U.S. patent application number 13/930221 was filed with the patent office on 2013-10-31 for using the light adjustable lens (lal) to increase the depth of focus by inducing targeted amounts of asphericity.
The applicant listed for this patent is Calhoun Vision, Inc. Invention is credited to Eloy Angel, Pablo Artal, Christian A. Sandstedt.
Application Number | 20130289153 13/930221 |
Document ID | / |
Family ID | 47881246 |
Filed Date | 2013-10-31 |
United States Patent
Application |
20130289153 |
Kind Code |
A1 |
Sandstedt; Christian A. ; et
al. |
October 31, 2013 |
Using the Light Adjustable Lens (LAL) to Increase the Depth of
Focus by Inducing Targeted Amounts of Asphericity
Abstract
In general, the present invention relates to optical elements,
which can be modified post-manufacture such that different versions
of the element will have different optical properties. In
particular, the present invention relates to lenses, such as
intraocular lenses, which can be converted into aspheric lenses
post-fabrication. Also, the present invention relates to a method
for forming aspheric lenses post-fabrication.
Inventors: |
Sandstedt; Christian A.;
(Pasadena, CA) ; Artal; Pablo; (Molina De Segura,
ES) ; Angel; Eloy; (Alicante, ES) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Calhoun Vision, Inc |
Pasadena |
CA |
US |
|
|
Family ID: |
47881246 |
Appl. No.: |
13/930221 |
Filed: |
June 28, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13488099 |
Jun 4, 2012 |
|
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13930221 |
|
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|
61535793 |
Sep 16, 2011 |
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Current U.S.
Class: |
522/148 ;
525/478 |
Current CPC
Class: |
A61F 2/1635 20130101;
C08J 2383/06 20130101; C08G 77/20 20130101; C08J 3/246 20130101;
C08G 77/12 20130101; C08J 2383/07 20130101; C08J 3/28 20130101;
B29C 35/00 20130101; C08L 83/04 20130101; A61F 2/1637 20130101;
B29D 11/00442 20130101; A61F 2/164 20150401; C08L 83/04 20130101;
C08L 83/00 20130101 |
Class at
Publication: |
522/148 ;
525/478 |
International
Class: |
A61F 2/16 20060101
A61F002/16 |
Claims
1. A method of forming an aspheric optical element, comprising the
steps of: (a) forming a first polymer matrix wherein the step of
forming the first polymer matrix is done in the presence of a
modifying composition; (b) forming a second polymer matrix wherein
the step of forming the second polymer matrix further comprises the
step of polymerizing the modifying composition to form an
interpenetrating network with the first polymer matrix.
2. The method of claim 1, wherein the aspheric optical element is
created by irradiating with a spatially defined irradiance
profile.
3. The method of claim 2, wherein the spatially defined irradiance
profile induces asphericity according to the following equation:
Asph(.rho.)=A.rho..sup.4-B.rho..sup.2+1 wherein: Asph(.rho.) is the
irradiance profile coefficient A is equal to 4; coefficient B is
equal to 4 .rho. is a radial coordinate.
4. The method of claim 2, wherein the spatially defined irradiance
profile induces asphericity to provide increased depth of focus
according to the following equation: Profile(.rho.)=SCN
(.rho.)+.beta.Asph(.rho.) wherein SCN(.rho.) refers to either a
spherical, spherocylindrical or power neutral spatial irradiance
profile, Asph(.rho.) is: Asph(.rho.)=A.rho..sup.4-B.rho..sup.2+1
wherein: Asph(.rho.) is the irradiance profile coefficient A is
equal to 4; coefficient B is equal to 4 .rho. is a radial
coordinate coefficient .beta. is a weighting factor that ranges
from 0 to 1.
5. The method of claim 4 wherein, wherein the remaining amount of
the modifying composition is polymerized with the first polymer
matrix.
6. The optical element of claim 5, wherein the first polymer matrix
is a polyacrylate, a polymethacrylate, a polyvinyl, a polysiloxane,
a polyphosphazenes and/or copolymers of thereof.
7. The optical element of claim 6, wherein the polysiloxane is a
polydimethylsiloxane.
8. The optical element of claim 7, wherein the polydimethylsiloxane
has the formula: ##STR00029##
9. The optical element of claim 8, wherein the first polymer matrix
is formed in the presence of a crosslinker
10. The optical element of claim 9, wherein the crosslinker has the
formula: ##STR00030##
11. The optical element of claim 4, wherein the modifying
composition has the formula: ##STR00031##
12. The optical element of claim 11, wherein the modifying
composition has the formula ##STR00032##
13. The optical element of claim 6, wherein the polyacrylate is a
polyalkyl acrylates, a polyhydroxyalkyl acrylate and/or a
combination thereof.
14. The optical element of claim 6, wherein the polymethacrylate is
a polymethyl methacrylate, a polyhydroxyethyl methacrylate, a
polyhydroxypropyl methacrylate and/or a combination thereof.
15. The optical element of claim 6, wherein the polyvinyl is a
polystyrene, a polyvinylpyrrolidone and/or a combination
thereof.
16. A method of forming an aspheric lens, comprising the steps of:
(a) forming a first polymer matrix wherein the step of forming the
first polymer matrix is done in the presence of a modifying
composition; (b) forming a second polymer matrix wherein the step
of forming the second polymer matrix further comprises the step of
reacting the first polymer matrix with the modifying
composition.
17. The method of claim 16, wherein the aspheric lens has a
spatially defined irradiance profile.
18. The method of claim 17, wherein the spatially defined
irradiance profile induces asphericity according to the following
equation: Asph(.rho.)=A.rho..sup.4-B.rho..sup.2+1 wherein:
Asph(.rho.) is the irradiance profile coefficient A is equal to 4;
coefficient B is equal to 4 .rho. is a radial coordinate.
19. The method of claim 17, wherein the spatially defined
irradiance profile induces asphericity to provide increased depth
of focus according to the following equation:
Profile(.rho.)=SCN(.rho.)+.beta.Asph(.rho.) wherein SCN(.rho.)
refers to either a spherical, spherocylindrical or power neutral
spatial irradiance profile, Asph(.rho.) is:
Asph(.rho.)=A.rho..sup.4-B.rho..sup.2+1 wherein: Asph(.rho.) is the
irradiance profile coefficient A is equal to 4; coefficient B is
equal to 4 .rho. is a radial coordinate coefficient .beta. is a
weighting factor that ranges from 0 to 1.
20. The method of claim 19, wherein the remaining amount of the
modifying composition is polymerized with the first polymer
matrix.
21. The optical element of claim 20, wherein the first polymer
matrix is a polyacrylate, a polymethacrylate, a polyvinyl, a
polysiloxane, a polyphosphazenes and/or copolymers of thereof.
22. The optical element of claim 21, wherein the polysiloxane is a
polydimethylsiloxane.
23. The optical element of claim 21, wherein the
polydimethylsiloxane has the formula: ##STR00033##
24. The optical element of claim 23, wherein the first polymer
matrix is formed in the presence of a crosslinker.
25. The optical element of claim 24, wherein the crosslinker has
the formula: ##STR00034##
26. The optical element of claim 19, wherein the modifying
composition has the formula: ##STR00035##
27. The optical element of claim 26, wherein the modifying
composition has the formula ##STR00036##
28. The optical element of claim 21, wherein the polyacrylate is a
polyalkyl acrylates, a polyhydroxyalkyl acrylate and/or a
combination thereof.
29. The optical element of claim 21, wherein the polymethacrylate
is a polymethyl methacrylate, a polyhydroxyethyl methacrylate, a
polyhydroxypropyl methacrylate and/or a combination thereof.
30. The optical element of claim 21, wherein the polyvinyl is a
polystyrene, a polyvinylpyrrolidone and/or a combination thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 13/488,099 to Sandstedt et al. filed on Jun. 4, 2012, and
entitled "Using the Light Adjustable Lens (LAL) to Increase the
Depth of Focus by Inducing Targeted Amounts of Asphericity," which
claims the priority of benefit of U.S. Provisional Application No.
61/535,793 filed on Sep. 16, 2011, both which are incorporated
herein by reference in their entirety.
TECHNICAL FIELD
[0002] The field of the invention includes at least medical and
surgical instruments; treatment devices; surgery and surgical
supplies; and, medicine. In general, the field of subject matter of
the invention includes ophthalmology. More specifically, the
disclosure relates to optical elements, which can be modified
post-manufacture such that different versions of the element will
have different optical properties. In particular, the disclosure
relates to lenses, such as intraocular lenses, which can be
converted into aspheric lenses post-fabrication.
BACKGROUND OF THE INVENTION
[0003] An intraocular lens (IOL) is a surgically implanted,
polymeric lens designed to replace the natural crystalline lens in
the human eye, typically in patients who have developed visually
significant cataracts. Since their inception in the late 1940's,
IOLs have provided improved uncorrected visual acuity (UCVA)
compared to that of the cataractous or aphakic state; however,
problems in predictably achieving emmetropia persist as most
post-cataract surgery patients rely on spectacles or contact lenses
for optimal distance vision. Compounding the issues related to
achieving optimum distance vision, patients undergoing cataract
surgery lose their ability to accommodate, i.e. the ability to see
objects at both near and distance.
[0004] The determination of IOL power required for a particular
post-operative refraction is dependent on the axial length of the
eye, the optical power of the cornea, and the predicted location of
the IOL within the eye. Accurate calculation of IOL power is
difficult because the determination of axial length, corneal
curvature, and the predicted position of the IOL in the eye is
inherently inaccurate. (Narvaez et al., 2006; Olsen, 1992;
Preussner et al., 2004; Murphy et al., 2002). Surgically induced
cylinder and variable lens position following implantation will
create refractive errors, even if preoperative measurements were
completely accurate. (Olsen, 1992) Currently, the options for IOL
patients with less than optimal uncorrected vision consist of
post-operative correction with spectacles, contact lenses or
refractive surgical procedures. Because IOL exchange procedures
carry significant risk, secondary surgery to remove the IOL and
replace the first IOL with a different power IOL is generally
limited to severe post-operative refractive errors.
[0005] With current methods of IOL power determination, the vast
majority of patients achieve a UCVA of 20/40 or better. A much
smaller percentage achieves optimal vision without spectacle
correction. Nearly all patients are within two diopters (D) of
emmetropia.
[0006] In a study of 1,676 patients, 1,569 (93.6%) patients were
within two diopters of the intended refractive outcome. (Murphy et
al., 2002). In 1,320 cataract extractions on patients without
ocular co-morbidity, Murphy and co-workers found that 858 (65%) had
uncorrected visual acuity greater than 20/40. (Murphy et al.,
2002). A 2007 survey of cataract surgeons reported that incorrect
IOL power remains a primary indication for foldable IOL
explantation or exchange. (Mamalis et al., 2008; and Jin et al.,
2007)
[0007] In addition to imprecise IOL power determinations,
post-operative uncorrected visual acuity is most often limited by
pre-existing astigmatism. Staar Surgical (Monrovia, Calif.) and
Alcon Laboratories (Ft. Worth, Tex.) both market a toric IOL that
corrects pre-existing astigmatic errors. These IOLs are available
in only two to three toric powers (2.0, 3.5 D and 1.50, 2.25 and
3.0 D, respectively at the IOL plane) and the axis must be
precisely aligned at surgery. Other than surgical repositioning,
there is no option to adjust the IOL's axis which may shift
post-operatively. (Sun et al., 2000) Furthermore; individualized
correction of astigmatism is limited by the unavailability of
multiple toric powers.
[0008] An additional problem associated with using pre-implantation
corneal astigmatic errors to gauge the required axis and power of a
toric IOL is the unpredictable effect of surgical wound healing on
the final refractive error. After the refractive effect of the
cataract wound stabilizes, there is often a shift in both magnitude
and axis of astigmatism which off-sets the corrective effect of a
toric IOL. Therefore, a means to post-operatively adjust (correct)
astigmatic refractive errors after lens implantation and surgical
wound healing is very desirable. While limbal relaxing incision is
a widely accepted technique for treating corneal astigmatism, the
procedure is typically performed during cataract surgery;
therefore, the procedure does not address the effect of
post-implantation wound healing.
[0009] In the United States alone, approximately one million eyes
undergo corneal refractive procedures which subsequently develop
cataracts, thus, presenting a challenge with respect to IOL power
determination. Corneal topographic alterations induced by
refractive surgery reduce the accuracy of keratometric
measurements, often leading to significant post-operative
ametropia. (Feiz et al., 2005; Wang et al., 2004; Latkany et al.,
2005; Mackool et al., 2006; Packer et al., 2004; Fam and Lim, 2008;
Chokshi et al., 2007; Camellin and Calossi, 2006). Recent studies
of patients who have had corneal refractive surgery
(photorefractive keratectomy, laser in situ keratomileusis, radial
keratotomy) and subsequently required cataract surgery frequently
demonstrate refractive "surprises" post-operatively. As the
refractive surgery population ages and develops cataracts,
appropriate selection of IOL power for these patients has become an
increasingly challenging clinical problem. The ability to address
this problem with an adjustable IOL is valuable to patients seeking
optimal distance vision after cataract surgery.
