U.S. patent application number 13/829498 was filed with the patent office on 2013-08-08 for ionic silicone hydrogels comprising pharmaceutical and/or nutriceutical components and having improved hydrolytic stability.
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 Azaam Alli, Scott L. Joslin, Thomas L. Maggio, Shivkumar Mahadevan, Sharmila Muthukrishnan, Ranganath Raja, R. Sridhara, C. Surendran.
Application Number | 20130203812 13/829498 |
Document ID | / |
Family ID | 48903436 |
Filed Date | 2013-08-08 |
United States Patent
Application |
20130203812 |
Kind Code |
A1 |
Raja; Ranganath ; et
al. |
August 8, 2013 |
IONIC SILICONE HYDROGELS COMPRISING PHARMACEUTICAL AND/OR
NUTRICEUTICAL COMPONENTS AND HAVING IMPROVED HYDROLYTIC
STABILITY
Abstract
The present invention relates to ionic silicone hydrogel
polymers displaying improved thermal stability. More specifically,
the present invention relates to a polymer formed from reactive
components comprising at least one silicone component and at least
one ionic component comprising at least one anionic group. The
polymers of the present invention display good thermal stability
and desirable protein uptake.
Inventors: |
Raja; Ranganath;
(Jacksonville, FL) ; Muthukrishnan; Sharmila;
(Chennai, IN) ; Surendran; C.; (The Nilgris,
IN) ; Sridhara; R.; (Chennai, IN) ; Mahadevan;
Shivkumar; (Orange Park, FL) ; Maggio; Thomas L.;
(Jacksonville, FL) ; Alli; Azaam; (Jacksonville,
FL) ; Joslin; Scott L.; (Ponte Vedra Beach,
FL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Johnson & Johnson Vision Care, Inc.; |
Jacksonville |
FL |
US |
|
|
Assignee: |
Johnson & Johnson Vision Care,
Inc.
Jacksonville
FL
|
Family ID: |
48903436 |
Appl. No.: |
13/829498 |
Filed: |
March 14, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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12567352 |
Sep 25, 2009 |
8470906 |
|
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13829498 |
|
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|
61101455 |
Sep 30, 2008 |
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Current U.S.
Class: |
514/324 ;
514/772.3 |
Current CPC
Class: |
A61K 47/34 20130101;
C08F 290/068 20130101; C08F 290/068 20130101; C08L 51/085 20130101;
C08F 220/04 20130101; C08F 230/08 20130101; G02B 1/043 20130101;
C08F 220/06 20130101; G02B 1/043 20130101 |
Class at
Publication: |
514/324 ;
514/772.3 |
International
Class: |
A61K 47/34 20060101
A61K047/34 |
Claims
1. A polymer formed from reactive components comprising about 10 to
about 20 mmol/100 gm reactive mixture of at least one anionic
component and at least one silicone component selected from the
group consisting of reactive polydialkylsiloxane selected from
compounds of Formula I: ##STR00006## where b=2 to 20; terminal
R.sup.1 are independently selected from monovalent groups
comprising at least one ethylenically unsaturated moiety,
monovalent alkyl group having 2 to 16 carbon atoms, provided that
one terminal R.sup.1 comprises an ethylenically unsaturated moiety,
and the remaining R.sup.1 are selected from monovalent alkyl groups
having 1 to 16 carbon atoms, wherein said reactive components
comprise less than 5 wt % TRIS, are free of linear polysiloxane
crosslinkers and wherein said contact lens further comprises at
least one pharmaceutical or neutraceutical component.
2. The contact lens of claim 1 wherein said reactive components are
free of TRIS.
3. The contact lens of claim 2 wherein said ionic component
comprises at least one polymerizable group and three to ten carbon
atoms.
4. The contact lens of claim 2 where said ionic component comprises
three to eight carbon atoms.
5. The contact lens of claim 1 wherein said ionic component is a
carboxylic acid containing component selected from the group
consisting of free radical reactive carboxylic acids comprising 1-8
carbon atoms.
6. The contact lens of claim 1 wherein said ionic component
comprises at least one carboxylic acid group.
7. The contact lens of claim 1 wherein said carboxylic
acid-containing component is selected from the group consisting of
(meth)acrylic acid, acrylic acid, itaconic acid, crotonic acid,
cinnamic acid, vinylbenzoic acid, fumaric acid, maleic acid,
N-vinyloxycarbonyl alanine, 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, b is 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.
8. The contact lens of claim 1 wherein said carboxylic
acid-containing component comprises methacrylic acid,
3-acrylamidopropionic acid, 4-acrylamidobutanoic acid,
5-acrylamidopentanoic acid, N-vinyloxycarbonyl-.alpha.-alanine,
N-vinyloxycarbonyl-.beta.-alanine (VINAL), and mixtures
thereof.
9. The contact lens of claim 8 wherein said carboxylic
acid-containing component comprises methacrylic acid.
10. The contact lens of claim 1 wherein said at least one silicone
component is selected from the group consisting of
mono(meth)acryloxypropyl terminated mono-n-C.sub.1-4-alkyl
terminated polydialkylsiloxane, (meth)acryloxypropyl-terminated
polydialkylsiloxane, mono-(3-methacryloxy-2-hydroxypropyloxy)propyl
terminated, mono-C.sub.1-4alkyl alkyl terminated
polydialkylsiloxane and combinations thereof.
11. The contact lens of claim 1 wherein said at least one silicone
component is selected from mono(meth)acryloxypropyl terminated
mono-n-butyl terminated polydimethylsiloxane,
mono(meth)acryloxypropyl terminated polydimethylsiloxane,
mono-(3-methacryloxy-2-hydroxypropyloxy)propyl terminated,
mono-butyl terminated polydialkylsiloxane
mono-(3-methacryloxy-2-hydroxypropyloxy)propyl terminated,
mono-methyl terminated polydialkylsiloxane combinations thereof and
the like.
12. The contact lens of claim 1 wherein said at least one silicone
component is selected from monomethacryloxypropyl-terminated
mono-n-butyl terminated polydimethysiloxane,
methacryloxypropyl-terminated polydimethylsiloxane and
mono-(3-methacryloxy-2-hydroxypropyloxy)propyl terminated,
mono-butyl terminated polydimethylsiloxane and mixtures
thereof.
13. The contact lens of claim 1 wherein said at least one
pharmaceutical pharmaceutical or neutraceutical component is
cationic.
14. 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.
15. 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.
16. The contact lens of claim 1 wherein said at least one
pharmaceutical pharmaceutical or neutraceutical 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.
17. The contact lens of claim 1, 14, 15 or 16, wherein said at
least one pharmaceutical or neutraceutical component in a symptom
mitigating effective amount.
18. The contact lens of claims 17 wherein said symptom mitigating
effective amount is between about 5 .mu.g and about less than 200
.mu.g.
19. The contact lens of claims 17 wherein said symptom mitigating
effective amount is between about 9 .mu.g and about 100 .mu.g.
20. The contact lens of claims 17 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.
21. The contact lens of claim 1 wherein said contact lens absorbs
at least about 50 .mu.g lysozyme.
22. The contact lens of claim 1 wherein said contact lens absorbs
at least about 100 .mu.g lysozyme.
23. The contact lens of claim 1 wherein said contact lens absorbs
at least about 200 .mu.g lysozyme.
24. The contact lens of claim 1 wherein said contact lens absorbs
about 3 .mu.g or less lipocalin.
25. The contact lens of claim 1 wherein at least about 60% of all
proteins absorbed in or on said contact lens are in native
form.
26. The contact lens of claim 1 wherein at least about 75% of all
proteins absorbed in or on said contact lens are in native
form.
27. The contact lens of claim 1 further comprising a water content
of at least about 15%.
28. The contact lens of claim 1 further comprising a Dk of at least
about 50.
29. The contact lens of claim 28 wherein at least about 75% of all
proteins absorbed in or on said contact lens are in native
form.
30. A contact lens formed by polymerizing components comprising at
least one silicone component and at least one ionic component
comprising at least one carboxylic acid group in molar
concentrations up to about 9.3 mmol/100 gm and wherein said contact
lens absorbs at least about 10 .mu.g lysozyme, less than about 5
.mu.g lipocalin and wherein at least about 50% of proteins absorbed
in or on said contact lens are in native form.
Description
RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 12/567,352, filed Sep. 25, 2009, the contents
of which are relied upon and incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to ionic silicone hydrogels,
and ophthalmic devices formed therefrom, which display desirable
protein uptake profiles, improved hydrolytic stability 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.
