Note: Descriptions are shown in the official language in which they were submitted.
CA 02582371 2007-04-05
, Y y(
Title: - Functionalized dyes and use thereof in ophthalmic lens material.
The invention relates to transparent polymer material containing a
dye which absorbs light above 400 nm. It furthermore relates to methods for
producing the polymer material and a lens comprising the polymer material.
In particular, the invention relates to an intraocular lens (IOL) suitable for
implantation in mammals, which IOL has visible light transmission properties
comparable to those of the human crystalline lens.
In healthy adults the retina is generally protected from the most
severe forms of light-induced damage by the outer eye structures including the
cornea and crystalline lens. The cornea is a transparent proteinaceous ocular
tissue located before the iris and is the oniy eye structure exposed directly
to
the environment. It is important for protecting the delicate internal
structures
from damage and facilitates the transmission of light through the aqueous
media to the crystalline lens. The cornea is the primary light filter and
therefore is particularly susceptible to excessive ligbt exposure-related
damage
including corneo-coniunctival diseases such as pterygium, droplet climatic
keratopathy, and pingueeula. In the healthy eye the comea, in conjunction
with the aqueous medium, absorbs, or blocks, wavelengths in the short
ultraviolet UV-B and UV-C region (less than 320 nm).
The crystal.line lens is an accommodating biological lens lying directly
belxind the iria and cornea and facilitates the convergence of both far and
near
images onto the retina. The natural crystalline lens blocks near IN radiation
(YJV-A) (320 to 400 nm) from reaching the retina. Therefore, most of the
damaging LTV A, B and C radiation are prevented from reaching the retina in
healthy people with an intact crystaIli,ne leus and cornea. Thus in the normal
mammali,an eye only wavelengths between 400 and 1400 nm can reach the
zetina. However, h,igh transmittance levels of violet-to-blue light
(wavelengths
from about 400 to about 515 nm) has been linked to retinal damage, macular
CA 02582371 2007-04-05
. ir
2
degenexation, retinitis pigmentosa, and night blindness. In addition, blue
light
tends to be scattered in the atmosphere, especially in haze, fog, rain, and
snow,
which in part can cause glare, and diminished visua], acuity, As the eye ages,
the ciystal.iine lens begins to take on a yellow tint that does not adversely
affect visual acuity but does absorb the majority of near UV radiation. By age
54, the human lens will not transmit light below 400 nm and the transmission
of light between 400 and 515 nm is greatly diminished. Thus, the natural
crystalline lens protects the eye's delicate retina from near LTV light
throughout life and subtly yellows to orange-brown with age, increasing the
amount of shorter wavelength blue light that ie absorbed.
The natural crystalline lens is also susceptible to age-related
degenerative eye diseases such as cataract and indireetly age-related macular
disease (AMD). Cataract is a major cauae of visual impairment and blindness
worldwide. Cataract is a clouding of the crystaIIin.e lens caused by the
coagulation of lens proteins wittbin the eapsular sac. Laboratory studies have
implicated UV radiation as a cause of cataract. Furthermore, epidezniological
studies have shown that certain types of cataract are associated with a
history
of higher ocular exposure to UV and especially tTV-B radiatxon.
Cataracts develop slowly in most people and eventually reach the
point where vision is substantiaUy impaired resulting in neaar to total
blindness. In these persons lens removal and replacement with synthetic
polymer IOLs is the preferred means for restoring normal sight. However, once
the natural crystalline lens is removed, the retina is left unprotected from
damaging LTV and short wavelength blue light. Early synthetic TOLs were
provided with UV absorbing compounds euch as benzophenone and
benzotriazole-based LTV light absorbers which block radiation up to about 400
nm. ZOLs provided with UV absorbing compounds soon became common-place
and are found in va,rtually all ZOLs. Moreover, ben7,ophenones and
benzotri,azoleQ can be made polymerizable and can thus be stably integrated
CA 02582371 2007-04-05
a .
aS
uxto most modern ZOI. compositions including, but not limited to
(meth)acrylates, si]icoro.es, and polyurethanes.
Recently, blue light absorbing dyes'have been incorporated into IOL
materials in order to approximate the blue light blocking effects of the aging
adult natural cxystalline lens. A number of TOL manufacturers have designed
lenses that contain yellow dyes at concentrations that absorb, or block
visible
light in the blue region.
For example, US 5,374,668 of Hoya Corporation discloses non-
covalently linked yellow dyes including Solvent Yellow numbers 16, 29 and
others incorporated into a polymethylmethacrylate (PMMA) polymer matrix.
Moreover, Hoya also owns US 6,310,215 that discloses acxylic-functiona,lized
pyrazolone dyes suitable fox use in aMlic azsd silicone IOLs. US patents Nos.
5,470,932, 5,528, 322; 5,543, 504; and 5,662,707 in the name of Alcon dasclose
acrylic-functionalized yellow azo dyes having an inert chemical spacer between
the dye and acrylic portions of the ioaolecule. Because the dye is acrylic-
functionalized, it is polymerizable with the len.s polymer and thus stably
incorporated into the IOL polymer matrix. Similarly, US 6,277,940 and US
6,326,448 in the name of Menicon describe specific ac.rylic-modified azo dyes
structurally similar to Alcon's. IOLs with blue light filtering capability are
marketed by Alcon under the tradename AcrySofl4 Natural.
JP10195324 in the name of Hoya Corporation relates to the
manufacture of a soft yellow intraocular lens for correcting blue blindness by
using a copolymer obtained by polym.erizing a mixture obtained by mWng a
yellow reactive dye with n-butyl acrylate, pbenylethyl methacrylate, a
fluorine
compound, a ultraviolet absorber and a cxoss-lin,king in the presence of a
polymerization initiator.
EP1293541 of Canon-Staar Co. discloses two types of yellow dyes
capable of chemical bonding to a silicone, which is a material for an
intraocu.laac
lens. The dyes have a maximum absorbance of about 350-450 an. The first
type of the Canon-Staar dye is an azo-pyrozolone compound which is based on
CA 02582371 2007-04-05
i x
4
Solvent Yellow 16. The second type has a phenylazophenyl core structure
which is functionalized by hT-linked allyl groups to allow for covalent
attachment to silicone material. The transmission spectra of polymers
containing exemplary yellow dyes disclosed in EI'1293641, optionally in
combination with a conventional LN absorber, show that the material is
capable of blocking light up to about- 380 nm, after which the transmission
curve fairly steeply increases to 90% transmission at about 500 nm.