[0010] Accommodation, as it relates to the human visual system,
refers to the ability of a person to use their unassisted ocular
structure to view objects at both near (e.g. reading) and far (e.g.
driving) distances. The mechanism whereby humans accommodate is by
contraction and relaxation of the ciliary body, which connects onto
the capsular bag surrounding the natural lens. Under the
application of ciliary stress, the human lens will undergo a shape
change effectively altering the radius of curvature of the lens.
(Ciuffreda, 1998). This action produces a concomitant change in the
power of the lens. However, as people grow older the ability for
their eyes to accommodate reduces dramatically. This condition is
known as presbyopia and currently affects more than 90 million
people in the United States. The most widely accepted theory to
explain the loss of accommodation was put forth by Helmholtz.
According to Helmholtz, as the patient ages, the crystalline lens
of the human eye becomes progressively stiffer prohibiting
deformation under the applied action of the ciliary body.
(Helmholtz, 1969). People who can see objects at a distance without
the need for spectacle correction, but have lost the ability to see
objects up close are usually prescribed a pair of reading glasses
or magnifiers. For those patients who have required previous
spectacle correction due to preexisting defocus and/or astigmatism,
they are prescribed a pair of bifocals, trifocals, variable, or
progressive focus lenses which allows the person to have both near
and distance vision. Compounding this condition is the risk of
cataract development as the patient ages.
[0011] To effectively treat both presbyopia and cataracts, the
patient can be implanted with a multifocal IOL. The two most widely
adopted multifocal IOLs currently sold in the United States are the
ReZoom.RTM. (Abbott Medical Optics, Santa Ana, Calif.) and
ReStor.RTM. (Alcon, Fort Worth, Tex.) lenses. The ReZoom.RTM. lens
is comprised of five concentric, aspheric refractive zones. (U.S.
Pat. No. 5,225,858). Each zone is a multifocal element and thus
pupil size should play little or no role in determining final image
quality. However, the pupil size must be greater than 2.5 mm to be
able to experience the multifocal effect. Image contrast is
sacrificed at the near and far distances, to achieve the
intermediate and has an associated loss equivalent to one line of
visual acuity. (Steiner et al., 1999). The ReStor.RTM. lenses, both
the 3.0 and 4.0 versions, provide simultaneous near and distance
vision by a series of concentric, apodized diffractive rings in the
central, three millimeter diameter of the lenses. The mechanism of
diffractive optics should minimize the problems associated with
variable pupil sizes and small amounts of decentration. The
acceptance and implantation of both of these lenses has been
limited by the difficulty experienced with glares, rings, halos,
monocular diplopia, and the contraindication for patients with an
astigmatism of greater than or equal to 2.0 D. (Hansen et al.,
1990; and, Ellingson, 1990). Again precise, preoperative
measurements and accurate IOL power calculations are critical to
the success of the refractive outcome, and neither the ReZoom nor
the ReStor lenses provide an opportunity for secondary power
adjustment post implantation. (Packer et al., 2002).
[0012] One of the newest concepts proposed to tackle the dual
problems of cataracts and presbyopia are through the use of
accommodating IOLs. Two companies, Bausch & Lomb (Rochester,
N.Y.) and Human Optics AG (Erlangen, Germany) have developed IOLs
that attempt to take advantage of the existing accommodative
apparatus of the eye in post implantation patients to treat
presbyopia. Bausch & Lomb's lens offers a plate haptic
configured IOL with a flexible hinged optic (CrystaLens.RTM.).
Human Optics's lens (AKKOMMODATIVE.RTM. 1CU) is similar in design,
but possesses four hinged haptics attached to the edge of the
optic. The accommodative effect of these lenses is caused by the
vaulting of the plate IOL by the contraction of the ciliary body.
This vaulting may be a response of the ciliary body contraction
directly or caused by the associated anterior displacement of the
vitreous body. Initial reports of the efficacy of these two lenses
in clinical trials was quite high with dynamic wavefront
measurement data showing as much as 2 D to 3 D (measured at the
exit pupil of the eye) of accommodation. However, the FDA
Ophthalmic Devices' panel review of Bausch & Lomb's clinical
results concluded that only a 1 D accommodative response (at the
spectacle plane) was significantly achieved by their lens, which is
nearly identical to the pseudo-accommodation values achieved for
simple monofocal IOLs.
[0013] A need exists for an intraocular lens which is adjusted post
operatively in-vivo to form a presbyopia correcting intraocular
lens. This type of lens can be designed in-vivo to correct to an
initial emmetropic state (light from infinity forming a perfect
focus on the retina) and then the presbyopia correction is added
during a second treatment. Such a lens would (1) remove the guess
work involved in presurgical power selection, (2) overcome the
wound healing response inherent to IOL implantation, and (3) allow
the amount of near vision to be customized to correspond to the
patient's requirements. Also, an intraocular lens which is adjusted
post operatively in-vivo to form an aspheric optical element would
result in the patient having an increased depth of focus (DOF),
which allows the patient to see both distance and near (e.g. 40 cm)
through the same lens.
BRIEF SUMMARY OF THE INVENTION
[0014] General embodiments of the present invention provide a first
optical element whose properties may be adjusted post-manufacture
to produce a second optical element, wherein the second optical
element is capable of providing an increased depth of focus to a
patient. Specifically, the invention relates to a spherical
intraocular lens that is capable of being transformed
post-operatively into an aspheric optical element. Through this
approach, the intraocular and/or focal zones of the aspheric
optical element can be more precisely adjusted after the lens has
been subjected to any post-operative migration. Also, the
adjustment of the aspheric optical element can be based on input
from the patient and/or the adjustment of the aspheric optical
element can be accomplished through standard refraction techniques
rather than making the adjustment through preoperative
estimation.
[0015] The alteration of the spherical IOL is accomplished via a
modifying composition ("MC") dispersed throughout the spherical
IOL. The MC is capable of polymerization when exposed to an
external stimulus such as heat or light. The stimulus can be
directed to one or more regions of the element causing
polymerization of the MC only in the exposed regions. The
polymerization of the MC causes changes in the optical properties
of the element within the exposed regions. In some embodiments, the
optical properties changed though the polymeriztion of the MC
include a change in the radius of curvature and/or a change in the
refractive index.
[0016] The method for providing an aspheric lens begins with the
formation of the first polymer matrix in the presence of the
modifying composition. The next step is the formation of a second
polymer matrix comprising polymerized MC. The formation of this
polymer network changes the optical properties of the element,
namely the refractive index. In addition, when the MC is
polymerized to form the second polymer matrix, a gradient or a
difference in the chemical potential between the polymerized and
unpolymerized regions is induced. This in turn causes the
unpolymerized MC to diffuse within the element, which reestablishes
a thermodynamic equilibrium within the optical element. If the
optical element possesses sufficient elasticity, this migration of
MC can cause swelling of the element in the area exposed to the
stimulus. This, in turn, changes the shape of the element, causing
changes in the optical properties (i.e., radius of curvature and/or
refractive index). Whether the radius of curvature of the element
and/or the refractive index of the element change depends upon (1)
the nature of the optical element, (2) the MC incorporated into the
element, (3) the duration that the element is exposed to a
stimulus, and (4) the spatial intensity profile of the
stimulus.
[0017] By controlling the radiant exposure (i.e., beam irradiance
and duration), spatial irradiance profile, and target area,
physical changes in the radius of curvature of the lens surface are
achieved, thereby modifying the refractive power of an implanted
lens (1) to correct spherical refractive errors, (2) to correct
sphero-cylindrical refractive errors, (3) to induce a targeted
amount of asphericity and/or a combination thereof. Once the
appropriate refractive adjustment is achieved, the entire aspheric
lens is irradiated to polymerize the remaining unreacted MC under
conditions that prevent any additional change in lens power. By
irradiating the entire lens, MC diffusion is prevented thus no
change in lens power results. This second irradiation procedure is
referred to as "lock-in".
[0018] In another aspect of the present invention, the optical
elements are self-contained in that once fabricated, no material is
either added or removed from the lens to obtain the desired optical
properties.
[0019] The foregoing has outlined rather broadly the features and
technical advantages of the present invention in order that the
detailed description of the invention that follows may be better
understood. Additional features and advantages of the invention
will be described hereinafter which form the subject of the claims
of the invention. It should be appreciated by those skilled in the
art that the conception and specific embodiment disclosed may be
readily utilized as a basis for modifying or designing other
structures for carrying out the same purposes of the present
invention. It should also be realized by those skilled in the art
that such equivalent constructions do not depart from the spirit
and scope of the invention as set forth in the appended claims. The
novel features which are believed to be characteristic of the
invention, both as to its organization and method of operation,
together with further objects and advantages will be better
understood from the following description when considered in
connection with the accompanying figures. It is to be expressly
understood, however, that each of the figures is provided for the
purpose of illustration and description only and is not intended as
a definition of the limits of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] For a more complete understanding of the present invention,
reference is now made to the following descriptions taken in
conjunction with the accompanying drawing.
[0021] FIG. 1 shows a schematic representation of the depth of
focus.
[0022] FIG. 2 shows a collimated beam of light being refracted by a
spherical lens.
[0023] FIG. 3 shows a schematic of the adaptive optics simulator
used to determine the optimized values for 4.sup.th order spherical
aberration and defocus.
[0024] FIG. 4 shows a schematic of positive power adjustment
mechanism; wherein (a) is a schematic representation of selective
irradiation of the central zone of the lens in which the
polymerization of the MC creates a difference in the chemical
potential between the irradiated and non-irradiated regions, (b) to
reestablish equilibrium, excess MC diffuses into the irradiated
region causing swelling, and (c) irradiation of the entire lens
"locks" the remaining MC and the shape change.
[0025] FIG. 5 shows a plot of the aspheric function described in
Equation 1.
[0026] FIG. 6 shows cross-sectional plots of Equation 2 generated
by combining a power neutral profile with weighted amounts
(.beta.=0 to 0.57) of the aspheric profile.
[0027] FIG. 7 shows a plot of induced 4.sup.th and 6.sup.th order
spherical aberration as a function of increasing .beta. value. The
measurement aperture was 4 mm and none of these LALs received any
type of prior adjustment.
[0028] FIG. 8 shows a plot of incduced 4.sup.th and 6.sup.th order
spherical aberration as a function of increasing .beta. value for
LALs receiving a hyperopic, myopic, and no prior adjustment. The
measurement aperture for both the 4.sup.th and 6.sup.th order
spherical aberration was 4 mm.
[0029] FIG. 9 shows the monocular visual acuity data for eyes
receiving an initial refractive adjustment followed by an aspheric
treatment (n=32) versus those eyes treated only for distance
emmetropia (n=12).
[0030] FIG. 10 shows the segregation of the monocular visual acuity
data into high (n=9) and low (n=23) induced spherical aberration
values. For comparison, those eyes (n=12) adjusted for distance
emmetropia are also shown.
[0031] FIG. 11 shows a comparison of the monocular and the
binocular visual acuities for a series of patients that were
corrected for distance emmetropia in one eye and received an
aspheric treatment in their fellow eye. The amount of induced
asphericity ranged from -0.04 .mu.m to -0.10 .mu.m, referenced to a
4 mm pupil.
[0032] FIG. 12 shows a comparison of the monocular and binocular
visual acuities for a series of patients that were corrected for
distance emmotropia in one eye and received an aspheric treatment
in their fellow eye. The amount of induced asphericity ranged from
-0.11 .mu.m to -0.23 .mu.m, referenced to a 4 mm pupil.
DETAILED DESCRIPTION OF THE INVENTION
[0033] As used herein the specification, "a" or "an" may mean one
or more. As used herein in the claim(s), when used in conjunction
with the word "comprising", the words "a" or "an" may mean one or
more than one. As used herein "another" may mean at least a second
or more. Furthermore, as used herein, the terms "comprise," "have"
and "include" are open-ended linking verbs. Any forms or tenses of
one or more of these verbs, such as "comprises," "comprising,"
"has," "having," "includes" and "including," are also open-ended.
For example, any method that "comprises," "has" or "includes" one
or more steps is not limited to possessing only those one or more
steps and also covers other unlisted steps.
[0034] Throughout this application, the term "about" is used to
indicate that a value includes the inherent variation of error for
the device, the method being employed to determine the value, or
the variation that exists among the experimental test articles.