However, silicone hydrogel lenses have different rates for adverse
events than conventional hydrogels, and it would be desirable to
maintain the oxygen transmissibility of a silicone hydrogel, but
achieve the low adverse event rate of the best conventional
hydrogel 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. For example, the modulus
of Purevision lenses (Bausch & Lomb) increase from 155 psi to
576 psi when heated at 95.degree. C. for one week. It is believed
that the cause of this increase in modulus is the hydrolysis of
terminal siloxane groups followed by condensation reactions to form
new siloxane bonds and introduce new crosslinks. Even though
Purevision lenses contain about 1 weight % ionicity, they uptake
relatively low lysozyme levels (less than about 50 .mu.g), and a
majority of the protein uptaken is denatured.
[0005] It has been suggested that the instability of ionic silicone
hydrogels could be reduced by using silicones components having
bulky alkyl or aryl groups instead of silicone monomers such as
3-methacryloxypropyltris(trimethylsiloxy)silane ("TRIS") or
2-methyl-,2-hydroxy-3-[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disi-
loxanyl]propoxy]propyl ester ("SiGMA"). However, the bulky siloxane
monomers are not commercially available and may be expensive to
make.
SUMMARY OF THE INVENTION
[0006] The present invention relates to ionic silicone hydrogel
polymers displaying improved thermal stability and desirable
protein uptake. More specifically, the present invention relates to
silicone hydrogel polymers and contact lenses formed from reactive
components comprising at least one silicone component and at least
one anionic component in an amount between about 0.1 and 0.8 wt
%.
[0007] The present invention relates to ionic silicone hydrogel
polymers displaying improved thermal stability and desirable
protein uptake. More specifically, the present invention relates to
silicone hydrogel polymer and contact lenses formed from reactive
components comprising at least one silicone component and at least
one anionic component comprising at least one carboxylic acid group
in an amount between about 0.1 and about 10 mmol/gm.
DESCRIPTION OF THE FIGURES
[0008] FIG. 1 is a graph showing the change in modulus at
55.degree. C. of the lenses of Examples 1-4 and Comparative Example
1 as a function of time.
[0009] FIGS. 2-4 are graphs showing, for the lenses of Examples
6-7, the change in modulus, toughness and elongation at 55.degree.
C. as a function of time.
[0010] FIG. 5 is graph showing the concentrations of PQ-1 and
lysozyme uptaken in the polymer formed in Examples 10-18 and
Comparative Example 2.
[0011] FIG. 6 is a graph showing the release of ketotifen fumarate
from the lenses of Examples 19-12 and Comparative Examples 3 and
4.
DETAILED DESCRIPTION
[0012] It has been surprisingly found that ionic silicone hydrogel
polymers and articles made therefrom may be made having acceptable
thermal stability and desirable protein uptake characteristics.
[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 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 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. As used herein "uptake" means associated in, with
or on the lens, deposited in or on the lens.
[0017] 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 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
neutriceutical 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.
[0018] 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. Examples of anionic groups
include carboxylate groups, phosphates, sulfates, sulfonates,
phosphonates, borates, mixtures thereof and the like. In one
embodiment the anionic groups comprise three to ten carbon atoms,
and in another, three to eight carbon atoms. In an embodiment the
anionic groups comprise carboxylic acid groups.
[0019] Reactive groups include groups that can undergo free radical
and/or cationic polymerization under polymerization conditions.
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.1-6alkyl(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. Non-limiting examples of
cationic reactive groups include vinyl ethers or epoxide groups and
mixtures thereof. In one embodiment the reactive groups comprises
(meth)acrylate, acryloxy, (meth)acrylamide, and mixtures
thereof.
[0020] Any chemical name preceded by (meth), for example
(meth)acrylate, includes both the unsubstituted and methyl
substituted compound.
[0021] Examples of suitable anionic components include reactive
carboxylic acids, including alkylacryl 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; N-vinyloxycarbonyl
alanine (VINAL), reactive sulfonate salts, including
sodium-2-(acrylamido)-2-methylpropane sulphonate,
3-sulphopropyl(meth)acrylate potassium salt,
3-sulphopropyl(meth)acrylate sodium salt, b is 3-sulphopropyl
itaconate di sodium, b is 3-sulphopropyl itaconate di potassium,
vinyl sulphonate sodium salt, vinyl sulphonate salt, styrene
sulfonate, sulfoethyl 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 one embodiment the ionic component
comprises methacrylic acid.
[0022] In one embodiment, the anionic components is included in the
reactive mixture in amounts between about 0.05 and about 2 weight %
and in some embodiments between about 0.1 and about 0.8 weight %.
In one embodiment, the anionic components is included in the
reactive mixture in amounts between about 0.05 and about 5 mol %
and in some embodiments between about 0.1 and about 0 mol %.
[0023] In another embodiment, the anionic component comprises at
least one carboxylic acid group and is present in the reactive
mixture in amounts between about 10 mmol/100 g and about 20
mmol/100 g, and in another embodiment between about 11 and about 10
mmol/100 g. By maintaining the concentration of anioinic component
within the ranges recited herein with the specified silicone
components, the stability of the polymer may be improved, and
uptake of certain cationic pharmaceutical compounds is increased.
Surprisingly, it has also been found that polymers having the
amounts of anionic component recited herein have desirable protein
uptake profiles in addition to improved stability.
[0024] The silicone hydrogel polymers of the present invention
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 eight weeks, at 55.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
at 55.degree. C. The ionic silicone hydrogel polymers of the
present invention also display stable modulus. In other embodiments
the ionic silicone hydrogel lenses of the present invention display
stable modulii 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.
[0025] Silicone components are reactive and non-reactive components
which comprise at least one "--Si--O--Si--" group. It is preferred
that silicone and its attached oxygen account for about 10 weight
percent of said silicone component, more preferably more than about
20 weight percent.
[0026] Prior attempts to add anionic components to silicone
hydrogels have generally resulted in polymers which display modulii
which increase over time or when exposed to heat. It is believed
that the cause of the increasing modulus is the hydrolysis of
terminal siloxane groups followed by condensation reactions to form
new siloxane bonds and introduce new crosslinks. Hydrolytic
stability of silicone groups (specifically the silicon-oxygen bond)
is believed to be influenced by the substituents on the Si atom.
Bulkier groups provide greater hydrolytic stability through
increased steric hindrance. The substituents can be alkyl groups
(methyl, ethyl, propyl, butyl etc.), aryl (e.g. benzyl) or even
other silicon-containing groups. On the basis of steric hindrance,
silicone materials containing trimethylsilyl (--OSiMe.sub.3) groups
(such as SiMAA or TRIS) are generally less hydrolytically stable in
the presence of ionic components than compounds containing
polydimethylsiloxane [(--OSiMe.sub.2).sub.n] chains, such as mPDMS.
Thus, in this embodiment, the stability of the polymer is further
improved by selection of the silicone containing components in
combination with controlling the concentration of the anionic
component.
[0027] In one embodiment, the silicone component comprises,
consists or consists essentially of at least one
polydimethylsiloxane chain, and in another embodiment, comprise
less than 5 wt % components comprising at least one TMS group and
in another embodiment all silicone components are free of TMS
groups. In another embodiment the silicone components comprise less
than 5 wt % TRIS, and in another embodiment, are free of TRIS.
Still further, the reactive mixtures of the present invention are
free of linear polysiloxane crosslinkers.
[0028] In yet another embodiment the silicone components comprise,
consists or consists essentially only one reactive group and at
least one polydimethylsiloxane chain. In another embodiment the
reactive mixture is free of multifunctional silicone component
which comprise polyalkylsiloxane groups, and particularly
polydimethylsiloxane chains in the backbone of the molecule
(multifunctional, linear polydialkylsiloxanes). Silicone hydrogels
comprising multifunctional, linear polydialkylsiloxanes, such as
linear polydimethylsiloxane crosslinkers have been disclosed to be
thermalytically unstable.
[0029] Silicone-containing components which contain no TMS groups
include those disclosed in WO2008/0412158, and reactive PDMS
components of Formula I:
##STR00001##
wherein b is 2 to 20, 3 to 15 or in some embodiments 3 to 10; at
least one terminal R.sup.1 comprises a monovalent reactive group,
the other terminal R.sup.1 comprises a monovalent reactive group or
a monovalent alkyl group having 1 to 16 carbon atoms, 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, for example, a (meth)acryloxy C.sub.1-6 alkyl, which may be
further substituted with at least one hydrophilic group, such as
hydroxyl, ether or a combination thereof, 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. In one embodiment one terminal R.sup.1
is (meth)acryloxy C.sub.1-6 alkyl, which is optionally substituted
with ether or hydroxyl, the other terminal R.sup.1 is a C.sub.1-4
alkyl, and the remaining R.sup.1 are methyl or ethyl. Non-limiting
examples of PDMS components of this embodiment include
(mono-(2-hydroxy-3-methacryloxypropyl)-propyl ether terminated
polydimethylsiloxane (400-1000 MW)) ("HO-mPDMS"), and
monomethacryloxypropyl terminated mono-n-C.sub.1-4 alkyl terminated
polydimethylsiloxanes, including monomethacryloxypropyl terminated
mono-n-butyl terminated polydimethylsiloxanes (800-1000 MW),
("mPDMS") and monomethacryloxypropyl terminated methyl terminated
polydimethylsiloxanes (800-1000 MW), ("mPDMS"). In one embodiment
all silicone in the reactive mixture are PDMS components.