Whereas the known second generation "blue-light-blockiing" IOLs
show improved absorption characteristics as compared to the first generation
of TJV-absoxbing IOL,s, the transmission properties of current yellow IOLs are
still not comparable to those of the aged human crystalline lens. The specific
filtering of violet and blue light by the yellow dye is not physiological and
results, among others, in reduced vision at dusk. Also during daylight, a
yellow
! filter is inferior to the light filtering properties of a physiological
lens.
Importantly, the transmission of known bZue-light-blocking yellow IOI,,e at
500
nna is typically around 90-95% and none of them displays the softly rounded
transmission curve of an aged human lens with a transmission of about 40% at
450 nm and only about 60% at 500nm. As will be understood, any deviation in
an IOL from the natural transmission spectrum has adverse effects on colour
perception by and overaU comfort of the operated patient.
Therefore, it is an object of the present invention, to provide a
polymer material which is suitably used in an ophthalmic lens, such as an
IOL, and which more closely imitates the softly rounded transmission curve
above 400 xxm of an aged human lens as compared to existing optical polymers.
In particular, it is an object to provide an IOL which fuUy blocks rays op to
and
including 400 nm and displays 70% or less transmission of the blue light at
500 nm.
CA 02582371 2007-04-05
D
These objects were met by the provision of a transparent polymer
material containing at least one covalently bound bia-azo dye o#'the general
formula (I):
R'
R' Ri
Rz
, I z
N R
R1 Ni-;~" R3
R~ R3
R a
N
R2
Formula I R3 ' R3
13
6 R
wherein
each o~Ri is independently selected from hydrogen, sulf'onate, nitro,
halogen, nitril, phenyl, carboxylate, -(CHQ)õ-Xa-H and -Xz-(CIda)n-CHg,
wherein
Xl is 0, Ni, CH2 or S; X2 is 0, NH, S, S(=0)z, C(=0)O; and n is an integer in
the range 0 to 20.
each of R2 is independently selected from hydrogen, suMnate, nitro,
halogen, nitril, phenyl, carboxylate, -(CHz)n-Xa -H and -X2-(CH2)õ-CH3,
wherein
Xz is 0, NH, CH2 or S; X2 is 0, NH; S, S(=0)2, C(=O)O; and n is an integer in
the range 0 to 20; or wherein two R2 groups together with the C-atoms to
which they are bound form a benzene ring;
each of Ra is independently selected from hydrogen, sulfonate, nitro,
halogen, nitril, phenyi, carboxylate, -(CHx)õ-XI-H and -XQ-(CHz)õ-CHa, wherein
Xi is 0, NH, CH2 or S; X2 is 0, NH, S, S(= O)a, C(--O)O; and n is an integer
in
the range 0 to 20,
CA 02582371 2007-04-05
6
pxovided that at least one Ra is a linker moiety L th,xough which the
dye is covalently bound to the polymer.
The aliphatic moieties of the substituents can be branched or linear.
A transparent polymer comprising the above bia-azo dye is not
known or suggested in the pzior art. JPQ1299560 and JP01280464 in the name
of Menikon disclose a transparent polymer material for contact lenses.
comprising a co-polymerisation product methylmethacrylate and the red dye -1-
(4'-(phenylazo)-phenyl)(azo)-2-hydroxy 3-xnethacryloyl naphtalene. The
naphtalene-based dye used by Menikon is distinct from the bis-azo dye
according to Formula I above.
It was found that a"bisazo" (also referred to as "disazo" or "di-azo")
dye of formula I is particularly suitable for the manufacture of transparent
polymer material hava,ng visible light txansmission properties essentially
identical to those reported for an aged huriman crystalline lens. Figure 1
shows
the transmission spectrum of a transparent polymer of the invention
containing a bisazo dye of Formula I("Ophtec-orange") and a conventional UV
absorbing compound. The polymer has an orange to orange-brown appearance.
Also shown are the spectra of two known yellow "blue-light absorbing" IOLs
(AcrySof Natural IOL from Alcon and Hoya IOL (HOYA YA-60BB) and the
reported transmission epectrum of an aged human lens (Boethner. E.A. and
Wolter. J.R., "Transmiesxon of the Ocular Media", Investigative
Ophthalmology, Vol. 776-783, 1962). Clearly, the polymer material of the
invention more closely imitates the softly rounded transmission curve above
400 nm, of an aged human lens; it efficiently blocks rays up to about 400-410
nm and transmission at 450 and 500 nm is appxoximately 35% and 60%,
respectively. In contrast, the Alcon and Hoya materials transmit
approximately 50% of the light at 450 nm and nearly 90% at 500 nm.
Without wishing to be bound by tb.eory, it is believed that the extended
conjugated system of the (substituted) phenylazophenylazophenyl structure
depicted in Formula I is responsible for the softly rounded transmission curve
CA 02582371 2007-04-05
M
above 400 nm, and the relatively low transmission in the 450-550 ILM region,
which is not observed for the heretofore known blue light blocking ZdLs. The
phenyl carrying the Rl groups will herein be referred to as the "first phenyl
rix,.g", the phenyl carrying the R2 groups wiU be referred to as the "secon,d
phenyl ring"' and the phenyl carrying the Rs groups will herein be referred to
as the "third phenyl ring".
Witaereas either one or all three phenyl rings can be fully substituted,
it is preferred that at least three, more preferably four RI groups are
hydrogen.
Likewise, preferably at least two R2 groups axe hydrogen andlor at least two
R9
groups are hqdrogen. Preferred positions for Rl and Rs subetituents other than
hydrogen are the para-position on the first phenyl ring and the meta- and
para-positions on the third phenyl ring. As used herein, any position of a
substituent on a phenyl ring (ortho- , meta- or para-) is made with reference
to
the azo-group connecting the ring to its neighbouring phenyl ra,ng.
