U.S. patent application number 13/829592 was filed with the patent office on 2013-08-08 for medical devices having homogeneous charge density and methods for making same.
This patent application is currently assigned to Johnson & Johnson Vision Care, Inc.. The applicant listed for this patent is Johnson & Johnson Vision Care, Inc.. Invention is credited to Carrie L. Davis, Zohra Fadli, James D. Ford, Eric R. George, Leah Hansen, Scott L. Joslin, Thomas L. Maggio, Shivkumar Mahadevan, Sharmila Muthukrishnan, Ranganath Raja, Charles W. Scales, C. Surendran, Kunisi Venkatasubban.
Application Number | 20130203813 13/829592 |
Document ID | / |
Family ID | 48903437 |
Filed Date | 2013-08-08 |
United States Patent
Application |
20130203813 |
Kind Code |
A1 |
Mahadevan; Shivkumar ; et
al. |
August 8, 2013 |
MEDICAL DEVICES HAVING HOMOGENEOUS CHARGE DENSITY AND METHODS FOR
MAKING SAME
Abstract
The present invention relates to ionic silicone hydrogel
polymers comprising at least one pharmaceutical or nutriceutical
component and displaying improved lysozyme uptake, low contact
angle and reduced water soluble polymeric ammonium salt uptake.
Inventors: |
Mahadevan; Shivkumar;
(Orange Park, FL) ; Fadli; Zohra; (Jacksonville,
FL) ; Scales; Charles W.; (St. Augustine, FL)
; Maggio; Thomas L.; (Jacksonville, FL) ;
Venkatasubban; Kunisi; (Jacksonville, FL) ; George;
Eric R.; (St. Augustine, FL) ; Ford; James D.;
(Orange Park, FL) ; Davis; Carrie L.; (St.
Augustine, FL) ; Hansen; Leah; (Jacksonville, FL)
; Joslin; Scott L.; (Ponte Vedra Beach, FL) ;
Raja; Ranganath; (Jacksonville, FL) ; Muthukrishnan;
Sharmila; (Chennai, IN) ; Surendran; C.; (The
Nilgris, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Johnson & Johnson Vision Care, Inc.; |
Jacksonville |
FL |
US |
|
|
Assignee: |
Johnson & Johnson Vision Care,
Inc.
Jacksonville
FL
|
Family ID: |
48903437 |
Appl. No.: |
13/829592 |
Filed: |
March 14, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13449413 |
Apr 18, 2012 |
|
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13829592 |
|
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61482379 |
May 4, 2011 |
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Current U.S.
Class: |
514/324 ;
514/772.3 |
Current CPC
Class: |
A61K 9/0051 20130101;
A61K 31/4535 20130101; A61K 47/34 20130101; G02B 1/041 20130101;
G02B 1/043 20130101; C08L 83/04 20130101; C08L 101/14 20130101;
G02B 1/043 20130101; G02B 1/043 20130101 |
Class at
Publication: |
514/324 ;
514/772.3 |
International
Class: |
A61K 47/34 20060101
A61K047/34; A61K 31/4535 20060101 A61K031/4535 |
Claims
1. An anionic, silicone hydrogel contact lens comprising in or on
said silicone hydrogel at least one statistical copolymer
comprising units derived from at least 10 weight % of at least one
non-ionic hydrophilic monomer and at least one anionic monomer and
wherein said contact lens comprises at least one pharmaceutical or
nutraceutical component and has a contact angle of about 70.degree.
or less, at least about 50 .mu.g/lens lysozyme uptake, and less
than about 10% uptake of at least one polycationic component when
contacted with 3 mL of an ophthalmic solution comprising said 0.001
wt % polycationic component, 0.56% citrate dihydrate and 0.021%
citric acid monohydrate (wt/wt).
2. The contact lens of claim 1 wherein said statistical copolymer
is non-reactive and is associated with or entangled in said
silicone hydrogel contact lens.
3. The contact lens of claim 2 wherein said statistical copolymer
comprises about 20 to about 80 mol % units from said anionic
monomer.
4. The contact lens of claim 2 wherein said statistical copolymer
comprises about 20 to about 60 mol % units from said anionic
monomer.
5. The contact lens of claim 3 wherein said statistical copolymer
comprises about 80 to about 20 mol % units from said non-ionic
hydrophilic monomer.
6. The contact lens of claim 3 wherein said statistical copolymer
comprises about 80 to about 40 mol % units from said non-ionic
hydrophilic monomer.
7. The contact lens of claim 2 wherein said statistical copolymer
is associated with at least part of said silicone hydrogel contact
lens.
8. The contact lens of claim 18 wherein said statistical copolymer
is present in or on said contact lens in a concentration sufficient
to provide a concentration of units from said anionic monomer of
about 0.1 to about 5 mol %.
9. The contact lens of claim 18 wherein said statistical copolymer
is present in or on said contact lens in a concentration sufficient
to provide a concentration of units from said anionic monomer of
about 0.2 to about 4 mol %.
10. The contact lens of claim 2 wherein said statistical copolymer
is formed by RAFT polymerization, free radical polymerization, or
step growth polymerization
11. The contact lenses of claim 2 wherein said non-reactive
statistical copolymer further comprises a hydrophobic block on at
least one terminus.
12. The contact lens of claim 11 wherein said hydrophobic block
comprises polydialkylsiloxane, polydiarylsiloxane and mixtures
thereof.
13. The contact lens of claim 12 wherein said alkyl is selected
from C.sub.1-C.sub.4 alkyl.
14. The composition of claim 12 wherein said hydrophobic block
comprises polydimethylsiloxane or polydiethylsiloxane.
15. The contact lens of claim 12 wherein said hydrophobic block
comprises between about 6 and about 200 siloxy units.
16. The contact lens of claim 12 wherein said hydrophobic block
comprises between about 6 and about 200 siloxy units.
17. The contact lens of claim 2 wherein said units from said
non-ionic hydrophilic monomer and said anionic monomer when
polymerized have a degree of polymerization of at least about
300.
18. The contact lens of claim 1 wherein said silicone hydrogel is
said statistical copolymer.
19. The contact lens of claim 1, 2 or 18 wherein said anionic
monomer and said non-ionic hydrophilic monomer have the same
reactive functionality.
20. The contact lenses of claim 19 wherein said anionic monomer and
said non-ionic hydrophilic monomer are selected from
(meth)acrylamides.
21. The contact lenses of claim 19 wherein said anionic monomer and
said non-ionic hydrophilic monomer are selected from
(meth)acrylates.
22. The contact lenses of claim 19 wherein said anionic monomer and
said non-ionic hydrophilic monomer are selected from vinyls.
23. The contact lens of claim 1 wherein said lysozyme uptake is at
least about 70 .mu.g/lens.
24. The contact lens of claim 1 wherein said lysozyme uptake is at
least about 100 .mu.g/lens.
25. The contact lens of claim 1 wherein said polycationic component
is selected from the group consisting of cationic water soluble
polymeric ammonium salts, polyquaternium containing compounds,
water soluble polymeric tetraalkyl phosphonium salts and mixtures
thereof.
26. The contact lens of claim 1 wherein said polycationic component
is selected from the group consisting of biguanides, bisbiguanides,
polycationic polymers having quartenary ammonium centers and
combinations thereof.
27. The contact lens of claim 1 wherein said polycationic component
is selected from the group consisting of polyhexamethylene
biguanide PQ-1, PQ-42, and mixtures thereof.
28. The contact lens of claim 1 further comprising a water content
of between about 20% and about 70%.
29. The contact lens of claim 1 further comprising a water content
of between about 25% and about 65%.
30. The contact lens of claim 20 wherein said anionic monomer is
selected from the group consisting of 3-acrylamidopropionic acid,
4-acrylamidobutanoic acid, 5-acrylamidopentanoic acid,
sodium-2-(acrylamido)-2-methylpropane sulphonate,
2-acrylamido-2-methylpropane sulfonic acid and combinations
thereof.
31. The contact lens of claim 21 wherein said anionic monomer is
selected from the group consisting of (meth)acrylic acid, acrylic
acid, 3-sulphopropyl (meth)acrylate potassium salt, 3-sulphopropyl
(meth)acrylate sodium salt, sulphoethyl methacrylate, and mixtures
thereof.
32. The contact lens of claim 21 wherein said anionic monomer
comprises (meth)acrylic acid.
33. The contact lens of claim 21 wherein said anionic monomer is
selected from the group consisting of
N-vinyloxycarbonyl-.alpha.-alanine,
N-vinyloxycarbonyl-.beta.-alanine,
2-vinyl-4,4-dimethyl-2-oxazolin-5-one, vinyl sulphonate sodium
salt, vinyl sulphonate salt, and mixtures thereof.
34. A silicone hydrogel formed from a reactive mixture comprising
major polymerizable components comprising at least one reactive
silicone-containing component, at least one reactive ionic monomer,
optional reactive hydrophilic components and crosslinker; and minor
polymerizable components selected from the group consisting of
visibility tint and dyes, UV absorbers, photochromic compounds,
pharmaceutical compounds, nutriceutical compounds, and mixtures
thereof; wherein said major polymerizable components comprise a
single reactive functionality.
35. The silicone hydrogel of claim 34 wherein said single reactive
functionality is selected from the group consisting of acrylate,
methacrylate, acrylamide, methacrylamide, vinyl and styryl.
36. The silicone hydrogel of claim 34 wherein said single reactive
functionality is selected from the group consisting of acrylamide,
methacrylamide and vinyl.
37. A silicone hydrogel contact lens comprising between about 50
ppm and about 1 wt % of at least one uncrosslinked statistical
copolymer comprising at least about 10 weight % of at least one
non-ionic hydrophilic monomer and at least about 20 mol % of at
least one anionic repeating unit distributed randomly throughout
said polymer.
38. The contact lens of claim 37 wherein said copolymer is present
in an amount between about 20 ppm and 2000 ppm.
39. The contact lens of claim 37 wherein said copolymer is present
in an amount between about 50 ppm and 1500 ppm.
40. The silicone hydrogel of claim 34 wherein said single reactive
functionality is methacrylamide and said reactive ionic monomer
comprises at least one acrylamido sulphonic acid or acrylamido
sulphonic acid salt.
41. The silicone hydrogel of claim 40 wherein said acrylamido
sulphonic acid comprises an alkylene group comprising 2 to 4 carbon
atoms.
42. The silicone hydrogel of claim 40 wherein said acrylamido
sulphonic acid comprises 2-acrylamido-2-methylpropane sulfonic acid
salt.
43. The contact lens of claim 1 wherein said at least one
pharmaceutical pharmaceutical or nutraceutical component is
cationic.
44. The contact lens of claim 1 wherein said at least one
pharmaceutical pharmaceutical or neutraceutical component is
selected from the group consisting of atropine, pirenzepine,
doxycycline, brimonidine, brinzolamide, dorzolamide, betaxolol,
apraclonidine, ccr2 antagonist, olopatadine, alcaftadine,
betaxolol, bupivacaine, carbachol, carteolol, chlortetracycline,
cyclopentolate, dibutoline, dipivefrin, ephedrine, erythromycin,
gentamycin, gramicidin, homatropine ketotifen, levobunolol,
levocabastine, lidocaine, lignocaine, lomefloxacin, mepivacaine,
naphazoline, neomycin, ofloxacin, oxybuprocaine, pheniramine,
physostigmine, pilocarpine, polymyxin B, proparacaine, pyrilamine,
tetracaine, tetracycline, tetrahydrozoline, timolol, tropicamide,
vidarabine, pharmaceutically acceptable salts thereof and
combinations thereof and the like.
45. The contact lens of claim 1 wherein said at least one
pharmaceutical pharmaceutical or neutraceutical component is
selected from the group consisting of atropine, pirenzepine,
doxycycline, brimonidine, brinzolamide, dorzolamide, betaxolol,
apraclonidine, ccr2 antagonist, olopatadine, alcaftadine,
betaxolol, bupivacaine, carbachol, carteolol, chlortetracycline,
cyclopentolate, dibutoline, dipivefrin, erythromycin, gentamycin,
gramicidin, homatropine ketotifen, levobunolol, levocabastine,
lidocaine, lignocaine, lomefloxacin, mepivacaine, naphazoline,
ofloxacin, pheniramine, physostigmine, pilocarpine, polymyxin B,
proparacaine, pyrilamine, tetracaine, tetrahydrozoline, timolol,
tropicamide pharmaceutically acceptable salts thereof and
combinations thereof and the like.
46. The contact lens of claim 1 wherein said at least one
pharmaceutical pharmaceutical or nutraceutical component is
selected from the group consisting of atropine, ketotifen,
olopatadine, alcaftadine, levocabastine, pirenzepine, doxycycline,
brimonidine, brinzolamide, dorzolamide, betaxolol, apraclonidine,
ccr2 antagonist, olopatadine pharmaceutically acceptable salts
thereof and combinations thereof and the like.
47. The contact lens of claim 1, 44, 45 or 46, wherein said at
least one pharmaceutical or nutraceutical component in a symptom
mitigating effective amount.
48. The contact lens of claim 47 wherein said symptom mitigating
effective amount is between about 5 .mu.g and about less than 200
.mu.g.
49. The contact lens of claim 47 wherein said symptom mitigating
effective amount is between about 9 .mu.g and about 100 .mu.g.
50. The contact lens of claim 47 wherein said symptom mitigating
effective amount alleviates symptoms for between about 5 minutes,
and about 12 hours from insertion of said contact lens on a human's
eye.
51. The contact lens of claim 47 wherein said contact lens
comprises a modulus which increases less than about 30% after three
autoclave cycles.
Description
RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 13/449,413, filed on Apr. 18, 2012 entitled
MEDICAL DEVICES HAVING HOMOGENEOUS CHARGE DENSITY AND METHODS FOR
MAKING SAME, the contents of which are incorporated by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to ionic silicone hydrogels,
and ophthalmic devices formed therefrom, which display desirable
tear and polycationic ophthalmic solution component uptake profiles
and desirable drug uptake.
BACKGROUND OF THE INVENTION
[0003] 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 formed from hydrophilic polymers and copolymers
containing repeating units from hydroxyethylmethylacrylate (HEMA).
Of these contact lenses formed from copolymers of HEMA and
methacrylic acid, are among the most comfortable, and have the
lowest rate of adverse events. Contact lenses formed from
copolymers of HEMA and MAA, such ACUVUE contact lenses, display
substantial amounts of lysozyme uptake (greater than 500 .mu.g) and
retain a majority of the uptaken proteins in their native state.
However, hydrogel contact lenses generally have oxygen
permeabilities that are less than about 30.
[0004] Contact lenses made from silicone hydrogels have been
disclosed. These silicone hydrogel lenses have oxygen
permeabilities greater than about 60, and many provide reduced
levels of hypoxia compared to conventional hydrogel contact lenses.