[0030] In another embodiment, the multifunctional silicone
components which are excluded from the reactive mixtures comprise
those where 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.
[0031] In another embodiment, one R.sup.1 comprises a vinyl
carbonate or carbamate of the formula:
##STR00002##
wherein: Y denotes O--, S-- or NH--; R denotes, hydrogen or methyl;
q is 1, 2, 3 or 4; and b is 1-50. In these embodiments care must be
taken to make sure the vinyl carbonate or carbamate silicone
component does not also comprising TMS groups.
[0032] Suitable silicone-containing vinyl carbonate or vinyl
carbamate monomers specifically include:
1,3-bis[4-(vinyloxycarbonyloxy)but-1-yl]tetramethyl-disiloxane;
and
##STR00003##
wherein R.sup.1 is as defined for a non-reactive terminal group
above.
[0033] Where biomedical devices with modulus below about 200 are
desired, only one R.sup.1 shall comprise a monovalent reactive
group.
[0034] 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.
[0035] Another class of silicone-containing components includes
polyurethane macromers of the following formulae:
(*D*A*D*G).sub.a*D*D*E.sup.1; Formulae IV-VI
wherein: D denotes an alkyl diradical, an alkyl cycloalkyl
diradical, a cycloalkyl diradical, an aryl diradical or an
alkylaryl diradical having 6 to 30 carbon atoms, G denotes an alkyl
diradical, a cycloalkyl diradical, an alkyl cycloalkyl diradical,
an aryl diradical or an alkylaryl diradical having 1 to 40 carbon
atoms and which may contain ether, thio or amine linkages in the
main chain; * denotes a urethane or ureido linkage; .sub.a is at
least 1; A denotes a divalent polymeric radical of formula:
##STR00004##
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; E.sup.1 independently denotes a
polymerizable unsaturated organic radical represented by
formula:
##STR00005##
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--, --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.
[0036] In one embodiment of the present invention, a modulus of
less than about 120 psi is desired. 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.
[0037] The silicone containing components may be present in amounts
up to about 95 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.
[0038] The reactive mixture may also comprise at least one
hydrophilic component in addition to the ionic component.
Hydrophilic monomers can be any of the hydrophilic monomers known
to be useful to make hydrogels.
[0039] One class of suitable hydrophilic monomers include acrylic-
or vinyl-containing monomers. Such hydrophilic monomers may
themselves be used as crosslinking agents, however, where
hydrophilic monomers having more than one polymerizable functional
group are used, their concentration should be limited as discussed
above to provide a contact lens having the desired modulus. The
term "vinyl-type" or "vinyl-containing" monomers refer to monomers
containing the vinyl grouping (--CH.dbd.CH.sub.2) and are generally
highly reactive. Such hydrophilic vinyl-containing monomers are
known to polymerize relatively easily.
[0040] "Acrylic-type" or "acrylic-containing" monomers are those
monomers containing the acrylic group: (CH.sub.2.dbd.CRCOX) wherein
R is H or CH.sub.3, and X is O or N, which are also known to
polymerize readily, such as N,N-dimethyl acrylamide (DMA),
2-hydroxyethyl methacrylate (HEMA), glycerol methacrylate,
2-hydroxyethyl methacrylamide, polyethyleneglycol monomethacrylate,
mixtures thereof and the like.
[0041] Hydrophilic vinyl-containing monomers which may be
incorporated into the silicone hydrogels of the present invention
include monomers such as N-vinyl amides, N-vinyl lactams (e.g.
NVP), N-vinyl-N-methyl acetamide, N-vinyl-N-ethyl acetamide,
N-vinyl-N-ethyl formamide, N-vinyl formamide, with NVP being
preferred.
[0042] Other hydrophilic monomers that can be employed in the
invention include polyoxyethylene polyols having one or more of the
terminal hydroxyl groups replaced with a functional group
containing a polymerizable double bond. Examples include
polyethylene glycol, ethoxylated alkyl glucoside, and ethoxylated
bisphenol A reacted with one or more molar equivalents of an
end-capping group such as isocyanatoethyl methacrylate ("IEM"),
methacrylic anhydride, methacryloyl chloride, vinylbenzoyl
chloride, or the like, to produce a polyethylene polyol having one
or more terminal polymerizable olefinic groups bonded to the
polyethylene polyol through linking moieties such as carbamate or
ester groups.
[0043] Still further examples are the hydrophilic vinyl carbonate
or vinyl carbamate monomers disclosed in U.S. Pat. No. 5,070,215,
and the hydrophilic oxazolone monomers disclosed in U.S. Pat. No.
4,910,277. Other suitable hydrophilic monomers will be apparent to
one skilled in the art.
[0044] In one embodiment the hydrophilic comprises at least one
hydrophilic monomer such as DMA, HEMA, glycerol methacrylate,
2-hydroxyethyl methacrylamide, NVP, N-vinyl-N-methyl acrylamide,
polyethyleneglycol monomethacrylate, and combinations thereof. In
another embodiment, the hydrophilic monomers comprise at least one
of DMA, HEMA, NVP and N-vinyl-N-methyl acrylamide and mixtures
thereof. In another embodiment, the hydrophilic monomer comprises
DMA.
[0045] The hydrophilic monomers may be present in a wide range of
amounts, depending upon the specific balance of properties desired.
Amounts of hydrophilic monomer up to about 50 and preferably
between about 5 and about 50 weight %, based upon all reactive
components are acceptable. For example, in one embodiment lenses of
the present invention comprise a water content of at least about
25%, and in another embodiment between about 30 and about 70%. For
these embodiments, the hydrophilic monomer may be included in
amounts between about 20 and about 50 weight %.
[0046] 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 US2003/162,862 and US2003/2003/125,498, ultra-violet
absorbing compounds, medicinal agents, antimicrobial compounds,
copolymerizable and nonpolymerizable dyes, release agents, reactive
tints, pigments, combinations thereof and the like. 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.
[0047] A polymerization catalyst may be included in the reaction
mixture. The polymerization initiators includes compounds such as
lauryl peroxide, benzoyl peroxide, isopropyl percarbonate,
azobisisobutyronitrile, and the like, that generate free radicals
at moderately elevated temperatures, and photoinitiator systems
such as aromatic alpha-hydroxy ketones, alkoxyoxybenzoins,
acetophenones, acylphosphine oxides, bisacylphosphine oxides, and a
tertiary amine plus a diketone, mixtures thereof and the like.
Illustrative examples of photoinitiators are 1-hydroxycyclohexyl
phenyl ketone, 2-hydroxy-2-methyl-1-phenyl-propan-1-one,
bis(2,6-dimethoxybenzoyl)-2,4-4-trimethylpentyl phosphine oxide
(DMBAPO), bis(2,4,6-trimethylbenzoyl)-phenyl 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.).
[0048] 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.
[0049] 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.
[0050] 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.
[0051] 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 methyl ether (TPME), butoxy
ethyl acetate, mixtures thereof and the like.
[0052] 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.
[0053] 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.
[0054] 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
organic solvents, such as alcohols or may be extracted using
aqueous solutions.
[0055] 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 release agents,
wetting agents, slip agents, pharmaceutical and nutraceutical
components, combinations thereof and the like.
[0056] The lense of the present invention display surprisingly
efficient uptake of cationic drugs compared to uncharged silicone
hydrogel lenses and to anionic conventional lenses, such as
etafilcon A. The uptake drug/[ionic component], may be calculated
using the following equation:
[(drug uptake.sub.ionic lens/drug uptake.sub.non-ionic lens)/[ionic
component].sub.ionic lens].times.100
[0057] Lenses of the present invention display drug uptake/[ionic
component] of greater than 100, greater than about 200, and in some
embodiments greater than about 250. Because the lenses of the
present invention are more efficient at uptaking the selected
cationic compound, less concentrated loading solutions may be
used.
[0058] Suitable 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.
[0059] 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.
[0060] 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.
[0061] 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.
[0062] 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.
[0063] 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
[0064] So, for Example 20 (59.1/18.4)/1=320.
[0065] 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.
[0066] 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.
[0067] 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.
[0068] 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.
[0069] 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.
[0070] 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.
[0071] These and other similar processes can provide an acceptable
means of releasing the lens.
[0072] 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.
[0073] The lenses may be sterilized by known means such as, but not
limited to autoclaving.
[0074] In addition to displaying desirable stability, the lenses of
the present invention also display compatibility with the
components of human tears.
