U.S. patent application number 12/334615 was filed with the patent office on 2009-07-02 for segmented interactive block copolymers.
Invention is credited to Jay F. Kunzler, Jeffrey G. Linhardt, Devon A. Shipp, David Vanderbilt.
Application Number | 20090171027 12/334615 |
Document ID | / |
Family ID | 40797822 |
Filed Date | 2009-07-02 |
United States Patent
Application |
20090171027 |
Kind Code |
A1 |
Linhardt; Jeffrey G. ; et
al. |
July 2, 2009 |
SEGMENTED INTERACTIVE BLOCK COPOLYMERS
Abstract
This invention is directed toward interactive segmented block
copolymers useful to treat the surface of a substrate by means of
interactive functionalities of the interactive segmented block
copolymer material binding with complementary surface
functionalities of the polymer substrate.
Inventors: |
Linhardt; Jeffrey G.;
(Fairport, NY) ; Shipp; Devon A.; (Potsdam,
NY) ; Kunzler; Jay F.; (Canandaigua, NY) ;
Vanderbilt; David; (Webster, NY) |
Correspondence
Address: |
Bausch & Lomb Incorporated
One Bausch & Lomb Place
Rochester
NY
14604-2701
US
|
Family ID: |
40797822 |
Appl. No.: |
12/334615 |
Filed: |
December 15, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61016844 |
Dec 27, 2007 |
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61016845 |
Dec 27, 2007 |
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61016841 |
Dec 27, 2007 |
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61016843 |
Dec 27, 2007 |
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Current U.S.
Class: |
525/209 ;
525/203; 525/212; 525/217; 525/218 |
Current CPC
Class: |
Y10T 428/31663 20150401;
C08F 293/005 20130101; C08F 230/00 20130101; C08F 130/08 20130101;
C08F 2438/03 20130101; C08J 7/056 20200101; Y10T 428/31536
20150401; G02B 1/043 20130101; C08J 2343/04 20130101; A61L 31/10
20130101; C08J 2383/00 20130101; A61M 25/0045 20130101; A61L 27/34
20130101 |
Class at
Publication: |
525/209 ;
525/212; 525/218; 525/217; 525/203 |
International
Class: |
C08F 299/00 20060101
C08F299/00 |
Claims
1. An interactive segmented block copolymer comprising a chemical
binding unit block and a hydrophilic block.
2. The interactive segmented block copolymer of claim 1 wherein the
chemical binding unit is a monomer selected from the group
consisting of styrene boronic acid, 3-methacrylamido styrene
boronic acid, trimethyl, 2-methacryloyloxyethylsulfonate salts,
3-methacrylamidopropyl-N,N,N-trimethyammonium salts,
2-methacryloyloxyethyl-N,N,N-trimethylammonium salts, and
amine-containing monomers, such as
3-methacrylamidopropyl-N,N-dimethyl amine.
3. The interactive segmented block copolymer of claim 1 wherein the
hydrophilic block comprises monomers selected from the group
consisting of 2-hydroxyethyl methacrylate, glycerol methacrylate,
methacrylic acid, acrylic acid, methacrylamide, acrylamide,
N,N'-dimethylmethacrylamide, N,N'-dimethylacrylamide; ethylenically
unsaturated poly(alkylene oxide).sub.s, cyclic lactams,
N-vinyl-2-pyrrolidone, hydrophilic vinyl carbonate, hydrophilic
vinyl carbamate monomers, 2-hydroxyethyl acrylate,
2-(2-ethoxyethoxy)ethyl(meth)acrylate, glyceryl(meth)acrylate,
poly(ethylene glycol (meth)acrylate),
tetrahydrofurfuryl(meth)acrylate, N-vinyl acetamide, copolymers,
derivatives and combinations thereof.
4. The interactive segmented block copolymer of claim 1 wherein the
block of the chemical binding unit comprises between 1 and about
1,000 units.
5. The interactive segmented block copolymer of claim 1 wherein the
block of the chemical binding unit comprises between 1 and about
100 units.
6. The interactive segmented block copolymer of claim 1 wherein the
block of the chemical binding unit comprises between 1 and about 30
units.
7. The interactive segmented block copolymer of claim 1 wherein the
hydrophilic block comprises between 1 and about 10,000 units.
8. The interactive segmented block copolymer of claim 1 wherein the
hydrophilic block comprises between about 10 and about 1,000
units.
9. The interactive segmented block copolymer of claim 1 wherein the
hydrophilic block comprises between about 20 and about 300
units.
10. An interactive segmented block copolymer having the following
generic formula (I): R1-[(A)m]p-[(B)n]q-X (I) wherein R1 is a
reactive residue of a moiety capable of acting as an initiator for
Atom Transfer Radical Polymerization, A is a chemical binding unit
block, B is a hydrophilic unit block, m is 1 to 10,000, n is 1 to
10,000, p and q are natural numbers, and X is a halogen capping
group of an initiator for Atom Transfer Radical Polymerization or a
derivatized reaction product with the proviso that when A is an
ionic block, B will be a nonionic block.
11. An interactive segmented block copolymers having the following
generic formula (II): R1-[(A)m]p-[(B)n]q-R2 (II) wherein R1 is a
radical forming residue of a RAFT agent or free radical initiator,
A is a chemical binding unit block, B is a hydrophilic unit block,
m is 1 to 10,000, n is 1 to 10,000, p and q are natural numbers,
and R2 is a thio carbonyl fragment of the chain transfer agent or a
derivatized reaction product with the proviso that when A is an
ionic block, B will be a nonionic block.
12. An interactive segmented block copolymers having the following
generic formula (III): R1-[(B)n]q-[(A)m]p-R2-[(A)m]p-[(B)n]q-R1
(III) wherein R1 is a radical forming residue of a RAFT agent or
free radical initiator, A is a chemical binding unit block, B is a
hydrophilic unit block, m is 1 to 10,000, n is 1 to 10,000, p and q
are natural numbers, and R2 is a thio carbonyl thio group.
13. The interactive segmented block copolymer of claim 10 wherein
one of the chemical binding unit block or the hydrophilic block is
a statistical copolymerization or compositionally heterogeneous
block.
14. The interactive segmented block copolymer of claim 11 wherein
one of the chemical binding unit block or the hydrophilic block is
a statistical copolymerization or compositionally heterogeneous
block.
15. The interactive segmented block copolymer of claim 12 wherein
one of the chemical binding unit block or the hydrophilic block is
a statistical copolymerization or compositionally heterogeneous
block.
16. The interactive segmented block copolymer of claim 10 further
comprising at least one block selected from the group consisting of
nonbinding blocks, nonhydrophilic blocks and combinations
thereof.
17. The interactive segmented block copolymer of claim 11 further
comprising at least one block selected from the group consisting of
nonbinding blocks, nonhydrophilic blocks and combinations
there.
18. The interactive segmented block copolymer of claim 12 further
comprising at least one block selected from the group consisting of
nonbinding blocks, nonhydrophilic blocks and combinations thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of Provisional Patent
Application No. 61/016,844 filed Dec. 27, 2007; Provisional Patent
Application No. 61/016,845 filed Dec. 27, 2007; Provisional Patent
Application No. 61/016,841 filed Dec. 27, 2007; and Provisional
Patent Application No. 61/016,843 filed Dec. 27, 2007.
FIELD OF INVENTION
[0002] This invention relates to a new class of tailored polymers
useful as surface coatings for ophthalmic devices. These polymers
can be specifically tailored using controlled radical
polymerization processes and contain functional domains. Controlled
radical polymerization allows the facile synthesis of segmented
block copolymers with tunable chemical composition that, as a
result, show different chemical properties than those prepared via
conventional free radical polymerization. Segmented block
copolymers with substrate binding domain(s) containing functional
groups such as boronic acids, hydrogen bonding groups and
electrostatic groups and hydrophilic domain(s) show good surface
properties when interactively bound to substrates containing
complimentary functionality.
BACKGROUND OF THE INVENTION
[0003] Medical devices such as ophthalmic lenses are made from a
wide variety of materials. In the contact lens field materials are
broadly categorized into conventional hydrogels or silicone
hydrogels. Recently, the use of silicone-containing materials
(silicone hydrogels) has been preferred. These materials can vary
greatly in water content. However, regardless of their water
content, silicone materials tend to be relatively hydrophobic,
non-wettable, and have a high affinity for lipids. Methods to
modify the surface of silicone devices by increasing their
hydrophilicity and improving their biocompatibility are of great
importance.