Unfortunately, attempts to add anionic components to silicone
hydrogels in the past have produced contact lenses which are not
hydrolytically stable and display moduli which increase when
exposed to water and heat. Also, while adding ionicity to silicone
hydrogels has increased lysozyme uptake, it has also often
increased uptake of positively charged components from contact lens
multipurpose solutions. One such component is PQ1, a polyquaternium
disinfecting compound. Also, many silicone hydrogels have higher
than desired contact angles.
SUMMARY OF THE INVENTION
[0005] The present invention relates to anionic, silicone hydrogel
contact lens comprising in or on said silicone hydrogel at least
one statistical copolymer comprising units derived from at least 10
weight % of at least one non-ionic hydrophilic monomer and at least
one anionic monomer and wherein said contact lens comprises at
least one pharmaceutical or nutraceutical component and has a
contact angle of about 70.degree. or less, at least about 50
.mu.g/lens lysozyme uptake, and less than about 10% uptake of at
least one polycationic component when contacted with 3 mL of an
ophthalmic solution comprising said 0.001 wt % polycationic
component, 0.56% citrate dihydrate and 0.021% citric acid
monohydrate (wt/wt).
[0006] In another embodiment the present invention relates to an
anionic, silicone hydrogel contact lens comprising in or on said
silicone hydrogel at least one statistical copolymer comprising
units derived from at least 10 weight % of at least one non-ionic
hydrophilic monomer and at least one anionic monomer and wherein
said contact lens has a contact angle of about 70.degree. or less,
at least about 50 .mu.g/lens lysozyme uptake, and less than about
10% uptake of at least one polycationic component when contacted
with 3 mL of an ophthalmic solution comprising said 0.001 wt %
polycationic component, 0.56% citrate dihydrate and 0.021% citric
acid monohydrate (wt/wt)
[0007] In another embodiment the present invention relates to a
silicone hydrogel formed from a reactive mixture comprising
[0008] major polymerizable components comprising at least one
reactive silicone-containing component, at least one reactive ionic
monomer, optional reactive hydrophilic components and crosslinker;
and
[0009] minor polymerizable components selected from the group
consisting of visibility tint and dyes, UV absorbers, photochromic
compounds, pharmaceutical compounds, nutriceutical compounds, and
mixtures thereof;
[0010] wherein said major polymerizable components comprise a
single reactive functionality.
[0011] In another embodiment, the silicone hydrogels of the present
invention comprise at least one statistical copolymer comprising
units derived from at least one anionic monomer and at least 10
weight % of at least one non-ionic hydrophilic monomer.
DETAILED DESCRIPTION
[0012] The present invention relates to control of the spatial
density and concentration of anionic charges in silicone hydrogel
materials and articles made therefrom. It has been found that ionic
silicone hydrogel polymers and articles made therefrom may be made
having desirably increased tear component uptake (including
lysozyme) and low or no uptake of polycationic components from
cleaning and care solutions. The silicone hydrogels and articles
made therefrom may be made from ionic statistical copolymers or may
have associated therewith, at least one non-crosslinked (soluble),
ionic statistical copolymer. In this embodiment the ionic
statistical copolymer associates with the lens either through
entanglement, association or a combination thereof. For example the
contact lens may comprise NVP or PVP as a component in the lens
body. In this embodiment, the anionic statistical copolymer forms a
persistent association with the lactam moiety of the pyrrolidone.
Alternatively the anionic statistical copolymer may comprise a
hydrophobic block on at least one terminus. The hydrophobic block
of the anionic statistical copolymer associates with the silicone
in the silicone hydrogel contact lens.
[0013] As used herein, a "biomedical device" is any article that is
designed to be used while either in or on mammalian tissues or
fluid. Examples of these devices include but are not limited to
catheters, implants, stents, and ophthalmic devices such as
intraocular lenses, inlay lenses and contact lenses.
[0014] As used herein an "ophthalmic device" is any device which
resides in or on the eye or any part of the eye, including the
cornea, eyelids and ocular glands. These devices can provide
optical correction, cosmetic enhancement, vision enhancement,
therapeutic benefit (for example as bandages) or delivery of active
components such as pharmaceutical and neutraceutical components, or
a combination of any of the foregoing. Examples of ophthalmic
devices include lenses and optical and ocular inserts, including,
but not limited to punctal plugs and the like.
[0015] As used herein, the term "lens" refers to ophthalmic devices
that reside in or on the eye. The term lens includes but is not
limited to soft contact lenses, hard contact lenses, intraocular
lenses, overlay lenses.
[0016] The medical devices, ophthalmic devices and lenses of the
present invention are, in one embodiment, made from silicone
elastomers or hydrogels, which include but are not limited to
silicone hydrogels, and silicone-fluorohydrogels. These hydrogels
contain hydrophobic and hydrophilic monomers that are covalently
bound to one another in the cured lens.
[0017] As used herein "uptake" means associated in, with or on the
lens, deposited in or on the lens. "Percent (%) uptake" of
polycationic components means the percent of the polycationic
component which associates in, with or on the lens or deposits in
or on the lens compared to the total amount of that polycationic
component in the ophthalmic solution prior to contact with the
silicone hydrogels of the present invention.
[0018] As used herein "reactive mixture" refers to the mixture of
components (both reactive and non-reactive) which are mixed
together and subjected to polymerization conditions to form the
ionic silicone hydrogels of one embodiment of the present
invention. The reactive mixture comprises reactive components such
as monomers, macromers, prepolymers, cross-linkers, initiators,
diluents and additives such as wetting agents, release agents,
dyes, light absorbing compounds such as UV absorbers and
photochromic compounds, any of which may be reactive or
non-reactive but are capable of being retained within the resulting
medical device, as well as pharmaceutical and nutriceutical
compounds. It will be appreciated that a wide range of additives
may be added based upon the medical device which is made, and its
intended use. Concentrations of components of the reactive mixture
are given in weight % of all components in the reaction mixture,
excluding diluent. When diluents are used their concentrations are
given as weight % based upon the amount of all components in the
reaction mixture and the diluent.
[0019] As used herein a statistical copolymer is a polymer having
at least one segment formed from reactive components having
substantially similar reaction rate constants, k for reaction with
themselves and with each other. For example, statistical copolymers
include crosslinked polymer matrices which are formed from reactive
components having the same reactive functionality, polymers formed
from reactive components having the same reactive functionality and
block copolymers where at least one block is formed from reactive
components having the same reactive functionality. Generally,
substantially similar reaction rate constants are within about 10%.
Reactive components which have the same reactive functionality have
substantially similar reaction rate constants.
[0020] As used herein, cationic tear components include cationic
proteins including lactoferrin, lysozyme, serum albumin, and
secretory immunoglobulin A. Lysozyme is a preferred cationic tear
component.
[0021] As used herein, ophthalmic solutions are solutions which are
instilled in the eye or are used to condition or clean devices
which are placed in the ocular environment. Examples of ophthalmic
solutions include eye drops, rewetting drops, contact lens
multipurpose solutions, packaging solutions for ophthalmic devices,
including contact lenses.
[0022] Contact lens multipurpose solutions frequently contain
polycationic components. Polycationic components include positively
charged organic compounds, such as cationic water soluble polymeric
ammonium salts, such as biguanides, bisbiguanides and
polyquaternium containing compounds, also called "polyquats" or PQ
compounds. Polyhexamethylene biguanide (PHMB) is a common biguanide
used in contact lens, multipurpose, cleaning and care solutions.
Examples of water soluble polymeric ammonium salts include
polycationic polymers having quartenary ammonium centers. Examples
include PQ-1, PQ-42 (poly[oxyethylene(dimethyliminio)ethylene
(dimethyliminio)ethylene dichloride]), and the like. Cationic water
soluble polymeric tetraalkyl phosphonium salts may also be used in
place of the ammonium salts. Non-polymeric cationic organic
components having two or more cations such as chlorhexidine
(N',N'''''-hexane-1,6-diylbis[N-(4-chlorophenyl)(imidodicarbonimidic
diamide)], or CHG), and the like may also be included. Inorganic
charged ions, such as sodium ions are not cationic components as
defined herein.
[0023] PQ1 is a cationic copolymer having quarternary ammonium ions
in its polymer backbone. Specifically PQ1 is
poly[(dimethyliminio)-2-butene-1,4-diyl chloride (1:1)],
.alpha.-[4-[tris(2-hydroxyethyl)ammonio]-2-buten-1-yl]-.omega.-[tris(2-hy-
droxyethyl)ammonio]-, chloride (CAS 75345-27-6). Contact lens
solutions, including multipurpose solutions and cleaning solutions,
generally also contain citrates such as citrate dihydrate and
citric acid monohydrate to help prevent PQ1 uptake by contact
lenses. However, the addition of anionicity to silicone hydrogel
lenses can result in undesirable PQ1 uptake by the lens, even in
the presence of citrates. In another embodiment, the present
invention further provides desirably low uptake of water soluble
polymeric ammonium salts.
[0024] RAFT refers to reversible addition fragmentation-chain
transfer polymerization, a form of "pseudo-living" free radical
polymerization.
[0025] Hydrophilic components are components that are at least 10%
soluble in water. So, if 10 weight parts of the monomer are
combined with 90 weight parts of water, a clear, single phase
solution is formed with mixing at room temperature.
[0026] Anionic components are components comprising at least one
anionic group and at least one reactive group. Anionic groups are
groups which bear a negative charge at neutral pH. Examples of
anionic groups include carboxylate groups, phosphates, sulphates,
sulphonates, phosphonates, borates, mixtures thereof and the like.
In one embodiment the anionic components comprise three to ten
carbon atoms, and in another, three to eight carbon atoms. In an
embodiment the anionic groups comprise carboxylate groups or
sulphonate groups. Anionic components also include ionizable salts
of any of the foregoing, for examples salts containing calcium,
sodium, lithium, magnesium and mixtures thereof.
[0027] Reactive functionality or groups include those that can
undergo chain reaction polymerizations, such as free radical and/or
cationic polymerization under polymerization conditions. It is also
possible to synthesize silicone copolymers via step reaction
polymerization such as polyesters from the reaction of diols and
diacids and polyurethanes from the reaction of diols and
di-isocyanates or via thiol-ene reactions. In general,
polymerizable groups can be classified as activated or unactivated
polymerizable groups.
[0028] Activated polymerizable components are those that have at
least two double bonds in conjugation:
##STR00001##
[0029] R are independently selected from H, carboxyl groups, ester
groups, halides groups, C.sub.1-C.sub.4 alkyl groups, which may be
further substituted with carboxylic acid or ester groups. In
another embodiment R is selected from H and unsubstituted
--C.sub.1-4 alkyl groups; and in another embodiment from H and
methyl, --COOH, --CH.sub.2COOH, in another embodiment H and
--CH.sub.3;
[0030] R' is O or N which is further substituted a group selected
from H, C.sub.1-3 alkyl groups which may be further substituted
with hydroxyl groups, carboxyl groups or carboxyester groups; or R'
may be an alkenylene, which taken with R'' forms a phenyl ring. In
one embodiment R' is O or N substituted with H or unsubstituted
C.sub.1-3 alkyl.
[0031] R'' is O or an alkenylene which when taken with R' forms a
phenyl ring.
[0032] Examples of activated polymerizable groups include acrylate
or methacrylate esters, itaconic acid esters, fumaric or maleic
acid esters, acrylamides or methacrylamides, or styrenes.
[0033] Unactivated polymerizable groups have a carbon-carbon double
bond, but do not have a second double bond in conjugation:
##STR00002##
in which each R may be H, C.sub.1-C.sub.4 alkyl groups which may be
unsubstituted or substituted with hydroxyl, carboxy, carboxyester,
Cl, Br, O, or N(R.sup.2)COR.sup.3, R.sup.2 is H or COR.sup.3,
unsubstituted C1-3 alkyl, R.sup.3H or unsubstituted C1-3, and Rx
and Ry may together be propylene, O may be substituted with C1-3
alkyl or CORx provided that the atom bonded to the carbon-carbon
bond is not itself doubly or triply bonded. Examples of unactivated
polymerizable groups include vinyl lactams, vinyl amides, vinyl
carbonates, vinyl carbamates, allyl ethers, allyl alcohols and the
like.
[0034] Non-limiting examples of free radical reactive groups
include (meth)acrylates, styryls, vinyls, vinyl ethers,
C.sub.1-6alkyl(meth)acrylates, (meth)acrylamides,
C.sub.1-6alkylmeth)acrylamides, N-vinyllactams, N-vinylamides,
C.sub.2-12alkenyls, C.sub.2-12alkenylphenyls,
C.sub.2-12alkenylnaphthyls, C.sub.2-6alkenylphenylC.sub.1-6alkyls,
O-vinylcarbamates and O-vinylcarbonates. Non-limiting examples of
cationic reactive groups (groups that can polymerize under cationic
polymerization conditions) include vinyl ethers or epoxide groups
and mixtures thereof. In one embodiment the reactive groups
comprises (meth)acrylate, acryloxy, (meth)acrylamide, and mixtures
thereof.
[0035] Any chemical name preceded by (meth), for example
(meth)acrylate, includes both the unsubstituted and methyl
substituted compound.
[0036] A statistical copolymer is formed between reactive
comonomers, for example A and B, when their reactivity ratios,
r.sub.A and r.sub.B, approximate each other and approach unity. The
"statistical" or "non-statistical" copolymerization of these two
monomers is characterized by the relative mole fractions of
monomers A and B that incorporate into the backbone of the
copolymer as it is undergoing polymerization. The mole fraction of
monomer A, F.sub.A, incorporated into a copolymer of A and B, for
example, is predicted by the Mayo-Lewis Equation:
F A = r A f A 2 + f A f B r A f A 2 + 2 f A f B + r B f B 2
##EQU00001## where r A = k AA k AB , r B = k BB k BA ,
##EQU00001.2##
and f.sub.A and f.sub.B are the relative mole fractions of A and B.
The reactivity ratios, r.sub.A and r.sub.B, are defined by four
propagation rate constants, k.sub.AA, k.sub.AB, k.sub.BA, and
k.sub.BB. For a propagating copolymer in a comonomer mixture of A
and B, there are four possible radical addition scenarios that
yield four distinct propagation rate constants:
##STR00003##
[0037] Generally, the relative values of r.sub.A and r.sub.B, the
mole fractions of both monomers, and the extent of conversion of
the copolymerization are the major factors which dictate the
microstructure of the resultant copolymer. In general there are
limiting cases for r.sub.A and r.sub.B that apply specifically to
the invention disclosed herein. In cases where r.sub.A and r.sub.B
are equal and approach unity (e.g. r.sub.A=r.sub.B.apprxeq.1) the
copolymerization is considered to be "random" or "statistical,"
i.e. there is an equal probability that monomer A will add to
itself and to monomer B, and monomer B will add to itself and
monomer A with equal probability also. In one embodiment "similar"
reactivity ratios are those for which the reactivity ratios of the
fastest and slowest reactive components in the reactive mixture are
within 25% of each other, and in another embodiment within about
10% of each other, and in another embodiment within about 5% of
each other. In some embodiments minor reactive additives, such as
reactive dyes or UV absorbers can have reactivity ratios which are
greater than the herein disclosed ranges. The reactivity ratios may
be determined by measuring the relative depletion of monomer A and
B from the polymerization solution and the relative incorporation
of A and B into the resultant copolymer. This measurement is taken
at low total monomer conversion, i.e. around 10-20%, and is
repeated across a range of initial monomer compositions between
1-99% A or 99-1% B.