According to the invention, the at least one blue-light absorbing
bisazo dye of Formula I is chemically bound to the polymer material to ensure
that the polymer is colourfast and the dye is non-extractable (i.e. ovill not
bleed
or leach out of the polymer material). It is to be understood that the dye is
present essentiaBy throughout the transparent material, and not as a layer or
coating which is applied onto existing polymer material. Especially if the
polymer material of the invention is to be used for the manufacture of an
ophthalmic lens, like an IOL, or other object to be inserted i.z1 the body, it
is
important that the dye does not leak out of the polymer matrix after it is
inserted in the bodv.
Preferably, the dye is covalently bound by one linker moiety L to the
transparent polymer. A prefexxed position of the linker moiety is the para-
position. Suitable linker moieties for the covalent attachment of dyes to
optical
polymers are known in the art. See for example the teaching of EP1293541.
Also suitable are the polymerizable acrylatelmethacxylate groups comprising a
spacer moiety for attachment to the polymer as disclosed in US 5,470,932. In
CA 02582371 2007-04-05
8
one embodiment, a linker moiety is $elected froni the group consisting of -
(CHx)a-CH2-CH2-; -(CHz)b-ZI-(CH2)o-CH$-CH2-; -(CHZ)b- C(--O)-Zl-(CH2)0-
CH(R,s)-CH2-; -(CHZ)b,Zl-C(-0)-(CHs)a-CH(RG)-CHz-; -Zz-(CHQ)e-Zl-(CH$)a-
CId(Rr,)-CHz-; -Zz-(CHz)c-C(=O)-Z~.-(CH2)a-CH(R6)-CId2- and -Zz-(CHa),,-ZI-C(--
O)-
6 (CH2)a-CH(R1)-CH2- ; wherein a and b are independently an integer from 0 to
and wherein c is an integer from I to 10; wherein Zz and Z2 are
independently -0- or -NRs-; and wherein R6 and RB are independently
hydrogen, or linear or branched alkyl of Cl-Cio.
In one embodiment, b is 0. Preferably, Zl is oxygen. For example, the dye is
10 covalently bound to the polymer by --O-CHa-CIdz-; -NH-CH2-CH2-; -O-C(=O)-
CIi(CHs)-CHa-; --O-C(=0)-CHs-CHz-, -O-CH2-CH2-0-C(=O)-CH(CHs)-CHE- or --
O-CbIz-CHa-O-CHz-CHz-, wherein the oxygen or nitrogen is attached to the
dye, preferably at tbLe para-position, and wherein the CH2 is attached to the
polymer.
In one embodiment, at least one Rs at the naeta-positi,oxa is a linear or
branched Cx-Clo alkyl, preferably a Cl-C4 alkyl, moxe preferably a methylene.
For example, the dye has the general formula II:
R'
R' Ri
R2
I ,
R1 ryoN R2 ~= R3
I , N R3
2 f
2. i
R
Formula II R3 L
CH3
wherein
CA 02582371 2007-04-05
s
each of Rl, Rz and Rs is andependen,tly selected i'xom hydrogen,
sulfonate, nitro, halogen, nitril, phenyl, carboxylate, -(CH$).-Xi-H and -X$-
(CH2)õ-CH3: wherein XI is 0, NH, CH2 or S; XQ xs 0, NH, S, S(= O)z, C(=0)O;
and n is an integer in the range 0 to 20;or wherein two R2 groupe together
with
the C-atome to which they are bound form a benzene ring; and wherein L is a
linker moiety through which the dye is 'covalently bound to the polymer.
In a specific aspect, the dye is of the formula ZI wherein Ri, R2 aad RS are
hydrogen. Such a dye is readily prepared from the dye 4-[(p-
(phenylazo)phenyl]azo]-o-cresol, which is commercially available under the
name Disperse Yellow 7. The hydroxyl group on the third phenyl ring is
advantageously used to provide the dye with a linker moiety (see further
below), for example the dye can be fiuactionalized with an 0-linked allyl or O-
linlCed (meth)acryloyl according to methods known in the art.
In another aspect of the invention, Rl at the para-position is a sulfonate and
wherein at least one Rs at the meta-position is a carboxylate. The terms
"'eulfonate" and "carboxylate" as used herein are meant to itnclude both the
acid and salts (e.g. sodium) of the respective substituents. Preferably, a
linker
moiety at the para-position chemically links.the dye to the polymer.
CA 02582371 2007-04-05
For example, the dye is of the formula III:
Formula III
3
R'
HO3S R,
R2
R
R' N R3
1 I = 3
R R2 N~ N R
. 2 ~
R = R3 L
CO2H
The Rl, R2 and R9 groups of Formula III are as defined for Foruiula II herein
above. Preferably, the Rs at the meta-position is a linear or branched Cl-C.Ia
14 alkyl subetituent. Preferably, the alkyl is a C1-C4 alkyl, more preferably,
R$ is
CHa= In a specific aspect, the dye is of the fornaula III wherein aD, of Rl
and Itz
an,d at least two of R3 are hydrogen. Dyes of Formula III can be prepared by
coupling diazotized 4-(4-amino-phenylazo)benzene sulfouic acid to a suitable
acid, e.g. 2,3-cresotic acid or salicylic acid. Exemplary dyes include those
based
on the commercially available dyes Mordant Orange 10 and Mordant Orange
Ei.
CA 02582371 2007-04-05
11
In yet another aspect, the dye is a bisazo dye in which the second phenyl ring
is substituted by two R2 groups which, together with the C-atoms of the phenyl
ring to which they are bound, form a benzene ring. Thus, togetbLer with the
second phenyl ri,ng the Rg groups form a naphthalene. An example of such a
dye is represented by Formula IV, wherein Rl, R2 and R3 are as defined above
for Formula TI.
R
Ri Ri
R Z R
2
R~ N~ R 3
q ~ 3
R N R
N
R3 L
R3
Formula XV
In a preferred embodiment, each of 13,1, R2 and Ra of Formula IV i.s
independently hydrogen or Cy,-C4 alkyl. Dyes of Formula IV can be prepared by
coupling diazotized aniline to ].-naphtyiamine, then isolating the product,
diazotizing and coupling to phenol The phenol group can be used to attach a
16 linker moiety. Exemplary dyes include those based on the commercially
available dye Disperse Orange 13, also known under the name Solvent Orange
52.