[0004] A number of copolymers for surface coatings have been
investigated. U.S. Pat. No. 6,958,169 discloses providing a medical
device formed from a monomer mixture comprising a hydrophilic
device-forming monomer including a copolymerizable group and an
electron donating moiety, and a second device-forming monomer
including a copolymerizable group and a interactive functional
group; and, contacting a surface of the medical device with a
wetting agent including a proton donating moiety reactive with the
functional group provided by the second lens-forming monomer and
that complexes with the electron donating moiety provided by the
hydrophilic lens-forming monomer.
[0005] U.S. Pat. No. 6,858,310 discloses a method of modifying the
surface of a medical device to increase its biocompatibility or
hydrophilicity by coating the device with a removable hydrophilic
polymer by means of reaction between reactive functionalities on
the hydrophilic polymer with functionalities that are complementary
on or near the surface of the medical device.
[0006] U.S. Pat. No. 6,599,559 discloses a method of modifying the
surface of a medical device to increase its biocompatibility or
hydrophilicity by coating the device with a removable hydrophilic
polymer by means of reaction between reactive functionalities on
the hydrophilic polymer which functionalities are complementary to
reactive functionalities on or near the surface of the medical
device.
[0007] U.S. Pat. No. 6,428,839 discloses a method for improving the
wettability of a medical device, comprising the steps of: (a)
providing a medical device formed from a monomer mixture comprising
a hydrophilic monomer and a silicone-containing monomer, wherein
said medical device has not been subjected to a surface oxidation
treatment; (b) contacting a surface of the medical device with a
solution comprising a proton-donating wetting agent, whereby the
wetting agent forms a complex with the hydrophilic monomer on the
surface of the medical device in the absence of a surface oxidation
treatment step and without the addition of a coupling agent.
[0008] Many copolymers are currently made using conventional free
radical polymerization techniques with the structure of the polymer
being completely random or controlled by the reactivity ratios of
the respective monomers. By using controlled free radical
polymerization techniques one is able to assemble copolymers in a
controlled fashion and, in turn, they show completely different
solution and coating properties than copolymers prepared using
conventional free radical polymerization techniques. Controlled
free radical polymerization can be conducted by a variety of
methods, such as ATRP (atom transfer radical polymerization) and
RAFT (Reversible addition-fragmentation chain transfer
polymerization).
SUMMARY
[0009] In accordance with the present disclosure, the invention
relates generally to interactive segmented block copolymers useful
for forming bound coatings in the manufacture of medical devices.
As used herein the terms "bound", "binding", or terms of similar
import, refer to various chemical interactions such as,
electrostatic, ionic, complexation, hydrogen bond or other
interaction between the interactive segmented block copolymer and
the surface functionality of the device which results in the
association of the coating composition with the device. Examples of
suitable devices include contact lenses, intraocular lenses,
vascular stents, phakic intraocular lenses, aphakic intraocular
lenses, intraocular lens inserters, corneal implants, catheters,
implants, and the like.
[0010] Interactive segmented block copolymers prepared through Atom
Transfer Radical Polymerization ("ATRP") methods in accordance with
the invention herein have the following generic formula (I):
R.sub.1-[(A).sub.m].sub.p-[(B).sub.n].sub.q--X (I)
[0011] wherein R.sub.1 is the reactive residue of a moiety capable
of acting as an initiator for Atom Transfer Radical Polymerization,
A is a chemical binding unit block, B is a hydrophilic unit block,
m is 1 to 10,000, n is 1 to 10,000, p and q are natural numbers,
and X is a halogen capping group of the initiator for Atom Transfer
Radical Polymerization with the proviso that when A is an ionic
block, B will be a nonionic block. It should be noted, that there
are many processes for the post polymerization removal or
transformation of the halogen capping group of an initiator for
Atom Transfer Radical Polymerization which are known to one of
ordinary skill in the art. Therefore polymers prepared using ATRP
according to the invention herein would include those where X is a
halogen capping group of the initiator for Atom Transfer Radical
Polymerization and those polymers that have undergone post
polymerization removal or transformation of the halogen capping
group of an initiator for Atom Transfer Radical Polymerization
(i.e., derivatized reaction product). The polymers which contain
halogen end-groups can be utilized in a host of traditional alkyl
halide organic reactions. In one example, the addition of
tributyltin hydride to the polymeric alkyl halide in the presence
of a radical source (AIBN, or Cu(I) complex) leads to a saturated
hydrogen-terminated polymer. In another example, by replacing
tributyltin hydride with allyl tri-n-butylstannane, polymers with
allyl end groups can be prepared. The terminal halogen can also be
displaced by nucleophilic substitution, free-radical chemistry, or
electrophilic addition catalyzed by Lewis acids to yield a wide
variety of telechelic derivatives, such as alkenes, alkynes,
alcohols, thiols, alkanes, azides, amines, phosphoniums, or epoxy
groups, to mention a few.
[0012] Interactive segmented block copolymers prepared through
Reversible addition-fragmentation chain transfer polymerization
("RAFT") methods in accordance with the invention herein have the
following generic formula (II):
R.sub.1-[(A).sub.m].sub.p-[(B).sub.n].sub.q--R.sub.2 (II)
wherein R.sub.1 is a radical forming residue of a RAFT agent or
free radical initiator, A is a chemical binding unit block, B is a
hydrophilic unit block, m is 1 to 10,000, n is 1 to 10,000, p and q
are natural numbers, and R.sub.2 is a thio carbonyl thio fragment
of the chain transfer agent with the proviso that when A is an
ionic block, B will be a nonionic block. RAFT agents based upon
thio carbonyl thio chemistry are well known to those of ordinary
skill in the art and would include, for example, xanthates,
trithiocarbonates and dithio esters. It should be noted, that there
are many processes for the post polymerization removal or
transformation of the thio carbonyl thio fragment of the chain
transfer agent which are known to one of ordinary skill in the art.
Therefore polymers prepared using RAFT agent according to the
invention herein would include those where R.sub.2 is a thio
carbonyl thio fragment of the chain transfer agent and those
polymers that have undergone post polymerization removal or
transformation of the thio carbonyl thio fragment of the chain
transfer agent (i.e., a derivatized reaction product). One example
of such a transformation is the use of free radical reducing agents
to replace the thio carbonyl thio group with hydrogen. Others
include thermolysis of the end group or conversion of the thio
carbonyl thio groups to thiol groups by aminolysis. A wide variety
of telechelic derivatives can be prepared, such as alkenes,
alkynes, alcohols, thiols, alkanes, azides, amines, phosphoniums,
or epoxy groups, to mention a few.
[0013] Reactive segmented block copolymers prepared through
reversible addition-fragmentation chain transfer polymerization
("RAFT") methods in accordance with the invention herein have the
following generic formula (III):
R1-[(B)n]q-[(A)m]p-R2-[(A)m]p-[(B)n]q-R1 (III)
wherein R1 is a radical forming residue of a RAFT agent or free
radical initiator, A is a chemical binding unit block, B is a
hydrophilic unit block, m is 1 to 10,000, n is 1 to 10,000, p and q
are natural numbers, and R2 is a thio carbonyl thio group.
[0014] For each of the polymers of generic formula I, II and III
the order of the block units is not critical and the interactive
segmented block copolymer can contain more than two blocks.
Therefore the interactive segmented block copolymers can be
multiblock copolymers and include repetition of one or more blocks.
As examples please see the nonlimiting representations below, each
of which is intended to fall within generic formula I, II and
III:
-(A).sub.m-(B).sub.n-- (1)
--(B).sub.n-(A).sub.m- (2)
-(A).sub.m-(B).sub.n-(A).sub.m- (3)
[0015] Interactive segmented block copolymers according to the
invention herein may also contain blocks that would not be
considered to be binding or hydrophilic, for example, polystyrene
or polymethyl methacrylate. The presence of non binding or non
hydrophilic block(s) within a polymer is contemplated as being
within the scope of the claimed reactive segmented block copolymers
and formulae I, II and III of the invention herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 is a schematic example of atom-transfer radical
polymerization (ATRP) used to make a segmented block copolymer in
which there is an oligomeric block of the chemical binding unit at
one end of the polymer followed by a large hydrophilic block;
[0017] FIG. 2 is the structural formula of various monomers which
may be used to provide the interactive functionality of the
segmented block copolymers of the invention herein;
[0018] FIG. 3 is a reaction schematic showing how RAFT
polymerization can be used to polymerize block copolymers with
functional domains.