[0038] In another embodiment, the random or statistical copolymers
are formed from charged monomers and other monomers comprising the
same reactive double-bonds (anionic charge-bearing
acrylamido-monomers being paired with other acrylamido-comonomers
or anionic charge-bearing methacrylic-monomers being paired with
other methacrylate-comonomers). As shown by the Examples herein,
the consumption of charge-bearing monomers with other monomers that
contain the same reactive functionality produce lenses which
display the desired selective uptake of cationic tear components,
such as lysozyme over polycationic components, such as PQ1.
Reactive mixtures comprising reactive components having the same
reactive functionality and similar reactivity ratios (that approach
unity), which produce the homogeneous distribution of charge across
the surface and throughout the bulk of the lens.
[0039] Where r.sub.A=r.sub.B.apprxeq.0, the probabilities of
monomers A and B adding to themselves is very low. This results in
the formation of alternating copolymers of A and B, and lens
materials having the desired distribution of charge throughout the
lens and the desired selective uptake of cationic tear components
over polycationic components.
[0040] Where r.sub.A>1>r.sub.B, statistical copolymers of the
present invention are not formed. In this case early in the
polymerization, monomer A is consumed at a higher rate than monomer
B. At this early point in the copolymerization, copolymers that are
formed are very rich in monomer A. As the polymerization progresses
and monomer A is depleted over monomer B, thus changing the
relative mole fractions in favor of monomer B, the copolymer
microstructure shifts from being rich in monomer A to rich in
monomer B. This occurs until all or most of monomer A is consumed,
at which point the polymer that is formed is completely or mostly
composed of monomer B. This is also known to those skilled in the
art as "compositional drift." In a comparative example of this
invention, an anionic acrylamido-monomer is copolymerized in a
mixture of methacrylates and other acrylamides to make a contact
lens or medical device. In this case, it is believed that the
methacrylates are consumed at a much higher rate, compared to the
acrylamido-monomers early in the polymerization. This continues
until all or most of the methacrylates are consumed, after which
point the acrylamido-monomers are consumed and the polymerization
reaches 100% conversion. Because the anionic charge-bearing
acrylamido-monomer has a much higher probability of being consumed
later in the reaction, the charge in and on the bulk and surface of
the substrate is not homogeneously distributed throughout the
polymer bulk. This leads to a significant amount of PQ1 uptake as
well as lysozyme, which is undesirable.
[0041] When r.sub.A=r.sub.B>1, blocky-type copolymers are
formed. In this case monomer A has a high probability of adding to
itself over monomer B and monomer B has a high probability of
adding to itself over monomer A. In extreme cases, where A would
rarely add to B and vice versa, i.e. where
r.sub.A=r.sub.B>>1, formation of a mixture of homopolymers is
anticipated. These cases are believed to produce a heterogeneous
distribution of charge in and on the resulting substrate.
[0042] It has been found that by selecting the components of the
reactive mixture such that reactivity rates are substantially
matched, statistical copolymers can be made wherein the units from
the anionic monomers are randomly distributed throughout either the
polymer or at least one segment of the polymer, depending upon the
embodiment of the present invention. The random distribution of
negative charge throughout the polymer is believed to provide a
delocalization of charge, which provides increased uptake by the
polymer of beneficial proteins such as lysozyme, but low uptake of
positively charged components in contact lens solutions, including
polyquarternium salts, such as, but not limited to PQ1.
[0043] Thus, in one embodiment the non-ionic hydrophilic monomer
and the anionic monomer are either both activated or both
unactivated. In another embodiment the reactive functionality for
both the non-ionic hydrophilic monomer and the anionic monomer are
the same, for example both the non-ionic hydrophilic monomer and
the anionic monomer are both are methacrylates. In another
embodiment both the non-ionic hydrophilic monomer and the anionic
monomer are methacrylamides. Non-limiting examples of such
combinations are included in the Examples below.
[0044] Examples of suitable anionic components include reactive
carboxylic acids, including alkylacrylic acids, such as
(meth)acrylic acid, acrylic acid, itaconic acid, crotonic acid,
cinnamic acid, vinylbenzoic acid, fumaric acid, maleic acid,
monoesters of furmaric acid, maelic acid and itaconic acid;
3-acrylamidopropionic acid, 4-acrylamidobutanoic acid,
5-acrylamidopentanoic acid, N-vinyloxycarbonyl-.alpha.-alanine,
N-vinyloxycarbonyl-.beta.-alanine (VINAL),
2-vinyl-4,4-dimethyl-2-oxazolin-5-one (VDMO), reactive sulphonate
salts, including sodium-2-(acrylamido)-2-methylpropane sulphonate,
3-sulphopropyl (meth)acrylate potassium salt, 3-sulphopropyl
(meth)acrylate sodium salt, bis 3-sulphopropyl itaconate di sodium,
bis 3-sulphopropyl itaconate di potassium, vinyl sulphonate sodium
salt, vinyl sulphonate salt, styrene sulphonate, 2-sulphoethyl
methacrylate and mixtures thereof and the like. In one embodiment
the anionic component is selected from reactive carboxylic acids,
in another from methacrylic acid and N-vinyloxycarbonyl alanine. In
another embodiment, where the reactive monomers comprise acrylamido
reactive groups the anionic monomer comprises an acrylamide acid,
such as 3-acrylamidopropionic acid, 4-acrylamidobutanoic acid,
5-acrylamidopentanoic acid, 2-acrylamido-2-methylpropane sulphonic
acid, salts of said acrylamido acids and combinations thereof.
Suitable salts include ophthalmically compatible salts including
sodium, potassium and calcium salts.
[0045] It has been surprisingly found that the acrylamido sulphonic
acid or acrylamido sulphonic acid salts are compatible with the all
acrylamide formulations of the present invention. The acrylamido
sulphonic acid or acrylamido sulphonic acid salts are generally too
polar to be soluble in silicone hydrogel reactive mixtures, even at
the low molar concentrations disclosed herein. However, when the
single reactive functionality is methacrylamide acrylamido
sulphonic acid or acrylamido sulphonic acid salt may be directly
incorporated into the reactive mixture in amounts up to about 5
mole %, in some embodiments up to about 3 mol %, and in other
embodiments between about 0.1 to about 2 mol %.
[0046] In another embodiment the reactive components comprise
methacrylate groups and the ionic component comprises methacrylic
acid. It is understood that these monomers may be copolymerized in
a non-ionic (ester) form, and then deprotonated or hydrolyzed to
form ionic groups in the final product.
[0047] Those of skill in the art will understand that the foregoing
anionic monomers are selected based upon the functionality of the
other reactive components. For example, when the major
polymerizable components comprise acrylamide reactive functionality
the anionic monomer may be 3-acrylamidopropionic acid,
4-acrylamidobutanoic acid, 5-acrylamidopentanoic acid,
sodium-2-(acrylamido)-2-methylpropane sulphonate,
2-acrylamido-2-methylpropane sulfonic acid and combinations
thereof.
[0048] When the major polymerizable components comprise
(meth)acrylate functionality the anionic monomer may be
(meth)acrylic acid, itaconic acid, crotonic acid, cinnamic acid,
fumaric acid, maleic acid, monoesters of furmaric acid,
3-sulphopropyl (meth)acrylate potassium salt, 3-sulphopropyl
(meth)acrylate sodium salt, bis 3-sulphopropyl itaconate di sodium,
bis 3-sulphopropyl itaconate di potassium, sulphoethyl
methacrylate, and mixtures thereof. In another embodiment the major
polymerizable components comprise (meth)acrylate functionality, and
the anionic monomer may be (meth)acrylic acid, 3-sulphopropyl
(meth)acrylate potassium salt, 3-sulphopropyl (meth)acrylate sodium
salt, sulphoethyl methacrylate, and mixtures thereof.
[0049] When the major polymerizable components comprise vinyl
functionality the anionic monomer may be
N-vinyloxycarbonyl-.alpha.-alanine,
N-vinyloxycarbonyl-.beta.-alanine,
2-vinyl-4,4-dimethyl-2-oxazolin-5-one, vinyl sulphonate sodium
salt, vinyl sulphonate salt, and mixtures thereof.
[0050] Suitable non-ionic hydrophilic monomers include N,N-dimethyl
acrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), glycerol
methacrylate, 2-hydroxyethyl methacrylamide, polyethyleneglycol
monomethacrylate, N-vinyl amides, N-vinyl lactams (e.g. NVP),
N-vinyl-N-methyl acetamide, N-vinyl-N-ethyl acetamide,
N-vinyl-N-ethyl formamide, N-vinyl formamide. Vinyl carbonate or
vinyl carbamate monomers, such as those disclosed in U.S. Pat. No.
5,070,215, and the hydrophilic oxazolone monomers disclosed in U.S.
Pat. No. 4,910,277 may also be used.
[0051] The hydroxyl-containing (meth)acrylamide monomers of Formula
c0, disclosed in US 2011-0230589 A1 may also be used:
##STR00004##
[0052] wherein, R.sup.1 is hydrogen or methyl; at least one of
R.sup.14 and R.sup.15 is substituted with a C1-C20 alkyl
substituted with at least one hydroxyl group, with the proviso that
when i) one of R.sup.14 and R.sup.15 is hydrogen, ii) the other of
R.sup.14 and R.sup.15 is a C1-C20 alkyl group substituted with two
or more hydroxyl groups. In one embodiment, the non-silicone
(meth)acrylamide monomer comprises two or more hydroxyl groups in
the molecule. In some embodiments R.sup.1 is a hydrogen atom and at
least one of R.sup.14 and R.sup.15 is selected from hydrogen,
optionally substituted C1-C20 alkyl group, or optionally
substituted C6-C20 aryl group with the proviso that the total
number of hydroxyl groups in R.sup.14 and R.sup.15 is two or more.
In one embodiment R.sup.14 and R.sup.15 is are independently
selected from C1-C10 alkyl group which may be substituted with at
least one more hydroxyl group, and in other embodiments C1-C6 alkyl
group which may be substituted with at least one more hydroxyl
group, so long as the hydrophilic (meth)acrylamide meets the
proviso above.
[0053] Examples of R.sup.14 and R.sup.15 include hydrogen atoms,
methyl groups, ethyl groups, propyl groups, n-propyl groups,
i-propyl groups, n-butyl groups, s-butyl groups, t-butyl groups,
n-pentyl groups, i-pentyl groups, s-pentyl groups, neopentyl
groups, hexyl groups, heptyl groups, octyl groups, nonyl groups,
decyl groups, dodecyl groups, eicosyl groups, phenyl groups,
naphthyl groups, 2-hydroxyethyl groups, 2-hydroxypropyl groups,
3-hydroxypropyl groups, 2,3-dihydroxypropyl groups, 4-hydroxy butyl
groups, 2-hydroxy-1,1-bis(hydroxymethyl)ethyl groups,
2-hydroxymethylphenyl groups, 3-hydroxymethylphenyl groups,
4-hydroxymethylphenyl groups and the like. These alkyl and
hydroxyalkyl groups can be straight or branched. A particularly
preferable example of a non-silicone type (meth)acrylamide monomer
containing two or more hydroxyl groups in the molecule include the
monomers expressed by the following general formulae (c1) through
(c3).
##STR00005##
[0054] In chemical formulae (c1) through (c3), R.sup.1
independently represents a hydrogen atom or a methyl group.
[0055] In another embodiment, the hydroxyl-containing
(meth)acrylamide monomer comprises one hydroxyl group and no amide
hydrogen in the molecule. In chemical formula (c0) of this
embodiment, R.sup.1 represents methyl and R.sup.14 and R.sup.15 are
independently selected from optionally substituted C1-C20 alkyl
group, or optionally substituted C6-C20 aryl group with the proviso
that one of R.sup.14 and R.sup.15 is substituted with at least one
hydroxyl group. Examples of R.sup.14 and R.sup.15 include methyl
groups, ethyl groups, propyl groups, n-propyl groups, i-propyl
groups, n-butyl groups, s-butyl groups, t-butyl groups, n-pentyl
groups, i-pentyl groups, s-pentyl groups, neopentyl groups, hexyl
groups, heptyl groups, octyl groups, nonyl groups, decyl groups,
dodecyl groups, eicosyl groups, phenyl groups, naphthyl groups,
2-hydroxyethyl groups, 2-hydroxypropyl groups, 3-hydroxypropyl
groups, 4-hydroxy butyl groups, 2-hydroxymethylphenyl groups,
3-hydroxymethylphenyl groups, 4-hydroxymethylphenyl groups and the
like. These alkyl groups can be straight or branched. Examples of
hydroxyl-containing acrylamide monomer of this embodiment include
the monomers expressed by the following general formulae (c11)
through (c13).
##STR00006##
[0056] In chemical formulae (c11) through (c13), R.sup.1
independently represents a methyl group.
[0057] In some embodiments acrylamide monomer comprising one
hydroxyl group and one amide hydrogen in the molecule may be used.
Examples of a mono-hydroxyl functionalized acrylamide monomer
include N-(mono-hydroxyl substituted C1-C20 alkyl)acrylamide and
N-(mono-hydroxyl substituted C6-C20 aryl)acrylamide. More specific
examples include N-(2-hydroxyethyl)acrylamide,
N-(2-hydroxypropyl)acrylamide, N-(3-hydroxypropyl)acrylamide,
N-(2-hydroxybutyl)acrylamide, N-(3-hydroxybutyl)acrylamide,
N-(4-hydroxy butyl)acrylamide, N-(2-hydroxymethylphenyl)acrylamide,
N-(3-hydroxymethylphenyl)acrylamide,
N-(4-hydroxymethylphenyl)acrylamide and the like. In some
embodiments, N-(mono-hydroxyl substituted C2-C4 alkyl)acrylamide
and particularly N-(2-hydroxyethyl)acrylamide may be preferred.
[0058] The amount of the anionic monomer is also important. Even
when a desirable charge distribution has been achieved, if the
concentration of the anionic monomer is too high, undesirable PQ-1
uptake may occur. Thus, in embodiment, where the anionic monomer is
a component of a reusable silicone hydrogel contact lens, the
anionic monomer may be included in amounts up to about 5 mol %, in
some embodiments between about 0.1 and about 5 mol %, between about
0.1 and about 4 mol %, and in other embodiments between about 0.2
and about 4 mol %. In embodiments where the contact lens is worn
for only a single day and then thrown away, higher amounts of the
anionic monomer may be included. The upper limit for the anionic
monomer in these embodiments may be selected to provide the desired
level of lysozyme or other team components, and a water content of
less than about 70% water, in some embodiments less than 70% water,
and in others less than about 65% water.