[0035] Chemical Group Definitions
[0036] When used in the context of a chemical group, "hydrogen"
means --H; "hydroxy" means --OH; "oxo" means .dbd.O; "halo" means
independently --F, --Cl, --Br or --I; "amino" means --NH.sub.2 (see
below for definitions of groups containing the term amino, e.g.,
alkylamino); "hydroxyamino" means --NHOH; "nitro" means --NO.sub.2;
imino means .dbd.NH (see below for definitions of groups containing
the term imino, e.g., alkylimino); "cyano" means --CN; "isocyanate"
means --N.dbd.C.dbd.O; "azido" means --N.sub.3; in a monovalent
context "phosphate" means --OP(O)(OH).sub.2 or a deprotonated form
thereof; in a divalent context "phosphate" means --OP(O)(OH)O-- or
a deprotonated form thereof; "mercapto" means --SH; and "thio"
means .dbd.S
[0037] In the context of chemical formulas, the symbol "--" means a
single bond, ".dbd." means a double bond, and ".ident." means
triple bond. The symbol "" represents an optional bond, which if
present is either single or double. The symbol "" represents a
single bond or a double bond. Thus, for example, the structure
##STR00001##
includes the structures
##STR00002##
As will be understood by a person of skill in the art, no one such
ring atom forms part of more than one double bond. The symbol "",
when drawn perpendicularly across a bond indicates a point of
attachment of the group. It is noted that the point of attachment
is typically only identified in this manner for larger groups in
order to assist the reader in rapidly and unambiguously identifying
a point of attachment. The symbol "" means a single bond where the
group attached to the thick end of the wedge is "out of the page."
The symbol "" means a single bond where the group attached to the
thick end of the wedge is "into the page". The symbol "" means a
single bond where the conformation (e.g., either R or S) or the
geometry is undefined (e.g., either E or Z).
[0038] Any undefined valency on an atom of a structure shown in
this application implicitly represents a hydrogen atom bonded to
the atom. When a group "R" is depicted as a "floating group" on a
ring system, for example, in the formula:
##STR00003##
[0039] then R may replace any hydrogen atom attached to any of the
ring atoms, including a depicted, implied, or expressly defined
hydrogen, so long as a stable structure is formed. When a group "R"
is depicted as a "floating group" on a fused ring system, as for
example in the formula:
##STR00004##
[0040] then R may replace any hydrogen attached to any of the ring
atoms of either of the fused rings unless specified otherwise.
Replaceable hydrogens include depicted hydrogens (e.g., the
hydrogen attached to the nitrogen in the formula above), implied
hydrogens (e.g., a hydrogen of the formula above that is not shown
but understood to be present), expressly defined hydrogens, and
optional hydrogens whose presence depends on the identity of a ring
atom (e.g., a hydrogen attached to group X, when X equals --CH--),
so long as a stable structure is formed. In the example depicted, R
may reside on either the 5-membered or the 6-membered ring of the
fused ring system. In the formula above, the subscript letter "y"
immediately following the group "R" enclosed in parentheses,
represents a numeric variable. Unless specified otherwise, this
variable can be 0, 1, 2, or any integer greater than 2, only
limited by the maximum number of replaceable hydrogen atoms of the
ring or ring system.
[0041] For the groups and classes below, the following
parenthetical subscripts further define the group/class as follows:
"(Cn)" defines the exact number (n) of carbon atoms in the
group/class. "(C.ltoreq.n)" defines the maximum number (n) of
carbon atoms that can be in the group/class, with the minimum
number as small as possible for the group in question, e.g., it is
understood that the minimum number of carbon atoms in the group
"alkenyl(.sub.c.ltoreq.8)" or the class "alkene.sub.(C.ltoreq.8)"
is two. For example, "alkoxy.sub.(C.ltoreq.10)" designates those
alkoxy groups having from 1 to 10 carbon atoms (e.g., 1, 2, 3, 4,
5, 6, 7, 8, 9, or 10, or any range derivable therein (e.g., 3 to 10
carbon atoms). (Cn-n') defines both the minimum (n) and maximum
number (n') of carbon atoms in the group. Similarly,
"alkyl.sub.(C2-10)" designates those alkyl groups having from 2 to
10 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10, or any range
derivable therein (e.g., 3 to 10 carbon atoms)).
[0042] The term "saturated" as used herein means the compound or
group so modified has no carbon-carbon double and no carbon-carbon
triple bonds, except as noted below. The term does not preclude
carbon-heteroatom multiple bonds, for example a carbon oxygen
double bond or a carbon nitrogen double bond. Moreover, it does not
preclude a carbon-carbon double bond that may occur as part of
keto-enol tautomerism or imine/enamine tautomerism.
[0043] The term "aliphatic" when used without the "substituted"
modifier signifies that the compound/group so modified is an
acyclic or cyclic, but non-aromatic hydrocarbon compound or group.
In aliphatic compounds/groups, the carbon atoms can be joined
together in straight chains, branched chains, or non-aromatic rings
(alicyclic). Aliphatic compounds/groups can be saturated, that is
joined by single bonds (alkanes/alkyl), or unsaturated, with one or
more double bonds (alkenes/alkenyl) or with one or more triple
bonds (alkynes/alkynyl). When the term "aliphatic" is used without
the "substituted" modifier only carbon and hydrogen atoms are
present. When the term is used with the "substituted" modifier one
or more hydrogen atom has been independently replaced by --OH, --F,
--Cl, --Br, --I, --NH.sub.2, --NO.sub.2, --CO.sub.2H,
--CO.sub.2CH.sub.3, --CN, --SH, --OCH.sub.3, --OCH.sub.2CH.sub.3,
--C(O)CH.sub.3, --N(CH.sub.3).sub.2, --C(O)NH.sub.2,
--OC(O)CH.sub.3, or --S(O).sub.2NH.sub.2.
[0044] The term "alkyl" when used without the "substituted"
modifier refers to a monovalent saturated aliphatic group with a
carbon atom as the point of attachment, a linear or branched,
cyclo, cyclic or acyclic structure, and no atoms other than carbon
and hydrogen. Thus, as used herein cycloalkyl is a subset of alkyl.
The groups --CH.sub.3 (Me), --CH.sub.2CH.sub.3 (Et),
--CH.sub.2CH.sub.2CH.sub.3 (n-Pr), --CH(CH.sub.3).sub.2 (iso-Pr),
--CH(CH.sub.2).sub.2 (cyclopropyl),
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3 (n-Bu),
--CH(CH.sub.3)CH.sub.2CH.sub.3 (sec-butyl),
--CH.sub.2CH(CH.sub.3).sub.2 (iso-butyl), --C(CH.sub.3).sub.3
(tert-butyl), --CH.sub.2C(CH.sub.3).sub.3 (neo-pentyl), cyclobutyl,
cyclopentyl, cyclohexyl, and cyclohexylmethyl are non-limiting
examples of alkyl groups. The term "alkanediyl" when used without
the "substituted" modifier refers to a divalent saturated aliphatic
group, with one or two saturated carbon atom(s) as the point(s) of
attachment, a linear or branched, cyclo, cyclic or acyclic
structure, no carbon-carbon double or triple bonds, and no atoms
other than carbon and hydrogen. The groups, --CH.sub.2--
(methylene), --CH.sub.2CH.sub.2--,
--CH.sub.2C(CH.sub.3).sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, and
##STR00005##
are non-limiting examples of alkanediyl groups. The term
"alkylidene" when used without the "substituted" modifier refers to
the divalent group .dbd.CRR' in which R and R' are independently
hydrogen, alkyl, or R and R' are taken together to represent an
alkanediyl having at least two carbon atoms. Non-limiting examples
of alkylidene groups include: .dbd.CH.sub.2,
.dbd.CH(CH.sub.2CH.sub.3), and .dbd.C(CH.sub.3).sub.2. When any of
these terms is used with the "substituted" modifier one or more
hydrogen atom has been independently replaced by --OH, --F, --Cl,
--Br, --I, --NH.sub.2, --NO.sub.2, --CO.sub.2H, --CO.sub.2CH.sub.3,
--CN, --SH, --OCH.sub.3, --OCH.sub.2CH.sub.3, --C(O)CH.sub.3,
--N(CH.sub.3).sub.2, --C(O)NH.sub.2, --OC(O)CH.sub.3, or
--S(O).sub.2NH.sub.2. The following groups are non-limiting
examples of substituted alkyl groups: --CH.sub.2OH, --CH.sub.2Cl,
--CF.sub.3, --CH.sub.2CN, --CH.sub.2C(O)OH,
--CH.sub.2C(O)OCH.sub.3, --CH.sub.2C(O)NH.sub.2,
--CH.sub.2C(O)CH.sub.3, --CH.sub.2OCH.sub.3,
--CH.sub.2OC(O)CH.sub.3, --CH.sub.2NH.sub.2,
--CH.sub.2N(CH.sub.3).sub.2, and --CH.sub.2CH.sub.2Cl. The term
"haloalkyl" is a subset of substituted alkyl, in which one or more
hydrogen has been substituted with a halo group and no other atoms
aside from carbon, hydrogen and halogen are present. The group,
--CH.sub.2Cl is a non-limiting examples of a haloalkyl. An "alkane"
refers to the compound H--R, wherein R is alkyl. The term
"fluoroalkyl" is a subset of substituted alkyl, in which one or
more hydrogen has been substituted with a fluoro group and no other
atoms aside from carbon, hydrogen and fluorine are present. The
groups, --CH.sub.2F, --CF.sub.3, and --CH.sub.2CF.sub.3 are
non-limiting examples of fluoroalkyl groups. An "alkane" refers to
the compound H--R, wherein R is alkyl.
[0045] The term "alkenyl" when used without the "substituted"
modifier refers to an monovalent unsaturated aliphatic group with a
carbon atom as the point of attachment, a linear or branched,
cyclo, cyclic or acyclic structure, at least one nonaromatic
carbon-carbon double bond, no carbon-carbon triple bonds, and no
atoms other than carbon and hydrogen. Non-limiting examples of
alkenyl groups include: --CH.dbd.CH.sub.2 (vinyl),
--CH.dbd.CHCH.sub.3, --CH.dbd.CHCH.sub.2CH.sub.3,
--CH.sub.2CH.dbd.CH.sub.2 (allyl), --CH.sub.2CH.dbd.CHCH.sub.3, and
--CH.dbd.CH--C.sub.6H.sub.5. The term "alkenediyl" when used
without the "substituted" modifier refers to a divalent unsaturated
aliphatic group, with two carbon atoms as points of attachment, a
linear or branched, cyclo, cyclic or acyclic structure, at least
one nonaromatic carbon-carbon double bond, no carbon-carbon triple
bonds, and no atoms other than carbon and hydrogen. The groups,
--CH.dbd.CH--, --CH.dbd.C(CH.sub.3)CH.sub.2--,
--CH.dbd.CHCH.sub.2--, and
##STR00006##
are non-limiting examples of alkenediyl groups. When these terms
are used with the "substituted" modifier one or more hydrogen atom
has been independently replaced by --OH, --F, --Cl, --Br, --I,
--NH.sub.2, --NO.sub.2, --CO.sub.2H, --CO.sub.2CH.sub.3, --CN,
--SH, --OCH.sub.3, --OCH.sub.2CH.sub.3, --C(O)CH.sub.3,
--N(CH.sub.3).sub.2, --C(O)NH.sub.2, --OC(O)CH.sub.3, or
--S(O).sub.2NH.sub.2. The groups, --CH.dbd.CHF, --CH.dbd.CHCl and
--CH.dbd.CHBr, are non-limiting examples of substituted alkenyl
groups. An "alkene" refers to the compound H--R, wherein R is
alkenyl.
[0046] The term "alkynyl" when used without the "substituted"
modifier refers to an monovalent unsaturated aliphatic group with a
carbon atom as the point of attachment, a linear or branched,
cyclo, cyclic or acyclic structure, at least one carbon-carbon
triple bond, and no atoms other than carbon and hydrogen. As used
herein, the term alkynyl does not preclude the presence of one or
more non-aromatic carbon-carbon double bonds. The groups, --CCH,
--C.ident.CCH.sub.3, and --CH.sub.2C.ident.CCH.sub.3, are
non-limiting examples of alkynyl groups. The term "alkynediyl" when
used without the "substituted" modifier refers to a divalent
unsaturated aliphatic group, with two carbon atoms as points of
attachment, a linear or branched, cyclo, cyclic or acyclic
structure, at least one carbon-carbon triple bond, and no atoms
other than carbon and hydrogen. When these terms are used with the
"substituted" modifier one or more hydrogen atom has been
independently replaced by --OH, --F, --Cl, --Br, --I, --NH.sub.2,
--NO.sub.2, --CO.sub.2H, --CO.sub.2CH.sub.3, --CN, --SH,
--OCH.sub.3, .sup.--OCH.sub.2CH.sub.3, --C(O)CH.sub.3,
--N(CH.sub.3).sub.2, --C(O)NH.sub.2, --OC(O)CH.sub.3, or
--S(O).sub.2NH.sub.2. An "alkyne" refers to the compound H--R,
wherein R is alkynyl.