As will be understood, the dyes of Formula's ZZ, III and IV represent
specifie examples of dyes of general Formula I. The total amount of the dye of
CA 02582371 2007-04-05
12
general formul8L I in a transparent polymer material can vary according to the
desired application of the material. Typically, it is less than 10 parts by
weight
(10 wt%) with respect to 100 parts by weight of the monomers maldng up the
polymer material. Preferably, it is less than 5 wt%. For use in ophthalmic
lenses such as TOLa, it is generally lees than about 1 wt%, preferably less
than
about 0.1 wt%, more preferably less than 0.025 wt%.
In addition, to one or more dyes of the general Formula Z, a transparent
polymer of the invention may contain one or more additional dyes capable of
absorbing light within the visible light spectrum. Together with a dye of the
invention, the combination of dyes may provide the polymer with a desired
transmission characteristic. Exemplary yellow dyes i.nclude, without .
limitation, those mentioned in patent US 5,470,932, patent applications EP
0799864, EP 1,293541 and W02005/066694.
A,n ultraviolet (UV) absorbing compound can also be included in the
polymeric material of this invention. The UV absorbing material can be any
compound which absorbs UV light, i.e., light having a wavelengtlx shorter than
about 400 nm, but does not absorb any substantial amount of visible light. The
UV absorbing compound is typi,cally incorporated into the monomer mixture
and is entrapped in the polymer matrix when the monomer, mixture is
polymerized. Suitable UV absoxbing compounds include substituted
benzophenones, such as 2-hydroxybenzophenone, and 2-(2-
hydroxyphenyl,)benzotxxazoles. It is preferred to use an UV absorbing
compound which is copolymerizable with the monomers and is thereby
covalently bound to the polymer matrix. In this way possible leaching of the
ultraviolet absorbing compound out of the lens and into the iuterior of the
eye
is minimized. Suitable copolymrizable UV absorbing compounds are the
substituted 2-hydroxybenzophenones disclosed in US 4,304,895 and the 2-
hydroxy-5-acryloxyphenyl-2H-benzotxi,azoles disclosed in US 4,528,811. The
most preferred UV absorbing compound is 2-(3'=methallyl-2'-hydroxy-5' methyl
80 phenyl)benzotriazole, also known as ortho-methallyl TinUVin P("oMZ'P").
CA 02582371 2007-04-05
IS
In a further aspect, the invention provides a method for preparing a
transparent, blue-light blocking polymer of the invention. It comprises
providing a functional,a,zed bisazo dye and incorporating the dye in a
transparent polymer such that it is oovalentiy bound and can not leak out of
the polymer matrix. Incorporation of the dye can be achieved by
copolymerizing a monomer mixture (e.g. (meth)acrylates) in the'presexxce of at
least one functionalized, polymerizable dye. Alternatively, a functionalized
dye
is reacted with a(co)polymez, such as a silicone polymer.
A method of the invention is characterized by the covalent incorporation of at
least one dye of the gezaeralFormula V:
R
Ri R'
Z
R' N N \ R R3
1 ~ 3
R Rz ~/' N~ N R
'
Formula V 2
R33 R3
3
R
wherein
each of Rl, Rx and R3 is independently selected from hydrogen,
sulfonate, nitro, halQgen, nitril, phenyl, carboxylate, -(CH2)n-X1-H and -Xz-
(Cldz)n-CHa, wherein Xl is 0, NH, CH2 or S; X$ ie 0, NH, S, S(=0)2, C(=p)0;
and zx is an integer in the range 0 to 20, or wherein two R2 groups together
with the C-atoms to which they are bound form a benzene ring;
CA 02582371 2007-04-05
w
14
each of Rs is independently selected from hydrogen, eulfonate, nitro,
halogen, nitril, phenyl, carboxylate, -(CHz)n-Xi-H and -X2-(CH2)n-CHa, wherein
Xi is b, NH, CH2 or S; X2 is 0, NH, S, S(=0)2, C(=0)0; and n is an integer in
the range 0 to 20, provided that at least one R3 is a functional group through
which the dye can be covalently bound to the polymer.
Pxeferred dyes are those having the Rl, R2 and R,s groups as defined iua,
the Formula's II, II and IV herein above.
Dyes for use in the present invention can be synthesized according
to standard organic synthetic procedures or they may be commercial].y
obtained. Preferably, a bisazo dye is used which is comrnercially available.
If necessary, a linker group can be attached to the dye using standard
derivatization techniques. Because various commercially available bisazo dyes
contain a hydroxyl group at the third phenyi ring of the general formula, they
can be readily derivatized to a dye of Formula V by converting the hydroxyl
group to an O-linked linker moiety.
Methods to provide a functionalized dye are known in the swrt. See for example
EP1293541. Of course, it is preferred to use a commercially available bi8azo
dye which can be readily functionalized to obtain a dye of Formula V. Suitable
dyes for use in a method of the invention include Disperse Yellow 7, Disperse
Orange 13, Mordant Orange 10 and Mordant Orange 6. Many types of
functional groups capable of covalent binding to a polymer have been described
in the art. They comprise acryloyl, methacryloyZ, allyl, vinyl azxd isoprenyl
gxoups.
In one embodiment, said functional group is selected from the group
consisting of --(CHa)o-CH-CHQ; -(CH2)b-Zz-(CH2)n-CH=CH2; -(CH2)b- C(=O)-Zl-
(CH2)a-C(R1;)=CH2; -(CH2)b-ZI-C(= 0)-(CHx)a-C(R)=CH9; -Z2-(CHz)o-ZI-(CH2)*-
C(R6)=CH2; -Z2-(CH2)o-C(=C1)-Zi-(CH2)a-C(R5)=CH$; and -Z$-(CH2)c-ZI-C(=0)-
(CHx)õ-C(R5),CHa, wherein a and b are independently selected from an integer
from 0 to 10 and wherein c is an integer from I to 10; wherein Zx and Z2 aixe
CA 02582371 2007-04-05
independently selected from -0- and --NRs-; and wherein RB and Re are
independently hydrogezi, or linear or branched alkyl of Ci-Cio.