[0059] The anionic monomer and non-ionic hydrophilic monomer may be
copolymerized (either alone or with additional components) to form
a water soluble, uncrosslinked polymer or may be included in a
silicone hydrogel reaction mixture and cured to form the silicone
hydrogel contact lens.
[0060] When the anionic monomer and non-ionic, hydrophilic monomer
are copolymerized to form an uncrosslinked statistical copolymer,
the anionic monomer is present in the uncrosslinked statistical
copolymer in amounts between about 20 to about 80 mol %, and in
some embodiments between about 20 to about 60 mol %. The non-ionic,
hydrophilic monomer may be present in amounts between about 80 to
about 20 mol % and in some embodiments between about 80 to about 40
mol %. If the polymer contains a hydrophobic segment or block, as
described below, these mol % are based upon the hydrophilic segment
of the polymer only.
[0061] The hydrophilic segment of the uncrosslinked statistical
copolymers of the present invention have a degree of polymerization
of at least about 300.
[0062] The uncrosslinked statistical copolymers may be formed by a
number of methods including, but not limited to, step growth
polymerization, such as thiol-ene chemistry, and chain reaction
polymerization, such as free radical polymerization and RAFT.
[0063] In one embodiment the uncrosslinked statistical copolymer
further comprises a hydrophobic block on at least one terminal end
of the uncrosslinked statistical copolymer. The hydrophobic block
may be a hydrocarbon block, a siloxane block, or any other block
which is capable of associating with the silicone hydrogel contact
lens. In another embodiment the uncrosslinked statistical copolymer
has a hydrophobic block which is capable of associating with
another polymeric biomedical device such as a stent, a rigid
contact lens, a catheter, stent or other implant.
[0064] In one embodiment, the hydrophobic block comprises
polydialkylsiloxane, polydiarylsiloxane and mixtures thereof. The
alkyls may be independently selected from C.sub.1-C.sub.4 alkyl,
and in one embodiment the hydrophobic block comprises
polydimethylsiloxane or polydiethylsiloxane, either of which may be
terminated by a C.sub.1-12 alkyl, C.sub.1-C.sub.4 alkyl, aryl or in
some embodiments methyl or n-butyl.
[0065] The hydrophobic block may comprise between about 6 and about
200 siloxy units, between about 6 and about 60 siloxy units, 6 and
about 20 siloxy units, 6-15 siloxy units and 6 to 12 siloxy
units.
[0066] The uncrosslinked, statistical copolymers may be dissolved
in solutions which swell the medical device and contacted with the
medical device. In one embodiment where the device is a silicone
hydrogel contact lens the uncrosslinked, statistical copolymers are
dissolved in water or an aqueous solution and contacted with the
contact lens during processing, packaging or cleaning or storage of
the lens. For example the uncrosslinked, statistical copolymers may
be incorporated into a hydration or packaging solution or may be
included in a multipurpose or cleaning solution which is used by
the contact lens wearer.
[0067] The amount of uncrosslinked, statistical copolymers included
in the solutions will depend in part on the concentration of the
anionic monomer in the uncrosslinked, statistical copolymers. For
example, uncrosslinked, statistical copolymers containing 30 mol %
anionic monomer can be added in higher amounts than uncrosslinked,
statistical copolymers having 80 mol % anionic monomer, as is shown
the Examples. It is desirable to balance the concentration of
anionic monomer in the uncrosslinked, statistical copolymers with
the concentration of uncrosslinked, statistical copolymers in the
solution to achieve the desired levels of lysozyme and PQ1 uptake.
Concentrations of uncrosslinked, statistical copolymers of up to
about 2000 ppm, and in some embodiments between about 20 ppm and
2000 ppm and in other embodiments between about 50 and about 1500
ppm are desirable.
[0068] In another embodiment the anionic monomer and the non-ionic
hydrophilic monomer are included in the silicone hydrogel reactive
mixture to form a silicone hydrogel polymer having a homogeneously
distributed anionic charge throughout the polymer. In this
embodiment the resulting contact lens has a contact angle of less
than about 70.degree., less than about 50.degree. and in some
embodiments less than about 30.degree. all as measured by sessile
drop.
[0069] In this embodiment substantially all of the polymerizable
components in the reaction mixture have the same reactive
functionality. Non-reactive components, such as wetting agents may
also be present. Contact lens formulations may contain small
amounts of components, such as, but not limited to handling tints
and UV absorbers, which because of their small concentration, do
not need to have the same reactive functionality. Generally, the
concentration of reactive components in the reaction mixture which
have different functionality should be limited to less than about
0.5 mol %. Non-reactive components, such as non-reactive wetting
agents may be present in greater amounts (up about 15 weight %, and
in some embodiments up to about 20 weight %) as they do not
participate in the reaction.
[0070] In this embodiment the anionic monomer is present in the
reactive mixture in concentrations in amounts up to about 5 mol %,
in some embodiments between about 0.1 and about 5 mol %, between
about 0.1 and about 4 mol %, and in other embodiments between about
0.2 and about 4 mol %. The non-ionic hydrophilic monomer is present
in amounts of at least about 10 wt %, and in some embodiments
between about 10 wt % and about 70 wt %, between about 20 and about
60% and in other embodiments, between about 20 and about 50 weight
%.
[0071] The reaction mixture further comprises at least one
silicone-containing component. A silicone-containing component is
one that contains at least one [--Si--O--] group, in a monomer,
macromer or prepolymer. In one embodiment, the Si (silicon) and
attached O are present in the silicone-containing component in an
amount greater than 20 weight percent, and in another embodiment
greater than 30 weight percent of the total molecular weight of the
silicone-containing component. Useful silicone-containing
components comprise polymerizable functional groups such as
(meth)acrylate, (meth)acrylamide, 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 EP080539. All of the patents cited
herein are hereby incorporated in their entireties by reference.
These references disclose many examples of olefinic
silicone-containing components.
[0072] Suitable silicone-containing components include compounds of
Formula I
##STR00007##
[0073] where R.sup.1 is independently selected from monovalent
reactive groups, siloxane chain, monovalent alkyl groups, or
monovalent aryl groups. The monovalent alkyl and aryl groups
further comprise functionality selected from hydroxy, amino, oxa,
carboxy, alkyl carboxy, alkoxy, amido, carbamate, carbonate,
halogen or combinations thereof; and monovalent siloxane chains
comprising 1-100 Si--O repeat units which may further comprise
functionality selected from alkyl, hydroxy, amino, oxa, carboxy,
alkyl carboxy, ether, amido, carbamate, halogen or combinations
thereof;
where b=0 to 500, where it is understood that when b is other than
0, b is a distribution having a mode equal to a stated value;
wherein at least one R.sup.1 comprises at least one monovalent
reactive group, and in some embodiments between one and 3 R.sup.1
comprise monovalent reactive groups.
[0074] As used herein "monovalent reactive groups" are groups that
can undergo polymerization such as free radical, anionic and/or
cationic polymerization. Non-limiting examples of free radical
reactive groups include (meth)acrylates, styryls, vinyls, vinyl
ethers, substituted or unsubstituted C.sub.1-6alkyl(meth)acrylates,
(meth)acrylamides, substituted or unsubstituted
C.sub.1-6alkyl(meth)acrylamides, N-vinyllactams, N-vinylamides,
C.sub.2-12alkenyls, C.sub.2-12alkenylphenyls,
C.sub.2-12alkenylnaphthyls, C.sub.2-6alkenylphenylC.sub.1-6alkyls,
O-vinylcarbamates and O-vinylcarbonates. Suitable substituents on
said C1-6 alkyls include ethers, hydroxyls, carboxyls, halogens and
combinations thereof. Non-limiting examples of cationic reactive
groups include vinyl ethers or epoxide groups and mixtures thereof.
In one embodiment the free radical reactive groups comprises
(meth)acrylate, acryloxy, (meth)acrylamide, and mixtures
thereof.
[0075] Suitable monovalent alkyl and aryl groups include
unsubstituted monovalent C.sub.1 to C.sub.16alkyl groups,
C.sub.6-C.sub.14 aryl groups, such as substituted and unsubstituted
methyl, ethyl, propyl, butyl, 2-hydroxypropyl, propoxypropyl,
polyethyleneoxypropyl, combinations thereof and the like.
[0076] In one embodiment on R.sup.1 is selected from
C.sub.1-6alkyl(meth)acrylates, and C.sub.1-6alkyl(meth)acrylamides,
which may be unsubstituted or substituted with hydroxyl, alkylene
ether or a combination thereof. In another embodiment R.sup.1 is
selected from propyl(meth)acrylates and propyl (meth)acrylamides,
wherein said propyl may be optionally substituted with hydroxyl,
alkylene ether or a combination thereof.
[0077] In one embodiment b is zero, one R.sup.1 is a monovalent
reactive group, and at least 3 R.sup.1 are selected from monovalent
alkyl groups having one to 16 carbon atoms, and in another
embodiment from monovalent alkyl groups having one to 6 carbon
atoms. Non-limiting examples of silicone components of this
embodiment include
2-methyl-,2-hydroxy-3-[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disi-
loxanyl]propoxy]propyl ester ("SiGMA"),
2-hydroxy-3-methacryloxypropyloxypropyl-tris(trimethylsiloxy)silane,
3-methacryloxypropyltris(trimethylsiloxy)silane ("TRIS"),
3-methacryloxypropylbis(trimethylsiloxy)methylsilane and
3-methacryloxypropylpentamethyl disiloxane.
[0078] In another embodiment, b is 2 to 20, 3 to 15 or in some
embodiments 3 to 10; at least one terminal R.sup.1 comprises at
least one monovalent reactive group and the remaining R.sup.1 are
selected from monovalent alkyl groups having 1 to 16 carbon atoms,
and in another embodiment from monovalent alkyl groups having 1 to
6 carbon atoms. In yet another embodiment, b is 3 to 15, one
terminal R.sup.1 comprises a monovalent reactive group selected
from substituted or unsubstituted C.sub.1-6alkyl(meth)acrylates,
substituted or unsubstituted C.sub.1-6alkyl(meth)acrylamides, the
other terminal R.sup.1 comprises a monovalent alkyl group having 1
to 6 carbon atoms and the remaining R.sup.1 comprise monovalent
alkyl group having 1 to 3 carbon atoms. Non-limiting examples of
silicone components of this embodiment include
(mono-(2-hydroxy-3-methacryloxypropyl)-propyl ether terminated,
n-butyl terminated polydimethylsiloxane (400-1000 MW))
("OH-mPDMS"), monomethacryloxypropyl terminated mono-n-butyl
terminated polydimethylsiloxanes (800-1000 MW), ("mPDMS"),
N-(2,3-dihydroxypropane)-N'-(propyl
tetra(dimethylsiloxy)dimethylbutylsilane)acrylamide, and
methacryamide silicones of the following formulae (s1) through
(s6);
##STR00008##
[0079] In another embodiment b is 5 to 400 or from 10 to 300, both
terminal R.sup.1 comprise monovalent reactive groups and the
remaining R.sup.1 are independently selected from monovalent alkyl
groups having 1 to 18 carbon atoms which may have ether linkages
between carbon atoms and may further comprise halogen.
[0080] In another embodiment, one to four R.sup.1 comprises an
allyl or vinyl carbonate or carbamate of the formula:
##STR00009##
[0081] wherein: Y denotes O--, S-- or NH--;
[0082] R denotes, hydrogen or methyl; d is 1, 2, 3 or 4; and q is 0
or 1.
[0083] The silicone-containing carbonate or carbamate monomers
specifically include:
1,3-bis[4-(vinyloxycarbonyloxy)but-1-yl]tetramethyl-disiloxane;
3-(vinyloxycarbonylthio)propyl-[tris(trimethylsiloxy)silane];
3-[tris(trimethylsiloxy)silyl]propyl allyl carbamate;
3-[tris(trimethylsiloxy)silyl]propyl vinyl carbamate;
trimethylsilylethyl vinyl carbonate; trimethylsilylmethyl vinyl
carbonate, and
##STR00010##
[0084] In another embodiment, where an acrylamide system is used,
the (meth)acrylamide silicones of US2011/0237766 may be used with
acrylamide hydrophilic monomers such as DMA and HEAA and acrylamide
anionic monomers such as 3-acrylamidopropanoic acid (ACA1) or
5-acrylamidopentanoic acid (ACA2).
[0085] Where biomedical devices with modulus below about 200 are
desired, only one R.sup.1 shall comprise a monovalent reactive
group and no more than two of the remaining R.sup.1 groups will
comprise monovalent siloxane groups.
[0086] 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 weight % and in some
embodiments between about 20 and 70% wt silicone-containing
components based on total weight of reactive monomer components
from which the polymer is made.
[0087] Another class of silicone-containing components includes
polyurethane macromers of the following formulae:
(*D*A*D*G).sub.a*D*D*E.sup.1;
E(*D*G*D*A).sub.a*D*G*D*E.sup.1 or;
E(*D*A*D*G).sub.a*D*A*D*E.sup.1 Formulae XIII-XV
wherein:
[0088] 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,
[0089] 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;
[0090] * denotes a urethane or ureido linkage;
[0091] .sub.a is at least 1;
[0092] A denotes a divalent polymeric radical of formula:
##STR00011##
[0093] R.sup.11 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
E.sup.1 independently denotes a polymerizable unsaturated organic
radical represented by formula:
##STR00012##
[0094] wherein: R.sup.12 is hydrogen or methyl; R.sup.13 is
hydrogen, an alkyl radical having 1 to 6 carbon atoms, or a
--CO--Y--R.sup.15 radical wherein Y is --O--, Y--S-- or --NH--;
R.sup.14 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.
[0095] In one embodiment the silicone-containing component
comprises a polyurethane macromer represented by the following
formula:
##STR00013##
[0096] wherein R.sup.16 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.
##STR00014##
[0097] Other silicone-containing components suitable for use in
this invention include those described is WO 96/31792 such as
macromers containing polysiloxane, polyalkylene ether,
diisocyanate, polyfluorinated hydrocarbon, polyfluorinated ether
and polysaccharide groups. Another class of suitable
silicone-containing components includes silicone containing
macromers made via GTP, such as those disclosed in U.S. Pat. Nos.
5,314,960, 5,331,067, 5,244,981, 5,371,147 and 6,367,929. 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.