[0047] The term "aryl" when used without the "substituted" modifier
refers to a monovalent unsaturated aromatic group with an aromatic
carbon atom as the point of attachment, said carbon atom forming
part of a one or more six-membered aromatic ring structure, wherein
the ring atoms are all carbon, and wherein the group consists of no
atoms other than carbon and hydrogen. If more than one ring is
present, the rings may be fused or unfused. As used herein, the
term does not preclude the presence of one or more alkyl group
(carbon number limitation permitting) attached to the first
aromatic ring or any additional aromatic ring present. Non-limiting
examples of aryl groups include phenyl (Ph), methylphenyl,
(dimethyl)phenyl, --C.sub.6H.sub.4CH.sub.2CH.sub.3 (ethylphenyl),
naphthyl, and the monovalent group derived from biphenyl. The term
"arenediyl" when used without the "substituted" modifier refers to
a divalent aromatic group, with two aromatic carbon atoms as points
of attachment, said carbon atoms forming part of one or more
six-membered aromatic ring structure(s) wherein the ring atoms are
all carbon, and wherein the monovalent group consists of no atoms
other than carbon and hydrogen. As used herein, the term does not
preclude the presence of one or more alkyl group (carbon number
limitation permitting) attached to the first aromatic ring or any
additional aromatic ring present. If more than one ring is present,
the rings may be fused or unfused. Non-limiting examples of
arenediyl groups include:
##STR00007##
[0048] When these terms are used with the "substituted" modifier
one or more hydrogen atom has been independently replaced by --OH,
--F, --Cl, --Br, --I, --NH.sub.2, --NO.sub.2, --CO.sub.2H,
--CO.sub.2CH.sub.3, --CN, --SH, --OCH.sub.3, --OCH.sub.2CH.sub.3,
--C(O)CH.sub.3, --N(CH.sub.3).sub.2, --C(O)NH.sub.2,
--OC(O)CH.sub.3, or --S(O).sub.2NH.sub.2. An "arene" refers to the
compound H--R, wherein R is aryl.
[0049] The term "aralkyl" when used without the "substituted"
modifier refers to the monovalent group-alkanediyl-aryl, in which
the terms alkanediyl and aryl are each used in a manner consistent
with the definitions provided above. Non-limiting examples of
aralkyls are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl. When
the term is used with the "substituted" modifier one or more
hydrogen atom from the alkanediyl and/or the aryl has been
independently replaced by --OH, --F, --Cl, --Br, --I, --NH.sub.2,
--NO.sub.2, --CO.sub.2H, --CO.sub.2CH.sub.3, --CN, --SH,
--OCH.sub.3, --OCH.sub.2CH.sub.3, --C(O)CH.sub.3,
--N(CH.sub.3).sub.2, --C(O)NH.sub.2, --OC(O)CH.sub.3, or
--S(O).sub.2NH.sub.2. Non-limiting examples of substituted aralkyls
are: (3-chlorophenyl)-methyl, and 2-chloro-2-phenyl-eth-1-yl.
[0050] The term "heteroaryl" when used without the "substituted"
modifier refers to a monovalent aromatic group with an aromatic
carbon atom or nitrogen atom as the point of attachment, said
carbon atom or nitrogen atom forming part of an aromatic ring
structure wherein at least one of the ring atoms is nitrogen,
oxygen or sulfur, and wherein the group consists of no atoms other
than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and
aromatic sulfur. As used herein, the term does not preclude the
presence of one or more alkyl group (carbon number limitation
permitting) attached to the aromatic ring or any additional
aromatic ring present. Non-limiting examples of heteroaryl groups
include furanyl, imidazolyl, indolyl, indazolyl (Im),
methylpyridyl, oxazolyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl,
quinolyl, quinazolyl, quinoxalinyl, thienyl, and triazinyl. The
term "heteroarenediyl" when used without the "substituted" modifier
refers to an divalent aromatic group, with two aromatic carbon
atoms, two aromatic nitrogen atoms, or one aromatic carbon atom and
one aromatic nitrogen atom as the two points of attachment, said
atoms forming part of one or more aromatic ring structure(s)
wherein at least one of the ring atoms is nitrogen, oxygen or
sulfur, and wherein the divalent group consists of no atoms other
than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and
aromatic sulfur. As used herein, the term does not preclude the
presence of one or more alkyl group (carbon number limitation
permitting) attached to the first aromatic ring or any additional
aromatic ring present. If more than one ring is present, the rings
may be fused or unfused. Non-limiting examples of heteroarenediyl
groups include:
##STR00008##
[0051] When these terms are used with the "substituted" modifier
one or more hydrogen atom has been independently replaced by --OH,
--F, --Cl, --Br, --I, --NH.sub.2, --NO.sub.2, --CO.sub.2H,
--CO.sub.2CH.sub.3, --CN, --SH, --OCH.sub.3, --OCH.sub.2CH.sub.3,
--C(O)CH.sub.3, --N(CH.sub.3).sub.2, --C(O)NH.sub.2,
--OC(O)CH.sub.3, or --S(O).sub.2NH.sub.2.
[0052] The term "acyl" when used without the "substituted" modifier
refers to the group --C(O)R, in which R is a hydrogen, alkyl, aryl,
aralkyl or heteroaryl, as those terms are defined above. The
groups, --CHO, --C(O)CH.sub.3 (acetyl, Ac), --C(O)CH.sub.2CH.sub.3,
--C(O)CH.sub.2CH.sub.2CH.sub.3, --C(O)CH(CH.sub.3).sub.2,
--C(O)CH(CH.sub.2).sub.2, --C(O)C.sub.6H.sub.5,
--C(O)C.sub.6H.sub.4CH.sub.3, --C(O)CH.sub.2C.sub.6H.sub.5,
--C(O)(imidazolyl) are non-limiting examples of acyl groups. A
"thioacyl" is defined in an analogous manner, except that the
oxygen atom of the group --C(O)R has been replaced with a sulfur
atom, --C(S)R. When either of these terms are used with the
"substituted" modifier one or more hydrogen atom has been
independently replaced by --OH, --F, --Cl, --Br, --I, --NH.sub.2,
--NO.sub.2, --CO.sub.2H, --CO.sub.2CH.sub.3, --CN, --SH,
--OCH.sub.3, --OCH.sub.2CH.sub.3, --C(O)CH.sub.3,
--N(CH.sub.3).sub.2, --C(O)NH.sub.2, --OC(O)CH.sub.3, or
--S(O).sub.2NH.sub.2. The groups, --C(O)CH.sub.2CF.sub.3,
--CO.sub.2H (carboxyl), --CO.sub.2CH.sub.3 (methylcarboxyl),
--CO.sub.2CH.sub.2CH.sub.3, --C(O)NH.sub.2 (carbamoyl), and
--CON(CH.sub.3).sub.2, are non-limiting examples of substituted
acyl groups.
[0053] The term "alkoxy" when used without the "substituted"
modifier refers to the group --OR, in which R is an alkyl, as that
term is defined above. Non-limiting examples of alkoxy groups
include: --OCH.sub.3, --OCH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2,
--OCH(CH.sub.2).sub.2, --O-cyclopentyl, and --O-cyclohexyl. The
terms "alkenyloxy", "alkynyloxy", "aryloxy", "aralkoxy",
"heteroaryloxy", and "acyloxy", when used without the "substituted"
modifier, refers to groups, defined as --OR, in which R is alkenyl,
alkynyl, aryl, aralkyl, heteroaryl, and acyl, respectively.
Similarly, the term "alkylthio" when used without the "substituted"
modifier refers to the group --SR, in which R is an alkyl, as that
term is defined above. When any of these terms is used with the
"substituted" modifier one or more hydrogen atom has been
independently replaced by --OH, --F, --Cl, --Br, --I, --NH.sub.2,
--NO.sub.2, --CO.sub.2H, --CO.sub.2CH.sub.3, --CN, --SH,
--OCH.sub.3, --OCH.sub.2CH.sub.3, --C(O)CH.sub.3,
--N(CH.sub.3).sub.2, --C(O)NH.sub.2, --OC(O)CH.sub.3, or
--S(O).sub.2NH.sub.2. The term "alcohol" corresponds to an alkane,
as defined above, wherein at least one of the hydrogen atoms has
been replaced with a hydroxy group.
[0054] The term "alkylamino" when used without the "substituted"
modifier refers to the group --NHR, in which R is an alkyl, as that
term is defined above. Non-limiting examples of alkylamino groups
include: --NHCH.sub.3 and --NHCH.sub.2CH.sub.3. The term
"dialkylamino" when used without the "substituted" modifier refers
to the group --NRR', in which R and R' can be the same or different
alkyl groups, or R and R' can be taken together to represent an
alkanediyl. Non-limiting examples of dialkylamino groups include:
--N(CH.sub.3).sub.2, --N(CH.sub.3)(CH.sub.2CH.sub.3), and
N-pyrrolidinyl. The terms "alkoxyamino", "alkenylamino",
"alkynylamino", "arylamino", "aralkylamino", "heteroarylamino", and
"alkylsulfonylamino" when used without the "substituted" modifier,
refers to groups, defined as --NHR, in which R is alkoxy, alkenyl,
alkynyl, aryl, aralkyl, heteroaryl, and alkylsulfonyl,
respectively. A non-limiting example of an arylamino group is
--NHC.sub.6H.sub.5. The term "amido" (acylamino), when used without
the "substituted" modifier, refers to the group --NHR, in which R
is acyl, as that term is defined above. A non-limiting example of
an amido group is --NHC(O)CH.sub.3. The term "alkylimino" when used
without the "substituted" modifier refers to the divalent group
.dbd.NR, in which R is an alkyl, as that term is defined above.
When any of these terms is used with the "substituted" modifier one
or more hydrogen atom has been independently replaced by --OH, --F,
--Cl, --Br, --I, --NH.sub.2, --NO.sub.2, --CO.sub.2H,
--CO.sub.2CH.sub.3, --CN, --SH, --OCH.sub.3, --OCH.sub.2CH.sub.3,
--C(O)CH.sub.3, --N(CH.sub.3).sub.2, --C(O)NH.sub.2,
--OC(O)CH.sub.3, or --S(O).sub.2NH.sub.2. The groups
--NHC(O)OCH.sub.3 and --NHC(O)NHCH.sub.3 are non-limiting examples
of substituted amido groups.
[0055] The term "alkylphosphate" when used without the
"substituted" modifier refers to the group --OP(O)(OH)(OR), in
which R is an alkyl, as that term is defined above. Non-limiting
examples of alkylphosphate groups include: --OP(O)(OH)(OMe) and
--OP(O)(OH)(OEt). The term "dialkylphosphate" when used without the
"substituted" modifier refers to the group --OP(O)(OR)(OR'), in
which R and R' can be the same or different alkyl groups, or R and
R' can be taken together to represent an alkanediyl. Non-limiting
examples of dialkylphosphate groups include: --OP(O)(OMe).sub.2,
--OP(O)(OEt)(OMe) and --OP(O)(OEt).sub.2. When any of these terms
is used with the "substituted" modifier one or more hydrogen atom
has been independently replaced by --OH, --F, --Cl, --Br, --I,
--NH.sub.2, --NO.sub.2, --CO.sub.2H, --CO.sub.2CH.sub.3, --CN,
--SH, --OCH.sub.3, --OCH.sub.2CH.sub.3, --C(O)CH.sub.3,
--N(CH.sub.3).sub.2, --C(O)NH.sub.2, --OC(O)CH.sub.3, or
--S(O).sub.2NH.sub.2.
[0056] The terms "alkylsulfonyl" and "alkylsulfinyl" when used
without the "substituted" modifier refers to the groups
--S(O).sub.2R and --S(O)R, respectively, in which R is an alkyl, as
that term is defined above. The terms "alkenylsulfonyl",
"alkynylsulfonyl", "arylsulfonyl", "aralkylsulfonyl", and
"heteroarylsulfonyl", are defined in an analogous manner. When any
of these terms is used with the "substituted" modifier one or more
hydrogen atom has been independently replaced by --OH, --F, --Cl,
--Br, --I, --NH.sub.2, --NO.sub.2, --CO.sub.2H, --CO.sub.2CH.sub.3,
--CN, --SH, --OCH.sub.3, --OCH.sub.2CH.sub.3, --C(O)CH.sub.3,
--N(CH.sub.3).sub.2, --C(O)NH.sub.2, --OC(O)CH.sub.3, or
--S(O).sub.2NH.sub.2.
[0057] The term "effective," as that term is used in the
specification and/or claims, means adequate to accomplish a
desired, expected, or intended result. "Effective amount," or
"Therapeutically effective amount" when used in the context of
treating a patient or subject with a stimulus means that the amount
of the stimulus which, when administered to a subject or patient
for treating a condition, is sufficient to effect such treatment
for the condition.
[0058] As used herein, the term "patient" or "subject" refers to a
living mammalian organism, such as a human, monkey, cow, sheep,
goat, dog, cat, mouse, rat, guinea pig, or transgenic species
thereof. In certain embodiments, the patient or subject is a
primate. Non-limiting examples of human subjects are adults,
juveniles, infants and fetuses.
[0059] As generally used herein "pharmaceutically acceptable"
refers to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues, organs, and/or bodily
fluids of human beings and animals without excessive toxicity,
irritation, allergic response, or other problems or complications
commensurate with a reasonable benefit/risk ratio.