[0019] The present invention relates generally to interactive
segmented block copolymers. The interactive segmented block
copolymers are useful in various compositions including ophthalmic
compositions comprising the interactive segmented block copolymers
for use in providing surface bound coatings in the manufacture of
medical devices. In preferred embodiments, the present invention
relates to interactive segmented block copolymers having
interactive functionality that is complimentary to surface
functionality of a medical device such as an ophthalmic lens. It
should be understood that the term "surface" is not to be limited
to meaning "at least one complete surface". Surface coverage does
not have to be even or complete to be effective for surface
functionality. The interactive segmented block copolymers of the
present invention are useful as coatings for biocompatible
materials including both soft and rigid materials commonly used for
ophthalmic lenses, including contact lenses.
[0020] Interactive segmented block copolymers prepared through Atom
Transfer Radical Polymerization ("ATRP") methods in accordance with
the invention herein have the following generic formula (I):
R.sub.1-[(A).sub.m].sub.p-[(B).sub.n].sub.q--X (I)
wherein R.sub.1 is the reactive residue of a moiety capable of
acting as an initiator for Atom Transfer Radical Polymerization, A
is a chemical binding unit block, B is a hydrophilic unit block, m
is 1 to 10,000, n is 1 to 10,000, p and q are natural numbers, and
X is a halogen capping group of the initiator for Atom Transfer
Radical Polymerization with the proviso that when A is an ionic
block, B will be a nonionic block. It would be recognized by one of
ordinary skill in the art that X being an alkyl halide can be
converted to another functionality through subsequent chemical
reaction. It should be noted, that there are many processes for the
post polymerization removal or transformation of the halogen
capping group of an initiator for Atom Transfer Radical
Polymerization which are known to one of ordinary skill in the art.
Therefore polymers prepared using ATRP according to the invention
herein would include those where X is a halogen capping group of
the initiator for Atom Transfer Radical Polymerization and those
polymers that have undergone post polymerization removal or
transformation of the halogen capping group of an initiator for
Atom Transfer Radical Polymerization (i.e., derivatized reaction
product). The polymers which contain halogen end-groups can be
utilized in a host of traditional alkyl halide organic reactions.
In one example, the addition of tributyltin hydride to the
polymeric alkyl halide in the presence of a radical source (AIBN,
or Cu(I) complex) leads to a saturated hydrogen-terminated polymer.
In another example, by replacing tributyltin hydride with allyl
tri-n-butylstannane, polymers with allyl end groups can be
prepared. The terminal halogen can also be displaced by
nucleophilic substitution, free-radical chemistry, or electrophilic
addition catalyzed by Lewis acids to yield a wide variety of
telechelic derivatives, such as alkenes, alkynes, alcohols, thiols,
alkanes, azides, amines, phosphoniums, or epoxy groups, to mention
a few.
[0021] Interactive segmented block copolymers prepared through
Reversible addition-fragmentation chain transfer polymerization
("RAFT") methods in accordance with the invention herein have the
following generic formula (II):
R.sub.1-[(A).sub.m].sub.p-[(B).sub.n].sub.q--R.sub.2 (II)
wherein R.sub.1 is a radical forming residue of a RAFT agent or
free radical initiator, A is a chemical binding unit block, B is a
hydrophilic unit block, m is 1 to 10,000, n is 1 to 10,000, p and q
are natural numbers, and R.sub.2 is a thio carbonyl thio fragment
of the chain transfer agent with the proviso that when A is an
ionic block, B will be a nonionic block. It would be recognized by
one of ordinary skill in the art that R.sub.2 being a thio carbonyl
thio fragment can be cleaved from the end of the polymer or
converted to another functionality through subsequent chemical
reaction. RAFT agents based upon thio carbonyl thio chemistry are
well known to those of ordinary skill in the art and would include,
for example, xanthates, trithiocarbonates and dithio esters. It
should be noted, that there are many processes for the post
polymerization removal or transformation of the thio carbonyl thio
fragment of the chain transfer agent which are known to one of
ordinary skill in the art. Therefore polymers prepared using RAFT
agent according to the invention herein would include those where
R.sub.2 is a thio carbonyl thio fragment of the chain transfer
agent and those polymers that have undergone post polymerization
removal or transformation of the thio carbonyl thio fragment of the
chain transfer agent (i.e., a derivatized reaction product). One
example of such a transformation is the use of free radical
reducing agents to replace the thio carbonyl thio group with
hydrogen. Others include thermolysis of the end group or conversion
of the thio carbonyl thio groups to thiol groups by aminolysis. A
wide variety of telechelic derivatives can be prepared, such as
alkenes, alkynes, alcohols, thiols, alkanes, azides, amines,
phosphoniums, or epoxy groups, to mention a few.
[0022] Reactive segmented block copolymers prepared through
reversible addition-fragmentation chain transfer polymerization
("RAFT") methods in accordance with the invention herein have the
following generic formula (III):
R1-[(B)n]q-[(A)m]p-R2-[(A)m]p-[(B)n]q-R1 (III)
wherein R1 is a radical forming residue of a RAFT agent or free
radical initiator, A is a chemical binding unit block, B is a
hydrophilic unit block, m is 1 to 10,000, n is 1 to 10,000, p and q
are natural numbers, and R2 is a thio carbonyl thio group.
[0023] For each of the polymers of generic formula I, II and III
the order of the block units is not critical and the interactive
segmented block copolymer can contain more than two blocks.
Therefore the interactive segmented block copolymers can be
multiblock copolymers and include repetition of one or more blocks.
As examples please see the nonlimiting representations below, each
of which is intended to fall within generic formula I, II and
m:
-(A).sub.m-(B).sub.n-- (1)
--(B).sub.n-(A).sub.m- (2)
-(A).sub.m-(B).sub.n-(A).sub.m- (3)
[0024] Interactive segmented block copolymers according to the
invention herein may also contain blocks that would not be
considered to be binding or hydrophilic, for example, polystyrene
or polymethyl methacrylate. The presence of non binding or non
hydrophilic block(s) within a polymer is contemplated as being
within the scope of the claimed interactive segmented block
copolymers and formulae I, II and III of the invention herein.
[0025] The present invention provides materials useful for surface
modifying contact lenses and like medical devices through the use
of complementary interactive functionality. Although only contact
lenses will be referred to hereinafter for purposes of simplicity,
such reference is not intended to be limiting since the subject
method is suitable for surface modification of other medical
devices such as phakic and aphakic intraocular lenses and corneal
implants as well as contact lenses. Surface interactive groups of
the polymeric materials of the contact lenses and other biomedical
devices are used to form chemical linkages, i.e., binding, with the
interactive segmented block copolymers of the invention herein. The
preferred interactive segmented block copolymers in the present
invention are selected based on the specific interactive surface
groups of the polymeric material to be coated. In accordance with
the present invention, the one or more interactive segmented block
copolymers selected for surface modification should have
complementary interactive chemical functionality to that of the
surface of the substrate. Such complementary interactive chemical
functionality enables a chemical reaction between the interactive
segmented block copolymers and the complementary surface
functionality of the substrate to form electrostatic, ionic,
complexation, hydrogen bond or other interactions there between.
The one or more interactive segmented block copolymers are thus
bound to the surface of the contact lens or like medical device to
achieve surface modification thereof.
[0026] The interactive segmented block copolymer comprises a
chemical binding unit block to provide the desired surface binding
of the molecule. The chemical binding unit block can be varied and
is determined based upon the intended use of the interactive
segmented block copolymers. That is, the chemical binding unit
block of the interactive segmented block copolymers is selected to
provide functionality that is complementary with the surface
functionality of the device. The chemical binding unit block will
contain functional groups such as boronic acids, hydrogen bonding
groups and electrostatic groups.
[0027] Selection of the chemical binding unit monomer of the block
copolymer is determined by the functional groups on the surface of
the device. For example, if the interactive molecule on the surface
of the device contains a carboxylic acid group, a quaternary amine
containing monomer can be a chemical binding unit monomer of the
interactive segmented block copolymer. If the interactive molecule
on the surface of the device contains hydroxy or amino
functionality, boronic acid containing monomers can be a chemical
binding unit monomer of the interactive segmented block copolymer.
