U.S. patent application number 09/738432 was filed with the patent office on 2001-08-23 for methods and apparatus for accelerated orthokeratology.
Invention is credited to DeVore, Dale, Oefinger, Rory H..
Application Number | 20010016731 09/738432 |
Document ID | / |
Family ID | 21768765 |
Filed Date | 2001-08-23 |
United States Patent
Application |
20010016731 |
Kind Code |
A1 |
DeVore, Dale ; et
al. |
August 23, 2001 |
Methods and apparatus for accelerated orthokeratology
Abstract
An accelerated method of orthokeratology includes the steps of
softening of the cornea with a softening agent, applying a mold to
reshape the cornea to a desired anterior curvature, and rapidly
restabilizing or "fixing" the corneal tissues so that the cornea
retains its new configuration. A chemical softening agent, such as
glutaric anhydride is applied to the cornea to soften the cornea,
after which a specially designed mold of predetermined curvature
and configuration is applied to the cornea. Slight downward
pressure is applied to the mold for a predetermined period of time
to re-shape the cornea. The mold is maintained in position while a
stabilizing agent, such as a UV light source, is positioned above
the mold. The stabilizing agent, i.e. UV light, is applied to the
cornea for a predetermined time, wherein the stabilizing agent
immediately restabilizes the corneal tissue so that the cornea
immediately retains its shape upon removal of the mold. The
stabilization process can also be used for patients having already
undergone traditional orthokeratology to eliminate the need to
continue wearing a retainer to maintain the shape of the
cornea.
Inventors: |
DeVore, Dale; (Chelmsford,
MA) ; Oefinger, Rory H.; (Westerly, RI) |
Correspondence
Address: |
BARLOW, JOSEPHS & HOLMES, LTD.
101 DYER STREET
5TH FLOOR
PROVIDENCE
RI
02903
US
|
Family ID: |
21768765 |
Appl. No.: |
09/738432 |
Filed: |
December 15, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09738432 |
Dec 15, 2000 |
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09014955 |
Jan 28, 1998 |
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6161544 |
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Current U.S.
Class: |
606/1 ; 607/101;
607/88; 607/94 |
Current CPC
Class: |
A61F 2009/00872
20130101; A61F 9/013 20130101; A61F 2009/00853 20130101; A61P 27/02
20180101; A61F 2009/00882 20130101; G02C 7/047 20130101; A61F 9/008
20130101; A61F 9/009 20130101 |
Class at
Publication: |
606/1 ; 607/88;
607/94; 607/101 |
International
Class: |
A61B 017/00 |
Claims
What is claimed is:
1. A method of correcting refractive errors of the eye comprising
the steps of: destabilizing the corneal tissue of the eye so that
the anterior curvature of the cornea can be reshaped from a first
configuration to a second desired configuration; shaping the
softened cornea from the first configuration to the second desired
configuration by applying a mold to the cornea and applying
pressure thereto, said mold having a predetermined posterior
curvature and configuration which engages with the anterior
curvature of the cornea; and restabilizing the corneal tissues
while the anterior curvature of the cornea is positioned in said
second desired configuration.
2. The method of claim 1 wherein said step of destabilizing the
corneal tissues comprises administering to the cornea a softening
agent which is effective for destabilizing cross-linking between
the collagen fibrils of the stroma of the cornea.
3. The method of claim 2 wherein said softening agent is selected
from the group consisting of: anhydrides, acid chlorides, sulfonyl
chlorides, sulfonic acids, and combinations thereof.
4. The method of claim 1 wherein said step of restabilizing the
corneal tissues comprises exposing the corneal tissues to light
energy.
5. The method of claim 1 wherein said step of restabilizing the
corneal tissues comprises heating of the corneal tissues.
6. The method of claim 1 wherein heating of the corneal tissues
comprises heating by means of laser thermal keratoplasty.
7. The method of claim 1 wherein said step of restabilizing the
corneal tissues comprises administering to the cornea a chemical
crosslinking agent which is effective for cross-linking between the
collagen fibrils of the stroma of the cornea.
8. The method of claim 1 wherein said step of restabilizing the
corneal tissues comprises exposing the corneal tissues to microwave
energy.