[0098] In one embodiment of the present invention where a modulus
of less than about 120 psi is desired, the majority of the mass
fraction of the silicone-containing components used in the lens
formulation should contain only one polymerizable functional group
("monofunctional silicone containing component"). In this
embodiment, to insure the desired balance of oxygen
transmissibility and modulus it is preferred that all components
having more than one polymerizable functional group
("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.
[0099] In another embodiment, the reaction mixtures are
substantially free of silicone containing components which contain
trimethylsiloxy groups.
[0100] The silicone containing components may be present in amounts
up to about 85 weight %, and in some embodiments between about 10
and about 80 and in other embodiments between about 20 and about 70
weight %, based upon all reactive components.
[0101] 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 U.S. Pat. No. 6,367,929,
WO03/22321, WO03/22322, compatibilizing components, such as those
disclosed in US2003/162862 and US2003/125498, ultra-violet
absorbing compounds, medicinal agents, antimicrobial compounds,
copolymerizable and nonpolymerizable dyes, including photochromic
dyes, release agents, reactive tints, pigments, pharmaceutical and
nutriceutical compounds, combinations thereof and the like. The sum
of additional components may be up to about 20 wt %. In one
embodiment the reaction mixtures comprise up to about 18 wt %
wetting agent, and in another embodiment, between about 5 and about
18 wt % wetting agent.
[0102] A polymerization catalyst may be included in the reaction
mixture. The polymerization initiators includes compounds such as
lauroyl 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 phosphineoxide
(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-dimethylamino)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 Cationic & Anionic
Photopolymerization, 2.sup.nd Edition by J. V. Crivello & K.
Dietliker; 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.RTM.) 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.RTM.).
[0103] The reactive components (silicone containing component,
hydrophilic monomers, wetting agents, and other components which
are reacted to form the lens) are mixed together either with or
without a diluent to form the reaction mixture.
[0104] 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, .delta.p. In certain embodiments, the
.delta.p is less than about 10, and preferably less than about 6.
Suitable diluents are further disclosed in U.S. Ser. No. 60/452,898
and U.S. Pat. No. 6,020,445.
[0105] 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, polyethers, 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 miscibility. 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.
[0106] In one embodiment the diluents are selected from
1,2-octanediol, t-amyl alcohol, 3-methyl-3-pentanol, decanoic acid,
3,7-dimethyl-3-octanol, tripropylene glycol methyl ether (TPME),
butoxy ethyl acetate, mixtures thereof and the like.
[0107] In one embodiment the diluents are selected from diluents
that have some degree of solubility in water. In some embodiments
at least about three percent of the diluent is miscible water.
Examples of water soluble diluents include 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, dodecanoic
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)-2,5,8,10,13,16-hexaoxaheptadecane,
3,5,7,9,11,13-hexamethoxy-1-tetradecanol, mixtures thereof and the
like.
[0108] 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. Pat. Nos.
3,408,429 and 3,660,545, and static casting methods are disclosed
in U.S. Pat. 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.
[0109] After curing the lens is subjected to extraction to remove
unreacted components and release the lens from the lens mold. The
extraction may be done using conventional extraction fluids, such
as organic solvents, such as alcohols or may be extracted using
aqueous solutions.
[0110] Aqueous solutions are solutions which comprise water. In one
embodiment the aqueous solutions of the present invention comprise
at least about 30% water, in some embodiments at least about 50%
water, in some embodiments 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 the
uncrosslinked statistical copolymers of the present invention,
release agents, wetting agents, slip agents, pharmaceutical and
nutraceutical components, combinations thereof and the like.
[0111] Pharmaceutical and nutraceutical components are known and
include cationic drugs and neutriceuticals. Examples include those
for the treatment of dry eye mitigation and/or prevention
(including contact lens related dry eye, excessive tear evaporation
and Non-Sjogren's aqueous tear deficiency), glaucoma, allergies
(including antihistimines and mast cell inhibitors), ocular
inflammation, ocular redness, ocular itching, bacterial, viral and
fungal infections, prevention or slowing of myopia progression, and
anaesthetics. Examples of cationic drugs include atropine,
pirenzepine, doxycycline, brimonidine, brinzolamide, dorzolamide,
betaxolol, apraclonidine, ccr2 antagonist, olopatadine,
alcaftadine, betaxolol, bupivacaine, carbachol, carteolol,
chlortetracycline, cyclopentolate, dibutoline, dipivefrin,
ephedrine, erythromycin, gentamycin, gramicidin, homatropine
ketotifen, levobunolol, levocabastine, lidocaine, lignocaine,
lomefloxacin, mepivacaine, naphazoline, neomycin, ofloxacin,
oxybuprocaine, pheniramine, physostigmine, pilocarpine, polymyxin
B, proparacaine, pyrilamine, tetracaine, tetracycline,
tetrahydrozoline, timolol, tropicamide, vidarabine,
pharmaceutically acceptable salts thereof and combinations thereof
and the like. In another embodiment suitable pharmaceutical
components include atropine, pirenzepine, doxycycline, brimonidine,
brinzolamide, dorzolamide, betaxolol, apraclonidine, ccr2
antagonist, olopatadine, alcaftadine, betaxolol, bupivacaine,
carbachol, carteolol, chlortetracycline, cyclopentolate,
dibutoline, dipivefrin, erythromycin, gentamycin, gramicidin,
homatropine ketotifen, levobunolol, levocabastine, lidocaine,
lignocaine, lomefloxacin, mepivacaine, naphazoline, ofloxacin,
pheniramine, physostigmine, pilocarpine, polymyxin B, proparacaine,
pyrilamine, tetracaine, tetrahydrozoline, timolol, tropicamide
pharmaceutically acceptable salts thereof and combinations thereof
and the like.
[0112] In another embodiment the cationic drugs include atropine,
ketotifen, olopatadine, alcaftadine, levocabastine, pirenzepine,
doxycycline, brimonidine, brinzolamide, dorzolamide, betaxolol,
apraclonidine, ccr2 antagonist, olopatadine pharmaceutically
acceptable salts thereof and combinations thereof and the like.
[0113] The drugs may be incorporated into the lenses in a symptom
mitigating effective amount. Suitable amounts will vary for each
drug, but include those between about the weight of the drug
contained in an ophthalmic device prior to its use by a patient
wherein such minimum effective amount alleviates the symptoms of
the condition being treated. The minimum effective amount may vary
depending upon the efficacy of a particular drug. General ranges
include between about 5 .mu.g and about less than 200 .mu.g, and in
some embodiments between about 9 .mu.g and about less than 100
.mu.g, with the symptom mitigating effective amount being selected
to achieve the desired clinical result while minimizing undesired
side effects.
[0114] For example, if the anti-allergic agent is ketotifen
fumarate, the minimum effective amount is between greater than
about 9 .mu.g and about less than 90 .mu.g, more particularly
between about 40 .mu.g and greater than about 9 .mu.g, most
preferably about 20 .mu.g.
[0115] It is preferred that the minimum effective amount of drug
alleviates the symptoms for between about 5 minutes, and about 24
hours from insertion of the ophthalmic device into the eye of a
user, more preferably between about 5 minutes and about 16 hours,
most preferably between about 5 minutes and about 12 hours.
[0116] The lenses of the present invention display surprisingly
improved drug uptake compared to uncharged silicone hydrogel lenses
and to anionic conventional lenses, such as etafilcon A. This is
illustrated by the increase in uptake efficiency, uptake/[MAA],
which was calculated using the following equation:
[(Ketotifen uptake.sub.ionic lens/Ketotifen uptake.sub.non-ionic
lens)/[MAA].sub.ionic lens].times.100
[0117] Thus in one embodiment the lenses of the present invention
display uptake efficiencies greater than about 200, greater than
about 250, and in some embodiments, greater than about 300. While
efficiency in the uptake of drug is increased, the uptake in
polycationic ophthalmic solution component uptake, such as PQ1
uptake is maintained at a desirable level.
[0118] The ionic silicone hydrogel polymers of the present
invention also display stable modulus. As used herein, stable
modulus are those which increase less than about 30%, and in some
embodiments less than about 20% over three autoclave cycles (20
minutes at 121.degree. C.). In some embodiments the silicone
hydrogel polymers of the present invention display modulus that
increase by less than about 20% over 20 weeks over three autoclave
cycles. In another embodiment, the ionic silicone hydrogels of the
present invention display modulii which change less than about 30%,
about 20% or even less than about 10% over 12 or 18 months at
25.degree. C. and ambient humidity.
[0119] Still further the invention includes a method of making an
ophthalmic device comprising about a minimum effective amount of an
anti-allergic agent comprising the step of treating an ophthalmic
device with a solution comprising said anti-allergic agent, wherein
the amount of said anti-allergic agent in said solution exceeds the
minimum effective amount. It is preferred that the minimum
effective amount is exceeded by between about 1.0% and about 1000%,
in a volume of solution that is between about 500 .mu.L and about
5000 .mu.L preferably between about 50% and about 500%, in a volume
of solution that is between about 500 .mu.L and about 3000 .mu.L
most preferably about 50% in a volume of solution that is about
1000 .mu.L.
[0120] As used herein treating means physical methods of contacting
the solution containing an anti-allergic agent and the ophthalmic
device. Preferably treating refers to physical methods of
contacting the anti-allergic agent with the ophthalmic devices
prior to selling or otherwise delivering the ophthalmic devices to
a patient. The ophthalmic devices may be treated with the
anti-allergic agent anytime after they are polymerized.
[0121] 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.
[0122] In various embodiments, extraction 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, extraction 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 or
ultrasonic agitation of the lens; 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.
The foregoing may be conducted in batch or continuous processes,
with or without the addition of heat, agitation or both.
[0123] Some 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.
[0124] These and other similar processes can provide an acceptable
means of releasing the lens.
[0125] 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 99.degree. C. for
less than about 1 hour.
[0126] The lenses may be sterilized by known means such as, but not
limited to autoclaving. The uncrosslinked, statistical copolymers
may be added before or after polymerization.
[0127] In one embodiment, ophthalmic devices formed from the
polymers of the present invention display excellent compatibility
with the components of human tears.
[0128] Human tears are complex and contain a mixture of proteins,
lipids and other components which help to keep the eye lubricated.
Examples of proteins which are found in human tears include
lactoferrin, lysozyme, lipocalin, serum albumin, and secretory
immunoglobulin A.
[0129] Lysozyme is generally present in human tears in substantial
concentrations. Lysozyme is bacteriolytic and believed to protect
the eye against bacterial infection. The amount of lysozyme which
associates with commercially available contact lenses when worn,
varies greatly from only a few micrograms to over 800 micrograms
for etafilcon A contact lenses (commercially available from Johnson
& Johnson Vision Care, Inc., under the ACUVUE and ACUVUE2 brand
names). Etafilcon A contact lenses have been commercially available
for many years and display some of the lowest adverse event rates
of any soft contact lens. Thus, contact lenses which uptake
substantial levels of lysozyme are desirable. The lenses of the
present invention uptake at least about 50 .mu.g, 100 .mu.g, 200
.mu.g, 500 .mu.g of lysozyme and in some embodiments at least about
800 .mu.g lysozyme, all from a 2 mg/ml solution over 72 hours
incubation at 35.degree. C. In another embodiment the silicone
hydrogels of the present invention display both desirable lysozyme
uptake and water content. Desirable water contents are those
between about 20 and about 70%, between about 25 and about 70%, and
in some embodiments between about 25 and about 65 wt %. The
foregoing ranges may be combined in any variation.
[0130] In addition to lysozyme, lactoferrin is another important
cationic protein in the tears, mainly by the virtue of its
anti-bacterial and anti-inflammatory properties. Upon wear, contact
lenses uptake various amounts of lactoferrin, depending upon their
polymer composition (for non-surface modified lenses) and the
composition and integrity of the surface coating (for surface
modified contact lenses). In one embodiment of the present
invention, lenses uptake at least about 5 .mu.g, and in some
embodiments, at least about 10 micrograms lactoferrin following
overnight soaking of the lenses in 2 mls of a 2 mg/ml lactoferrin
solution. The lactoferrin solution contains lactoferrin from human
milk (Sigma L-0520) solubilized at a concentration of 2 mg/ml in
phosphate saline buffer. Lenses are incubated in 2 ml of the
lactoferrin solution per lens for 72 hours at 35.degree. C., using
the procedure described below for lysozyme. Lactoferrin and
lysozyme also act synergistically as bactericidal agents.
[0131] The form of the proteins in, on and associated with the lens
is also important. Denatured proteins are believed to contribute to
corneal inflammatory events and wearer discomfort. Environmental
factors such as pH, ocular surface temperature, wear time and
closed eye wear are believed to contribute to the denaturation of
proteins. However, lenses of different compositions can display
markedly different protein uptake and denaturation profiles. In one
embodiment of the present invention, a majority of the proteins
uptaken by the lenses of the present invention are and remain in
the native form during wear. In other embodiments at least about
50%, at least about 70 and at least about 80% of uptaken proteins
are and remain native after 24 hours, 3 days and during the
intended wear period.
[0132] In one embodiment the ophthalmic devices of the present
invention also uptake less than about 20%, in some embodiments less
than about 10%, and in other embodiments less than about 5%
Polyquaternium-1 ("PQ1") from an ophthalmic solution containing
0.001 wt % PQ1 and citrate dihydrate and citric acid
monohydrate.
[0133] The lenses of the present invention have a number of
desirable properties in addition to the protein uptake
characteristics described herein. In one embodiment the lenses have
an oxygen permeability greater than about 50 and in other
embodiments greater than about 60, in other embodiments greater
than about 80 and in still other embodiments at least about 100. In
some embodiments the lenses have tensile moduli less than about 100
psi.
[0134] The biomedical devices, and particularly ophthalmic lenses
of the present invention have a balance of properties which makes
them particularly useful. Such properties include clarity, water
content, oxygen permeability and contact angle. Silicone hydrogel
contact lenses formed from the polymers of the present invention
display contact angles of less than about 70.degree., less than
about 50.degree. and in some embodiments less than about 30.degree.
all as measured by sessile drop, and decreases in contact angle of
about 30% and in some embodiments about 50% or more.
[0135] In one embodiment, the biomedical devices are contact lenses
having a water content of greater than about 20% and more
preferably greater than about 25%.
[0136] As used herein clarity means substantially free from visible
haze. Preferably clear lenses have a haze value of less than about
150%, more preferably less than about 100%.
[0137] Suitable oxygen permeabilities for silicone containing
lenses are preferably greater than about 40 barrer and more
preferably greater than about 60 barrer.
[0138] In some embodiments the articles of the present invention
have combinations of the above described oxygen permeability, water
content and contact angle. All combinations of the above ranges are
deemed to be within the present invention.
[0139] 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.