A wide variety of suitable combinations of functional group
containing monomers of the chemical binding unit complementary to
interactive groups on the surface of the device will be apparent to
those of ordinary skill in the art. For example, the chemical
binding unit block may comprise a moiety selected from styrene
boronic acid, 3-methacrylamido styrene boronic acid, trimethyl,
2-methacryloyloxyethylsulfonate salts,
3-methacrylamidopropyl-N,N,N-trimethyammonium salts,
2-methacryloyloxyethyl-N,N,N-trimethylammonium salts, and
amine-containing monomers, such as
3-methacrylamidopropyl-N,N-dimethyl amine. Examples of
complementary functionality are provided below in Table 1.
TABLE-US-00001 TABLE 1 MONOMER/RESIDUE HAVING A COMPLEMENTARY
INTERACTIVE INTERACTIVE FUNCTIONAL GROUP SURFACE FUNCTIONALITY
##STR00001## Hydroxyl, amine, geminal diols, cis diols ##STR00002##
Anionic groups, Carboxylic acid Carboxylic acids, sulfonic acids,
Cationic groups phosphonic acids ##STR00003##
[0028] The chemical binding unit block of the interactive segmented
block copolymers is oligomeric or polymeric and is sized to provide
suitable binding to the surface of the medical device to be coated.
Therefore the variable m of formula I, II or III can be between 1
and about 1000, preferably between 1 and about 100, most preferably
between 1 and about 30.
[0029] In addition to the chemical binding unit, the interactive
segmented block copolymers of the invention herein will also
contain hydrophilic domain(s) showing good surface properties when
the block copolymer is covalently bound to substrates containing
complimentary functionality. The hydrophilic domain(s) will
comprise at least one hydrophilic monomer, such as, HEMA, glycerol
methacrylate, methacrylic acid ("MAA"), acrylic acid ("AA"),
methacrylamide, acrylamide, N,N'-dimethylmethacrylamide, or
N,N'-dimethylacrylamide; copolymers thereof; hydrophilic
prepolymers, such as ethylenically unsaturated poly(alkylene
oxide).sub.s, cyclic lactams such as N-vinyl-2-pyrrolidone ("NVP"),
or derivatives thereof. Still further examples are the hydrophilic
vinyl carbonate or vinyl carbamate monomers. Hydrophilic monomers
can be nonionic monomers, such as 2-hydroxyethyl methacrylate
("HEMA"), 2-hydroxyethyl acrylate ("HEA"),
2-(2-ethoxyethoxy)ethyl(meth)acrylate, glyceryl (meth)acrylate,
poly(ethylene glycol (meth)acrylate),
tetrahydrofurfuryl(meth)acrylate, (meth)acrylamide,
N,N'-dimethylmethacrylamide, N,N'-dimethylacrylamide ("DMA"),
N-vinyl-2-pyrrolidone (or other N-vinyl lactams), N-vinyl
acetamide, and combinations thereof. Still further examples of
hydrophilic monomers are the vinyl carbonate and 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. The
contents of these patents are incorporated herein by reference. The
hydrophilic monomer also can be an anionic monomer, such as
2-methacryloyloxyethylsulfonate salts. Substituted anionic
hydrophilic monomers, such as from acrylic and methacrylic acid,
can also be utilized wherein the substituted group can be removed
by a facile chemical process. Non-limiting examples of such
substituted anionic hydrophilic monomers include trimethylsilyl
esters of (meth)acrylic acid, which are hydrolyzed to regenerate an
anionic carboxyl group. The hydrophilic monomer also can be a
cationic monomer selected from the group consisting of
3-methacrylamidopropyl-N,N,N-trimethyammonium salts,
2-methacryloyloxyethyl-N,N,N-trimethylammonium salts, and
amine-containing monomers, such as
3-methacrylamidopropyl-N,N-dimethyl amine. Other suitable
hydrophilic monomers will be apparent to one skilled in the
art.
[0030] The hydrophilic monomer block will be sized to provide the
desirable surface coating property of the interactive segmented
block copolymer. The size of the hydrophilic oligomeric or
polymeric block may vary depending upon the substrate to be coated
and the intended use. Therefore the variable n of formula I or II
can be between 1 and about 10000, preferably between about 10 and
about 1000, and more preferably between about 20 and about 300.
[0031] Atom-transfer radical polymerization (ATRP) can be used to
prepare segmented block copolymers in which the molecular weight of
each of the blocks and the entire polymer can be precisely
controlled. As shown in FIG. 1, atom-transfer radical
polymerization (ATRP) can be used to make a segmented block
copolymer in which there is a block of the chemical binding unit at
one end of the polymer followed by a large hydrophilic block. It
should be understood that the order of addition of the monomer
comprising the chemical binding unit domain and the monomer
comprising the hydrophilic domain is not critical. A large number
of monomers are available for the assembly of polymers (For
example, see FIG. 2). Reversible addition-fragmentation chain
transfer polymerization (RAFT) can also be used to prepare
segmented block copolymers in which the molecular weight of each of
the blocks and the entire polymer can be precisely controlled (see
FIG. 3).
[0032] The interactive segmented block copolymers of the invention
herein are useful in providing coatings for substrates. Examples of
substrate materials useful with the present invention are taught in
U.S. Pat. Nos. 5,908,906 to Kunzler et al.; 5,714,557 to Kunzler et
al.; 5,710,302 to Kunzler et al.; 5,708,094 to Lai et al.;
5,616,757 to Bambury et al.; 5,610,252 to Bambury et al.; 5,512,205
to Lai; 5,449,729 to Lai; 5,387,662 to Kunzler et al.; 5,310,779 to
Lai and 6,891,010 to Kunzler et al.; which patents are incorporated
by reference as if set forth at length herein.
[0033] The present invention contemplates the use of interactive
segmented block copolymers with medical devices including both
"hard" and "soft" contact lenses. As disclosed above, the invention
is applicable to a wide variety of materials. Hydrogels in general
are a well-known class of materials that comprise hydrated,
cross-linked polymeric systems containing water in an equilibrium
state. Silicon containing hydrogels generally have water content
greater than about 5 weight percent and more commonly between about
10 to about 80 weight percent. Such materials are usually prepared
by polymerizing a mixture containing at least one silicon
containing monomer and at least one hydrophilic monomer. Typically,
either the silicon containing monomer or the hydrophilic monomer
functions as a crosslinking agent (a crosslinker being defined as a
monomer having multiple polymerizable functionalities) or a
separate crosslinker may be employed. Applicable silicon containing
monomeric units for use in the formation of silicon containing
hydrogels are well known in the art and numerous examples are
provided in U.S. Pat. Nos. 4,136,250; 4,153,641; 4,740,533;
5,034,461; 5,070,215; 5,260,000; 5,310,779; and 5,358,995.
[0034] Examples of applicable silicon-containing monomeric units
include bulky polysiloxanylalkyl(meth)acrylic monomers. An example
of bulky polysiloxanylalkyl (meth)acrylic monomers are represented
by the following Formula IV:
##STR00004##
wherein: X denotes --O-- or --NR--; each R.sub.1 independently
denotes hydrogen or methyl; each R.sub.2 independently denotes a
lower alkyl radical, phenyl radical or a group represented by
##STR00005##
wherein each R'.sub.2 independently denotes a lower alkyl or phenyl
radical; and h is 1 to 10. Some preferred bulky monomers are
methacryloxypropyl tris(trimethyl-siloxy)silane or
tris(trimethylsiloxy)silylpropyl methacrylate, sometimes referred
to as TRIS.
[0035] Another class of representative silicon-containing monomers
includes silicon containing vinyl carbonate or vinyl carbamate
monomers such as:
1,3-bis[4-vinyloxycarbonyloxy)butyl]tetramethyl-disiloxane;
3-(trimethylsilyl)propyl vinyl carbonate;
3-(vinyloxycarbonylthio)propyl-[tris(trimethylsiloxy)silane];
3-[tris(trimethylsiloxy)silyl]propyl vinyl carbamate;
3-[tris(trimethylsiloxy)silyl]propyl allyl carbamate;
3-[tris(trimethylsiloxy)silyl]propyl vinyl carbonate;
t-butyldimethylsiloxyethyl vinyl carbonate; trimethylsilylethyl
vinyl carbonate; and trimethylsilylmethyl vinyl carbonate.