9. The method of claim 4 wherein said step of restabilizing the
corneal tissues comprises exposing the corneal tissues to visible
light energy.
10. The method of claim 4 wherein said step of restabilizing the
corneal tissues comprises exposing the corneal tissues to UV light
energy.
11. The method of claim 4 further comprising the step of applying a
photoinitiator chemical to the eye to rapidly initiate cross
linking of the collagen matrix.
12. The method of claim 2 wherein said step of restabilizing the
corneal tissues comprises exposing the corneal tissues to UV light
energy.
13. The method of claim 12 further comprising the step of
administering a photochemical initiator to the eye to rapidly
initiate cross linking of the collagen matrix.
14. The method of claim 2 wherein said step of administering said
chemical softening agent comprises the steps of positioning the
lower rim of an annular staging device to the surface of the cornea
so that the staging device encircles the area of the cornea to be
treated, and administering the chemical softening agent into the
interior of the staging device.
15. The method of claim 14 wherein the step of reshaping the cornea
comprises positioning the mold within the staging device and
applying downward pressure for a predetermined period of time.
16. The method of claim 15 wherein said mold is fabricated from a
transparent and ultraviolet light transmittable material, and said
step of restabilizing the corneal tissues comprises positioning an
ultraviolet light source within the staging device on top of the
mold and energizing the light source for a predetermined period of
time whereby UV light passes through the mold to the corneal
tissues.
17. The method of claim 14 wherein said step of restabilizing the
corneal tissues comprises positioning an ultraviolet light source
within the staging device and energizing the light source for a
predetermined period of time whereby light is directed onto the
corneal tissues.
18. The method of claim 16 further comprising the step of
administering a photochemical activating agent to the cornea prior
to exposing the cornea to said dosage of ultraviolet light.
19. The method of claim 17 further comprising the step of
administering a photochemical activating agent to the cornea prior
to exposing the cornea to said dosage of ultraviolet light.
20. A method of correcting refractive errors of the eye comprising
the steps of: positioning the lower rim of an annular staging
device to the surface of the cornea so that the staging device
encircles the area of the cornea to be treated; administering a
chemical softening agent into the interior of the staging device
wherein said chemical softening agent is effective for
destabilizing cross-linking between the collagen fibrils of the
stroma of the cornea so that the anterior curvature of the cornea
can be reshaped from a first configuration to a second desired
configuration; reshaping the softened cornea from the first
configuration to the second desired configuration by applying a
mold to the cornea, said mold having a predetermined posterior
curvature and configuration which engages with the anterior
curvature of the cornea, said mold being positioned within the
staging device and thereafter having downward pressure applied for
a predetermined period of time to achieve said reshaping; and
restabilizing the corneal tissues while the anterior curvature of
the cornea is positioned in said second desired configuration by
exposing the corneal tissues to a predetermined dosage of
ultraviolet light.
21. The method of claim 20 wherein said mold is fabricated from a
transparent and ultraviolet light transmittable material, and said
step of restabilizing the corneal tissues comprises positioning an
ultraviolet light source within the staging device on top of the
mold and energizing the light source for a predetermined period of
time whereby light passes through the mold to the corneal
tissues.
22. A method of correcting refractive errors of the eye comprising
the steps of: reshaping the cornea from a first configuration to
the second desired configuration by sequentially applying a series
of orthotic contact lenses having predetermined curvatures and
configurations intended to gradually render the cornea emmetropic;
and restabilizing the corneal tissues while the anterior curvature
of the cornea is positioned in said second desired configuration by
exposing the corneal tissues to a predetermined dosage of
ultraviolet light.
23. The method of claim 22 wherein said step of stabilizing the
corneal tissues comprises positioning the lower rim of an annular
staging device to the surface of the cornea so that the staging
device encircles the area of the cornea to be treated, positioning
an ultraviolet light source within the staging device, and
energizing the light source for a predetermined period of time
whereby light is directed onto the corneal tissues.
24. The method of claim 22 further comprising the step of flushing
the cornea with a mildly alkaline buffer solution prior to
restabilizing the cornea.
25. The method of claim 24 wherein said alkaline buffer solution
contains a chemical photoactivator to aid in stabilization of the
corneal tissue.