[0060] A "repeat unit" is the simplest structural entity of certain
materials, for example, frameworks and/or polymers, whether
organic, inorganic or metal-organic. In the case of a polymer
chain, repeat units are linked together successively along the
chain, like the beads of a necklace. For example, in polyethylene,
-[--CH.sub.2CH.sub.2--]-, the repeat unit is --CH.sub.2CH.sub.2--.
The subscript "n" denotes the degree of polymerization, that is,
the number of repeat units linked together. When the value for "n"
is left undefined or where "n" is absent, it simply designates
repetition of the formula within the brackets as well as the
polymeric nature of the material. The concept of a repeat unit
applies equally to where the connectivity between the repeat units
extends three dimensionally, such as in, modified polymers,
thermosetting polymers, etc.
[0061] "Treatment" or "treating" includes (1) inhibiting a disease
in a subject or patient experiencing or displaying the pathology or
symptomatology of the disease (e.g., arresting further development
of the pathology and/or symptomatology), (2) ameliorating a disease
in a subject or patient that is experiencing or displaying the
pathology or symptomatology of the disease (e.g., reversing the
pathology and/or symptomatology), and/or (3) effecting any
measurable decrease in a disease in a subject or patient that is
experiencing or displaying the pathology or symptomatology of the
disease.
[0062] The above definitions supersede any conflicting definition
in any of the reference that is incorporated by reference herein.
The fact that certain terms are defined, however, should not be
considered as indicative that any term that is undefined is
indefinite. Rather, all terms used are believed to describe the
invention in terms such that one of ordinary skill can appreciate
the scope and practice the present invention.
Compositions of the Invention
[0063] Compositions of the present disclosure may be made using the
methods described above and in Example 1 below. These methods can
be further modified and optimized using the principles and
techniques of organic chemistry and/or polymer chemistry as applied
by a person skilled in the art. Such principles and techniques are
taught, for example, in March's Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure (2007), and/or in R. J. Young
& P. A. Lovell, Introduction to Polymers, (Chapman & Hall
1991), which are incorporated by reference herein.
Discussion of General Embodiments
[0064] From a pure optical standpoint, the depth of focus (DOF) for
an optical system (e.g. the eye) is simply defined as the maximum
movement away from the ideal image plane, which may be made without
causing a serious deterioration of the image. According to the
Rayleigh limit, there will be no appreciable deterioration of the
image, i.e., no marked change from the Airy pattern, provided the
maximum phase difference between disturbances arriving at the
center of the pattern, does not exceed .pi./2. With reference to
FIG. 1, this is mathematically stated as:
.delta. 1 = .+-. .lamda. 8 n ' sin 2 U ' 2 ##EQU00001##
[0065] where AP represents a spherical wave converging to the image
point B, .lamda. is the wavelength, n' is the refractive index in
the image space, U' is the slope of the refracted ray, and .delta.1
is the DOF. Therefore, an optical system such as the human eye will
have an inherent amount of depth of focus even for a perfectly
imaging system.
[0066] An additional property of optical systems that can be
exploited to further increase the depth of focus, and therefore
provide for both distance and near vision, is spherical aberration.
In simple terms, spherical aberration is defined as the variation
of focus with aperture. FIG. 2 graphically depicts a collimated
beam of light being refracted by a spherical biconvex lens. Notice
that the rays closest to the optical axis come to a focus close to
the paraxial focus position. As the ray height at the lens
increases, the position of the ray's intersection with the optical
axis moves farther and farther away from the paraxial focus. The
distance from the paraxial focus to the axial intersection of the
ray is called longitudinal spherical aberration. The image of a
point formed by a lens with spherical aberration is usually a
bright dot surrounded by a halo of light. The effect of spherical
aberration on an extended image is to soften the contrast of the
image and blur its details. However, it should be possible to
induce a specific spherical aberration that increases the depth of
focus such that the softening of the focus and the image contrast
is acceptable.
[0067] The presence of spherical aberration increases the depth of
focus in the eye. In combination with a residual refractive error
(defocus), an induced spherical aberration can be used to provide
patients with good contrast images both for distance and near
objects. The key issue is to determine the required values of both
4.sup.th order spherical aberration and defocus that provide good
near vision without deteriorating the image quality for distance
objects. An experimental approach that permits determination of the
optimum values of spherical aberration and defocus is an adaptive
optics visual simulator. (Fernandez et al., 2002). An example of
this type of instrument is shown in FIG. 3. This instrument
consists of a wavefront sensor (Shack-Hartmann wavefront sensor), a
wavefront corrector (Liquid Crystal on Silicon (LCOS)), and an
additional optical path to present letters, e.g., a tumbling E, to
the subjects under test. The visual acuity of several subjects was
measured using a similar setup as that shown in FIG. 3. The visual
acuity of the subjects was measured through simulations that
consisted of a number of different combinations of residual defocus
and spherical aberration measurements for letter objects placed at
distances from 30 cm to distance emmetropia. The results of these
simulations indicate that the optimum values of negative spherical
aberration and defocus to maintain good vision between 40 cm and
distance emmetropia are -0.125 .mu.m of 4.sup.th order spherical
aberration in combination with -1.0 D of defocus.
[0068] The spherical IOL of the present invention is capable of
post-fabrication alteration of optical properties. The lens is
self-contained and does not require the addition or removal of
materials to change the optical properties. Instead, the optical
properties of the lens are altered by exposing a portion or
portions of the lens to an external stimulus which induces
polymerization of a MC within the lens. The polymerization of the
MC, in turn, causes the change in optical properties.
[0069] In some examples, the optical element of the invention has
dispersed within it a MC. The MC is capable of diffusion within the
lens; can be readily polymerized by exposure to a suitable external
stimulus; and is compatible with the materials used to make the
first polymer matrix of the lens.
[0070] The method for providing an aspheric lens begins with the
formation of the first polymer matrix. After the first polymer
matrix is formed, the second polymer matrix is formed by exposing
the first polymer matrix, which further comprises the MC, to an
external stimulus. During this second polymerization, several
changes occur within the optical element. The first change is the
formation of a second polymer matrix comprising polymerized MC. The
formation of the second polymer network can cause changes in the
optical properties of the element, namely the refractive index. In
addition, when the MC polymerizes, a difference in the chemical
potential between the polymerized and unpolymerized region is
induced. This in turn causes the unpolymerized MC to diffuse within
the element, which reestablishes thermodynamic equilibrium of the
optical element. If the optical element possesses sufficient
elasticity, this migration of MC can cause swelling of the element
in the area exposed to the stimulus. This, in turn, changes the
shape of the element, causing changes in the optical properties.
Whether the radius of curvature of the element and/or the
refractive index of the element change depends upon (1) the nature
of the optical element, (2) the MC incorporated into the element,
(3) the duration that the element is exposed to the stimulus, and
(4) the spatial intensity profile of the stimulus. A schematic
depicting the process for increasing the power of the lens is
displayed in FIG. 4.
[0071] The optical element is typically made of a first polymer
matrix. Illustrative examples of a suitable first polymer matrix
include: (1) polyacrylates such as polyalkyl acrylates and
polyhydroxyalkyl acrylates; (2) polymethacrylates such as
polymethyl methacrylate ("PMMA"), polyhydroxyethyl methacrylate
("PHEMA"), and polyhydroxypropyl methacrylate ("HPMA"); (3)
polyvinyls such as polystyrene and polyvinylpyrrolidone ("PNVP");
(4) polysiloxanes such as polydimethylsiloxane; polyphosphazenes,
and/or (5) copolymers thereof. U.S. Pat. No. 4,260,725 and patents
and references cited therein (which are all incorporated herein by
reference) provide more specific examples of suitable polymers that
may be used to form the first polymer matrix.
[0072] In preferred embodiments, where flexibility is desired, the
first polymer matrix generally possesses a relatively low glass
transition temperature ("T.sub.g") such that the resulting IOL
tends to exhibit fluid-like and/or elastomeric behavior, and is
typically formed by cross-linking one or more polymeric starting
materials wherein each polymeric starting material includes at
least one cross-linkable group. In the case of an intraocular lens,
the T.sub.g should be less than 25.degree. C. This allows the lens
to be folded, facilitating implantation.
[0073] The crosslinking reaction of the polymeric starting material
is accomplished via a hydrosilylation reaction. The general scheme
for the hydrosilylation reaction is shown below.
##STR00009##
[0074] During this crosslinking step, a high molecular weight long
vinyl-capped silicone polymer and multi-functional vinyl-capped
silicone resin are crosslinked using multifunctional hydrosilane
crosslinkers. This crosslinking step forms the first polymer matrix
in the presence of MC and photoinitiator.
[0075] In some embodiments, the high molecular weight, long
vinyl-capped silicone polymer has the following formula.
##STR00010##
[0076] In some examples, m represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, m representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0077] In some examples, n represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, n representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0078] In some embodiments, multi-functional vinyl-capped silicone
resin has the following formula.
##STR00011##
[0079] In some examples, x represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, x representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0080] In some examples, y represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, y representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0081] In some embodiments, multi-functional hydrosilane
crosslinker has the following formula.
##STR00012##
[0082] In some examples, n represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, n representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0083] Illustrative examples of suitable cross-linkable groups
include but are not limited to vinyl, hydride, acetoxy, alkoxy,
amino, anhydride, aryloxy, carboxy, enoxy, epoxy, halide, isocyano,
olefinic, and oxine. In more preferred embodiments, the polymeric
starting material includes terminal monomers (also referred to as
endcaps) that are either the same or different from the one or more
monomers that comprise the polymeric starting material but include
at least one cross-linkable group. In other words, the terminal
monomers begin and end the polymeric starting material and include
at least one cross-linkable group as part of its structure.
Although it is not necessary for the practice of the present
invention, the mechanism for cross-linking the polymeric starting
material preferably is different than the mechanism for the
stimulus-induced polymerization of the components that comprise the
refraction modulating composition. For example, if the refraction
modulating composition is polymerized by photoinduced
polymerization, then it is preferred that the polymeric starting
materials have cross-linkable groups that are polymerized by any
mechanism other than photoinduced polymerization.
[0084] An especially preferred class of polymeric starting
materials for the formation of the first polymer matrix is
polysiloxanes (also known as "silicones") endcapped with a terminal
monomer which includes a cross-linkable group selected from the
group consisting of vinyl, acetoxy, amino, alkoxy, halide, hydroxy,
and mercapto. Because silicone IOLs tend to be flexible and
foldable, generally smaller incisions may be used during the IOL
implantation procedure. An example of an especially preferred
polymeric starting materials are vinyl endcapped dimethylsiloxane
diphenylsiloxane copolymer, silicone resin, and silicone hydride
crosslinker that are crosslinked via an addition polymerization by
platinum catalyst to form the silicone matrix (see the above
reaction scheme). Other such examples may be found in U.S. Pat. No.
5,236,970; U.S. Pat. No. 5,376,694; U.S. Pat. No. 5,278,258; U.S.
Pat. No. 5,444,106; and, others similar to the described
formulations. U.S. Pat. No. 5,236,970; U.S. Pat. No. 5,376,694;
U.S. Pat. No. 5,278,258; and U.S. Pat. No. 5,444,106 are
incorporated herein by reference in their entirety.
[0085] The MC that is used in fabricating IOLs is as described
above except that it has the additional requirement of
biocompatibility. The MC is capable of stimulus-induced
polymerization and may be a single component or multiple components
so long as: (1) it is compatible with the formation of the first
polymer matrix; (2) it remains capable of stimulus-induced
polymerization after the formation of the first polymer matrix; and
(3) it is freely diffusible within the first polymer matrix. In
general, the same type of monomers that are used to form the first
polymer matrix may be used as components of the refraction
modulating composition. However, because of the requirement that
the MC macromer must be diffusible within the first polymer matrix,
the MC macromers generally tend to be smaller (i.e., have lower
molecular weights) than the starting polymeric materials used to
form the first polymer matrix. In addition to the one or more
monomers, the MC may include other components such as initiators
and sensitizers that facilitate the formation of the second polymer
network.
[0086] In preferred embodiments, the stimulus-induced
polymerization is photopolymerization. In other words, the one or
more monomers or macromers that comprise the refraction modulating
composition each preferably includes at least one group that is
capable of photopolymerization. Illustrative examples of such
photopolymerizable groups include but are not limited to acrylate,
allyloxy, cinnamoyl, methacrylate, stibenyl, and vinyl. In more
preferred embodiments, the refraction modulating composition
includes a photoinitiator (any compound used to generate free
radicals) either alone or in the presence of a sensitizer. Examples
of suitable photoinitiators include acetophenones (e.g.,
substituted haloacetophenones, and diethoxyacetophenone);
2,4-dichloromethyl-1,3,5-trazines; benzoin methyl ether; and
o-benzoyl oximino ketone. Examples of suitable sensitizers include
p-(dialkyiamino)aryl aldehyde; N-alkylindolylidene; and
bis[p-(dialkylamino)benzylidene]ketone.