[0140] Wettability of lenses was determined using a sessile drop
technique measured using KRUSS DSA-100.TM. instrument at room
temperature and using DI water as probe solution. The lenses to be
tested (3-5/sample) were rinsed in DI water to remove carry over
from packing solution. Each test lens was placed on blotting lint
free wipes which were dampened with packing solution. Both sides of
the lens were contacted with the wipe to remove surface water
without drying the lens. To ensure proper flattening, lenses were
placed "bowl side down" on the convex surface on contact lens
plastic moulds. The plastic mould and the lens were placed in the
sessile drop instrument holder, ensuring proper central syringe
alignment and that the syringe corresponds to the assigned liquid.
A 3 to 4 microliter of DI water drop was formed on the syringe tip
using DSA 100-Drop Shape Analysis software ensuring the liquid drop
was hanging away from the lens. The drop was released smoothly on
the lens surface by moving the needle down. The needle was
withdrawn away immediately after dispensing the drop. The liquid
drop was allowed to equilibrate on the lens for 5 to 10 seconds and
the contact angle was measured between the drop image and the lens
surface.
[0141] The water content may be measured as follows: lenses to be
tested were allowed to sit in packing solution for 24 hours. Each
of three test lens were removed from packing solution using a
sponge tipped swab and placed on blotting wipes which have been
dampened with packing solution. Both sides of the lens were
contacted with the wipe. Using tweezers, the test lens were placed
in a weighing pan and weighed. The two more sets of samples were
prepared and weighed as above. The pan was weighed three times and
the average is the wet weight.
[0142] The dry weight was measured by placing the sample pans in a
vacuum oven which has been preheated to 60.degree. C. for 30
minutes. Vacuum was applied until at least 0.4 inches Hg is
attained. The vacuum valve and pump were turned off and the lenses
were dried for four hours. The purge valve was opened and the oven
was allowed reach atmospheric pressure. The pans were removed and
weighed. The water content was calculated as follows:
Wet weight = combined wet weight of pan and lenses - weight of
weighing pan ##EQU00002## Dry weight = combined dry weight of pan
and lenses - weight of weighing pan ##EQU00002.2## % water content
= ( wet weight - dry weight ) wet weight .times. 100
##EQU00002.3##
[0143] The average and standard deviation of the water content are
calculated for the samples are reported.
[0144] Haze may measured by placing a hydrated test lens in borate
buffered saline in a clear 20.times.40.times.10 mm glass cell at
ambient temperature above a flat black background, illuminating
from below with a fiber optic lamp (Titan Tool Supply Co. fiber
optic light with 0.5'' diameter light guide set at a power setting
of 4-5.4) at an angle 66.degree. normal to the lens cell, and
capturing an image of the lens from above, normal to the lens cell
with a video camera (DVC 1300C:19130 RGB camera with Navitar TV
Zoom 7000 zoom lens) placed 14 mm above the lens platform. The
background scatter is subtracted from the scatter of the lens by
subtracting an image of a blank cell using EPIX XCAP V 1.0
software. The subtracted scattered light image is quantitatively
analyzed, by integrating over the central 10 mm of the lens, and
then comparing to a -1.00 diopter CSI Thin Lens.RTM., which is
arbitrarily set at a haze value of 100, with no lens set as a haze
value of 0. Five lenses are analyzed and the results are averaged
to generate a haze value as a percentage of the standard CSI
lens.
[0145] Oxygen permeability (Dk) may be determined by the
polarographic method generally described in ISO 9913-1: 1996(E),
but with the following variations. The measurement is conducted at
an environment containing 2.1% oxygen. This environment is created
by equipping the test chamber with nitrogen and air inputs set at
the appropriate ratio, for example 1800 ml/min of nitrogen and 200
ml/min of air. The t/Dk is calculated using the adjusted p.sub.O2.
Borate buffered saline was used. The dark current was measured by
using a pure humidified nitrogen environment instead of applying
MMA lenses. The lenses were not blotted before measuring. Four
lenses were stacked instead of using lenses of varied thickness. A
curved sensor was used in place of a flat sensor. The resulting Dk
value is reported in barrers.
[0146] Lysozyme uptake was measured as follows: The lysozyme
solution used for the lysozyme uptake testing contained lysozyme
from chicken egg white (Sigma, L7651) solubilized at a
concentration of 2 mg/ml in phosphate saline buffer supplemented by
Sodium bicarbonate at 1.37 g/l and D-Glucose at 0.1 g/l.
[0147] Three lenses for each example were tested using each protein
solution, and three were tested using PBS as a control solution.
The test lenses were blotted on sterile gauze to remove packing
solution and aseptically transferred, using sterile forceps, into
sterile, 24 well cell culture plates (one lens per well) each well
containing 2 ml of lysozyme solution. Each lens was fully immersed
in the solution. 2 ml of the lysozyme solution was placed in a well
without a contact lens as a control.
[0148] The plates containing the lenses and the control plates
containing only protein solution and the lenses in the PBS, were
sealed using parafilm to prevent evaporation and dehydration,
placed onto an orbital shaker and incubated at 35.degree. C., with
agitation at 100 rpm for 72 hours. After the 72 hour incubation
period the lenses were rinsed 3 to 5 times by dipping lenses into
three (3) separate vials containing approximately 200 ml volume of
PBS. The lenses were blotted on a paper towel to remove excess PBS
solution and transferred into sterile conical tubes (1 lens per
tube), each tube containing a volume of PBS determined based upon
an estimate of lysozyme uptake expected based upon on each lens
composition. The lysozyme concentration in each tube to be tested
needs to be within the albumin standards range as described by the
manufacturer (0.05 micogram to 30 micrograms). Samples known to
uptake a level of lysozyme lower than 100 .mu.g per lens were
diluted 5 times. Samples known to uptake levels of lysozyme higher
than 500 .mu.g per lens (such as etafilcon A lenses) are diluted 20
times.
[0149] 1 ml aliquot of PBS was used for all samples other than
etafilcon. 20 ml were used for etafilcon A lens. Each control lens
was identically processed, except that the well plates contained
PBS instead of lysozyme solution.
[0150] Lysozyme uptake was determined using on-lens bicinchoninic
acid method using QP-BCA kit (Sigma, QP-BCA) following the
procedure described by the manufacturer (the standards prep is
described in the kit) and is calculated by subtracting the optical
density measured on PBS soaked lenses (background) from the optical
density determined on lenses soaked in lysozyme solution.
[0151] Optical density was measured using a SynergyII Micro-plate
reader capable for reading optical density at 562 nm.
PQ-1 Uptake
[0152] PQ1 uptake was measured as follows: The HPLC is calibrated
using a series of standard PQ1 solutions prepared having the
following concentrations: 2, 4, 6, 8, 12 and 15 .mu.g/mL. Lenses
were placed into polypropylene contact lens case with 3 mL of
Optifree Replenish (which contains 0.001 wt % PQ1, 0.56% citrate
dihydrate and 0.021% citric acid monohydrate (wt/wt)) and is
commercially available from Alcon). A control lens case, containing
3 mL of solution, but no contact lens was also prepared. The lenses
and control solutions were allowed to sit at room temperature for
72 hours. 1 ml of solution was removed from each of the samples and
controls and mixed with trifluoroacetic acid (10 .mu.L). The
analysis was conducted using HPLC/ELSD and a Phenomenex Luna C4
(4.6 mm.times.5 mm; 5 .mu.m particle size) column and the following
conditions:
[0153] Instrument: Agilent 1200 HPLC or equivalent with Sedere
Sedex 85 ELSD
Sedex 85 ELSD: T=60.degree. C., Gain=10, Pressure=3.4 bar, Filter=1
s
Mobile Phase A: H.sub.2O (0.1% TFA)
Mobile Phase B: Acetonitrile (0.1% TFA)
Column Temperature: 40.degree. C.
Injection Volume: 100 .mu.L
TABLE-US-00001 [0154] TABLE I HPLC Conditions Time Flow Rate
(minutes) % A % B (mL/min) 0.00 100 0 1.2 1.00 100 0 1.2 5.00 0 100
1.2 8.50 0 100 1.2 8.60 100 0 1.2 12.00 100 0 1.2
Three lenses were run for each analysis, and the results were
averaged. The non-limiting examples below further describe this
invention. ACA1 3-acrylamidopropanoic acid ACA2
5-acrylamidopentanoic acid AMPS 2-Acrylamido-2-methylpropane
sulfonic acid, CAS 15214-89-8 Bis HEAA N,N
bis-(2-hydroxyethyl)acrylamide Blue Hema the reaction product of
Reactive Blue 4 and HEMA, as described in Example 4 of U.S. Pat.
No. 5,944,853 DMA N,N dimethyl acrylamide (Jarchem) D3O
3,7-dimethyl-3-octanol Norbloc
2-(2'-hydroxy-5-methacrylyloxyethylphenyl)-2H-benzotriazole
Irgacure 819 bis(2,4,6-trimethylbenzoyl)-phenylphosphineoxide MAA
methacrylic acid
MBA N,N'-Methylene-bisacrylamide (Sigma-Aldrich)
[0155] PVP polyvinyl pyrrolidone (K90) HO-mPDMS
mono-(2-hydroxy-3-methacryloxypropyl)-propyl ether terminated,
n-butyl terminated polydimethylsiloxane (400-1000 MW)) SA2
N-(2,3-dihydroxypropane)-N'-(propyl
tetra(dimethylsiloxy)dimethylbutylsilane)acrylamide, made by
working example 2 and shown in Formula 8 of US2011/0237766 PQ1
poly[(dimethyliminio)-2-butene-1,4-diyl chloride (1:1)],
.alpha.-[4-[tris(2-hydroxyethyl)ammonio]-2-buten-1-yl]-.omega.-[tris(2-hy-
droxyethyl)ammonio]-, chloride (CAS 75345-27-6)
Synthesis 1
S-hexyl-S-4-(2-(n-butylpolydimethylsiloxysilyl)ethyl)benzyl
carbonotrithioate
[0156] XG-1996 (shown in Formula I, MW distribution centered around
about 1000 g/mole, which corresponds to an average repeat, m of
10-12), (10 g, 10 moles), [0157] Formula I XG-1996:
Chloromethylphenylethylpolydimethylsiloxane MW.about.1000
g/mole
##STR00015##
[0158] was dissolved in approx. 250 mL of acetone in a 1 L round
bottom flask. Sodium hexyltrithiocarbonate (NaHTTC) was dissolved
in 100 mL acetone and added to the reaction mixture. The reaction
mixture was stirred overnight. A white solid precipitated out of
the bright yellow solution. Acetone was removed via
rotary-evaporation, and the crude product was partitioned between
250 mL DI water and 250 mL hexane. The hexane layer was separated
out and the aqueous layer was extracted with hexane (3.times.200
mL). All organic layers were combined, washed with brine (250 mL)
and dried over Na.sub.2SO.sub.4. The crude product in hexane was
passed over a silica gel plug to remove cloudiness. Hexane was
removed via rotary-evaporation leaving the product (XG-1996-HTTC)
in the form of a clear yellow oil. Structure was confirmed using
NMR spectroscopy.
Synthesis 2
3-acrylamidopropanoic acid
[0159] A fresh solution of sodium methoxide was prepared by
dissolving 4.6 g of metallic sodium in 250 mL of stirred methanol,
to which, Beta-alanine (3-aminopentanoic acid, 8.9 g, 0.1 mole) was
added.
[0160] Acryloyl chloride (10.0 g, 1.1 eq.) was added dropwise to a
stirred suspension of the given mixture, while maintaining the
temperature below 35 C at all times. The mixture was stirred for an
additional 30 minutes, concentrated to about 50 mL and filtered to
remove the sodium chloride formed. The hygroscopic product was
treated with pH 3 aqueous HCl, followed by evaporation of the
volatiles ad filtration through silica gel using 3-5% (v/v)
methanol in ethyl acetate.
Synthesis 3
5-Acrylamidopentanoic acid (ACA II)
[0161] A fresh solution of sodium methoxide was prepared by
dissolving 5.76 g of metallic sodium in 250 mL of stirred methanol.
Valeric acid (5-aminopentanoic acid, 14.68 g, 0.125 mole) was
dissolved in the given solution and 2.1 g of sodium carbonate was
added to the mixture.
[0162] Acryloyl chloride (12.31 g, 1.1 eq.) was added dropwise to a
stirred suspension of the given mixture, while maintaining the
temperature below 35 C at all times. The mixture was stirred for an
additional 30 minutes and filtered to remove the sodium chloride
and residual carbonate present.
[0163] Evaporation of the methanol and other volatiles at reduced
pressure, followed by washing the residue with 2.times.75 mL of
acetonitrile yielded 20.4 g of the sodium salt of
5-acrylamidopentanoic acid. The free carboxylic acid was obtained
pure after acidification of the salt in pH 3 aqueous HCl,
evaporation of the residual water, followed by filtration through
silica gel using 2-3% (v/v) methanol in ethyl acetate.
Preparation 1
[0164] N,N-dimethylacrylamide (DMA) and further purified via vacuum
distillation. 5-acrylamidopentanoic acid (ACA2) was prepared
according to Synthesis 3 The siloxy-functional
benzyltrithiocarbonate, S-XG-1996-S'-hexyl-trithiocarbonate, was
prepared according to Synthesis 1, above. Irgacure 819 was
dissolved in D3O (10 mg/mL).
[0165] The polymerization solution was prepared by dissolving 1.1 g
ACA2 in 3 mL of ethanol and 1.5 g DMA in an amber 20 mL glass vial.
Next, 166 mg S-XG-1996-S'-hexyl-trithiocarbonate, and 1.51 mg (151
ul of stock solution) Irgacure-819 were added to the monomer and
warmed/stirred to ensure homogeneity (CTA to initiator ratio=20).
The amber vial containing the final polymerization solution was
sealed with a rubber septum and purged for 20 minutes with N.sub.2
to remove O.sub.2 from the solution. Finally the sealed jar was
placed in an N.sub.2 glove-box for storage.
[0166] The polymerization solution was cured under an N.sub.2
atmosphere with 4 standard Phillips TL 20W/03 RS bulbs at intensity
of 2.0 mW/cm.sup.2 for 45 minutes. Prior to curing, the
polymerization solution was poured into an 80 mm diameter
crystallization dish, which was then placed on a reflective glass
surface.
[0167] After curing, the resulting highly viscous polymerized
material was dissolved in 5 mL of ethanol. The solution was stirred
then added drop-wise to vigorously stirring diethyl ether to
precipitate product. A 500 mL flask filled with 200 mL of ether was
used. The precipitated polymer was dried in vacuo for several
hours. The polymer was analyzed for MW and MWD via SEC-MALLS. The
degree of polymerization of the hydrophilic segment was about
300.
[0168] The reaction is shown below.
##STR00016##
Preparation 2
[0169] N,N-dimethylacrylamide (DMA) was purified via vacuum
distillation. 5-acrylamidopentanoic acid (ACA2) was prepared
according to Synthesis 3. The siloxy-functional
benzyltrithiocarbonate, S-XG-1996-S'-hexyl-trithiocarbonate, was
prepared according to Synthesis 1. Irgacure 819, was obtained from
Ciba Specialty Chemicals and dissolved in D30 (10 mg/mL).