[0075] Human tears are complex and contain a mixture of proteins,
lipids and other components which help to keep the eye lubricated.
Examples of lipids classes include wax ester, cholesterolesters and
cholesterol. Examples of proteins which are found in human tears
include lactoferrin, lysozyme, lipocalin, serum albumin, secretory
immunoglobulin A. Lipocalin is a lipid binding protein. The amount
of lipocalin uptake to a contact lens has been negatively
correlated to lens wettability (as measured via contact angle, such
as via sessile drop), the propensity of lenses to uptake lipids
from the tear film and consequently deposits on the front surface
of the lens. Lenses which uptake low levels of lipocalin are
therefore desirable. In one embodiment of the present invention,
the lenses uptake less than about 3 .mu.g lipocalin from a 2 mg/ml
lipocalin solution over 72 hours incubation at 35.degree. C.
[0076] 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 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.
[0077] 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 lipocalin and lysozyme.
[0078] 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.
[0079] 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
(dimethyl-bis[(E)-4-[tris(2-hydroxyethyl)azaniumyl]but-2-enyl]azanium
trichloride) ("PQ1") from an ophthalmic solution containing 0.001
wt % PQ1).
[0080] 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
embodiment 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.
[0081] 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.
[0082] Modulus (tensile modulus) is measured by using the crosshead
of a constant rate of movement type tensile testing machine
equipped with a load cell that is lowered to the initial gauge
height. A suitable testing machine includes an Instron model 1122.
A dog-bone shaped sample from a -1.00 power lens having a 0.522
inch length, 0.276 inch "ear" width and 0.213 inch "neck" width is
loaded into the grips and elongated at a constant rate of strain of
2 in/min. until it breaks. The initial gauge length of the sample
(Lo) and sample length at break (Lf) are measured. At least five
specimens of each composition are measured and the average is
reported. Tensile modulus is measured at the initial linear portion
of the stress/strain curve.
Percent elongation is=[(Lf-Lo)/Lo].times.100.
[0083] Diameter may be measured using the modulation image
generated from a Mach-Zehnder interferometer with the lenses
submersed in saline solution and mounted concave surface down in a
cuvette, as further described in US2008/0151236. The lenses are
equilibrated for 15 minutes at about 20.degree. C. before
measurement.
[0084] Water content is measured as follows. The lenses to be
tested are allowed to sit in packing solution for 24 hours. Each of
three test lens are 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 are contacted with
the wipe. Using tweezers, the test lens are placed in a weighing
pan and weighed. The two more sets of samples are prepared and
weighed as above. The pan and lenses are weighed three times and
the average is the wet weight.
[0085] The dry weight is measured by placing the sample pans in a
vacuum oven which has been preheated to 60.degree. C. for 30
minutes. Vacuum is applied until at least 0.4 inches Hg is
attained. The vacuum valve and pump are turned off and the lenses
are dried for four hours. The purge valve is opened and the oven is
allowed reach atmospheric pressure. The pans are removed and
weighed. The water content is calculated as follows:
Wet weight = combined wet weight of pan and lenses - weight of
weighing pan ##EQU00001## Dry weight = combined dry weight of pan
and lens - weight of weighing pan ##EQU00001.2## % water content =
( wet weight - dry weight ) wet weight .times. 100
##EQU00001.3##
[0086] The average and standard deviation of the water content are
calculated for the samples are reported.
[0087] Lysozyme and lipocalin uptake were measured out using the
following solutions and method.
[0088] The lysozyme solution 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.
[0089] The lipocalin solution contained B Lactoglobulin (Lipocalin)
from bovine milk (Sigma, L3908) 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.
[0090] 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.
[0091] The plates containing the lenses and the control plates
containing only protein solution and the lenses in the PBS, were
parafilmed 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.
[0092] 1 ml aliquot of PBS was used for samples 9, CE2 and the
balafilcon lenses, and 20 ml for etafilcon A lens. Each control
lens was identically processed, except that the well plates
contained PBS instead of either lysozyme or lipocalin solution.
[0093] Lysozyme and Lipocalin 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.
[0094] Optical density was measured using a SynergyII Micro-plate
reader capable for reading optical density at 562 nm.
[0095] Lysozyme activity was measured using the solution and
incubation procedure described above for lysozyme uptake.
[0096] After the 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, 24 well cell culture plates (one lens per well) each
containing 2 ml of extraction solution composed of a 50:50 mix of
0.2% of trifluoroacetic acid and acetonitrile (TFA/ACN) solution.
The lenses were incubated in the extraction solution for 16 hours
at room temperature.
[0097] In parallel, the lysozyme control solution was diluted in
the extraction buffer to a range of concentrations with bracket the
expected lysozyme uptake of the lenses being analyzed. For the
examples of the present application the expected lysozyme
concentrations were 10, 50, 100, 800 and the control solution were
diluted to those concentrations and incubated for 16 hours at room
temperature. The lysozyme extracts from both the lenses and the
controls were assayed for lysozyme activity using EnzChek.RTM.
Lysozyme Assay Kit (invitrogen) following the instructions
described by the manufacturer.
[0098] The EnzChek kit is a fluorescence based assay to measure
levels of lysozyme activity in solution down to 20 U/ml. The test
measures lysozyme activity on Micrococcus Lysodeikticus cell walls,
which are labelled in such a degree that the fluorescence is
quenched. Lysozyme action relieves this quenching, yielding an
increase in fluorescence that is proportional to lysozyme activity.
The fluorescence increase is measured using a fluorescence
microplate reader that can detect fluorescein using
excitation/emission wavelengths of 494/518 nm. A Synergy HT
microplate reader was used in the examples of the present
application.
[0099] The assay is based on the preparation of lysozyme standard
curve using the same lysozyme incubated with the lenses or as a
control. Lysozyme activity is expressed in fluorescence units and
plotted against lysozyme concentrations expressed in Units/ml.
Activity of lysozyme extracted from the lenses as well as lysozyme
control was measured and converted using standard curve to an
activity expressed in units per ml.
[0100] The percentage of active or native lysozyme is determined by
comparing lysozyme activity on lenses to that in the control
solution and is calculated following the formula below:
[0101] % of active or native lysozyme on lens=Lysozyme (unit/ml)
extracted from the lens.times.100/Lysozyme (unit per ml) obtained
from control.
[0102] 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, 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
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 [0103] TABLE I HPLC Conditions. Time (minutes) % A %
B Flow Rate (mL/min) 0.00 100 0 1.2 1.00 100 0 1.2 5.00 5 100 1.2
8.50 5 100 1.2 8.60 100 0 1.2 11.00 100 0 1.2
[0104] Three lenses were run for each analysis, and the results
were averaged.
[0105] Oxygen permeability (Dk) was 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 oxygen
concentration. 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.
[0106] These examples do not limit the invention. They are meant
only to suggest a method of practicing the invention. Those
knowledgeable in contact lenses as well as other specialties may
find other methods of practicing the invention. However, those
methods are deemed to be within the scope of this invention.
EXAMPLES
[0107] The following abbreviations are used in the examples
below:
Macromer Macromer prepared according to the procedure disclosed
under Macromer Preparation in Example 1, of US-2003-0052424-A1
acPDMS bis-3-acryloxy-2-hydroxypropyloxypropyl polydimethylsiloxane
(MW 2000, acrylated polydimethylsiloxane) from Degussa Blue HEMA
the reaction product of Reactive Blue 4 and HEMA, as described in
Example 4 of U.S. Pat. No. 5,944,853 CGI 819
bis(2,4,6-trimethylbenzoyl)-phenylphosphineoxide CGI 1850 1:1 (wgt)
blend of 1-hydroxycyclohexyl phenyl ketone and
bis(2,6-dimethoxybenzoyl)-2,4-4-trimethylpentyl phosphine oxide D3O
3,7-dimethyl-3-octanol
DMA N,N-dimethylacrylamide
[0108] EGDMA ethyleneglycol dimethacrylate HEMA 2-hydroxyethyl
methacrylate MAA methacrylic acid mPDMS monomethacryloxypropyl
terminated mono-n-butyl terminated polydimethylsiloxane,
manufactured by Gelest, molecular weight specified in the Examples
Norbloc 2-(2'-hydroxy-5-methacrylyloxyethylphenyl)-2H-benzotriazole
mPDMS-OH mono-(3-methacryloxy-2-hydroxypropyloxy)propyl terminated,
mono-butyl terminated polydimethylsiloxane, made according to
Example 8, molecular weight 612 PBS phosphate buffered saline,
containing calcium and magnesium (Sigma, D8662). PQ-1
Polyquaternium-1
(dimethyl-bis[(E)-4-[tris(2-hydroxyethyl)azaniumyl]but-2-enyl]azanium
trichloride) PVP poly(N-vinyl pyrrolidone) (K values noted) SiGMA
(3-methacryloxy-2-hydroxypropyloxy)propylbis(trimethylsiloxy)silane
TEGDMA tetraethyleneglycol dimethacrylate TPME tripropylene methyl
ether
Examples 1-3
[0109] Lenses having the formulations shown in Table 1 were made as
follows. The diluent for Examples 1-3 was a mixture of 18. 33 gm
PVP 2500/48.34 gm t-amyl alcohol. The diluent for Example 4 was
16.2 gm PVP 2500/64.8 gm t-amyl alcohol. The monomer mixes were
dispensed into Zeonor front and Zeonor:Polypropylene (55:45) back
curves. The monomer mixtures were cured under visible light
(Philips TL-03 bulbs) in a nitrogen atmosphere (about 3% O.sub.2)
using the following cure profile: 1 mW/cm.sup.2 for about 20
seconds at ambient temperature, 1.8.+-.0.5 mW/cm.sup.2 for about
270 seconds at 75.+-.5.degree. C., and 6.0.+-.0.5 mW/cm.sup.2 for
about 270 seconds at about 75.+-.5.degree. C.