In one embodiment, the functional group is an 0- or N-linked allyl or vinyl.
5 Examples of functional groups include --O-CFf=CIdz; -NH-CH=CH2; -O-C(-O)-
C(CHs)=CHz; --O-C(=0)-CII=CH2; -0-CHz-CH2-0-C(=0)-C(CHa)=CH2 and ,-0-
CH2-CH2-0-CH=CHz.
Procedures for attaching a functional group to a dye are known in the art.
10 Typically, they involve electrophilic substitution of the alcohol group,
leading
to ether formation, e.g. the Williamsion Ether Synthesis or ester $ynthesis
with electrophilic derivatives of cazboxylic, e.g. acyl chloride or acid
anhydride, and sulfonic acids, or by reacting the hydroxy group of the dye
with metharylic anhydride in, the presence of a weak base, such as
15 triethylamine, to yield a reactive metb.acrylic azo-dye.
Methods to prepare a transparent polymer of several types of monomers are
also well known in the art. The monomers used for the present invention are
not particularly limited so long as they can provide transparent polymer
materials. As used herein, the term "transparent" refers to a condition where
a
material is clear enough not to block the passage of radiant energy,
especially
light. A. "transparent polymer" is a material prepared from one or more types
of monomers which polymer is suitable as optical polymer, i.e. a polymer
allowing light to pass through and, preferably, allowing to be seen tbrougb.,
Typa,cally, a transparent polymer has a clear surface that is easily seen
through with little or no distortion. The monomers referred to above which
may be suitably used can be obtained from commercial sources. The
polymerization method, conditions, kinds of polymerization initiator and
crosslinkitng agexxt, the respective amounts thereof and the like can be
appropriately selected depending on the desired (co)polymer.
CA 02582371 2007-04-05
16
Suitable monomers for the manufacture of transparent polymers are known in
the art and include alkyl (meth)acrylates, phenylated (meth)acrylates,
hydrophilic monomers, silicon-containing monomers and fluorine-containing
mnomexs. In particular, there can be xnentioned, for example, Ii,near or
6 branched alkyl (meth)acrylates (the expression (meth)acrylate as used herein
refers to bot?a an acrylate and a methacrylate) such as methyl methacrylate,
butyl (meth)acrylate and cyclohexyl methacrylate; hydrophilic monomers such
as 2-hydroxyethyl methacrylate, glyceroi methacrylate, N-vbnylpyrrolidone,
dimethylacrylamide and methaerylic acid; silicon-containing monomers such
as tris(trimethylsilowy)silylpropyl (meth)acxylate,
trimethylsi.loxydimethylsilylpropyl (meth)aMlate and
bis(tximethylazloxy)methylsilylpropyl(meth)acrylate; and fluorine-containing
monomers such as trifluoroetlayl (meth)acrylate, hexafluoroisopropyl
(meth)acrylate and perfluorooctyletkxyloxypropylene (meth)acrylate and the
like. Other suitable monomers are vinylalcohol and vinylacetate,
polymerisable polyethyleneglycol, polypropylene glycol, perfluoropolyethers
and copolymers thereof. The monomers mentioned can be used alone or in any
combination.
For the manufacture of a silicone polymer material containing a covalently
bound dye, it is preferred to use a silicone compound having hydroeilyl groups
which allow for an addition reaction using a catalyst such as platinum.
Catalysts using in the addition reaction of dyes to silicone compounds are
desirably platinum compounds such as hydrogen chloroplatinate, platinum-
divinyltetramethyldisiloxane, and platinum.
tetramethyltetravinylcyclosaloxane. Further, a silicone bound to the dye
obtained by the above method may provide a silicone elastomer chemically
bound to the dye by cxossli,uking with a silicone having vinyl gyroupe.
In accordance with one example of the present invention a blue-light blocking
dye is chemically bound to silicone polymer material having hydrosilyl group'e
CA 02582371 2007-04-05
17
and then crosslinked with silicone having vinyl groups. Another method is that
the dye is mixed with silicone having hydroe;il,yl groups or silicone having
vinyl
groups, and the mixture is mixed with silicone having hydrosilyl groups and
silicone having vinyl groups, and then the mixture is cross-linked at the same
time as the dye is reacted to the hydrosilyl groups. .
Upon mixing of the silicone described above, it is preferable to
homogeneously disperse the dye by using an appropriate solvent. As such
solvents, acetone, ethanol, chloroform, toluene, tetrabydrofuran, and
di,chloxomethane can be exemplified. The dye is dissolved in the solvent and
mixed with silicone. Then, the solvent can be disti.lled away with an
evaporator, and the dye is uniformly dispersed in the silicone.
For a polymer material based on linear or branched alkyl or aryl
(meth)acrylate monomers, polymerization can be performed by conventional
methods used for the production of copolymers for contact lenses. For example,
radical polymerization, photopolymerization and the like can be used. The
croeslinking agent are for example, (meth)acrylates of po].yalcohol, i.e., di-
or
more hydric alcohol such as ethylene glycol di(meth)acrylate, di.ethylene
glycol
dx(meth)acryl,ate, triethylene glycol di(meth)acrylate and trimethylolpropane
tri(meth)acrylate and other compounds including allyl methacrylate, triallyl
i8ocyanurate, vinyl (meth)acrylate and the like can be used. The
polymerization initiator used for radical polymerization are for example,
those
known as common radical generators, for example, peroxides such as lauroyl
peroxide, bis(4-t-butylcyclohexyl)peroxydicarbonate and 1,1-bis(t-butylperoxy)
3,3,5-trimethylcyclohexane; and azo campounds such as 2,2'-
azobisisobutyronitrile, 2,2'-azobis(2,4-dim.ethylvaleroni,trile), 2,2'-
azobis(4-
11 methoxy-2,4-dimethylvaleronitrile) and 2,2'-azobis[2-(2-iumidazoline-2-
yI)propane]. Bis(4tert-butylcyr,lohexyl)peroxydi-carbonate is a preferred
peroxide and 2,2'-azobisisobutyronitrile is a preferred azo compound. A
suitable amount of the polymerization initiator is in a range of 0.05 to 0.1
part'
by weight for 100 partg by weight of the monomer mixture. The acrylic
CA 02582371 2007-04-05
, , =
~ 18
monomer mixture is fully stirred so that the components are mixed well,
introduced into a mold of rod, cup, or plate shape made of metal, plastic,
glass
or the like, and sealed. Then, polymerization is perforxned by raising
temperature stepwise in a temperature range of 25 to 150 C in a texnperature
controlled bath, It may be preferred as the case may be that the
polymerization is performed in a sealed vessel where gases such as oxygen and
the like are replaced with an inert gas such as nitrogen or argon.