[0036] An example of silicon-containing vinyl carbonate or vinyl
carbamate monomers are represented by Formula V:
##STR00006##
[0037] wherein: [0038] Y' denotes --O--, --S-- or --NH--; [0039]
RSi denotes a silicon containing organic radical; [0040] R3 denotes
hydrogen or methyl; [0041] d is 1, 2, 3 or 4; and q is 0 or 1.
[0042] Suitable silicon containing organic radicals R.sup.Si
include the following:
--(CH.sub.2).sub.n'Si[(CH.sub.2).sub.m'CH.sub.3].sub.3;
--(CH.sub.2).sub.n'Si[OSi(CH.sub.2).sub.m'CH.sub.3].sub.3;
##STR00007##
wherein: [0043] R.sub.4 denotes
##STR00008##
[0043] wherein p' is 1 to 6; [0044] R.sub.5 denotes an alkyl
radical or a fluoroalkyl radical having 1 to 6 carbon atoms; [0045]
e is 1 to 200; n' is 1, 2, 3 or 4; and m' is 0, 1, 2, 3, 4 or
5.
[0046] An example of a particular species within Formula V is
represented by Formula VI.
##STR00009##
[0047] Another class of silicon-containing monomers includes
polyurethane-polysiloxane macromonomers (also sometimes referred to
as prepolymers), which may have hard-soft-hard blocks like
traditional urethane elastomers. They may be end-capped with a
hydrophilic monomer such as HEMA. Examples of such silicon
containing urethanes are disclosed in a variety of publications,
including Lai, Yu-Chin, "The Role of Bulky Polysiloxanylalkyl
Methacrylates in Polyurethane-Polysiloxane Hydrogels," Journal of
Applied Polymer Science, Vol. 60, 1193-1199 (1996). PCT Published
Application No. WO 96/31792 discloses examples of such monomers,
which disclosure is hereby incorporated by reference in its
entirety. Further examples of silicon containing urethane monomers
are represented by Formulae VII and VIII:
E(*D*A*D*G).sub.a*D*A*D*E'; or (VII)
E(*D*G*D*A).sub.a*D*G*D*E'; (VIII)
[0048] wherein: [0049] 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; [0050] 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; [0051] * denotes a urethane or
ureido linkage; [0052] a is at least 1; [0053] A denotes a divalent
polymeric radical of Formula IX:
##STR00010##
[0053] wherein: [0054] each R.sub.s independently denotes an alkyl
or fluoro-substituted alkyl group having 1 to 10 carbon atoms which
may contain ether linkages between carbon atoms; [0055] m' is at
least 1; and [0056] p is a number which provides a moiety weight of
400 to 10,000; [0057] each of E and E' independently denotes a
polymerizable unsaturated organic radical represented by Formula
X:
##STR00011##
[0057] wherein:
[0058] R.sub.6 is hydrogen or methyl;
[0059] R.sub.7 is hydrogen, an alkyl radical having 1 to 6 carbon
atoms, or a --CO--Y--R.sub.9 radical wherein Y is --O--, --S-- or
--NH--;
[0060] R.sub.8 is a divalent alkylene radical having 1 to 10 carbon
atoms;
[0061] R.sub.9 is a alkyl radical having 1 to 12 carbon atoms;
[0062] X denotes --CO-- or --OCO--;
[0063] Z denotes --O-- or --NH--;
[0064] Ar denotes an aromatic radical having 6 to 30 carbon
atoms;
[0065] w is 0 to 6; x is 0 or 1; y is 0 or 1; and z is 0 or 1.
[0066] A more specific example of a silicon containing urethane
monomer is represented by Formula (XI):
##STR00012##
wherein m is at least 1 and is preferably 3 or 4, a is at least 1
and preferably is 1, p is a number which provides a moiety weight
of 400 to 10,000 and is preferably at least 30, R.sub.10 is a
diradical of a diisocyanate after removal of the isocyanate group,
such as the diradical of isophorone diisocyanate, and each E'' is a
group represented by:
##STR00013##
[0067] A preferred silicon containing hydrogel material comprises
(in the bulk monomer mixture that is copolymerized) 5 to 50
percent, preferably 10 to 25 percent, by weight of one or more
silicon containing macromonomers, 5 to 75 percent, preferably 30 to
60 percent, by weight of one or more
polysiloxanylalkyl(meth)acrylic monomers, and 10 to 50 percent,
preferably 20 to 40 percent, by weight of a hydrophilic monomer. In
general, the silicon containing macromonomer is a
poly(organosiloxane) capped with an unsaturated group at two or
more ends of the molecule. In addition to the end groups in the
above structural formulas, U.S. Pat. No. 4,153,641 to Deichert et
al. discloses additional unsaturated groups, including acryloxy or
methacryloxy. Fumarate-containing materials such as those taught in
U.S. Pat. Nos. 5,512,205; 5,449,729; and 5,310,779 to Lai are also
useful substrates in accordance with the invention. Preferably, the
silane macromonomer is a silicon-containing vinyl carbonate or
vinyl carbamate or a polyurethane-polysiloxane having one or more
hard-soft-hard blocks and end-capped with a hydrophilic
monomer.
[0068] Suitable hydrophilic monomers form hydrogels, such as
silicon-containing hydrogel materials useful in the present
invention. Examples of useful monomers include amides such as
dimethylacrylamide, dimethylmethacrylamide, cyclic lactams such as
n-vinyl-2-pyrrolidone and poly(alkene glycols) functionalized with
polymerizable groups. Examples of useful functionalized poly(alkene
glycols) include poly(diethylene glycols) of varying chain length
containing monomethacrylate or dimethacrylate end caps. In a
preferred embodiment, the poly(alkene glycol) polymer contains at
least two alkene glycol monomeric units. 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.
[0069] Device Forming Additives and Comonomers
[0070] The monomer mix may, further as necessary and within limits
not to impair the purpose and effect of the present invention,
comprise various additives such as antioxidant, coloring agent,
ultraviolet absorber and lubricant.
[0071] The monomer mix may be prepared by using, according to the
end-use and the like of the resulting shaped polymer articles, one
or at least two of the above comonomers and oligomers and, when
occasions demand, one or more crosslinking agents.
[0072] Where the shaped polymer articles are for example medical
products, in particular a contact lens, the monomer mix is suitably
prepared from one or more of the silicon compounds, e.g.
siloxanyl(meth)acrylate, siloxanyl(meth)acrylamide and silicon
containing oligomers, to obtain contact lenses with high oxygen
permeability.
[0073] The monomer mix may include additional constituents such as
crosslinking agents, internal wetting agents, hydrophilic monomeric
units, toughening agents, and other constituents as is well known
in the art.
[0074] Although not required, the monomer mix may include
toughening agents, preferably in quantities of less than about 80
weight percent e.g. from about 5 to about 80 weight percent, and
more typically from about 20 to about 60 weight percent. Examples
of suitable toughening agents are described in U.S. Pat. No.
4,327,203. These agents include cycloalkyl acrylates or
methacrylates, such as: methyl acrylate and methacrylate,
t-butylcyclohexyl methacrylate, isopropylcyclopentyl acrylate,
t-pentylcycloheptyl methacrylate, t-butylcyclohexyl acrylate,
isohexylcyclopentyl acrylate and methylisopentyl cyclooctyl
acrylate. Additional examples of suitable toughening agents are
described in U.S. Pat. No. 4,355,147. This reference describes
polycyclic acrylates or methacrylates such as: isobornyl acrylate
and methacrylate, dicyclopentadienyl acrylate and methacrylate,
adamantyl acrylate and methacrylate, and isopinocamphyl acrylate
and methacrylate. Further examples of toughening agents are
provided in U.S. Pat. No. 5,270,418. This reference describes
branched alkyl hydroxyl cycloalkyl acrylates, methacrylates,
acrylamides and methacrylamides. Representative examples include:
4-t-butyl-2-hydroxycyclohexyl methacrylate (TBE);
4-t-butyl-2-hydroxycyclopentyl methacrylate;
methacryloxyamino-4-t-butyl-2-hydroxycyclohexane;
6-isopentyl-3-hydroxycyclohexyl methacrylate; and
methacryloxyamino-2-isohexyl-5-hydroxycyclopentane.