[0087] Because of the preference for flexible and foldable IOLs, an
especially preferred class of MC monomers is polysiloxanes
endcapped with a terminal siloxane moiety that includes a
photopolymerizable group. Non-limiting examples of a suitable
photopolymerizable group include, but are not limited to acrylate,
allyloxy, cinnamoyl, methacrylate, stibenyl, and vinyl. An
illustrative representation of such a monomer is:
X--Y--X.sup.1
wherein Y is a siloxane which may be a monomer, a homopolymer or a
copolymer formed from any number of siloxane units, and X and
X.sup.1 may be the same or different and are each independently a
terminal siloxane moiety that includes a photopolymerizable group.
Non-limiting examples of a suitable photopolymerizable group
include, but are not limited to acrylate, allyloxy, cinnamoyl,
methacrylate, stibenyl, and vinyl. An illustrative example of Y
includes:
##STR00013##
wherein m and n are independently each an integer; and, R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 are independently each hydrogen,
alkyl (substituted, primary, secondary, tertiary, cycloalkyl),
aryl, or heteroaryl. In preferred embodiments, R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are independently C.sub.1-C.sub.10 alkyl or
phenyl. Because MC monomers with a relatively high aryl content
have been found to produce larger changes in the refractive index
of the inventive lens, it is generally preferred that at least one
of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 is an aryl, particularly
phenyl. In more preferred embodiments, R.sup.1, R.sup.2, and
R.sup.3 are the same and are methyl, ethyl or propyl with the
proviso that R.sup.4 is phenyl.
[0088] In some examples, m represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, m representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0089] In some examples, n represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, n representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0090] Illustrative examples of X and X.sup.1 (or X.sup.1 and X
depending on how the MC polymer is depicted) are:
##STR00014##
[0091] respectively wherein: R.sup.5 and R.sup.6 are independently
each hydrogen, alkyl, aryl, or heteroaryl; and Z is a
photopolymerizable group.
[0092] In preferred embodiments R.sup.5 and R.sup.6 are
independently each C.sub.1-C.sub.10 alkyl or phenyl and Z is a
photopolymerizable group that includes a moiety selected from the
group consisting of acrylate, allyloxy, cinnamoyl, methacrylate,
stibenyl, and vinyl. In more preferred embodiments, R.sup.5 and
R.sup.6 are methyl, ethyl, or propyl and Z is a photopolymerizable
group that includes an acrylate or methacrylate moiety.
[0093] In some embodiments, a MC macromer has the following
formula:
##STR00015##
[0094] wherein X and X.sup.1 are the same as defined above, and
wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are the same as
defined above. In some examples, m represents an integer having a
value between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500;
1 and 8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1
and 5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1
and 3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1
and 500 or any range found within any of the aforementioned ranges.
In some examples, m representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0095] In some examples, n represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, n representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0096] In general, a suitable modifying composition consists of a
lower molecular weight polydimethyl-siloxane macromer containing
polymerizable methacrylate functional end groups and a bezoin
photoinitiator. In some embodiments, a suitable modifying
composition has the following formula.
##STR00016##
[0097] The above structure is a polydimethyl siloxane end-capped
with photopolymerizable methacrylate functional groups. In some
examples, x represents an integer having a value between 1 and
10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and 8,000; 1 and
7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and 5,500; 1 and
5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and 3,000; 1 and
2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and 500 or any
range found within any of the aforementioned ranges. In some
examples, x representes an integer having an average value between
1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and 8,000; 1
and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and 5,500; 1
and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and 3,000; 1
and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and 500 or any
range found within any of the aforementioned ranges.
[0098] In some examples, n represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, n representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0099] In some embodiments, a suitable modifying composition has
the following formula.
##STR00017##
[0100] The above modifying composition has a structure comprising a
polydimethyl siloxane end-capped with benzoin photoinitiator. In
some examples, x represents an integer having a value between 1 and
10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and 8,000; 1 and
7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and 5,500; 1 and
5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and 3,000; 1 and
2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and 500 or any
range found within any of the aforementioned ranges. In some
examples, x representes an integer having an average value between
1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and 8,000; 1
and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and 5,500; 1
and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and 3,000; 1
and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and 500 or any
range found within any of the aforementioned ranges.
[0101] In some examples, n represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, n representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0102] Additional illustrative examples of such MC monomers include
dimethylsiloxane-diphenylsiloxane copolymer endcapped with a vinyl
dimethylsilane group (see below);
##STR00018##
[0103] In some examples, m represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, m representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0104] In some examples, n represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, n representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0105] Another illustrative examples of such MC monomers includes
dimethylsiloxane-methylphenylsiloxane copolymer endcapped with a
methacryloxypropyl dimethylsilane group (see below);
##STR00019##
[0106] In some examples, m represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, m representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0107] In some examples, n represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, n representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0108] A preferred modifying composition is the dimethylsiloxane
macromer endcapped with a methacryloxypropyldimethylsilane group
(see below).
##STR00020##
[0109] In some examples, x represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, x representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0110] In some examples, n represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, n representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0111] Although any suitable method may be used, a ring-opening
reaction of one or more cyclic siloxanes in the presence of triflic
acid has been found to be a particularly efficient method of making
a class of MC monomers. Briefly, the method comprises contacting a
cyclic siloxane with a compound of the formula:
##STR00021##
in the presence of triflic acid wherein R.sup.5 and R.sup.6 are
independently each hydrogen, alkyl, aryl, or heteroaryl; and Z is a
photopolymerizable group. The cyclic siloxane may be a cyclic
siloxane monomer, homopolymer, or copolymer. Alternatively, more
than one cyclic siloxane may be used. For example, a cyclic
dimethylsiloxane tetrameter and a cyclic methyl-phenylsiloxane
trimer are contacted with
bis-methacryloxypropyltetramethyldisiloxane in the presence of
triflic acid to form a dimethyl-siloxane methyl-phenylsiloxane
copolymer that is endcapped with a
methacryloxylpropyl-dimethylsilane group, an especially preferred
MC monomer, such as the MC monomer shown below.
##STR00022##
[0112] In some examples, x represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, x representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0113] In some examples, n represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, n representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0114] In addition to the silicone-based MCs described above,
acrylate-based MC can also be used in the practice of the
invention. The acrylate-based macromers of the invention have the
general structure wherein X and X.sup.1 may be the same or
different and/or are each independently a terminal siloxane moiety
that includes a photopolymerizable group. Non-limiting examples of
a suitable photopolymerizable group include, but are not limited to
acrylate, allyloxy, cinnamoyl, methacrylate, stibenyl, and
vinyl
X-A.sub.n-Q-A.sub.n-X.sup.1
or
X-A.sub.n-A.sup.1.sub.m-Q-A.sub.1.sub.m-A.sub.n-X.sup.1
wherein Q is an acrylate moiety capable of acting as an initiator
for Atom Transfer Radical Polymerization ("ATRP"), A and A.sup.1
have the general structure:
##STR00023##
[0115] wherein R.sup.1 is selected from the group comprising
alkyls, halogenated alkyls, aryls and halogenated aryls and X and
X.sup.1 are groups containing photopolymerizable moieties and m and
n are integers. In some examples, m represents an integer having a
value between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500;
1 and 8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1
and 5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1
and 3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1
and 500 or any range found within any of the aforementioned ranges.
In some examples, m representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0116] In some examples, n represents an integer having a value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges. In
some examples, n representes an integer having an average value
between 1 and 10,000; 1 and 9,500; 1 and 9,000; 1 and 8,500; 1 and
8,000; 1 and 7,500; 1 and 7,000; 1 and 6,500; 1 and 6,000; 1 and
5,500; 1 and 5,000; 1 and 4,500; 1 and 4,000; 1 and 3,500; 1 and
3,000; 1 and 2,500; 1 and 2,000; 1 and 1,500; 1 and 1,000; 1 and
500 or any range found within any of the aforementioned ranges.
[0117] In one embodiment the acrylate based MC macromer has the
formula:
##STR00024##
[0118] wherein R.sup.2 is alkyl or halogenated alkyl; R.sup.3 is
alkyl, halogenated alkyl, aryl or halogenated aryls; R.sup.4 is
alkyl, halogenated alkyl, aryl or halogenated aryl; and, with the
proviso that R.sup.3 and R.sup.4 are different. In some
embodiments, the value of n is between 1 and 200; 1 and 190; 1 and
180; 1 and 170; 1 and 160; 1 and 150; 1 and 140; 1 and 130; 1 and
120; 1 and 110; 1 and 100; 1 and 90; 1 and 80; 1 and 70; 1 and 60;
1 and 50; 1 and 40; 1 and 30; 1 and 20; 1 and 10; or any range in
between. For example, when the value of n is between 1 and 200,
this also contemplates a value of n between 17 and 24. In some
embodiments the value of m is between 1 and 200; 1 and 190; 1 and
180; 1 and 170; 1 and 160; 1 and 150; 1 and 140; 1 and 130; 1 and
120; 1 and 110; 1 and 100; 1 and 90; 1 and 80; 1 and 70; 1 and 60;
1 and 50; 1 and 40; 1 and 30; 1 and 20; 1 and 10; or any range in
between. For example, when the value of m is between 1 and 200,
this also contemplates a value of m between 17 and 24.
[0119] After the optical element is formed, it is then positioned
in the area where the optical properties are to be modified. For an
intraocular lens, this means implantation into the eye using known
procedures. Once the element is in place and is allowed to adjust
to its environment, it is then possible to modify the optical
properties of the element through exposure to an external
stimulus.
[0120] The nature of the external stimulus can vary but it must be
capable of reducing polymerization of the MC without adversely
affecting the properties of the optical element. Typical external
stimuli that can be used in practice of the invention include heat
and light, with light preferred. In the case of intraocular lenses,
ultraviolet or infrared radiation is preferred with ultraviolet
light most preferred.
[0121] When the element is exposed to the external stimulus, the MC
polymerization forms a second polymer matrix, interspersed within
the first polymer matrix. When the polymerization is localized or
when only a portion of the MC is polymerized, there is a difference
in the chemical potential between the reacted and unreacted regions
of the lens. The MC then migrates within the element to reestablish
the thermodynamic equilibrium within the optical element.
[0122] The formation of the second polymer matrix and the
re-distribution of the MC can each affect the optical properties of
the element. For example, the formation of the second polymer
matrix can cause changes in the refractive index of the element.
The migration of the modifying compound can alter the overall shape
of the element, further affecting the optical properties by
changing the radii of curvatures of the optical element.
[0123] It is possible to expose the optical element to a spatially
defined irradiance profile to create a lens with different optical
properties. In one embodiment, it is possible to create an
intraocular lens that can be converted into an aspheric lens after
implantation. This is accomplished by exposing the lens to a
mathematically defined spatial irradiance profile. An example of
the type of profiles that can be used to induce asphericity in the
lens are of the form
Asph(.rho.)=A.rho..sup.4-B.rho..sup.2+1 (Equation 1)
[0124] Where A and B are coefficients and p is a radial coordinate.
A normalized plot of this function, where A=B=4, is displayed in
FIG. 5.
[0125] Another approach is to linearly combine weighted amounts of
the profile (Asph) displayed in equation 1 with spatial irradiance
profiles that are currently used to correct for spherical
refractive errors and spherocylindrical refractive errors as well
as with Power Neutral Profiles, i.e., profiles that neither add or
subtract refractive power from the LAL. This approach has the dual
benefits of correcting the lower aberrations, e.g. sphere and
cylinder, along with imparting the requisite amount of induced
asphericity to provide increased depth of focus. This can be
described mathematically as follows:
Profile(.rho.)=SCN(.rho.)+.beta.Asph(.rho.) (Equation 2)
[0126] where SCN(.rho.) refers to either a spherical,
spherocylindrical or power neutral spatial irradiance profile,
Asph(.rho.) is the same as in equation 1, and .beta. is a weighting
factor that can range from 0 to 1. As an example of this approach,
consider the cross-sectional profiles shown in FIG. 6. These plots
were generated by combining weighted amounts of the profile
represented by equation 1 with a power neutral profile.
[0127] By way of a reaction sequence, the following example shows
how the formation of the second polymer matrix and the
re-distribution of the MC is accomplished. In the example provided
below, the MC having the formula:
##STR00025##
[0128] is exposed to UV light, thereby creating a radical species.
This process is represented schematically in the reaction scheme
below.
##STR00026##
[0129] After exposing the MC to UV light, the resulting radical
species are free to react with the first polymer matrix. In the
example, below the first polymer matrix was formed using a polymer
having the following structure:
##STR00027##
[0130] The radical species generated by exposing the MC to UV light
then reacts with the first polymer matrix according to the reaction
scheme below:
##STR00028##
[0131] The reaction scheme for photopolymerization of
photo-reactive MC in the presence of the first polymer lens matrix
is the same for the adjustment and lock-in procedures. The
difference between the adjustment procedure and lock-in procedure
is the spatial irradiance profiles applied to each procedure.