According to the invention, there is no limitation with respect to the
combination of specific dye(s) of formula V and the specifxc polymer material.
However, the skilled person will understand that some dyes are more suitable
for covalent attachment to a given polymer than other dyes. This primarily
concerns the solubility of the dye(s) in hydrophobic or hydrophili,c solvents,
monomers or polymers,
Preferred dyes for incorporation in sili.cone polymers or acrylate polymers
are
those which have a good solubility in organic solvents like chloroform and
ethylene glycol monomethyl ether (EGME). Examples of dyes which, in
solution are well miscible with silicone resin or acrylates include Disperse
Xellow 7 which has a solubi,lity in EGME of 80 mg/znl.
Conversely, for incorporation into hydxophilic polymers, such as
hydrophilxc acrylates, anionic dyes are preferred having a good solubility in
aqueous solvents, For instance, the solubility of Mordant Orange 6 and 10 in
water is 40 mg/ml,
Another factor which may affect the compatibility of dye and polymer
resides in the substituent(s) pxesent on the dye molecule. Amino eubstituents
are less favourable if the dye is to be incorporated to a silicone polymer,
since
they may interfere with the platinum eatal,yst used for cross-linking the
silicone polymer.
Based on the above togethex with his general knowledge, a person
skilded in the art will be able to select a suitable combination of dye and
80 polymer with undue burden.
CA 02582371 2007-04-05
19
The invention furthermore provides the use of a polyme;r material of the
invention, in particular for the manufacture of a lens. A functionalized dye
of
~ormula. V is also provided. Such a dye, optionally in combiunation with
additional compounds capable of absorbing light of predetermined wavelengths
in the UV or in the visible light spectrum (400 - 700 nm), is advantageousiy
incorporated in a number of transparent polymer materials in a variety of
applications where it is desirable to block or minimize the transmission of
light
with a wavelengtlx of about 400-550 nm. Such applications may include, for
example, contact lenses, eye glasses and sunglasses. Lenses for eyes, obtained
by bonding a dye of general Formula V and another UV absorbing agent to
gili.cone or by copolymerization of the dye with a monomer constituting
lenses,
can shut off the greater part of incident blue-to-violet light to the eyes,
thereby
reducing the bad influence of lower blue light upon eyes.
The invention furthermore provides an ophthalnaic lens comprising a
transparent polymer material containing at least one covalently bound dye of
the general formula 1. The term "ophthalmic lens", as used herein, refers to
lenses which are placed in intimate contact with the eye or tear fluid, such
as
contact lenses for vision correction (e.g., spherical, toric, bifocal),
coxxtact ienses
for modification of eye color, ophthalmic drug delivery devices, ocular tissue
protective devices (e.g., ophthalmic healing promoting lenses), intraocular
lenses, and the like.
Due to the unique absorption properties of the bisazo dyes discloged
herein, a lens according to the invention is capable of blocking at least 20-
30%
of the visible light in the 480-500 nm region. Furthermore, it displays a
sigaificant absorption at wavelengths above 500 nm. For example, a
txansmzssion of only 75% was observed at 550 nm, which is a good
approximation of the reported 55-70 1o transmission of an aged human
crystalline lens. In contrast, the prior art lens materials show 85% or more
transmission at 550 nm.
CA 02582371 2007-04-05
As an additional advantage, an optical lens made of a polymer of the
invention displays less chromatic aberratioaas as compared to lenses described
in the prior art. Chiomatito aberzations are wavelength-dependent artefacts
that occur because the refractive index of every optical lens formulation
varies
fi with wavelength. When white light passes through a simple or complex lens
system, the component wavelengths are refracted according to their frequency.
In most lenses, the refractive index is greater for shorter (blue) wavelengths
and changes at a more rapid rate as the wavelength is decreased. Blue light is
re#'xacted to the greatest extent followed by green and red light, a
phenomenon
10 commonly referred to as dispersion. The iuaabilaty of a lens to bring aIl
of the
colours into a common focus results in a slightly different image size and
focal
point for each predominant wavelength group. This leads to colored fringes
surrounding the image. Thanks to the close approximation of the natural
transmission spectrum in the visible light spectrum, the lens of the invention
15 suffers less from chromatic aberrations. Accordingly, the quality of
vision, in
particular the sharpness of the retinal image, when using a lens of the
invention is less coxnprolnised.
A particularly preferred ophthalmic lens is an intraocular lens
(IOL). As such, one embodiment of the invention is an YOL containing a dye of
20 the general formula 1, optionally in combination with one or more
additional
dyes, for example a TJV-absorbiag compound blocking xays up to 400 nm and/or
a seeond dye which blocks in the region above 400 nm. The term "xntraoculax
lens" refers to an artificial lens that may be surgicaflyy implanted in a
patient's
eye after removing the eye's natural lens, usually replacing the existing
crystalline lens because it bas been clouded over by a catazact. An IOL
usually
consists of a plastic lens with plastic side struts called hapts.cs to hold
the lens
xn, place within the capsular bag. Like a contact lens, it has a built-in
refractive
power tailored specifica)],y to the patient's visual conditxon. There are
numerous styles of ZOLs, including foldable IOLs and multifocal IOZ.,s.
CA 02582371 2007-04-05
21
In one exemplary embodiment, the IOL of present invention is a soft,
foldable, silicone IOL having incorporated therein at least one dye of formula
x.
However, it is understood that while the present invention wM be described
most extensively using a soft IOL as an example (see Examples 1 and 2 below),
it is not limited tb soft silicone IOLs. For example, the present invention is
equally suitable for soft acrylic IOI,s, aczylic-silicone ]aybrid f OLs and
b,ard
PMMA IOLs. Persons skilled in the art will readily understand to easily adapt
the paresent teachings for use with other IOZ. structural polymers.