[0075] In particular regard to contact lenses, the fluorination of
certain monomers used in the formation of silicon containing
hydrogels has been indicated to reduce the accumulation of deposits
on contact lenses made therefrom, as described in U.S. Pat. Nos.
4,954,587, 5,079,319, 5,010,141 and 6,891,010. Moreover, the use of
silicon containing monomers having certain fluorinated side groups,
i.e. --(CF2)-H, have been found to improve compatibility between
the hydrophilic and silicon containing monomeric units, as
described in U.S. Pat. Nos. 5,387,662 and 5,321,108.
[0076] As stated above, surface structure and composition determine
many of the physical properties and ultimate uses of solid
materials. Characteristics such as wetting, friction, and adhesion
or lubricity are largely influenced by surface characteristics. The
alteration of surface characteristics is of special significance in
biotechnical applications where biocompatibility is of particular
concern. Thus, it is desired to provide a silicon containing
hydrogel contact lens with an optically clear, hydrophilic surface
film that will not only exhibit improved wettability, but which
will generally allow the use of a silicon containing hydrogel
contact lens in the human eye for extended period of time. In the
case of a silicon containing hydrogel lens for extended wear, it be
further desirable to provide an improved silicon-containing
hydrogel contact lens with an optically clear surface film that
will not only exhibit improved lipid and microbial behavior, but
which will generally allow the use of a silicon-containing hydrogel
contact lens in the human eye for an extended period of time. Such
a surface treated lens would be comfortable to wear in actual use
and allow for the extended wear of the lens without irritation or
other adverse effects to the cornea.
[0077] It would also be desirable to apply these surface enhancing
coatings to implantable medical devices such as intraocular lens
materials to reduce the attachment of lens epithelial cells to the
implanted device and to reduce friction as the intraocular lens
passes through an inserter into the eye. It may also be desirable
to apply these surface enhancing coatings to the inserter
itself.
[0078] The present invention is useful for surface treatment of a
polymeric device. The surface treatment comprises the binding of
interactive segmented block copolymers to the surface of a
polymeric medical device substrate by reacting complementary
interactive functionalities of the interactive segmented block
copolymers with interactive functionalities along the polymeric
substrate surface.
[0079] As set forth above, for surface modification of contact
lenses in accordance with the segmented block copolymers of the
present invention, complementary functionality is incorporated
between the surface of the contact lens material (i.e., the
substrate) and the chemical binding unit block of the interactive
segmented block copolymer used as a surface modification treatment
polymer (surface modifying agent). For example, if a surface
modifying agent has a boronic acid containing functionality, then
the contact lens material to be treated must have a residue with
complementary functionality that will react with that of the
surface modifying agent. In such a case, the contact lens material
could include a hydroxyl containing monomer such as 2-Hydroxyethyl
methacrylate or glycerol methacrylate to interact with the surface
modifying agent boronic acid functionality. Likewise, if a contact
lens is formed from material having a residue providing boronic
acid, a surface modifying agent containing a 2-hydroxyethyl
methacrylate or glycerol methacrylate functionality could be used
for surface modification in accordance with the present invention.
Such complementary chemical functionality enables binding to occur
between the surface of the contact lens and the interactive groups
of the one or more surface modifying agent's. This binding between
functional groups forms chemical interactions there between. For
example, a contact lens containing prepolymer having surface
carboxylic acid groups preferably undergo surface modification
using surface modifying agents containing quaternary ammonia or
other cationic functional groups. Likewise, a contact lens having
surface cationic groups preferably undergo surface modification
using surface modifying agents containing carboxylic acid units,
sulfonic acid units, or other anionic functional units. The
reaction of the contact lens containing surface interactive
functional groups and the interactive surface modifying agent is
conducted under conditions known to those of skill in the art.
[0080] In the case where interactive groups are not present in the
substrate material, they can be added. For example, by using a
surface activation treatment such as oxygen plasma,
ammonia-butadiene-ammonia (ABA) treatments and
hydrogen-ammonia-butadiene-ammonia (HABA) treatments. Plasma
treatment of substrate materials is known and is described in U.S.
Pat. Nos. 6,193,369 Valint et al., 6,213,604 Valint et al. and
6,550,915 Grobe, III.
[0081] Methods of coating the substrate include dip coating of the
substrate into a solution containing the surface modifying agent.
The solution containing the surface modifying agent may contain
substantially the surface modifying agent in solvent or may contain
other materials such as cleaning and extracting materials. Other
methods could include spray coating the device with the surface
modifying agent. In order for the covalent bonding reaction to
occur, it may be necessary to use suitable catalysts, for example,
condensation catalyst. Alternatively, the substrate and the other
surface modifying agent may be subjected to autoclave conditions.
In certain embodiments, the substrate and the surface modifying
agent may be autoclaved in the packaging material that will contain
the coated substrate. Once the reaction between the substrate and
the surface modifying agent has occurred, the remaining surface
modifying agent could be substantially removed and packaging
solution be added to the substrate packaging material. Sealing and
other processing steps then proceed as they usually do.
Alternatively, the surface modifying agent could be retained in the
substrate packaging material during storage and shipping of the
substrate device to the end user.
[0082] The interactive segmented block copolymers useful in certain
embodiments of the present invention may be prepared according to
syntheses well known in the art and according to the methods
disclosed in the following examples.
EXAMPLES
Example A
Synthesis of MAAPBA/DMAPMA-b-NVP Copolymer
[0083] To a 500-mL 3-neck round bottom flask equipped with a
magnetic stir bar, thermocouple, condenser and SS sparging needle
was added 155 mg of AIBN and 10.93-g (0.0094 mol) of
3-methacrylamidophenylboronic acid (MAAPBA). To this was added a
solution of 3.21-g (0.0188 mol)
N-[3-(dimethylamino)propyl]methacrylamide (DMAPMA) and 0.50-g
(0.00236 mol) of benzyl O-ethylxanthate (BX) in 50-mL of methanol.
The solution was sparged with argon for 30-min. before applying
heat. Separately, in a 250-mL addition funnel, a solution of
49.21-g (0.443 mol) of N-vinylpyrrolidone (NVP) in 200-mL of
methanol was sparged with nitrogen for 15 minutes. The addition
funnel was transferred to the reaction flask replacing the argon
sparging needle. The system was maintained under argon
backpressure. The flask was heated to 60.degree. C. and held at
that temperature for 6 hours. The NVP solution was subsequently
added dropwise to the flask and the polymerization was maintained
at 60.degree. C. for an additional 66 hours. The solution was
cooled to RT and precipitated dropwise into 6-L of stirred ethyl
ether. The precipitate was isolated by filtration and dried in
vacuo at 65.degree. C. affording 38.89-g (71%) of white solid.
Reprecipitation from 200-mL of methanol into 6-L of ethyl ether
gave 37.00-g of product.
[0084] The product was characterized by proton NMR (DMSO-d6) and
GPC. Resonances attributable to the phenyl protons of MAAPBA were
observed at approximately 7.2 to 8.0 ppm. The DMAPMA resonances
could not be cleanly distinguished from the PVP resonances. GPC was
performed using a PLgel RESIpore column and DMF+1.0 M LiBr as
solvent with triple detection. Mn was estimated to be 31,000
Daltons (target=23,300 Daltons) with a polydispersity of 1.09.
Example B
Synthesis of MAAPBA/DMAPMA-b-DMA/MPC Copolymer
[0085] To a 500-mL 3-neck round bottom flask equipped with a
magnetic stir bar, thermocouple, condenser and SS sparging needle
was added 148 mg of AIBN and 1.84-g (0.0090 mol) of
3-methacrylamidophenylboronic acid (MAAPBA). To this was added a
solution of 3.06-g (0.0180 mol)
N-[3-(dimethylamino)propyl]methacrylamide (DMAPMA) and 0.50-g
(0.00225 mol) of ethyl-.alpha.-(O-ethylxanthyl) propionate (EEXP)
in 50-mL of methanol. The solution was sparged with argon for
25-min. before applying heat. Separately, in a 250-mL addition
funnel, a solution of 37.72-g (0.380 mol) of N,N-dimethylacrylamide
(DMA) and 12.48-g (0.0423 mol) of 2-methacryoyloxyethyl
phosphorylcholine (MPC) in 150-mL of methanol was sparged with
nitrogen for 15 minutes. The addition funnel was transferred to the
reaction flask replacing the argon sparging needle. The system was
maintained under argon backpressure. The flask was heated to
60.degree. C. and held at that temperature for 7 hours. The NVP
solution was subsequently added dropwise to the flask and the
polymerization was maintained at 60.degree. C. for an additional 48
hours. The solution was cooled to RT and precipitated dropwise into
6-L of stirred ethyl ether. The precipitate was isolated by
filtration and dried in vacuo at 65.degree. C. affording 49.05-g
(88%) of white solid.