[0110] After curing, the molds were opened, and the lenses released
in 70% IPA in DI water. After about 40-50 minutes the lenses were
transferred into: i) 70% IPA in DI water for about 40-50 minutes;
ii) 70% IPA in DI water for about 40-50 minutes; and iii) DI water
for at least about 30 minutes.
[0111] The lenses were packaged in 950+/-50 uL of borate buffered
sodium sulfate solution with 50 ppm methyl cellulose (SSPS) using
polypropylene bowls and foil, and autoclaved once (124.degree. C.,
18 minutes).
TABLE-US-00002 TABLE 1 Component Ex 1 Ex 2 Ex 3 Ex 4 CE 1 Macromer
0 0 0 6.93 0 HO-mPDMS 1000 0 0 0 45.54 0 SiGMA 30 30 30 0 28 acPDMS
2000 5 5 5 0 0 mPDMS 1000 28 28 28 0 31 DMA 19 19 19 19.8 24 HEMA
7.75 8.25 7.15 12.41 6 MAA 1 0.5 1.6 1 0 Norbloc 2 2 2 2.18 2 PVP
360,000 7 7 7 11.88 7 Blue HEMA 0.02 0.02 0.02 0.02 0.02 CGI 819
0.23 0.23 0.23 0.25 0.25* Sum of monomers 100 100 100 100 100
Diluent: 40 40 40 44.75 23** *CGI 1850 **D30
Example 4
[0112] Lenses were made using the formulation listed in Table 1,
for Example 4, and the conditions described in Example 1, except
that the cure profile was: 1 mW/cm.sup.2 (10-30 seconds, ambient
temperature), 1.5.+-.0.2 mW/cm.sup.2 (about 160 seconds, at
80.+-.5.degree. C.), 6.0.+-.0.2 mW/cm.sup.2 (about 320 seconds, at
about 80.+-.5.degree. C.)].
[0113] The molds were opened, and the lenses released in 70% IPA in
DI water. After 60 minutes the lenses were transferred into: i)
100% IPA for 60 minutes; ii) 70% IPA in DI water for 60 minutes;
iii) DI water for 30 minutes; iv) DI water for 30 minutes; v) DI
water for 30 minutes.
[0114] The lenses were silver-treated by exposure to aqueous sodium
iodide solution, followed by exposure to aqueous silver nitrate
solution. The lenses were packaged in 10 mL of SSPS in glass vials
with silicone stoppers, and autoclaved three times (121.degree. C.,
30 minutes).
[0115] Stability Evaluation
[0116] Lenses from Examples 1-4 and Comparative Example 1 were
placed in a chamber with temperature controlled at 55.degree. C.
Lenses were pulled from the chamber at established intervals, and
tested for modulus, maximum strain and diameter (for Examples 1-3,
lenses were pulled at each time point for measurement as follows:
8-10 lenses for diameter measurement, 9 lenses for % H.sub.20 and
8-10 lenses for mechanical property testing; for Example 4, 5
lenses were pulled at each time point as follows: 5 lenses for
diameter testing, 9 lenses for % H.sub.20 and 5 lenses for
mechanical properties). The stability data from Examples 1-4 is
shown in FIG. 1. In addition, stability data from lenses made
according to Comparative Example 1, below, which had no ionic
component, are also included as a non-ionic control.
[0117] The modulus of the lenses was measured at various time
intervals and is reported in Tables 2 and 3.
TABLE-US-00003 TABLE 2 Ex Stability [MAA] Time Modulus Elongation
Diameter # Product wt % MAA (wk) (psi) (%) (mm) 1 0.0017 1 0.12 0
81 + 7 252 + 47 13.66 + 0.06 1 0.0017 1 0.12 2 80 + 6 243 + 20
13.59 + 0.06 1 0.0017 1 0.12 5 88 + 6 163 + 28 13.59 + 0.14 1
0.0015 1 0.12 10 92 + 8 175 + 34 13.56 + 0.05 1 0.0017 1 0.12 18
117 + 11 112 + 34 13.54 + 0.1 2 0.0008 0.5 0.06 0 81 + 8 294 + 42
13.53 + 0.04 2 0.0008 0.5 0.06 2 81 + 5 284 + 41 13.59 + 0.05 2
0.0008 0.5 0.06 5 85 + 5 216 + 15 13.49 + 0.08 2 0.0008 0.5 0.06 10
NM NM NM 2 0.0008 0.5 0.06 18 118 + 8 144 + 20 13.49 + 0.12 3
0.0026 1.6 0.19 0 72 + 5 210 + 67 14.00 + 0.07 3 0.0026 1.6 0.19 2
81 + 6 169 + 37 13.94 + 0.05 3 0.0024 1.6 0.19 5 97 + 4 104 + 26
13.89 + 0.04 3 0.0026 1.6 0.19 10 131 + 7 81 + 15 13.72 + 0.06 3
0.0026 1.6 0.19 18 174 + 11 48 + 11 13.62 + 0.07 * Moles/100 gram
of reactive components
TABLE-US-00004 TABLE 3 Stability [MAA] Time Modulus Elongation
Diameter Ex # Product wt % MAA* (wk) (psi) (%) (mm) 4 0.00019 1
0.12 0 47 + 8 73 + 51 13.89 + 0.04 4 0.00019 1 0.12 1 56 + 11 169 +
97 13.94 + 0.09 4 0.00019 1 0.12 4 59 + 15 106 + 56 13.92 + 0.05 4
0.00019 1 0.12 6 NM NM NM 4 0.00019 1 0.12 8 53 + 1 140 + 73 13.91
+ 0.1 CE1 0 0 0 0 100 + 5 247 + 45 14.05 + 0.02 CE1 0 0 0 1 109 +
11 234 + 52 14.07 + 0.01 CE1 0 0 0 4 112 + 3 220 + 52 14.05 + 0.02
CE1 0 0 0 6 104 + 9 249 + 38 14.08 + 0.02 CE1 0 0 0 8 106 + 16 202
+ 61 14.05 + 0.01 *Moles/100 gram of reactive components
[0118] FIG. 1 is a graph showing of the modulus vs. time data
included in Tables 2 and 3, above. The lines for the comparative
Example and Example 4 are very flat, due to the small changes in
modulus over the time periods measured. As the concentration of
methacrylic acid and mole product increases, the slope of the line
also increases, with a substantial increase between Example 1
(having a concentration of 1 wt % methacrylic acid and a stability
product of 0.0017) and Example 3, having a concentration of 1.6 wt
% methacrylic acid and a mole product of 0.0024. The changes in
lens diameter and strain provide additional confirmation of trends
observed in the modulus.
[0119] FIG. 1 clearly shows the relationship between hydrolytic
stability of lenses, and the mole product of anionic group
(carboxylate) and TMS silicon content. Only moles of silicon (Si)
derived from trimethylsilyl-containing monomers (TRIS or SIMAA2)
were used in the calculation of the mole product listed in Tables 2
and 3. From these experiments it was surprisingly found that the
stability of silicone hydrogel lenses comprising a silicone
component having at least one TMS group and at least one anionic
component, such as methacrylic acid, display a sharp drop in
stability above a certain concentration of the anionic component.
Thus, Examples 1 and 2 have substantially similar stability even
though the Example 1 contains twice as much methacrylic acid (1%)
than Example 2 (0.5%). However, the stability of the lenses made in
Example 3 were much worse than Examples 2 and 3. This result was
unexpected, and provides a small formulating window for including
anionic components and silicone components comprising at least one
TMS group. The inclusion of TMS containing silicone monomer
components in amounts that provide the recited stability products
provides the ability to balance stability with other properties,
such as a desired modulus, elongation or tan delta. The stability
products, methacrylic acid concentrations and % change in modulus
are shown in Table 8, below.