26. A staging device for use in treating the corneal tissues of the
eye comprising a substantially cylindrical tube having upper and
lower rim portions, said lower rim portion having an outer diameter
of between about 10 mm and about 15 mm, said lower rim portion
being positionable on the eye so as to encircle the area of the
cornea to be treated.
27. The staging device of claim 26 wherein the lower rim portion is
inwardly tapered at a predetermined angle so as to conform to the
curved surface of the eye.
28. The staging device of claim 26 further comprising a flexible
gasket on the lower rim portion of the tube, said gasket forming a
flexible, water tight seal between the lower rim portion of the
tube and the surface of the eye so as to prevent solutions
administered within the staging device from leaking under the lower
rim portion.
29. The staging device of claim 26 wherein the outer surface of the
tube includes orientation markings to aid in proper placement of
the staging device onto the eye.
Description
BACKGROUND AND SUMMARY OF THE INVENTION
[0001] The present invention relates to orthokeratology, i.e.
shaping of the cornea to correct for refractive errors, and more
particularly to an accelerated method of reshaping the corneal
tissues wherein the cornea is softened, shaped with a mold, and
thereafter rapidly stabilized so that the cornea immediately
retains the new shape.
[0002] Millions of people worldwide have refractive errors of the
eye which cause them to seek out corrective eyeglasses and/or
contact lenses. Among the most common refractive errors are myopia
(inability to see distant objects), hyperopia (inability to see
near objects), and astigmatism (asymmetric sloping of the cornea
whereby the curvature is different in different planes). Each of
the above-noted defects is usually corrected by means of corrective
eyeglasses or contact lenses. Corrective eyeglasses correct
refractive errors by changing the angle of light with a lens before
it reaches the cornea. Contact lenses correct refractive errors by
replacing the misshapen anterior curvature of the cornea with a
curvature which is calculated to render the eye emmetropic. While
corrective eyeglasses and contact lenses are highly effective for
temporarily correcting these problems, i.e. while the glasses or
contacts are in place, the physical defects of the cornea are never
corrected and thus require lifetime wear of the glasses or
contacts. Accordingly, there has been an ongoing search for
effective methods of correcting refractive errors of the eye by
physically altering the anterior curvature of the cornea so that
corrective lenses are no longer required.
[0003] Among the many solutions to refractive eye problems are
surgical procedures in which the cornea is surgically altered.
While effective, the existing surgical modification techniques have
significant risk factors and drawbacks, including human error,
infection, long healing time, and temporary loss of sight during
recovery. Furthermore, there are significant psychological fears
associated with voluntary eye surgery. The chances of permanently
damaging the eye do not usually outweigh the discomfort of wearing
glasses or contacts in most cases. For obvious reasons, invasive
surgical modification of the cornea has not been well received as a
purely voluntary procedure.
[0004] A non-invasive technique for physically altering the
anterior curvature of the cornea which has received acceptance is
Laser Photorefractive Keratectomy wherein an excimer laser is used
to selectively strip away (ablate) outer layers of the cornea to
produce a more spherical curvature. The laser method has achieved a
high degree of success. However, there are certain drawbacks to
this procedure, including temporary reductions of visual acuity
during healing, delayed visual recovery, pain, stromal haze,
temporary hyperopia, night glare, halos, and infectious
keratitis.
[0005] A lesser known non-surgical technique, orthokeratology,
which forms the general basis for the present invention, involves
the use of a series of progressive contact lenses that are intended
to gradually reshape the cornea and produce a more spherical
anterior curvature. The process usually involves the fitting of 3
to 6 pairs of contact lenses, and usually takes approximately 3-6
months to achieve optimal reshaping. The theory behind
Orthokeratology is that the cornea is very pliable and can be
physically reshaped over time. The thickest layer of the cornea,
known as the stroma, is formed from alternating lamella of fine
collagen fibrils which form a pliable matrix of tissue. While the
collagen tissues are pliable, they unfortunately also exhibit shape
memory, and unless retainer lenses are worn daily to maintain the
desired shape, the cornea will rapidly regress to the original
shape.