[0086] The product was characterized by proton NMR (DMSO-d6) and
GPC. Resonances attributable to the phenyl protons of MAAPBA were
observed at approximately 7.2 to 8.0 ppm. The DMAPMA resonances
could not be cleanly distinguished from the DMA resonances.
Resonances attributable to MPC units were observed at 3.2 ppm
(trimethylammonium protons) and 3.6 to 4.1 ppm (methylene protons
adjacent to oxygen atoms). GPC was performed using a PLgel RESIpore
column and DMF+1.0 M LiBr as solvent with triple detection. The
polymer did not elute from the column.
Example C
Coating of Contact Lenses with Boronic Acid-Containing Polymers
[0087] Contact lenses made of Balafilcon A were cast and processed
under standard manufacturing procedures. Balafilcon A is a
copolymer comprised of 3-[tris(trimethylsiloxy)silyl]propyl vinyl
carbamate, N-vinyl-2-pyrrolidone (NVP),
1,3-bis[4-vinyloxycarbonyloxy)but-1-yl]polydimethylsiloxane and
N-vinyloxycarbonyl alanine. All Balafilcon A lenses were air-plasma
treated prior to exposure to coating polymer ("Test" Groups) or
just standard borate-buffered saline solution containing 300 ppm
EDTA ("Control" Groups), below.
[0088] For coating with the subject polymers, each lens was placed
in a polypropylene (PP) blister containing 3.8-mL of a 100 or 250
ppm (w/v) solution of the subject polymer dissolved in
borate-buffered saline (BBS) containing 300 ppm EDTA. The blisters
were sealed and autoclaved at 121.degree. C. for 30-min.
[0089] Table 2 reports various surface properties of several coated
samples and controls. Test sample A was coated with the polymer of
Example A, and Test sample B was coated with the polymer of Example
B. Atomic concentrations were determined by XPS, as described
below.
TABLE-US-00002 TABLE 2 XPS Atomic Concentrations % C % O % N % Si
Test Sample A 67.5 +/- 0.7 18.4 +/- 0.2 8.9 +/- 0.5 5.2 +/- 0.2
(100 ppm) Test Sample A 68.1 +/- 0.5 18.1 +/- 0.5 9.0 +/- 0.4 4.8
+/- 0.3 (250 ppm) Control 63.7 +/- 0.6 20.7 +/- 0.2 7.6 +/- 0.4 7.4
+/- 0.4 Sample A Test Sample B 66.9 +/- 1.0 19.3 +/- 0.5 9.2 +/-
0.4 4.7 +/- 0.4 (100 ppm) Test Sample B 66.9 +/- 0.5 19.1 +/- 0.6
9.4 +/- 0.4 4.5 +/- 0.3 (250 ppm) Control 63.0 +/- 0.5 21.5 +/- 0.4
7.5 +/- 0.2 7.1 +/- 0.2 Sample B
X-Ray Photoelectron Spectroscopy (XPS) Analysis
[0090] XPS data was collected using a Physical Electronics Quantera
SXM Scanning ESCA Microprobe. This instrument utilizes a
monochromatic Al anode operated at 18 kV and 100 Watts in the high
power mode and 15 kV and 0.25 Watts/micron in low power mode. All
high power acquisitions are rastered over a 1400 micron.times.100
micron analysis area. Dual beam neutralization (ions and electrons)
is used. The base pressure of the instrument was 5.times.10.sup.-10
torr and during operation the pressure was less than or equal to
1.times.10.sup.-7 torr. This instrument made use of a hemispherical
analyzer operated in FAT mode. A gauze lens was coupled to a
hemispherical analyzer in order to increase signal throughput.
Assuming the inelastic mean free path for a carbon Is photoelectron
is 35 .ANG., the practical measure for sampling depth for this
instrument at a sampling angle of 45 is approximately 75 .ANG.. The
governing equation for sampling depth in XPS is:
.theta..lamda. sin 3=d
where d is the sampling depth, .lamda. is the photoelectron
inelastic mean free path and .theta. is the angle formed between
the sample surface and the axis of the analyzer. Each specimen was
analyzed utilizing a low-resolution survey spectra (0-1100 eV) to
identify the elements present on the sample surface. Quantification
of elemental compositions was completed by integration of the
photoelectron peak areas. Analyzer transmission, photoelectron
cross-sections and source angle correction were taken into
consideration in order to give accurate atomic concentration
values.
Example D
Synthesis of DMA-b-DMAPMA/MAAPBA/DMA
[0091] To a 500-mL 3-neck round bottom flask containing a magnetic
stir bar, addition funnel and thermocouple was added 0.033-g AIBN
(20 mol % based on amount of RAFT agent), 0.354-g (0.0010 mol)
2-(dodecylthiocarbonylthio)propanoic acid, 20.0-g (0.202-mol) of
distilled N,N-dimethylacrylamide (DMA) and 80-mL of dioxane. The
addition funnel was charged with a solution of 1.37-g (0.0081-mol)
of deinhibited and distilled
N-[3-(dimethylamino)propyl]methacrylamide (DMAPMA), 0.83-g
(0.0040-mol) of 3-methacrylamidophenylboronic acid (MAAPBA) and
1.20-g (0.121-mol) of distilled N,N-dimethylacrylamide (DMA) in 30
mL dioxane. Both solutions were individually sparged with nitrogen
for at least 30-min before heating and were subsequently maintained
under a nitrogen blanket for the duration of the reaction. The
reaction was heated to 60.degree. C. After 2.75 h, the addition
funnel contents were added to the reaction flask. Heating was
discontinued after 12 h total heating time at which point the
cooled solution was added drop wise to 6 L of mechanically stirred
ethyl ether. The precipitate was isolated by vacuum filtration. The
solid was dried in vacuo at 40.degree. C. for a minimum of 18
hours, affording 22.55-g of pale yellow solid.
[0092] To remove the RAFT end group, the copolymer was dissolved in
100-mL 2-propanol containing 0.53-g (0.0032-mol) of AIBN. The
solution was sparged with nitrogen for 1 h and then heated at
80.degree. C. for 12 h under a nitrogen blanket. The cooled
solution was precipitated by dropwise addition into 6-L of
mechanically stirred ethyl ether. The white solid was collected by
vacuum filtration and vacuum dried at 85.degree. C. giving 18.75-g
of product.
[0093] *Note: This polymerization yields a block copolymer,
PDMA-block-(DMAPMA/MAAPBA/DMA), in which the second block is
actually a statistical copolymerization of any remaining DMA that
had not been polymerized at the time of the DMAPMA, MAAPBA, and DMA
addition. The second "block", is therefore compositionally
heterogeneous. A polymerization that yields a statistical
copolymerization or compositionally heterogeneous block as the
second block would also be considered to be a reactive segmented
block copolymer according to the invention herein.
[0094] The product was characterized by proton NMR (methanol-d4),
GPC, Karl-Fischer and elemental analysis. Resonances attributable
to the phenyl protons of MAAPBA were observed at approximately 7.1
to 7.8 ppm. The DMAPMA resonances could not be cleanly
distinguished from DMA resonances. GPC was performed at 35.degree.
C. in DMF containing 0.01 M lithium nitrate. The column set
consisted of three 8-mm by 300-mm GRAM Linear M columns from
Polymer Standards Services. Narrow MW PMMA reference standards were
used for calibration. The primary peak had a Mn of 17,900
(target=23,200) with a polydispersity of 1.8. The results for
elemental analysis were:
TABLE-US-00003 TABLE 3 Element Calculated Found C 60.6% 59.5% H
9.1% 9.2% N 14.0% 13.7% O 16.1% 17.7% B 0.19% 0.16% S trace 300 ppm
*Water content by Karl-Fischer analysis was 1.7%
Example F
Coating of Contact Lenses with Poly DMA-b-DMAPMA/MAAPBA/DMA
[0095] Contact lenses made of Balafilcon A were cast and processed
under standard manufacturing procedures. All Balafilcon lenses were
air-plasma treated prior to exposure to coating polymer ("Test"
Groups) or standard borate-buffered saline (BBS) containing 300 ppm
EDTA.