Comparative Example 1
[0120] The reactive monomer mixture listed in Table 1 under CE 1
was dosed into Zeonor front curves, and the molds were closed using
Zeonor back curves. The lenses were cured under visible light in a
nitrogen atmosphere. Cure profile: 1) Pre-cure (TLDK-30 W/03 bulbs,
30-120 sec, 60-80.degree. C.); 2) Cure (TLD-30 W/03 bulbs, 320-800
sec, 70-80.degree. C.). The molds were opened, and the lenses
released were extracted and hydrated in IPA/water mixtures. The
finished lenses were packaged in borate buffered saline.
Example 5
[0121] A monomer mixture was formed by mixing the components in the
amounts listed in Table 4. The monomer mixes were dispensed into
Zeonor front and Zeonor:Polypropylene (55:45) back curves. The
molds were closed and the filled, closed monomers were held at
65.degree. C. with no irradiation. The monomer mixtures were cured
under visible light (Philips TL-03 bulbs) at 65.degree. C. in a
nitrogen atmosphere (about 3% O.sub.2) using the following cure
profile: 1.5 mW/cm.sup.2 for about 330 seconds, 7.+-.01 mW/cm.sup.2
for about 440 seconds.
[0122] After curing, the molds were opened, and the lenses released
in 70% IPA in DI water. After about 60-70 minutes the lenses were
transferred into: i) 70% IPA in DI water for about 30-40 minutes;
ii) 70% IPA in DI water for about 30-40 minutes; and iii) DI water
for at least about 30 minutes.
[0123] The lenses were packaged in 950+/-50 uL of borate buffered
sodium sulfate solution with 50 ppm methyl cellulose (SSPS) using
polypropylene bowls and foil, and autoclaved once (124.degree. C.,
18 minutes).
TABLE-US-00005 TABLE 4 Component Wt % HO-mPDMS 1000 55 DMA 13.53
HEMA 12.5 TEGDMA 3 MAA 1.5 Norbloc 2.2 PVP 360,000 12 Blue HEMA
0.02 CGI 819 0.25 Sum of monomers 100 Diluent (TPME): 45
[0124] The lenses were placed in a chamber with the temperature
controlled at 55.degree. C. Lenses were pulled from the chamber at
5, 10 weeks, and tested for modulus, maximum strain, diameter and %
water. The results are shown in Table 5.
TABLE-US-00006 TABLE 5 Example 5, 100% TPME Properties Baseline 5
weeks 10 weeks Modulus (psi) 93 .+-. 10 105 .+-. 8 102 .+-. 13
Elongation (%) 231 .+-. 61 206 .+-. 43 196 .+-. 39 Gravimetric
H.sub.2O (%) 52.2 .+-. 0.2 52.2 .+-. 0.1 52.5 .+-. 0
Examples 6 and 7
[0125] Example 5 was repeated, except that the diluent was changed
to those shown in Tables 6-7 below. The lenses were placed in a
chamber with the temperature controlled at 55.degree. C. Lenses
were pulled from the chamber at 5, 10, 15 and 20 weeks, and tested
for modulus, maximum strain and diameter, % water. The stability
data from Examples 6-7 is shown in FIGS. 3 and 4.
TABLE-US-00007 TABLE 6 Example 6, 100% 3-methyl-3-pentanol 5 10 15
20 Baseline weeks weeks weeks weeks Modulus (psi) 98 85 86 87 94
Elongation (%) 179 182 174 163 147 Gravimetric H.sub.2O (%) 53.1
54.6 53.5 53.9 54.0 Diameter (mm) 12.62 12.44 12.42 12.45 12.50
(-6.00 lens)
TABLE-US-00008 TABLE 7 Example 7, 75% butoxy ethyl acetate/35%
3-methyl-3-pentanol 5 10 15 20 Properties Baseline weeks weeks
weeks weeks Modulus (psi) 84 83 71 75 83 Elongation (%) 232 184 209
169 178 Gravimetric H.sub.2O (%) 53.3 54.2 53.7 53.8 54.1 Diameter
(mm) 14.43 14.48 14.50 14.48 14.46 (-1.00 lens)
[0126] The stability product, weight % methacrylic acid and percent
change in modulus for each of the Examples is shown in Table 8,
below.
TABLE-US-00009 TABLE 8 Ex Stability [MAA] .DELTA. modulus .DELTA.
modulus # Product (wt %) [MAA]* @ 10 wk (%) @ 18 wk (%) 1 0.0017 1
0.012 14 44 2 0.0008 0.5 0.006 NM 46 3 0.0026 1.6 0.019 35 141 4
0.00019 1 0.006 13* NM CE1 0 0 0 12* NM 5 0 1.5 0.017 9.7 NM 6 0
1.5 0.017 -12 -4** 7 0 1.5 0.017 -15 -1** *measurements taken at 8
weeks **measurements taken at 20 weeks.
[0127] The modulus change noted for Comparative Example 1
illustrates that modulus can vary by as much as 10% without an
anionic component. This is also shown by the standard deviations
noted in Tables 2 and 3. The change in modulus reported for
Examples 6 and 7 are reported as negative values because the
modulus was slightly lower after 10 and 20 weeks. However, the
changes are within the standard deviation for the modulus test
method, and should be considered as representing no change. Table 8
also shows that the best results were achieved in formulations
which did not have any silicone monomers having TMS group(s) as a
component in the reaction mixture (Example 4, which had mPDMS and
macromer, and Examples 5-7 which had HO-mPDMS). The Examples which
had PDMS-type silicone as the only silicone (Examples 5-7)
displayed the best stability.
Example 8
[0128] To a stirred solution of 45.5 kg of
3-allyloxy-2-hydroxypropane methacrylate (AHM) and 3.4 g of
butylated hydroxy toluene (BHT) was added 10 ml of Pt (0)
divinyltetramethyldisiloxane solution in xylenes (2.25% Pt
concentration) followed by addition of 44.9 kg of
n-butylpolydimethylsilane. The reaction exotherm was controlled to
maintain reaction temperature of about 20.degree. C. After complete
consumption of n-butylpolydimethylsilane, the Pt catalyst was
deactivated by addition of 6.9 g of diethylethylenediamine. The
crude reaction mixture was extracted several times with 181 kg of
ethylene glycol until residual AHM content of the raffinate was
<0.1%. 10 g of BHT was added to the resulting raffinate, stirred
until dissolution, followed by removal of residual ethylene glycol
affording 64.5 kg of the OH-mPDMS. 6.45 g of 4-Methoxy phenol
(MeHQ) was added to the resulting liquid, stirred, and filtered
yielding 64.39 kg of final OH-mPDMS as colorless oil.
Example 9 and Comparative Example 2
[0129] The components listed in Table 9, (except PVP K90) were
mixed in a jar for at least 1 hour with stirring. The PVP K90 was
slowly added to the reactive mixture with stirring such that no
clumps were formed during the addition. After all the PVP had been
added the reactive mixture was stirred for an additional 30
minutes. The jar was sealed and put on a jar roller running at
.about.200 rpm over night.
[0130] The reactive mixture was degassed in a vacuum desiccator
(around 1 cm Hg pressure) for about 40 minutes. The plastic lens
molds and monomer dosing syringes were put in a N.sub.2 environment
(<2% O.sub.2) for at least 12 hours. The back curve mold was
made of 9544 polypropylene, and the front curve mold was made of
Zeonor.TM.. The reactive mixture (50 microliter) was dosed into
each FC curve, and then BC curve was slowly deposited to close the
molds. This process was carried out under N2 environment (<2%
O.sub.2).
[0131] The monomer mixtures were cured under visible light (Philips
TLK 40 W/03 bulbs) in a nitrogen atmosphere (about <2% O.sub.2)
using the following cure profile: 5.+-.0.5 mW/cm.sup.2 for about 10
minutes at about 50.+-.5.degree. C.
[0132] The base curve was the removed from the assembly by prying.
The lens remained with the front curve and the front curve was
press-inverted to separate the dry lens from the front curve.
[0133] The dry lenses were inspected. Passed lenses were packaged
in blister with 950 u1 borate buffered packing solution with 50 ppm
methyl ethyl cellulose for each lens. The lens was then sterilized
at 121.degree. C. for 18 minutes
TABLE-US-00010 TABLE 9 Wt % Component Ex. 9 CE 2 HO-mPDMS 55 55
TEGDMA 0.25 0.25 DMA 16.78 18.28 HEMA 12.5 12.5 MAA 1.5 0 PVP K-90
12 12 CGI 819 0.25 0.25 Norbloc 1.7 1.7 Blue HEMA 0.02 0.02
Lysozyme and lipocalin uptake were measured as described above.