EXAMPLES
[0132] The following examples are included to demonstrate preferred
embodiments of the invention. It should be appreciated by those of
skill in the art that the techniques disclosed in the examples
which follow represent techniques discovered by the inventor to
function well in the practice of the invention, and thus can be
considered to constitute preferred modes for its practice. However,
those of skill in the art should, in light of the present
disclosure, appreciate that many changes can be made in the
specific embodiments which are disclosed and still obtain a like or
similar result without departing from the spirit and scope of the
invention.
Example 1
[0133] A series of light adjustable lenses containing a
silicone-based MC were prepared using standard molding techniques
known to those skilled in the art. The lens had a first polymer
matrix prepared from a silicone hydride crosslinked vinyl endcapped
diphenylsiloxane dimethylsiloxane. The first polymer matrix
comprised about 70 weight % of the lens. The lens also comprised
about 30 weight % of a MC (methacrylate endcapped
polydimethylsiloxane), 1 weight % (based on MC) of a photoinitiator
(benzoin-tetrasiloxane-benzoin), and 0.04 weight % (based on MC) UV
absorber. The lenses had an initial nominal power of +20.0
diopters. Twelve groups, of four LALs each, were exposed to a
spatial irradiance profile defined by Equation 2 with beta values
ranging from 0.05 to 0.57. Table 1 summarizes the specific spatial
irradiance profile, average irradiance, and time applied to each of
the LAL groups. At 48 hours post irradiation, the wavefronts of
each of the lenses was measured. The measured 4.sup.th (Z12) and
6.sup.th (Z24) order spherical aberration values for each of the 12
irradiation groups were averaged together and plotted as a function
of increasing .beta. value as show in FIG. 7.
TABLE-US-00001 TABLE 1 Summary of treatment conditions and induced
spherical aberration for those lenses that did not receive a prior
adjustment. The measurement aperture was 4 mm for all spherical
aberration measurements. Duration Applied Power Bm Size .DELTA. 4th
Order SA .DELTA. 6th Order SA Lens ID Profile (sec) (mW) (mm)
.DELTA. Z12 (.mu.m) .DELTA. Z24 (.mu.m) 6699 In-vitro PN Profile +
Beta = 0.05 90 4.130 5.30 0.194 0.016 6701 In-vitro PN Profile +
Beta = 0.05 90 4.130 5.30 0.115 0.050 6706 In-vitro PN Profile +
Beta = 0.05 90 4.130 5.30 0.003 0.054 6708 In-vitro PN Profile +
Beta = 0.05 90 4.130 5.30 0.029 0.053 Average 0.085 0.043 St. Dev
0.087 0.018 189-26 In-vitro PN Profile + Beta = 0.10 90 3.820 5.30
-0.019 0.017 189-29 In-vitro PN Profile + Beta = 0.10 90 3.820 5.30
-0.024 0.017 189-31 In-vitro PN Profile + Beta = 0.10 90 3.820 5.30
-0.020 0.016 189-33 In-vitro PN Profile + Beta = 0.10 90 3.820 5.30
-0.036 0.013 Average -0.025 0.016 St. Dev 0.008 0.002 189-27
In-vitro PN Profile + Beta = 0.15 90 3.670 5.30 -0.056 0.013 189-30
In-vitro PN Profile + Beta = 0.15 90 3.670 5.30 -0.055 0.013 189-32
In-vitro PN Profile + Beta = 0.15 90 3.670 5.30 -0.054 0.012 189-34
In-vitro PN Profile + Beta = 0.15 90 3.670 5.30 -0.060 0.010
Average -0.056 0.012 St. Dev 0.003 0.001 189-35 In-vitro PN Profile
+ Beta = 0.20 90 3.510 5.30 -0.088 0.018 189-38 In-vitro PN Profile
+ Beta = 0.20 90 3.510 5.30 -0.088 0.013 189-40 In-vitro PN Profile
+ Beta = 0.20 90 3.510 5.30 -0.083 0.018 189-44 In-vitro PN Profile
+ Beta = 0.20 90 3.510 5.30 -0.081 0.013 Average -0.085 0.015 St.
Dev 0.003 0.003 189-37 In-vitro PN Profile + Beta = 0.25 90 3.360
5.30 -0.107 0.013 189-39 In-vitro PN Profile + Beta = 0.25 90 3.360
5.30 -0.111 0.006 189-41 In-vitro PN Profile + Beta = 0.25 90 3.360
5.30 -0.106 0.009 189-45 In-vitro PN Profile + Beta = 0.25 90 3.360
5.30 -0.130 0.006 Average -0.113 0.009 St. Dev 0.011 0.003 185-3-2
In-vitro PN Profile + Beta = 0.30 90 3.210 5.30 -0.151 0.010
185-3-15 In-vitro PN Profile + Beta = 0.30 90 3.210 5.30 -0.156
0.008 188-2-18 In-vitro PN Profile + Beta = 0.30 90 3.210 5.30
-0.163 0.012 189-47 In-vitro PN Profile + Beta = 0.30 90 3.210 5.30
-0.148 0.007 Average -0.155 0.009 St. Dev 0.007 0.002 185-3-11
In-vitro PN Profile + Beta = 0.35 90 3.060 5.30 -0.193 0.005
188-2-16 In-vitro PN Profile + Beta = 0.35 90 3.060 5.30 -0.194
0.003 189-46 In-vitro PN Profile + Beta = 0.35 90 3.060 5.30 -0.192
0.002 189-48 In-vitro PN Profile + Beta = 0.35 90 3.060 5.30 -0.182
0.002 Average -0.190 0.003 St. Dev 0.006 0.002 6700 In-vitro PN
Profile + Beta = 0.40 90 2.900 5.30 -0.240 0.013 6704 In-vitro PN
Profile + Beta = 0.40 90 2.900 5.30 -0.241 0.011 6707 In-vitro PN
Profile + Beta = 0.40 90 2.900 5.30 -0.222 0.011 6709 In-vitro PN
Profile + Beta = 0.40 90 2.900 5.30 -0.224 0.017 Average -0.232
0.013 St. Dev 0.010 0.003 6710 In-vitro PN Profile + Beta = 0.45 90
2.750 5.30 -0.277 0.004 6712 In-vitro PN Profile + Beta = 0.45 90
2.750 5.30 -0.284 0.003 6715 In-vitro PN Profile + Beta = 0.45 90
2.750 5.30 -0.274 0.006 6717 In-vitro PN Profile + Beta = 0.45 90
2.750 5.30 -0.266 -0.002 Average -0.275 0.003 St. Dev 0.007 0.003
6713 In-vitro PN Profile + Beta = 0.50 90 2.600 5.30 -0.303 0.001
6716 In-vitro PN Profile + Beta = 0.50 90 2.600 5.30 -0.322 -0.002
6718 In-vitro PN Profile + Beta = 0.50 90 2.600 5.30 -0.318 -0.009
Average -0.314 -0.003 St. Dev 0.010 0.005 6719 In-vitro PN Profile
+ Beta = 0.55 90 2.440 5.30 -0.356 -0.009 6723 In-vitro PN Profile
+ Beta = 0.55 90 2.440 5.30 -0.347 -0.016 6727 In-vitro PN Profile
+ Beta = 0.55 90 2.440 5.30 -0.350 -0.011 6729 In-vitro PN Profile
+ Beta = 0.55 90 2.440 5.30 -0.350 -0.021 Average -0.351 -0.014 St.
Dev 0.004 0.006 6721 In-vitro PN Profile + Beta = 0.57 90 2.380
5.30 -0.368 -0.015 6725 In-vitro PN Profile + Beta = 0.57 90 2.380
5.30 -0.350 -0.026 6728 In-vitro PN Profile + Beta = 0.57 90 2.380
5.30 -0.359 -0.019 6730 In-vitro PN Profile + Beta = 0.57 90 2.380
5.30 -0.385 -0.030 Average -0.366 -0.022 St. Dev 0.015 0.007
[0134] Inspection of the plot indicates several interesting
features. The first is the nearly linearly increase in induced
4.sup.th order spherical aberration as a function of increasing
.beta. value. The second feature is the nearly complete absence of
any 6.sup.th order spherical aberration induction, indicating that
the induced spherical aberration is essentially pure 4.sup.th order
spherical aberration. This is important because it has been shown
that the presence of 6.sup.th order spherical aberration will have
the affect of nulling out any induced depth of focus produced by
the induction of negative 4.sup.th order spherical aberration.
(Thibos et al., 2004) The third feature to note is the small
standard deviation in the average, induced 4.sup.th order spherical
aberration for a specific .beta. value. This fact indicates that it
is possible to adjust the amount of asphericity in the LAL by
targeted, discrete values, which will allow true customization of
patients' depth of focus. And finally, as written above, the
targeted amount of total ocular 4.sup.th order spherical aberration
for optimizing visual acuity between 40 cm and distance emmetropia
is -0.125 .mu.m. Inspection of the data in Table 2 and FIG. 7 and
assuming an average starting ocular spherical aberration at a 4 mm
aperture of +0.10 .mu.m, indicates that the profile with a beta
value of 0.40 would be ideal for inducing the requisite amount of
negative asphericity.
[0135] The above example involved irradiating LALs that had not
received a prior adjustment. However, there will be instances where
it is necessary to first adjust the spherical and/or
spherocylindrical power of the LAL before the aspheric adjustment.
The LAL is a closed thermodynamic system, i.e. we can't add or
remove particles, MC, from the lens. As a consequence, each
subsequent refractive adjustment consumes MC leaving less for
subsequent adjustments. In addition, upon polymerization of MC
during adjustment, the polymerized MC forms an interpenetrating
matrix with the host matrix polymer. This action has the effect of
increasing the stiffness of the lens. Because the refractive
change, i.e. spherical, spherocylindrical, aspheric, etc., of the
LAL is accomplished by a shape change, the amount of induced
asphericity after an initial adjustment should be reduced for same
treatment conditions as with the no prior adjustment cases
summarized in FIG. 7.
[0136] To investigate this, a series of LALs were initially given
either a myopic or hyperopic primary adjustment followed by an
aspheric treatment 48 hours post the initial, primary adjustment.
FIG. 8 displays both the 4.sup.th and 6.sup.th order spherical
aberration values for LALs that received either an initial
hyperopic or myopic adjustment followed by an aspheric treatment
with beta values ranging between 0.30 and 0.57. For comparison, the
LALs that received the aspheric treatment as a primary adjustment
are also plotted on the same graph.
[0137] Inspection and comparison of the data for the different
treatment conditions indicate several interesting trends. The first
overall theme is that, as expected, increasing the beta value,
which effectively increases the amount of aspheric character of the
treatment beam, has the effect of increasing the amount of induced
4.sup.th order asphericity in the LAL. This is true whether the LAL
initially received a primary adjustment or if the LAL has received
no prior adjustment. The second thing to note is that for a given
beta, mediated aspheric profile, the type of refractive adjustment
preceding the aspheric treatment directly impacts how much 4.sup.th
order asphericity is induced in the lens. For example, consider the
three different sets of LALs that were adjusted with the
.beta.=0.57 aspheric profile after a hyperopic adjustment, a myopic
adjustment, and no adjustment. Inspection of the graph indicates
that those lenses receiving no prior adjustment displayed the
largest amount of induced 4.sup.th order spherical aberration,
followed by the LALs that initially received a myopic adjustment,
with the LALs after a hyperopic adjustment showing the smallest
amount of induced asphericity. The reasons for this general trend
are twofold. The first, which was discussed above, is due to the
simple fact that the LALs that received no prior adjustment
obviously have more starting MC and the LAL matrix is not as stiff
as compared to the other two sets of LALs and thus, for the same
given aspheric dose, should show more 4.sup.th order asphericity
induction. The reasons why the LALs receiving an initial myopic
adjustment display greater amounts of induced 4.sup.th order
spherical aberration as compared to those LALs receiving a
hyperopic adjustment as their primary adjustment, even though the
magnitude of the refractive change (-1.0 D vs +1.0 D) is the same,
can be explained by the fact that the total energy underneath the
spatial irradiance profile for the given myopic adjustment is less
than that as compared to the hyperopic adjustment profile. Because
of this fact, more macromer will be consumed during the initial
hyperopic adjustment and a stronger, interpenetrating network will
be formed, thus preventing more aspheric induction. Another
important aspect of the data to note, is that regardless of prior
adjustment, the application of the aspheric treatment does not
induce any 6.sup.th order spherical aberration.
Example 2
[0138] To test the ability of the aspheric adjustment profiles to
induce enough asphericity to provide patients' with increased depth
of focus, a series of subjects were implanted with the light
adjustable lens after routine cataract surgery, given a prior
treatment to correct for postoperative residual sphere and
cylinder, and then given an aspheric adjustment using the corneal
compensated versions of the profiles described in Example 1. FIG. 9
and Table 2 summarize the monocular visual acuity data for a series
of 32 eyes adjusted with aspheric profiles possessing a beta value
between 0.40 and 0.57. For comparison, the average uncorrected
visual acuity values for 12 eyes implanted with a LAL and adjusted
for distance emmetropia only, are displayed as well. All of the
LALs received some type of primary adjustment before the
application of the aspheric profile.