Also provided is a method for the manufacture of an ophthalmic lens of
the invention, comprising a transparent polymer material of the invention and
furthermore comprising shaping said polymer material into a lens shape. In
one embodiment, said shaping is performed by injection moulding and
cxosslinking said polymer material into a lens shape mold. In case of an IOL,
the manufacture process typically also comprises the attachment of haptics.
Methods to prepaxe lenses, including XOLs, fxom transparent polymer material
are well known in the art (US6444106, W09631792, US4120570). In one
embodiment, it comprises the manufacture o~the desired polymer in the shape
of a rod or plate shape material, which material can be cut into button shape
blanks and made into a lens shape by cutting and polishing. Alternatively, by
pouring the above monomer mixture into a lens shape mold having a desired
curvature and polymerizing it, the monomer mixture may be directly made
into a lens shape.
In a specific aspect, the invention provides an IOL comprising a
transparent polymer material of the invention, wherein the transparent
polymer material containing the dye of formula I is present in a limited
region
of the lens. Specific reference is made to WO 2005/066694 disclosing an IOL
wherein a light absorbing dye is locali,zed to a specific part of the lens,
preferably the center porti,on.Advantages of this configuration are that it
affords the retina maximum protection in high intensity lighting condition
CA 02582371 2007-04-05
22
where protection is needed most, wbaile permitting a fuller spectrum of light
to
reach the retina in subdued, or low Jxght conditions. Furthermore, the li,ght
.
absorbing dye may be isolated within the IOL interior such that the dye itself
does not contact either the eye's anatomical structures or physiological
fluids.
The invention is exempUf'ied by the Examples herein below.
LEGENDS TO THE FIGURES
Figure 1: Transmission spectrum of a transparent polymer of the invention
containing a bisazo dye of Formula 1("Ophtec-oxange") and a conventional UV-
absorbing compound, Also shown are the spectra of two known yellow "blue-
light absorbing" IOLs (AcrySof Natural IOL from Alcon and Hoya IOL (ROYA
YA-60BE) and the reported transmission spectrum of an aged human lens
(Boethner. E.A. and Woltex, J.R., "Transmission of the Ocular Media".
Investigative Ophthalmology, Vol. 776-783, 1962).
Figure 2: LN-transuaission curves of treated and non-treated (control) lenses
demonstratiung the photostability of dye-containing polymer material of the
invention. For details see Examtsie 3.
Figure 3: LTV-transmission curves of extracted and non-extracted (control)
lenses demonstxating that the dye was covalently incorporated in the polymer
material. For details see Examnle 4.
EXPERIMENTAL SECTION
Example 1: k'unctionalizatxon of Disperse Yellow 7.
CA 02582371 2007-04-05
23
In this example, the commercially available dye Disperse YeUow 7 is
functionalized at its free hydroxyl with an allyl linker moiety to allow for
covalent attachment of the dye to a polymer, in this case a silicone polymer.
Materi_als:
o Disperse Ye11ow 7, supplier: Sigma Aldrich
o Allyl bromide, suppliexs: Acros/ Boom BV/ Fisher-Emergo
o Potassium carbonate (KaCOg)
o Sodium chloride
o Diethyl ether
o Magnesium sulfate (MgSO4)
o Acetone p.a.
o Hexane p.a.
~rocedure:
250 ml, acetone p.a. was added to 5 g of Disperse Yellow 7 and 3.3 g of K2COs.
The mixture was stirred at room temperature under nitrogen atmosphere and
then heated to 68 C under reflux for two bours, After eooling down to room
temperature, 2.87 g of allyl bromide was added dropwise. The temperature
was increased again to 68 C and the mixture was allowed to react under
stirring and refluxing of acetone overnight. Demineralized water (about 400
ml) was added under stirring. Next, 30 g of NaCi p.a. was added. De mixture
was transferred to a separating funnel of $000 ml and shaken with 200 ml
diethyl ether. The water/ acetone layer was separated from the layer of
diethylether. The mixture was shaken and separated with 100 mI of water for
two more times. Tb,e ether layer was dried over 40 g of MgSO4 , filtered and
evaporated. The product was dried under vacuum and dissolved ici aceton p.a..
Hexane p.a. was added until tlxe solution became opaque. Crystals of the
CA 02582371 2007-04-05
-i r =
24
purified product were formed overnight in the freezer. The crystals were
collected trough filtration and subsequently dried in a vacuuxn exeiccator.
Example 2: Covalent attachment of functionalized Disperse Xellow 7
to silicone co-polymer and preparation of intraocular lens (IOL).
In this example, an IOL is prepared from a silicone material comprising the
functionalized dye of Example 1. The polymer is prepared using the
commercially available two component system Silicone Med 6820 from NuSrd
Technology,
te 'r~alg
o Silicone Med 6820 component A (NuSil Technology)
o Silicone Med 6820 component $(NuSi17'echnology)
o Functionalized Disperse Yellow 7 (see Example 1)
o Functionalized 2,4 dihydroxybenzophenone UV-Blokker
(functionalization comparable to the functionalization of DispeTse
Yellow 7, example 1)
o Dichlororaethane
Etocedure:
500 g of component A, 1.9 g fixnctionali.zed LN blocker and 0. X g
functionalized
Disperse Yellow 7 were transfexred to a reaction vesael. The mixture was
dissolved in 1 liter dichloromethane and stirred for one hour. Thereafter, the
dichloromethane was evaporated using a rotation evaporator and the silicone
was simultaneously degassed. The procedure was repeated for component B
Component A and component B were mixed (1:1 volume ratio) in a static
mixer. The mixture was injected into a IOL-mould and cured at 120 C for 10
minutes. Subsequently, the polymer material was post-cured at 150 C for 2
CA 02582371 2007-04-05
hours. After moulding the IOZ.,'e were polished, extracted and cleaned. The
resulting ZOLs contain 0.02 wt% of the J~tnctionalized"dye and 0.88 wt% of the
W-bl.ocker.
5 Exampae 3: Photosta.bility test and cytotoxicity test of the dye-
containing intraocular lens (IOL).
