.