[0134] Lysozyme is a hydrolytic enzyme able to cleave the cell wall
of gram positive and some gram negative bacteria. Cleavage of the
peptidoglycan wall at the .beta.1-4 linkage between
N-acetyl-glucosamine and N acetyl galactosamine (muramate) results
in lysis of the bacteria.
[0135] Lysozyme activity was measured to determine the capacity of
lenses to maintain this protein in its native state. The level of
native lysozyme corresponds to the level of active lysozyme
determined following the procedure described above. The results are
shown in Table 10.
TABLE-US-00011 TABLE 10 [ion] Lysozyme Lipocalin % Native PQ 1 Ex.
# wt % [ion]* (.mu.g) (.mu.g) lysozyme uptake 9 1.5 0.017 103 + 5
4.6 .+-. 0.4 60 .+-. 7.7 90 CE 2 0 0 6.6 .+-. 0.3 6.5 .+-. 0.6 30
.+-. 3 6 Balafilcon 1 0.006 46 .+-. 6 7.8 .+-. 0.5 37 .+-. 8.3 6 A
Etafilcon 1.98 0.023 843 .+-. 23 1.8 .+-. 0.2 80 .+-. 11 2 A
*Moles/100 gram of reactive components Balafilcon A is the lens
material used to make Purevision .RTM. lenses commercially
available from Bausch & Lomb Etafilcon A is the lens material
used to make ACUVUE .RTM. AND ACUVUE .RTM. 2 lenses commercially
available from Johnson & Johnson Vision Care, Inc.
[0136] Preservatives uptake from lens care solutions can impact
contact lens performance, particularly contact lens induced corneal
staining Preservative uptake of the lenses of Example 9,
Comparative Example 2, and Purevision was measured by incubating
the above lenses in 3 ml of OptiFree.RTM. RepleniSH.RTM. for 72
hours at room temperature using the procedure described above to
lysozyme and lipocalin uptake. OptiFree.RTM. RepleniSH.RTM.
contains 0.001 wt % PQ1 as a disinfectant/preservative and citrate
dihydrate and citric acid monohydrate concentrations are 0.56% and
0.021% (wt/wt). The quantity of PQ1 uptake was determined using
HPLC analysis by comparing the level of PQ1 in the initial soak
solution to the level of PQ1 after 72 h soak in presence of the
test contact lens. The results are shown in Table 10.
Examples 10-18 & Comparative Example 2
[0137] Formulations were made as in Example 9, but varying the
concentration of methacrylic acid as shown in Table 11, below. The
lysozyme and PQ1 uptake were measured as in Example 9, and the
results are shown in Table 12, below. The results are also shown
graphically in FIG. 1.
TABLE-US-00012 TABLE 9 Wt % Component CE2 Ex 10 Ex 11 Ex 12 Ex 13
Ex 14 Ex 15 Ex 16 Ex 17 Ex 18 HO- 55 55 55 55 55 55 55 55 55 55
mPDMS TEGDMA 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 DMA
18.28 18.08 17.88 17.68 17.48 17.28 17.08 16.88 16.78 16.68 HEMA
12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 MAA 0 0.2 0.4 0.6
0.8 1.0 1.2 1.4 1.5 1.6 PVP K-90 12 12 12 12 12 12 12 12 12 12 CGI
819 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 Norbloc 1.7
1.7 1.7 1.7 1.7 1.7 1.7 1.7 1.7 1.7 Blue 0.02 0.02 0.02 0.02 0.02
0.02 0.02 0.02 0.02 0.02 HEMA
TABLE-US-00013 TABLE 10 MAA PQ1 (%) Lysozyme Ex # wt % [MAA] * per
lens (mg/lens) CE2 0 0 0 (0) 6.78 (0.48) 10 0.2 0.002 0.0 14.23
(1.7) 11 0.4 0.004 2.05 (2.0) 21.23 (2.31) 12 0.6 0.007 0.36 (0.5)
37.76 (3.51) 13 0.8 0.009 0.0 38.41 (2.93) 14 1 0.012 12.92 (4.4)
56.55 (10.39) 15 1.2 0.014 42.7 16 1.4 0.016 51.5 17 1.5 0.017 84.5
(7.8) 83 (7.21) 18 1.6 0.019 72.6 * Moles/100 gram of reactive
components
As is seen in FIG. 5, formulations can be made which display
desirable lysozyme uptake, and low PQ 1 uptake with existing
contact lens care solutions. Thus ophthalmic devices of the present
invention display a balance of desirable protein uptake,
compatibility with existing lens care solutions and thermal
stability.
Examples 19-21 and Comparative Examples 3 & 4
[0138] Lenses of Examples 19-21 were made from the formulations
listed in Table 11, using the following process.
[0139] A monomer mixture was formed by mixing the components in the
amounts listed in Table 10. The monomer mixes were dispensed into
Zeonor front and Zeonor back curves. The molds were closed and the
monomer was cured for about 15 minutes, under visible light
(Philips TL-03 bulbs, 1.5 mW/cm.sup.2) at .about.60.degree. C. in a
nitrogen atmosphere (about 0.5% O.sub.2).
[0140] After curing, the molds were opened, and the lenses released
in 70% IPA in DI water. After about 90 minutes the lenses were
transferred into: i) 70% IPA in DI water for about 90 minutes and
then ii) DI water for at least about 90 minutes.
[0141] The lenses were packaged in 950+/-50 uL of borate buffered
sodium sulfate solution with 50 ppm methyl cellulose using
polypropylene bowls and foil, and autoclaved once (124.degree. C.,
18 minutes).
[0142] Lenses of Comparative Example 3 were made using the
following process. The monomer mix was dispensed into 90/10
Zeonor:Tuftec Blend front and Zeonor back curves. The molds were
closed and the monomer was cured under visible light (Philips TLDK
30 w/13) at .about.60-65.degree. C. in a nitrogen atmosphere
(<3.0% O.sub.2) using the following cure profile: 1.0-2.5
mW/cm.sup.2 for 240 seconds followed by 4.5-6.5 mW/cm.sup.2 for 240
seconds.
[0143] After curing, the molds were opened, and the lenses released
in 0.45 wt. % sodium borate and deionized water solution. After
about 14 minutes the lenses were packaged in 950+/-50 uL of borate
buffered sodium sulfate solution with 50 ppm methyl cellulose using
polypropylene bowls and foil, and autoclaved once (124.degree. C.,
18 minutes).
TABLE-US-00014 TABLE 11 Ex. 19 Ex. 20 Ex. 21 CE3 Component (wt. %)
(wt. %) (wt. %) (wt. %) mPDMS 1000 29 29 29 0 HO-mPDMS 26 26 26
41.5 OH mPDMS 1 1 1 0 dimethacrylate TEGDMA 1.5 1.5 1.5 3 DMA 24 24
24 18.9 HEMA 9.24 8.24 7.74 22.13 PVP K-90 7 7 7 12 Irgacure 819
0.24 0.24 0.24 0.25 Norbloc 2 2 2 2.2 Blue HEMA 0.02 0.02 0.02 0.02
MAA 0 1 1.5 0 Monomers % 77 77 77 55 Decanoic Acid 60 60 60 60
t-amyl alcohol 40 40 40 40 Diluents % 23 23 23 45
Comparative Examples 4-6
[0144] Poly(HEMA) based lenses with varying amounts of methacrylic
acid were made from the formulations listed in Table 12, using
boric acid glycerol ester as diluent.
TABLE-US-00015 TABLE 12 Target (%) Components CE4 CE5 CE6 HEMA
97.72% 95.72% 93.72% MAA 0.00% 2.00% 4.00% EGDMA 0.78% 0.78% 0.78%
Irgacure 0.45% 0.45% 0.45% 1700 TMPTMA 0.10% 0.10% 0.10% Norbloc
0.95% 0.95% 0.95% M:D Ratio 40:60 50:50 60:40
[0145] The monomer mixes were dispensed into Zeonor front curves
and polypropylene back curves. The molds were closed and the
monomer was cured for about 15 minutes, under visible light
(Philips TL-03 bulbs, 2 mW/cm.sup.2) at .about.55.degree. C. in a
nitrogen atmosphere (<about 2% O.sub.2).
[0146] After curing, the molds were opened, and the lenses released
in DI water overnight at room temperature.
[0147] The lenses were packaged in 950+/-50 uL of borate buffered
sodium sulfate solution with 50 ppm methyl cellulose using
polypropylene bowls and foil, and autoclaved once (124.degree. C.,
18 minutes).