[0170] The polymerization solution was prepared by dissolving 2.07
g ACA2 in 6 mL ethanol and 300 mg DMA in an amber 20 mL glass vial.
Next, 58 mg S-XG-1996-S'-hexyl-trithiocarbonate, and 1.06 mg (106
ul of stock solution) Irgacure-819 were added to the monomer and
warmed/stirred to ensure homogeneity (CTA to initiator ratio=20).
The amber vial containing the final polymerization solution was
sealed with a rubber septum and purged for 20 minutes with N.sub.2
to remove O.sub.2 from the solution. Finally the sealed vial was
placed in an N.sub.2 glove-box for storage. The polymerization
solution was cured and purified as described in Preparation 1. The
polymer was analyzed for MW and MWD via SEC-MALLS. The degree of
polymerization of the hydrophilic segment was about 300.
Preparations 3 and 4
PDMA/ACA2 copolymer, dp=300
[0171] N,N-dimethylacrylamide (DMA) was obtained from Jarchem and
further purified via vacuum distillation.
S-benzyl-S'-hexyl-trithiocarbonate was prepared according to
Synthesis 1. Irgacure 819 (1.06 mg) was dissolved in D3O (10
mg/mL).
TABLE-US-00002 TABLE 2 Prep 3 Prep 4 Materials 80DMA/20ACA2
70DMA/30ACA2 CTA 14 mg 20 mg Ethanol 6 Ml 3 mL DMA 300 mg 1.5 g ACA
II 2.07 g 1.1 g Irgacure- 1.06 mg 1.51 mg 819
[0172] The polymerization solution was prepared by dissolving the
ACA2 in ethanol and DMA in an amber 20 mL glass vial. Next,
S-benzyl-S'-hexyl-trithiocarbonate, and (1.51 ul of stock solution)
Irgacure-819 were added to the monomer and warmed/stirred to ensure
homogeneity (CTA to initiator ratio=20). The amounts for each
component are shown in Table 2, above. The amber vial containing
the final polymerization solution was sealed with a rubber septum
and purged for 20 minutes with N.sub.2 to remove O.sub.2 from the
solution. Finally the sealed jar was placed in an N.sub.2 glove-box
for storage.
[0173] The polymerization solution was cured under an N.sub.2
atmosphere with 4 standard Phillips TL 20W/03 RS bulbs at intensity
of 2.0 mW/cm.sup.2 for 45 minutes. Prior to curing, the
polymerization solution was poured into an 80 mm diameter
crystallization dish, which was then placed on a reflective glass
surface.
[0174] The resulting polymerized material was dissolved in 5 mL of
ethanol. The solution was stirred then added drop-wise to
vigorously stirring diethyl ether to precipitate product. A 500 mL
flask filled with 200 mL of ether was used. The precipitated
polymer was dried in vacuo for several hours. The polymer was
analyzed for MW and MWD via SEC-MALLS. The reaction is shown
below.
##STR00017##
Examples 1-12
[0175] Three senofilcon lenses were removed from their packages and
transferred glass vials containing packing solution containing the
non-reactive polysiloxane terminated hydrophilic polymer ("NRPTHP")
produced in Preparation 1 through 4 in the concentrations shown in
Table 1. The lenses were re-packaged in the NRPTHP packing
solution, autoclaved at 121.degree. C. for 28 minutes and, after
sterilization, were allowed to soak in the NRPTHP packing solution
at ambient temperature for at least 24 hours. The contact angle,
lysozyme uptake and PQ-1 uptake of the lenses were measured and are
reported in Table 3. Untreated senofilcon lenses were also tested
as a control.
TABLE-US-00003 TABLE 3 [NRPTHP] % PQ1 Lysozyme Ex# Prep DMA:ionic
(ppm) CA.degree. uptake (.mu.g/lens) 1 1 70:30ACA2 50 24 .+-. 5 7
.+-. 1 19 .+-. 3 2 1 70:30ACA2 500 28 .+-. 6 0 .+-. 0 44 .+-. 7 3 1
70:30ACA2 1000 29 .+-. 7 0 .+-. 5 51 .+-. 6 4 2 80:20ACA2 50 24
.+-. 13 9 .+-. 0 33 .+-. 5 5 2 80:20ACA2 500 32 .+-. 18 24 .+-. 9
58 .+-. 7 6 2 80:20ACA2 1000 33 .+-. 16 46 .+-. 7 65 .+-. 4 7 3
80:20ACA2 50 17 .+-. 4 7 .+-. 5 23 .+-. 4 8 3 80:20ACA2 500 22 .+-.
12 13 .+-. 1 43 .+-. 5 9 3 80:20ACA2 1000 21 .+-. 6 5 .+-. 6 42
.+-. 2 10 4 70:30ACA2 50 30 .+-. 15 1 .+-. 0 23 .+-. 2 11 4
70:30ACA2 500 21 .+-. 19 24 .+-. 13 65 .+-. 3 12 4 70:30ACA2 1000
37 .+-. 20 25 .+-. 13 66 .+-. 5 CE1 5 70:30AA 500 NM 19 + 5 31 + 7
CE2 6 20:80AA 500 NM 65 + 21 65 + 5 CE3 7 70:30AA 500 NM 10 + 2 26
+ 3 CE4 8 20:80AA 500 NM 45 .+-. 9 73 + 4
[0176] The data in Table 3 shows that non-reactive hydrophilic
copolymers comprising a randomly copolymerized anionic monomer are
effective at reducing contact angle. The hydrophilic copolymer of
Preparations 1 and 2 contained an anionic component, APA which in
the concentrations of Examples 2 through 4 were effective in
increasing lysozyme uptake to at least about 50 .mu.g/lens and
decreasing PQ1 uptake. Lysozyme is a protein native to the eye
which, when uptaken in a contact lens in the native form, is
believed to improve the biocompatibility of the contact lens. PQ1
is a preservative commonly used in contact lens multipurpose
solutions. Uptake of PQ1 to a contact lens in amounts greater than
about 10% can cause staining and is therefore undesirable. Examples
1-12 display lower values of PQ1 uptake compared to the lenses
treated with acrylic acid containing polymers of Comparative
Examples 1-4. The lenses of Examples 2-4 and 9 display a desirable
balance of contact angle, lysozyme and PQ1 uptake.
Preparation Examples 5 and 6
[0177] DMA was purified via vacuum distillation. Acrylic acid
(Sigma Aldrich) was used as received.
S-XG-1996-S'-hexyl-trithiocarbonate, was prepared according to
Synthesis 1. Irgacure 819, was dissolved in decanol (10 mg/mL).
TABLE-US-00004 TABLE 3a [CE5-30%] [CE6-80%] Materials (gm) (gm) CTA
0.553 0.508 Pentanol 13.0 11.0 DMA 10.0 3.00 Acrylic Acid 3.12 8.73
Irgacure-819 0.00201 0.00211
[0178] The polymerization solution was prepared by adding distilled
DMA and acrylic acid to an amber 30 mL glass jar. Next, pentanol,
S-XG-1996-S'-hexyl-trithiocarbonate, and Irgacure-819 stock
solution were added to the monomer in the amounts in Table 3a and
warmed/stirred to ensure homogeneity (CTA to initiator ratio=100).
The amber jar containing the final polymerization solution was
sealed with a rubber septum and purged for 20 minutes with N.sub.2
to remove O.sub.2 from the solution. Finally the sealed jar was
placed in an N.sub.2 glove-box for overnight storage.
[0179] The polymerization solution was cured under an N.sub.2
atmosphere with 4 standard Phillips TL 20W/03 RS bulbs at intensity
of 2.0 mW/cm.sup.2 for 1 hour. Prior to curing, the polymerization
solution was poured into a 125 mm diameter crystallization dish,
which was then placed on a reflective glass surface.
[0180] After curing for 1 hour, the resulting highly viscous
polymerized material was dissolved in 30 mL of ethanol. The
solution was stirred overnight then transferred to an addition
funnel using 20 mL of ethanol to rinse out the crystallization
dish. The polymer solution was added drop-wise to vigorously
stirring diethyl ether to precipitate product. A 1 L flask filled
with 500 mL of ether was used. The precipitated polymer was dried
in vacuo for several hours and then subjected to further
purification via Soxhlet Extraction with diethyl ether. The polymer
was analyzed for MW and MWD via SEC-MALLS.
Synthesis 4
Synthesis of Sodium Hexyltrithiocarbonate
[0181] The amount of reactants are shown in Table 3b.
TABLE-US-00005 TABLE 3b Materials MW Mass (g) Moles Equivalents
Sodium Metal 23.0 9.74 0.423 1.0 1-Hexanethiol 118.2 50.0 0.423 1.0
Carbon Disulfide 76.1 48.3 0.635 1.5
[0182] Sodium in kerosene (Sigma Aldrich) was weighed and submerged
in a small beaker of hexane. It was added to 100 mL of methanol
stirring in a 125 mL flask under nitrogen in several chunks over
approximately 3 hours. Methanol was added to replace evaporated
solvent. Sodium methoxide solution was slowly added via addition
funnel to a 500 mL round bottom flask containing 1-hexanthiol
(Sigma Aldrich) stirring in 50 mL methanol. The flask was placed in
a cold water bath, and carbon disulfide (Sigma Aldrich) was added
slowly via syringe. The reaction mixture immediately turned yellow
and evolved heat. The mixture was stirred for approximately 15
minutes then evaporated to dryness under reduced pressure. Product
is a bright yellow solid. The reaction is shown below:
##STR00018##
Synthesis 5
Synthesis of S-benzyl-S'-hexyl-trithiocarbonate
[0183] The amount of reactants are shown in Table 3c.
TABLE-US-00006 TABLE 3c Materials MW Mass (g) Moles Equivalents
Sodium Metal 23.0 1.00 0.0435 1.0 1-Hexanethiol 118.2 5.14 0.0435
1.0 Carbon Disulfide 76.1 3.64 0.04785 1.1 Benzyl Bromide 171.0
7.44 0.0435 1.0
[0184] Sodium in kerosene (Sigma Aldrich) was added in pieces
slowly under nitrogen to 20 mL of methanol to form sodium
methoxide. This solution was added to a flask containing
1-hexanethiol (Sigma Aldrich) in several aliquots. Carbon disulfide
(Sigma Aldrich) was added drop-wise via syringe. The solution
turned yellow immediately. The solution was allowed to react for 15
minutes. Benzyl bromide (Sigma Aldrich) was then added dropwise via
syringe. A precipitate formed immediately. The reaction was allowed
to proceed for two hours. A yellow oil eventually formed at the
bottom of the flask. The methanol was roto-vapped off and the
product was separated from the sodium salt with deionized water and
hexane. The aqueous layer was approximately 50 mL and was extracted
three times with 50 mL of hexane. The hexane was combined, dried
over Na2SO4 and evaporated to dryness under pressure. The reaction
is shown below.
##STR00019##
Preparations 7-8
Preparation of PDMA Acrylic Acid
[0185] DMA was purified via vacuum distillation. Acrylic acid
(Sigma Aldrich) was used as received.
S-benzyl-S'-hexyl-trithiocarbonate was prepared according to
Procedure 1. Irgacure 819 was dissolved in decanol (10 mg/mL). The
components were used in the amounts shown in Table 3d, below.
TABLE-US-00007 TABLE 3d P7-30% P8-80% Materials (g) (g) CTA 0.137
0.144 Ethanol 13.0 11.0 DMA 10.00 3.00 Acrylic Acid 3.12 8.73
Irgacure-819 0.00201 0.00211
[0186] The polymerization solutions were prepared for each of
Preparation 5-7 by adding DMA and acrylic acid to an amber 30 mL
glass jar. Next, ethanol, S-benzyl-S'-hexyl-trithiocarbonate (CTA),
and Irgacure-819 were added to the monomer and warmed/stirred to
ensure homogeneity (CTA to initiator ratio=100). The amber jar
containing the final polymerization solution was sealed with a
rubber septum and purged for 20 minutes with N.sub.2 to remove
O.sub.2 from the solution. Finally the sealed jar was placed in an
N.sub.2 glove-box for storage.
[0187] The polymerization solution was cured under an N.sub.2
atmosphere with 4 standard Phillips TL 20W/03 RS bulbs at intensity
of 2.0 mW/cm.sup.2. Prior to curing, the polymerization solution
was poured into a 125 mm diameter crystallization dish, which was
then placed on a reflective glass surface. No increase in viscosity
was observed after 40 minutes under light. In each example another
dose of Irgacur 819 equal to the initial dose was added to the dish
lowering the CTA to initiator ratio to 50 to improve
polymerization. The solution was mixed with swirling then exposed
to light for another 30 minutes and became extremely viscous.
[0188] After curing, the resulting polymerized material was
dissolved in 40 mL of ethanol. The solution was stirred overnight
then transferred to an addition funnel using 20 mL of ethanol to
rinse out the crystallization dish. The polymer solution was added
drop-wise to vigorously stirring diethyl ether to precipitate
product. A 1 L flask filled with 800 mL of ether was used. The
precipitated polymer was dried in vacuo for several hours and then
subjected to further purification via Soxhlet Extraction with
diethyl ether. The polymers were analyzed for MW and MWD via
SEC-MALLS.
Examples 13-15
[0189] A base reactive mixture having the components listed in
Table 4, below was made by mixing the components in the amounts
listed with t-amyl alcohol (55 wt % components: 45 wt % t-amyl
alcohol).
TABLE-US-00008 TABLE 4 Component Wt % DMA 29.45 Blue HEMA 0.02
Norbloc 7966 2.2 Irgacure 819 0.25 MBA 1.10 SA2 55.98 PVP K90 8.00
Bis-HEAA 3.00
[0190] Separate formulations were made adding 3 mol % of the ionic
component listed in Table 5, below. The formulations were stirred
on a jar roller for 2 hours, and then filtered. Each reactive
mixture was degassed, dosed into molds (Zeonor FC/polypropylene BC)
and cured for 5 minutes, at about 55.degree. C., about 2.25
mW/cm.sup.2 intensity, and about 0.2% O.sub.2. The molds were
separated by hand. The lenses were released and extracted in 70/30
IPA/DI and finally hydrated in standard packing solution. The
lenses were sterilized at 121.degree. C. for 20 minutes. The
sterilized lenses were tested for lysozyme and PQ1 uptake.
[0191] Comparative Example 5 were lenses made from the formulation
in Table 4 without any ionic components added. Comparative Example
6 lenses were made from the formulation in Table 4 with 3% MAA as
the ionic component. Comparative Examples 7 and 8 are made from the
formulation in Table 6. The procedure for making the lenses of
Comparative Examples 7 and 8 are described below.