[0139] Inspection of the graph in FIG. 9 indicates several
important features. The first is that, on average, from 40 cm to
distance emmetropia, the patients adjusted with an aspheric
treatment profile possessed uncorrected visual acuities between
20/20 and 20/32. In fact, as summarized in Table 2, 75% of the eyes
treated with the aspheric profile treatment regimen, possess an
uncorrected visual acuity of 20/32 or better from 40 cm to distance
emmetropia. In contrast, inspection of the results for those eyes
receiving treatment to correct for residual spherical and
spherocylindrical refractive errors, only, show that while the
distance, uncorrected visual acuity results are better than the
aspheric cases (83%>20/20 and 100%>20/25 or better), these
eyes, as expected, have essentially no near vision capability, i.e.
8% (1/12) see at least 20/32 at 40 cm. Therefore, this data
indicates that the application of the aspheric profiles to
implanted LALs has the ability to increase the depth of focus of a
patients' eye.
TABLE-US-00002 TABLE 1 Monocular visual acuity (VA) results for
those eyes receiving an aspheric treatment (n = 32). VA FAR 60 cm
40 cm Far BCVA .gtoreq.20/20 9/32 (28%) 17/32 (53%) 2/32 (6%) 21/32
(65%) .gtoreq.20/25 23/32 (72%) 27/32 (84%) 11/32 (35%) 31/32 (97%)
.gtoreq.20/32 28/32 (88%) 32/32 (100%) 24/32 (75%) 32/32 (100%)
.gtoreq.20/40 32/32 (100%) 32/32 (100%) 31/32 (97%) 32/32 (100%)
.gtoreq.20/60 32/32 (100%) 32/32 (100%) 32/32 (100%) 32/32
(100%)
TABLE-US-00003 TABLE 2 Monocular visual acuity (VA) results for
those LAL eyes adjusted for distance visual acuity only (n = 12).
VA FAR 60 cm 40 cm Far BCVA .gtoreq.20/20 10/12 (83%) 1/12 (8%)
0/12 (0%) 12/12 (100%) .gtoreq.20/25 12/12 (100%) 3/12 (25%) 0/12
(0%) 12/12 (100%) .gtoreq.20/32 12/12 (100%) 8/12 (67%) 1/12 (8%)
12/12 (100%) .gtoreq.20/40 12/12 (100%) 12/12 (100%) 7/12 (58%)
12/12 (100%) .gtoreq.20/60 12/12 (100%) 12/12 (100%) 12/12 (100%)
12/12 (100%)
[0140] As indicated in FIG. 9, the total measured 4.sup.th order
spherical aberration over a 4 mm pupil in the 32 eyes ranged from
-0.04 .mu.m to -0.23 .mu.m. As stated above, theoretical
considerations indicate that the ideal amount of final 4.sup.th
order spherical aberration to provide optimal visual acuity between
40 cm and distance emmetropia is -0.125 .mu.m. To consider the
impact of this range of induced negative asphericity on the final
visual acuities at different object distances, FIG. 10 segregates
the 32 eyes into two groups: High Spherical Aberration (-0.10 .mu.m
to -0.23 .mu.m) and Low Spherical Aberration (-0.04 .mu.m to -0.10
.mu.m). As expected, those eyes with higher amounts of induced
negative spherical aberration, on average, show better visual
acuities at 40 cm (78% 7/9 patients.gtoreq.20/25 or J1) then those
with lower spherical aberration (22%, 5/23 patients.gtoreq.20/25 or
J1) with a slight decrease in their distance visual acuities (56%
vs 78% at 20/25). However, inspection of the VA acuity curves from
40 cm to distance emmetropia in FIG. 10, indicate that, on average,
the curve is quite flat and the majority of the eyes possess visual
acuities of 20/25 or better. Comparison again with the 12 eyes
adjusted for distance emmetropia only, indicates that from 40 cm to
distance emmetropia, the eyes that received some type of aspheric
induction achieve much greater range of vision, i.e. increased
depth of focus.
TABLE-US-00004 TABLE 3 Monocular visual acuity (VA) results for
those eyes with low amounts of final 4.sup.th order spherical
aberration, -0.04 to -0.10 .mu.m (n = 23). VA FAR 60 cm 40 cm Far
BCVA .gtoreq.20/20 (J1+) 7/23 (30%) 12/23 (8%) 0/23 (0%) 15/23
(65%) .gtoreq.20/25 (J1) 15/23 (74%) 19/23 (83%) 5/23 (22%) 22/23
(96%) .gtoreq.20/32 (J2) 20/23 (100%) 23/23 (100%) 15/23 (65%)
12/12 (100%) .gtoreq.20/40 (J3) 23/23 (100%) 23/23 (100%) 23/23
(100%) 12/12 (100%) .gtoreq.20/60 23/23 (100%) 23/23 (100%) 23/23
(100%) 12/12 (100%)
TABLE-US-00005 TABLE 4 Monocular visual acuity (VA) results for
those eyes with high amounts of final 4th order spherical
aberration, -0.11 to -0.23 .mu.m (n = 9). VA FAR 60 cm 40 cm Far
BCVA .gtoreq.20/20 (J1+) 2/9 (22%) 4/9 (8%) 2/9 (22%) 6/9 (67%)
.gtoreq.20/25 (J1) 5/9 (56%) 7/9 (78%) 7/9 (78%) 8/9 (89%)
.gtoreq.20/32 (J2) 8/9 (89%) 8/9 (89%) 9/9 (100%) 9/9 (100%)
.gtoreq.20/40 (J3) 9/9 (100%) 9/9 (100%) 9/9 (100%) 9/9 (100%)
.gtoreq.20/60 9/9 (100%) 9/9 (100%) 9/9 (100%) 9/9 (100%)
[0141] The above discussion considered the monocular visual
acuities of the treated eyes, only. However, one approach that will
optimize post LAL implantation patients' vision at all distances is
to correct one of the patients' eyes (usually the dominant eye) to
distance emmetropia and then to adjust the other eye of the patient
first to distance emmetropia followed by application of the
aspheric treatment. As an example of this procedure, consider the
data displayed in FIG. 11 and Table 6, which displays both the
monocular and binocular visual acuities for a series of patients
(n=10) that had a low (-0.04 .mu.m to -0.10 .mu.m) amount of
spherical aberration induced in one eye and the other eye was
implanted with a LAL and adjusted for distance emmetropia. For the
distance dominant eye, the final refraction varied between plano
and -0.50 D. Inspection of the monocular visual acuity results for
the two eyes displays the same visual characteristics already
discussed; namely, the eye corrected for distance emmetropia
displays excellent distance visual acuity, but rather poor near
vision and the aspheric eyes display improved depth of focus at the
expense of some distance visual acuity. However, the binocular
visual acuity data indicates that combining the two eyes provide
outstanding visual acuities from 40 cm to distance emmetropia. In
fact, 100% of the patients possessed a visual acuity of 20/25 or
better from 40 cm to distance emmetropia.
TABLE-US-00006 TABLE 5 Binocular visual acuity (VA) results for
those eyes with low amounts of final 4th order spherical
aberration, -0.04 to -0.10 mm in their non-dominant eye and with
their other eye adjusted for distance emmetropia. The refraction in
the dominant eye ranged from +0.25 D to -0.25 D (n = 10). VA FAR 60
cm 40 cm 30 cm .gtoreq.20/20 (J1+) 6/10 (60%) 8/10 (80%) 1/10 (10%)
0/10 (0%) .gtoreq.20/25 (J1) 10/10 (100%) 10/10 (100%) 4/10 (40%)
0/10 (0%) .gtoreq.20/32 (J2) 10/10 (100%) 10/10 (100%) 10/10 (100%)
3/10 (30%) .gtoreq.20/40 (J3) 10/10 (100%) 10/10 (100%) 10/10
(100%) 8/10 (80%) .gtoreq.20/60 10/10 (100%) 10/10 (100%) 10/10
(100%) 10/10 (100%)
[0142] Combining this binocular approach with those eyes having
high amounts of induced asphericity (-0.11 .mu.m to -0.23 .mu.m),
indicates that 100% (4/4) of the patients possessed an uncorrected
visual of 20/25 or better from 40 cm to distance emmetropia.
TABLE-US-00007 TABLE 6 Binocular visual acuity (VA) results for
those eyes with high amounts of final 4th order spherical
aberration, -0.11 to -0.23 .mu.m in their non-dominant eye and with
their other eye adjusted for distance emmetropia. The refraction in
the dominant eye ranged from +0.25 D to -0.25 D (n = 4). VA FAR 60
cm 40 cm 30 cm .gtoreq.20/20 (J1+) 4/4 (100%) 3/4 (75%) 1/10 (10%)
0/4 (0%) .gtoreq.20/25 (J1) 4/4 (100%) 4/4 (100%) 4/4 (100%) 1/4
(25%) .gtoreq.20/32 (J2) 4/4 (100%) 4/4 (100%) 4/4 (100%) 4/4
(100%) .gtoreq.20/40 (J3) 4/4 (100%) 4/4 (100%) 4/4 (100%) 4/4
(100%) .gtoreq.20/60 4/4 (100%) 4/4 (100%) 4/4 (100%) 4/4
(100%)
Example 3
[0143] General examples disclosed herein include an optical element
composed of matrix polymer and a modulating composition (MC) that
can be polymerized by an external stimulus (e.g. heat, light, etc)
to control the amount of induced asphericity.
[0144] In each of the aforementioned examples, the lens may include
an optical element that is a lens. In additional examples, the
optical element is an intraocular lens (IOL). Also, the amount of
induced asphericity is controlled by the application of a specific
spatial irradiance profile. In some examples, the amount of induced
asphericity is induced monocularly to induce extended depth of
focus.
[0145] In particular examples, the amount of induced asphericity is
tailored to provide intermediate vision (60-80 cm) or near vision
(30-40 cm). In specific embodiments, the amount of induced
asphericity can be customized for specific individual values.
[0146] In certain embodiments, the amount of induced asphericity is
induced binocularly to induce extended depth of focus. In
particular examples, one eye is tailored for intermediate (60-80
cm) vision by the induction of a particular value of asphericity
and the other eye is corrected for distance emmetropia. In
alternate embodiments, one eye is tailored for near vision (30-40
cm) by the induction of a particular value of asphericity and the
other eye is corrected for distance emmetropia. In further
embodiments, both eyes are tailored for intermediate (60-80 cm)
vision by the induction of particular value of asphericity. In yet
another embodiment, both eyes are tailored for near (30-40 cm)
vision by the induction of particular value of asphericity. In some
embodiments, one eye is tailored for intermediate (60-80 cm) vision
by the induction of negative asphericity and the other eye is
tailored for intermediate vision (60-80 cm) vision by the induction
of positive asphericity. In particular embodiments, one eye is
tailored for near vision (30-40 cm) vision by the induction of
negative asphericity and the other eye is tailored for near vision
(30-40 cm) vision by the induction of positive asphericity.
[0147] In some examples, the amount of induced asphericity of the
lens is tailored to compensate for the spherical aberration of the
cornea. In other examples, the amount of induced asphericity of
both lenses are tailored to compensate for the spherical aberration
of their respective corneas. In alternate examples, one lens is
adjusted to remove the spherical aberration of the entire eye and
the other lens is adjusted to induce asphercity for intermediate
vision (60-80 cm). In some examples, one lens is adjusted to remove
the spherical aberration of the entire eye and the other lens is
adjusted to induce asphercity for near vision (30-40 cm).
REFERENCES
[0148] All patents and publications mentioned in the specification
are indicative of the level of those skilled in the art to which
the invention pertains. All patents and publications are herein
incorporated by reference in their entirety to the same extent as
if each individual publication was specifically and individually
indicated to be incorporated by reference.
PATENTS
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[0152] U.S. Pat. No. 5,278,258
[0153] U.S. Pat. No. 5,376,694
[0154] U.S. Pat. No. 5,444,106
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[0178] Although the present invention and its advantages have been
described in detail, it should be understood that various changes,
substitutions and alterations can be made herein without departing
from the spirit and scope of the invention as defined by the
appended claims. Moreover, the scope of the present application is
not intended to be limited to the particular embodiments of the
process, machine, manufacture, composition of matter, means,
methods and steps described in the specification. As one of
ordinary skill in the art will readily appreciate from the
disclosure of the present invention, processes, machines,
manufacture, compositions of matter, means, methods, or steps,
presently existing or later to be developed that perform
substantially the same function or achieve substantially the same
result as the corresponding embodiments described herein may be
utilized according to the present invention. Accordingly, the
appended claims are intended to include within their scope such
processes, machines, manufacture, compositions of matter, means,
methods, or steps.
* * * * *