[0096] For coating with the subject polymers, each lens was placed
in a polypropylene (PP) blister containing 3.8-mL of a 500 ppm
(w/v) solution of subject polymer dissolved in BBS containing 300
ppm EDTA. The lens blisters were sealed and autoclaved at
121.degree. C. for 30-min.
TABLE-US-00004 TABLE 4 % C % O % N % Si Test Sample (500 ppm 67.5
(0.4) 18.6 (0.1) 10.2 (0.7) 3.8 (0.3) polymer) Control Sample (BBS)
63.2 (0.7) 21.9 (0.5) 7.6 (0.3) 7.1 (0.3)
Example G
Synthesis of a Matrix of GMA-b-DMA Copolymers where the MW of Each
of the Blocks is Varied (Demonstrates Control of MW with CRP)
TABLE-US-00005 [0097] TABLE 5 MW DMA MW GMA DMA DMA CTR CTR GMA GMA
block block Reaction (mL) (mol) (mgs) (mol) (mL) (mol)
(theoretical) (theoretical) 2748-114 20 0.194 350 0.00097 2.0
0.0146 19,800 2,140 2748-115 20 0.194 350 0.00097 4.0 0.0293 19,800
4,275 2748-116 20 0.194 350 0.00097 8.0 0.0586 19,800 8,550
2748-117 20 0.194 700 0.00194 2.0 0.0146 9,900 1,070 2748-118 20
0.194 700 0.00194 4.0 0.0293 9,900 2,140 2748-119 20 0.194 700
0.00194 8.0 0.0586 9,900 4,275 2748-120 10 0.097 700 0.00194 2.0
0.0146 4,950 1,070 2748-121 10 0.097 700 0.00194 4.0 0.0293 4,950
2,140 2748-122 10 0.097 700 0.00194 8.0 0.0586 4,950 4,275 *~33 mgs
of AIBN were added to all of the reactions
*Note: All reactions were carried out in a similar fashion using
the amounts shown in the table above. Reaction 2748-114 is
described below as an example of the procedure used. Weighed 350
mgs (0.97 mmol) of
S-1-Dodecyl-S-(.alpha.,.alpha.'-dimethyl-.alpha.''-acetic acid)
trithiocarbonate and 33 mgs of AIBN into a 250 ml round bottom
flask. Added 20 ml (194 mmol) of N,N-Dimethylacrylamide (DMA) and
60 ml of dioxane to the flask, sealed flask with a septum and then
purged with argon to deoxygenate for 30 mins. Placed flask in an
oil bath (50.degree. C.) for 6.0 hrs. In a separate container, 2.0
ml (14.66 mmol) of glycidyl methacrylate (GMA) was bubbled with
argon for 30 mins., then added to the flask after 6.0 hrs. *Note: A
small aliquot was taken from the flask immediately before GMA
addition and precipitated into diethyl ether. The reaction was
stopped 15 hours after GMA addition (19.5 hrs total reaction time).
The final product was precipitated out of the reaction mixture into
diethyl ether.
[0098] Both the first precipitate and the block copolymer of DMA
and GMA were characterized by proton NMR (CDCl3) and GPC. The GPC
shows a shift in the elution peak to shorter times (higher MW)
after the addition of the GMA block. In addition, the NMR spectra
of the block copolymer shows peaks for the glycidol methacrylate
contributions at 3.7 ppm and 4.3 ppm. GPC data for these polymers
using DMF as an eluent are shown below, using both PMMA standards
and PVP standards as calibrants. Although the trends in MW are the
same, PMMA standards show MW's much closer to the theoretically
expected value for polyDMA.
TABLE-US-00006 TABLE 6 PMMA Standards PVP Standards Sample Mw Mn Mw
Mn 2748-114 20,270 15,320 432,500 207,100 2748-115 -- -- 534,200
219,500 2748-116 -- -- 681,500 282,000 2748-117 8,950 6,430 147,800
71,700 2748-118 -- -- 182,400 74,100 2748-119 -- -- 245,900 72,300
2748-120 4,000 2,540 48,600 16,100 2748-121 -- -- 70,100 15,000
2748-122 -- -- 145,100 20,0
Example H
Synthesis of DMA-b-TMAQPMA
[0099] Weighed 350 mgs (0.97 mmol) of
S-1-Dodecyl-S-(.alpha.,.alpha.'-dimethyl-.alpha.''-acetic acid)
trithiocarbonate and 35 mgs of AIBN into a 250 ml round bottom
flask. Added 10 ml (97 mmol) of N,N-Dimethylacrylamide (DMA) and 30
ml of dioxane to the flask, sealed flask with a septum and then
purged with argon to deoxygenate for 30 mins. Placed flask in an
oil bath (50.degree. C.) for 6.0 hrs. In a separate container, 2.52
grams (14.8 mmol) of N,N-dimethylaminopropyl methacrylate (DMAPMA)
was bubbled with argon for 30 mins., then added to the flask after
6.0 hrs. *Note: A small aliquot was taken from the flask
immediately before DMAPMA addition and precipitated into diethyl
ether. The reaction was stopped 16 hours after addition (22 hrs
total reaction time). The final product was precipitated out of the
reaction mixture into diethyl ether.
[0100] Both the first precipitate and the block copolymer of DMA
and DMAPMA were characterized by proton NMR (CDCl3) and GPC. The
GPC shows a shift in the elution peak to shorter times (higher MW)
after the addition of the DMAPMA block. (Mn shifts from 11,000
Daltons to 12,000 Daltons using PMMA standards). In addition, in
the NMR spectra the DMAPMA resonances could not be cleanly
distinguished from the DMA resonances, however the influence of the
N-methyl resonances could be seen at around 2.2 ppm (shape of the
peak changed).
[0101] In a second quaternization step, 2 grams of the dried
polymer precipitated above was dissolved in 15 mL of
N,N-dimethylformamide. To this reaction was added 1.0 mL of
Iodomethane (stoichiometric excess). The reaction was stirred
overnight, concentrated on the rotary evaporator, and then
dissolved in methanol and precipitated into diethyl ether. This
reaction yielded the block copolymer DMA-b-TMAQPMA
*TMAPQMA=Trimethylaminoquat propyl methacrylate.
Example I
Synthesis of DMA-b-MAA
[0102] Weighed 350 mgs (0.97 mmol) of
S-1-Dodecyl-S-(.alpha.,.alpha.'-dimethyl-.alpha.''-acetic acid)
trithiocarbonate and 35 mgs of AIBN into a 250 ml round bottom
flask. Added 10 ml (97 mmol) of N,N-Dimethylacrylamide (DMA) and 30
ml of dioxane to the flask, sealed flask with a septum and then
purged with argon to deoxygenate for 30 mins. Placed flask in an
oil bath (50.degree. C.) for 6.0 hrs. In a separate container, 2.31
grams (14.6 mmol) of trimethylsilyl methacrylate (TMS-MA) was
bubbled with argon for 30 mins., then added to the flask after 6.0
hrs. *Note: A small aliquot was taken from the flask immediately
before TMS-MA addition and precipitated into diethyl ether. The
reaction was stopped 16 hours after addition (22 hrs total reaction
time). The final product was precipitated out of the reaction
mixture into diethyl ether.
[0103] Both the first precipitate and the block copolymer of DMA
and TMS-MA were characterized by proton NMR (CDCl3) and GPC. The
GPC shows a shift in the elution peak to shorter times (higher MW)
after the addition of the TMS-MA block. In addition, the NMR
spectra contained proton resonances at 0 ppm from the
trimethylsilyl units.
[0104] In a second deprotection step, 3 grams of the dried polymer
precipitated above was dissolved in 20 mL of dioxane, 1.0 mL of
water, and 1.0 mL of glacial acetic acid. The reaction was stirred
for 2 hours at 50.degree. C., concentrated on the rotary
evaporator, and precipitated into diethyl ether. This reaction
yielded the block copolymer DMA-b-MAA.
[0105] While there is shown and described herein certain specific
structures and compositions of the present invention, it will be
manifest to those skilled in the art that various modifications may
be made without departing from the spirit and scope of the
underlying inventive concept and that the same is not limited to
particular structures herein shown and described except insofar as
indicated by the scope of the appended claims.
* * * * *