TABLE-US-00009 TABLE 5 Ionic Ionic Lysozyme PQ1 Species Species
Uptake Uptake [H2O] Ex # (mol %) (mol/gm) (.mu.g/lens) (%) (%) CE5
None 0 5.5 .+-. 0.55 8 .+-. 3 43 .+-. 0.1 CE 6 3% MAA 1.33 .times.
10.sup.-4 143 .+-. 9 82 .+-. 1 52 .+-. 0.2 13 3% ACA1 1.35 .times.
10.sup.-4 142 .+-. 10 9 .+-. 1 53 .+-. 0.2 14 3% ACA2 1.35 .times.
10.sup.-4 98 .+-. 29 7 .+-. 1 54 .+-. 0.1 CE7 None 0 5.2 .+-. 0.2 6
.+-. 3 37 .+-. 0.2 CE8 1.5% MAA 6.5 .times. 10.sup.-5 116 .+-. 3
100 .+-. 0 47 .+-. 0.1
[0192] Comparative Example 6 is an ionic mixed methacrylate
(MAA)/methacrylamide (SA2, bisHEAA, DMA, MBA) system. The addition
of 3 mol % MAA greatly improved lysozyme uptake compared to
Comparative Example 5, which is the same formulation without any
ionic component. However, Comparative Example 6 displayed
dramatically increased PQ1 uptake. Examples 13 and 14 contain ACA1
and ACA2 as the ionic component, both of which are acrylamides.
They also display significantly improved lysozyme uptake, but show
no increase in PQ1 uptake compared to Comparative Example 5. The
lenses of the invention are formed from reaction mixtures
comprising the same reactive functionality (in Examples 13-14,
acrylamide). This provides a statistical copolymer with the anionic
charge evenly distributed throughout the lens. It is believed that
the desirable combination of properties results from this
consistent distribution of charge throughout the lenses of the
invention.
[0193] The formulations of Comparative Examples 7-8 contain
monomers having methacrylate functionality (mPDMS, HOmPDMS, HEMA)
and methacrylamide functionality (DMA). Thus, Comparative Example
8, displays very high PQ-1 uptake (100%).
Comparative Examples 7 and 8
[0194] Comparative Example lenses were formed by mixing the
components, in the amounts listed in Table 6 with D3O (23% D3O:77%
components). Comparative Example 8 used the same formulation, but
with 1.5 mol % MAA added to the formulation.
TABLE-US-00010 TABLE 6 Compound Wt % Mole % mPDMS 27.53 7.8 HOmPDMS
36.07 16.6 TEGDMA 1.33 1.3 DMA 21.31 60.8 HEMA 5.33 11.6 PVP K-90
6.22 1.83 Irgacure 819 0.43 0.29 Norbloc 7966 1.78 1.6 Blue HEMA
0.02 0.007
[0195] The formulations were dosed in to molds (Zeonor
FC/polypropylene BC) and cured for 5 minutes, at about 55.degree.
C., about 2.25 mW/cm.sup.2 intensity, and about 0.2% O.sub.2. The
lenses were released and extracted in 70/30 IPA/DI and finally
hydrated in standard packing solution. The lenses were sterilized
at 121.degree. C. for 20 minutes.
[0196] The lysozyme and PQ1 uptake were measured and are shown in
Table 5, above.
Examples 15-20
[0197] A base reactive mixture having the components listed in
Table 7, below was made by mixing the components in the amounts
listed with t-amyl alcohol (55 wt % components:45 wt % t-amyl
alcohol).
TABLE-US-00011 TABLE 7 Component Wt % DMA 30.90 Norbloc 2.00
Irgacure 819 0.125 MBA 1.300 SA2 55.65 PVP K90 7.00 bis-HEAA
3.02
[0198] Formulations were made adding ACA1 as the ionic component in
the amounts listed in Table 8, below. Comparative Example 9 was
formed from the formulation in Table 7, with no ACA1 added. The
formulations were stirred on a jar roller for 2 hours, and then
filtered.
[0199] Each reactive mixture was degassed, dosed into molds (Zeonor
TuffTec FC/polypropylene BC) and cured for 5 minutes, at about
60.degree. C., about 1.5 mW/cm.sup.2 intensity, and about 0.2%
O.sub.2. The molds were separated by hand. The lenses were released
and extracted in 70/30 IPA/DI and finally hydrated in standard
packing solution. The lenses were sterilized at 121.degree. C. for
20 minutes. The sterilized lenses were tested for water content,
lysozyme and PQ1 uptake. The results are shown in Table 8,
below.
TABLE-US-00012 TABLE 8 Lysozyme PQ1 [ACA1] [ACA1] Uptake Uptake
[H2O] Ex # (mol %) (mol/gm) (.mu.g/lens) (%) (%) CE9 0 0 5 .+-. 1 2
.+-. 3 40 .+-. 0.1 15 0.25 1.2 .times. 10.sup.-5 86 .+-. 11 4 .+-.
2 43 .+-. 0.3 16 0.5 2.4 .times. 10.sup.-5 150 .+-. 5 6 .+-. 1 43
.+-. 0.2 17 1.0 4.7 .times. 10.sup.-5 145 .+-. 7 5 .+-. 4 46 .+-.
0.2 18 1.5 7.0 .times. 10.sup.-5 152 .+-. 7 6 .+-. 1 49 .+-. 0.1 19
3.0 1.4 .times. 10.sup.-4 151 .+-. 7 5 .+-. 4 53 .+-. 0.2 20 6.0
2.8 .times. 10.sup.-4 163 .+-. 5 61 .+-. 2 62 .+-. 0.1
[0200] This series shows that a wide range (0.25 to 3 mol %)
anionic component can be used to achieve the desired increase in
lysozyme uptake without increasing PQ1 uptake or undesirably
increasing water content. Example 20 shows undesirable PQ1 uptake.
It is believed that even though the charges are evenly distributed
throughout the lens copolymer, the concentration is high enough to
attract significant quantities of PQ1. These lenses would be
undesirable for reusable lenses, but could be suitable for daily
disposable lenses which are not cleaned and are generally not
contacted with multipurpose solutions.
Comparative Examples 10-13
[0201] A base reactive mixture having the components listed in
Table 6, above was made by mixing the components in the amounts
listed with D3O (77 wt % components:23 wt % D3O).
[0202] Formulations were made adding MAA as the ionic component in
the amounts listed in Table 9, below. The formulations were stirred
on a jar roller for 2 hours, and then filtered.
[0203] Each reactive mixture was degassed, dosed into molds (Zeonor
TuffTec FC/polypropylene BC) and cured for 5 minutes, at about
60.degree. C., about 1.5 mW/cm.sup.2 intensity, and about 0.4%
O.sub.2. The molds were separated by hand. The lenses were released
and extracted in 70/30 IPA/DI and finally hydrated in standard
packing solution. The lenses were sterilized at 121.degree. C. for
20 minutes. The sterilized lenses were tested for water content,
lysozyme and PQ1 uptake. The results are shown in Table 9,
below.
TABLE-US-00013 TABLE 9 Lysozyme PQ1 [MAA] [MAA] Uptake Uptake [H2O]
Ex # (mol %) (mol/gm) (.mu.g/lens) (%) (%) CE10 0 0 5 .+-. 0.2 0.7
38 .+-. 0.2 CE11 0.5 2.2 .times. 10.sup.-5 29 .+-. 3 5 42 .+-. 0.2
CE12 0.8 3.6 .times. 10.sup.-5 42 .+-. 3 36 45 .+-. 0.1 CE13 1.1
5.1 .times. 10.sup.-5 67 .+-. 3 100 46 .+-. 0.0
[0204] The formulation in Table 9 contains both methacrylate
components (HO-mPDMS, HEMA and mPDMS) as well as acrylamide
components (DMA). Comparative Examples 10-13 show that such systems
cannot provide the desired balance of lysozyme uptake greater than
50 .mu.g/lens and PQ1 uptake of less than about 10%.
Examples 20-24
[0205] A base reactive mixture having the components listed in
Table 10, below was made by mixing the components in the amounts
listed with t-amyl alcohol (65 wt % components:35 wt % t-amyl
alcohol).
TABLE-US-00014 TABLE 10 Component Wt % DMA 39.41 Norbloc 7966 2.00
Irgacure 819 0.125 MBA 1.00 SA2 49.51 PVP K90 7.95
[0206] Formulations were made adding AMPS as the ionic component in
the amounts listed in Table 11, below. The formulations were
stirred on a jar roller for 2 hours, and then filtered. Each
reactive mixture was degassed, dosed into molds (Zeonor TuffTec
FC/polypropylene BC) and cured for 5 minutes, at about 60.degree.
C., about 1.9 mW/cm.sup.2 intensity, and about 0.2% O.sub.2. The
molds were separated by hand. The lenses were released and
extracted in 70/30 IPA/DI and finally hydrated in standard packing
solution. The lenses were sterilized at 121.degree. C. for 20
minutes. The sterilized lenses were tested for water content,
lysozyme and PQ1 uptake. The results are shown in Table 11,
below.
TABLE-US-00015 TABLE 11 Lysozyme PQ1 [AMPS] [AMPS] Uptake Uptake
[H2O] Ex # (mol %) (mol/gm) (.mu.g/lens) (%) (%) 20 0.25 1.2
.times. 10.sup.-5 87 .+-. 4 4 .+-. 1 50 .+-. 0.1 21 0.5 2.5 .times.
10.sup.-5 145 .+-. 2 3 .+-. 1 53 .+-. 0.2 22 1.0 5.1 .times.
10.sup.-5 143 .+-. 4 1 .+-. 1 58 .+-. 0.1 23 1.4 7.0 .times.
10.sup.-5 166 .+-. 11 6 .+-. 3 69 .+-. 0.2 24 3.0 1.4 .times.
10.sup.-4 Not tested 16 .+-. 3 72 .+-. 0.1
[0207] This series shows that a wide range (0.25 to 3 mol %)
anionic component can be used to achieve the desired increase in
lysozyme uptake without increasing PQ1 uptake. Example 24 shows
undesirable PQ1 uptake. It is believed that even though the charges
are evenly distributed throughout the lens copolymer, the
concentration is high enough to attract significant quantities of
PQ1. These lenses would be undesirable for reusable lenses, but
could be suitable for daily disposable lenses which are not cleaned
and are generally not contacted with multipurpose solutions. The
lenses of Example 24 were also fragile and displayed an undesirably
high water content. Thus, this Example series shows that
concentrations of AMPS between about 0.2 and about 1.5 mol %
provide a desirable combination of lysozyme and PQ1 uptake, and
water content.
Synthesis 4
Vinal
[0208] 4.82 g vinyl chloroformate (Aldrich) was added to 8.19 g
.beta.-alanine (Aldrich) dissolved in 74 ml acetonitrile. The
mixture was refluxed under nitrogen and with stirring for 2 hours.
It was cooled to room temperature for 2 hours, then filtered. The
solvent was removed under reduced pressure.
[0209] This crude product was dissolved in 30 ml water and washed
three times with ethyl acetate. The combined ethyl acetate
fractions were washed with 50 ml water. The solvent was stripped
off to yield 4.51 g VINAL as an off-white solid.
Synthesis 5
N-dodecyl-O-vinylcarbamate (DVC)
[0210] 3.0 g dodecylamine (Aldrich), 4.0 g Na.sub.2CO.sub.3 and 30
ml CH.sub.2Cl.sub.2 were placed into a 100 ml round bottomed flask
with a stir bar and thermocouple thermometer, and under nitrogen.
The flask was placed into a room temperature water bath. 1.9 g
vinylchloroformate (Aldrich) was added via a side armed addition
funnel. There was a modest exotherm. The mixture was stirred for
about 4 hours at room temperature, filtered and washed once with
1.0N HCl and twice with water. It was dried over Na.sub.2SO.sub.4
and the solvent was stripped off to yield the crude product as a
mushy solid.
[0211] The crude product was dissolved in a minimal amount of
methanol, and precipitated with water. The solvent was removed and
the crystals were dried under vacuum to yield 2.2 g product.
Preparation 9
PVP-co-VINAL (2 wt %)
[0212] 19.6 g N-vinylpyrrolidone (ACROS, 98%), 0.40 g VINAL and 10
.mu.l 2-hydroxy-2-methylpropiophenone (Aldrich) were combined to
form a clear blend. The solution was placed into two 14 mm diameter
polypropylene tubes. These tubes were irradiated with UV light from
4 Philips TL 20W/09N fluorescent bulbs for 4 hours in a nitrogen
environment. The solid polymer was removed from the tubes and
stirred in 150 ml tetrahydrofuran to dissolve. This solution was
poured into 700 ml diethyl ether with stirring to precipitate the
polymer. The solid was recovered by filtration, redissolved in THF,
and reprecipitated with diethyl ether. It was recovered by
filtration and dried for 48 hours under vacuum to yield polymer as
a soft white solid.
Preparation 10
PVP-co-VINAL(2 wt %)-co-DVC(2 wt %)
[0213] The procedure of Preparation 9 was used to form copolymer
from 4.8 g N-vinylpyrrolidone, 0.1 g VINAL, 0.1 g DVC and 6 .mu.l
2-hydroxy-2-methylpropiophenone.
Preparation 11
PVP
[0214] The procedure of Preparation 9 was used to form PVP
homopolymer from 10 g N-vinylpyrrolidone and 6 .mu.l
2-hydroxy-2-methylpropiophenone.
Comparative Examples 13-15
[0215] Solutions having a concentration of 1 wt % were formed by
adding 1 g of each of the polymers made in Preparations 9-11 in 100
g borate buffered saline solution (pH 7.4) and mixing for 2 hours
at 60.degree. C. 3 ml of each solution was placed into each of
several vials. One senofilcon A contact lens (ACUVUE OASYS.TM.
BRAND CONTACT LENSES with HYDRACLEAR.TM. Plus) was placed into each
vial. The vials were sealed and autoclaved at 121.degree. C. for 30
minutes. The lenses were rinsed in fresh borate buffered saline and
tested for contact angle using the sessile drop method. The results
are shown in Table 11.
TABLE-US-00016 TABLE 11 CE15 CE14 PVP-VINAL CE16 Polymer PVP-VINAL
(2%) (2%)-DVC (2%) PVP Contact angle 37 .+-. 6.degree. C. 38 .+-.
10.degree. C. 60 .+-. 10.degree. C. Lysozyme 5.75 .+-. 0.2 5.46
.+-. 0.12 NM (.mu.g/lens)
[0216] Desirable decreases in contact angle were achieved however,
the lysozyme uptake was not significantly increased. Comparing
Comparative Examples 14 and Example 19, which contained 2-4 mol %
anionic monomer to Examples 2-4, it is believed that increasing the
concentration of the anionic monomers in polymers used in
Comparative Examples 14 and 15 to at least about 20 mol % and in
some embodiments at least about 30 mol % or greater, will provide
the desired lysozyme uptake.
* * * * *