[0148] Preparation of Ophthalmic devices (25 .mu.g and 75 .mu.g of
Ketotifen Fumarate)
To prepare 1000 g of a 10 .mu.g/mL ketotifen fumarate ("K-25"):
[0149] 1. 9.10 g of boric acid
[0150] 2. 1.00 g of sodium borate decahydrate
[0151] 3. 8.30 g of sodium chloride
[0152] 4. 0.10 g of Ca.sub.2DTPA
[0153] 5. 981.475 g of deionized water
[0154] 6. 0.025 g of ketotifen fumarate
[0155] The system was maintained at room temperature throughout the
solution making process. Components 1-5 were added and stirred
using a magnetic or mechanical stirrer until the solution is
homogeneous. Ketotifen fumarate was added last and the mixture was
stirred to make the solution homogeneous (about 30 minutes).
[0156] The procedure to prepare a 75 ug/mL ketotifen fumarate
solution was identical to that described above, with the only
exceptions being the amount of ketotifen fumarate (0.075 g instead
of 0.025 g) and water (981.425 g instead of 981.475 g).
[0157] Lenses of Examples 19-21, Comparative Example 3 and 1-Day
Acuvue.RTM. Brand Contact Lenses (etafilcon A) (each -1.00 D power,
except Example 21, which was -0.50 D) were removed from their
packages and repackaged in glass vials containing 3.0 mL of the 25
.mu.g/mL or the 75 .mu.g/mL ketotifen fumarate solutions described
above to produce K-25 and K-75 lenses, respectively. The vials were
sealed with PTFE coated rubber stoppers and heated for 18 minutes
at 124.degree. C.
Extraction/Assay Procedure
[0158] Drug uptake in each of the lenses was measured as follows.
Lenses were removed from their containers using tweezers, blotted
and transferred to scintillation vials (one lens/vial).
[0159] Three mL of Eluent A (17% acetonitrile in 0.025 potassium
phosphate, monobasic buffer 0.2% triethylamine, 0.13% o-phosphoric
acid (balance deionized water)) were added to the vials and the
vials were sonicated for 1 hour at 35 C. The lenses were removed
from the scintillation vials and the remaining solution was
analyzed for ketotifen content by HPLC.
[0160] Eluent B (50% acetonitrile in 0.025 potassium phosphate,
monobasic buffer 0.2% triethylamine, 0.13% o-phosphoric acid
(balance deionized water)) was used as the mobile phase, and
ketotifen fumarate stock standard 72.72% ketotifen (balance Eluent
A).
[0161] The HPLC used an Agilent Zorbax Exlipse WDB-18 Rapid
Resolution HT 4.6 mm.times.1.8.mu., Guard Column: Phenomenex HPLC
Guard Cartridge System "Security Guard" and the detector has a
wavelength of 299 nm, a VW detector peak width Setting:">0.05
min", a Flow rate of 1.0 mL/min, and an injection volume of 100
.mu.L. The number of micrograms of ketotifen per lens was analyzed
by comparing the peak area of the extracted solutions versus peak
area of against peak areas of the ketotifen fumarate stock standard
and using standard equations. Drug uptake, the partition ratio and
diameter is shown in Table 13, below.
[0162] The diameter and water content were measured on lenses prior
to soaking in the drug solution.
[0163] The Partition ratio was calculated based on experimental
data:
[0164] Drug uptake by lens/(drug uptake by lens+amount drug in pkg.
soln.)
TABLE-US-00016 TABLE 13 [KF] Ketotifen Ketotifen Uptake (.mu.g/ MAA
In PS Uptake inc./ Partition Diameter [H.sub.2O] Ex. # mL) (wt %)
(.mu.g) (.mu.g) [MAA] Ratio (mm) (%) 19 75 0 45.0 (0.24) 18.4
(0.11) NA 0.12 (0.0009) 14.09 38.76 20 75 1 31.7 (0.43) 59.1 (0.51)
321 0.383 (0.005) 13.92 44.53 21 75 1.5 27.5 (0.57) 70.842 (1.75)
257 0.462 (0.011) 13.90 48.50 CE4 25 0 13.2 (0.18) 12.40 (0.81) NA
0.239 (0.016) 13.04 47.00 CE5 25 2 3.16 (0.24) 24.31 (0.91) 98
0.470 (0.015) 15.80 61.22 CE6 25 4 7.95 (0.54) 27.86 (1.68) 56.2
0.539 (0.032) N.M. 73.90 CE3 75 0 46.2 (0.41) 22.8098 (0.49) NA
0.141 (0.003) 14.20 48
[0165] The lenses of the present invention display surprisingly
improved drug uptake compared to uncharged silicone hydrogel lenses
(nearly four-fold increase in uptake between Example 21 to 19) and
to anionic conventional lenses, such as etafilcon A, (Example 21 to
Comparative Example 5). This is illustrated by the increase in %
uptake/[MAA], which was calculated using the following
equation:
[(Ketotifen uptake.sub.ionic lens/Ketotifen uptake.sub.ionic
lens)/[MAA].sub.ionic lens].times.100
[0166] So, for Example 20 (59.1/18.4)/1=320%.
[0167] Thus the data shows that the lenses of present invention
(Examples 20 and 21) display substantially higher percent drug
uptake (321 and 257%, respectively) for a given concentration of
anionic component than conventional ionic lenses, 98 and 56.3% for
Comparative Examples 5 and 6, respectively. Moreover, since the
percentages are calculated against a formulation which is the same,
except for the iconicity, the difference in ketotifen concentration
in the solutions is accounted for.
Drug Release
[0168] Lenses were removed from their respective containers,
blotted, and transferred to scintillation vials (one lens/vial).
Five (5) mL of packing solution was added to each vial and the
vials were shaken at 35 C. The solutions for 5 lenses of each of
Examples 19-20, and six (6) lenses for the Comparative Examples
were analyzed at 5, 30, 60, 120, 240 and 960 minutes for ketotifen
content by the extraction/assay procedure above. For Example 21,
the solution for 5 lenses were analyzed at 30, 60, 120, 240 and 960
minutes. The amount of ketotifen released by each lens type at each
time point is listed in Table 13 below, and shown in FIG. 6.
TABLE-US-00017 TABLE 13 % Ketotifen Release Ex # 0 min 5 min 10 min
30 min 60 min 120 min 240 min 960 min 19 0 15.6 .+-. 3.6 35.8 .+-.
1.8 58.4 .+-. 6 65.2 .+-. 3.3 .sup. 85 .+-. 3.5 83.5 .+-. 5.9 88.9
.+-. 1.5 20 0 9.6 .+-. 2.8 22.8 .+-. 6.2 28.2 .+-. 2 46.8 .+-. 3.3
70.4 .+-. 2.3 68.8 .+-. 6.1 79.4 .+-. 1.4 21 0 NM NM 24.9 .+-. 2
32.7 .+-. 6 53.2 .+-. 3 69.4 .+-. 1 73.8 .+-. 3.8 CE3 0 37.4 .+-.
3.5 48.3 .+-. 6.5 70.1 .+-. 2.4 77.8 .+-. 5.9 82.9 .+-. 6 89.2 .+-.
2.1 89.8 .+-. 2.8 CE4 0 13.6 .+-. 6.0 30.7 .+-. 4.7 39.5 .+-. 6.3
57.0 .+-. 4.3 79.7 .+-. 7.3 83.2 .+-. 1.5 82.4 .+-. 3.4
[0169] The modulus and water content of the lenses (-1.00 D) of
Examples 12-21 were measured after one and three autoclave cycles.
The results are reported in Table 14, below.
TABLE-US-00018 Ex # [MAA] AC Mod. (psi) [H.sub.2O] 19 0 1 101 39 19
0 3 113 40 20 1 1 120 46 20 1 3 116 46 21 1.5 1 112 48 21 1.5 3 106
48
[0170] Both water content and modulus remained stable through 3
autoclave cycles.
[0171] The lenses of Examples 19-21 were autoclaving (121.degree.
C. for 21 minutes) three times, and then evaluated for thermal
stability using the following conditions:
[0172] 25.degree. C..+-.2.degree. C., with ambient humidity ranging
from 17% to 56% RH.
[0173] The samples were stored in the stability chambers in
blisters without being cartoned. Originally, the blisters were
placed on their side, to expose the solution to all parts of the
container. The blister orientation was changed to horizontal, foil
side up .about.10 months into the study.
[0174] The modulus and water content were tested for the -1.00
lenses, stored at room temperature (25.degree. C..+-.2.degree. C.)
at intervals of 0 (baseline), 1.5, 6, 12 and 18 months. The results
are shown in Table 14, below.
TABLE-US-00019 TABLE 14 -1.00 Ex. # T (mo) [H.sub.2O] (%) Mod (psi)
19 0 40 113 0% 1.5 40 125 6 40 138 12 40 114 18 40* 110 20 0 46 116
1.0% 1.5 46 129 6 46 132 12 47 110 18 47 115 21 0 48 106 1.5% 1.5
49 130 6 49 131 12 49 108 18 49 113 *water content for the last
data point of Example 19% was measured at 21 months.
* * * * *