Proce ure
The IOL containing the covalently bound Disperse Yellow 7 was tested for its
10 susceptibility to photochemical degradation. In this study 451enses were
immersed in 2 ml saline solution and exposed to TJV-light (300-400 nm) with a
dose equivalent to 20 years of dayli.ght. After exposure an established in
vitro
cytotoxicity test (MEM Elution Test; for reference see standard 'Ophtalmie
implants - intraocular lenses - Part 5: Biocompatibility ISO 11979-5: 1999,
15 modified'). was performed on the saline solution. The UV-transmission
curves
of the lenses were studied before an after exposure.
rResu&ts Cvtotoxi.city (MEM Elution Test)
No biological reactivity (Grade 0) was observed in the L929 manamalian cells
20 at 48 hours, post exposure to the article extract and the treated blanc
saline.
The observed cellular response obtained fxom the positive control extract
(Grade 4) and the negative control extract (Grade 0) confirmed the
suitabi.lity
of the test system. These results demonstrate that the blue-light blocking IOL
of the invention is considered non-cytotoxic and meets the requirements of the
25 Elution test.
Rssylts3JV-Uansm~ission es of the dve-c=taining IOL's
The U'V-Transmission curves of the UV-irradiated and control lenses were
measured. The results are given in F'i,gare 2. The absorption characteristic
of
the orange IOL of the invention is preserved after the treatment equivalent to
CA 02582371 2007-04-05
a '
26
20 years of daylight. A decrease in transmission at 600 nm of only 3% is
observed. This corresponds to a loss of activity of only 5% of.the Disperse
Yellow 7 molecules in the material.
Example 4: Exhaustive Extraction test of the dye- containing IQL's.
Proceduure
To demonstrate that the dye was efficiently incorporated covalently in the
polymer material, the IQL's were extracted with toluene by using a soxhlet
apparatus. Toluene is a good solvent for Disperse Yellow 7 and the
crosslittked
silicone material swells considerably in toluene. The extraction was performed
in duplicate using sample sets of 20 lenses each, Five lenses per sample set
were subjected to WlVIS transmission spectroscopy before extraction, to serve
as controls.
Figure 3 shows the LN-Vis transmission spectroscopy results of the extracted
lenses as compared to the control lenses. The W-transmi.ssion of the lenses at
475 nm before and after extraction was 50 %, The overlapping spectra show
that the absorption characteristic of the lenses is preserved during
extraction,
indicating that Disperse Yellow 7 is covalently bound to the silicon material.
Example 5: Synthesis of functionalized Disperse Orange 13.
Azo Couplin of X-na hthvl red hYdxochloride tQ 2:phSnoxvpthMnol
isvpthe$ia aLcomvound D
Into a 100 ml beaker is added 200 ml water and 14,2 (100 mmol) of sodium
phosphate, dibasic (Na2 HP04) followed by the addition of 6N HC1 solution to
adjust the reaction solution to pH 2. After the phosphate buffer salt is
CA 02582371 2007-04-05
27
completely dissolved, 14.426 g (50.84 tamol) of 1-naphthyl red hydrochlox'ide
(Sigma Aldrich) is added to the solution. Ice is added to the reaction
solution to
cool it down to 0 C.
Into a separate beaker, 3.5151 g (50.94 mmol) of sodium nitrite, NaNO2, is
dissolved in 20 ml of water. Zce is added to cool the solution. The sodium
nitrile
solution is added dropwise with constant stirring to the reaction solution
while
constantly monitoring the pH of the reactiion. The pH of the reaction i,s
maintained to about 1.9 to 2.2 by addition of 6N HCI. After the addition of
Qodiurii nitrite solution is completed, more ice is added to the reaction to
keep
the temperature at 0 C-10 C and the reaction is stirred for about 15 minutes.
N
N N
Mctlyorylio Anhydrida ~
N I \..
NrN
II
i~
CA 02582371 2007-04-05
28
Into another beaker is placed 6.9743 (50.48 mmol) 2-phenoxyethanol (Sigma
Aldrich), 100 ml of water, and enough 6N HCI is added to dissolve the solid.
The 2-phenoxyethanol solution is added dropwise into the stirring xeaction
seolution, which was kept at 0 C-10 C by periodic addition of ice. After the
addition is completed the solution is stirred for about an hour and warmed up
to 10 C. then 50% w/v and 2N NaOH solutions were added to the reaction
solution to pH 6.9. The solid was filtered of and washed with watex.
The solid obtained from the reaction is recrystallized and dried.
FunctionaLisation of comnoumd Z(s,wuthesis of comnound I11
Into a 100 ml round bottomed flask is placed 5.011 mmol of compound I and
25 ml THF. Subsequently 1.5549 g (10.086 mmol) metbacrylic anhydride
(MAA) is added. After about 4 hours 1.0452 g (10.329 mmol) of triethylamine is
added dropwise to the reaction solution. The reaction is stirred for 2 days
and
then another aliquot of 4.1877 g(4]õ386 mmol) of triethylamine is added to the
reaction. The product is purifited by column chromatography. -
Example 6: Covalent attachment of functionalized Disperse Orange 13
to methacxyl.ate polymer and JOL preparatipn.
0.1 gram 2,2-axobis(2,4-dimethylvalea:-oxut:rile) as a polymerization
initiator is
mixed with 10 gram 2-phenoxyethyl acrylate, 80 gram 2-hydxoxyethyl
xnethacrylate, 10 gram methyl methacxyiate, 0.02 gram functionalxxed
Disperse Orange 13 (see Example 5) and 0.38 gram acrylate fixnctxoaalised
UV-blocker. The mixture is poured in a glass tube and the tube is put in a
water bath to polymerize it by maintaining at 35 C for about 40 hours and
heating at 50 C for 8 hours. Subsequently, the above-mentioned tube is
transferred to a circulating drier, and heated from 50 C to 120 C at a rate
of
10 C per 1.5 hou:rs, It is maintained at 130 C for 3 hours and allowed to
stand
CA 02582371 2007-04-05
29
to cool to room temperature to obtain a cylindrical transparent copolymer
comprising the dye. The material is cut into buttons. IOVs are prepared from
the buttons by machining and subsequently polishing according to standard
procedures.