[0006] Additional development work in the field of orthokeratology
has yielded accelerated methods of orthokeratology wherein
chemical, enzymatic and/or other agents are used to soften the
cornea. For example, the Neefe U.S. Pat. Nos. 3,760,807, 3,776,230
and 3,831,604 collectively describe the use of chemicals such as
proparacaine hydrochloride, dyclonine hydrochloride, chlorine in
solution, the application of heat to the cornea through heated
molds, the application of heat in the form of ultrasonic energy,
and the use of proteolytic enzymes to soften the cornea for
reshaping. Furthermore, the Kelman and DeVore U.S. Pat. Nos.
4,713,446, 4,851,513, 4,969,912, 5,201,764 and 5,492,135 each
describe various chemical agents for treating and/or softening both
natural and artificial collagen materials for ophthalmic uses.
[0007] Of the various prior art available in this subject area, the
Harris U.S. Pat. Nos. 5,270,051 and 5,626,865 are believed to be
the closest prior art to the subject matter of the invention of
which the applicant is aware. The Harris patents describe a method
of accelerated shaping of the cornea by releasing enzymes, such as
hyalurodinase, into the cornea to temporarily soften the cornea,
and thereafter fitting the cornea with a rigid contact lens which
has a curvature that will correct the refractive error. The
softened cornea then reshapes its curvature to the curvature of the
contact lens rendering the eye emmetropic. The speed of the shaping
process is significantly increased by the use of the softening
agent, and reduces the treatment period from months to days. After
shaping, a retainer lens is worn for a period of several days while
the enzyme is allowed to dissipate from the cornea, and the cornea
"hardens" to retain the new emmetropic configuration.
[0008] While softening of the corneal tissues does speed in
reshaping of the cornea, there has been very little success in
developing a successful method of rapidly restabilizing the corneal
tissues in their new configuration after reshaping. The methods as
described in the Harris U.S. Pat. Nos. 5,270,051 and 5,626,865
simply allow the softening agent to dissipate over time, after
which time the lens can be removed. The only prior art known to the
Applicant in the context of "active" corneal restabilization, is
the Neefe U.S. Pat. No. 3,760,807 which describes a method of
administering oral Vitamin C as a means for speeding the hardening
of the cornea after use of the corneal softening agent has been
discontinued. However, speeding up the hardening of the cornea in
this context means to possibly reduce the hardening time from weeks
to days.
[0009] The instant invention provides improved methods of
accelerated orthokeratology which focus on rapidly restabilizing
the corneal tissues in their new configuration after reshaping. The
successful development of a rapid method of restabilizing the
corneal tissues provides the final key step in a rapid non-surgical
treatment alternative for physically reshaping of the cornea. In
the context of the present invention, a patient could expect to
enter the doctor's office on an outpatient basis, have the entire
treatment completed within hours, and leave the office with a
completely and reshaped cornea and no need for further use of
contacts or glasses.
[0010] Generally speaking, the improved method as described herein
comprise a three step process of: 1) softening or "destabilizing"
the cornea with a chemical or enzymatic softening agent; 2)
applying a mold to reshape the cornea to a desired anterior
curvature; and 3) rapidly restabilizing the corneal tissues with a
"stabilizing agent" which is effective for immediately initiating
cross-linking of the collagen matrix. The term "stabilizing agent"
as used herein is intended to include both chemical agents as well
as external energy, such as light energy, applied to the cornea.
More specifically, the contemplated agents for restabilizing the
cornea include chemical cross linking agents, ultraviolet
irradiation, thermal radiation, visible light irradiation, and
microwave irradiation. The preferred method of restabilizing the
cornea presently comprises exposure UV light energy, in conjunction
with a photoactivator or initiator. The invention further provides
novel apparatus for use in the described methods.
[0011] In the preferred method an annular staging device is aligned
and secured with a biological glue over the cornea for guiding
delivery of the softening agents, mold and UV light to the cornea.
The staging device preferably includes an annular flexible gasket
on the lower rim to prevent leakage of the chemicals introduced
into the staging device. A chemical softening agent, such as
glutaric anhydride is introduced into the staging device to soften
the cornea. Glutaric anhydride is known to destabilize cross-links
between the collagen fibrils, and acts to soften the corneal tissue
enough to allow shaping with minimal external pressure. After
treatment with the chemical softener, a specially designed mold of
predetermined curvature and configuration is fitted into the
staging device. Slight downward pressure is applied to the mold for
a predetermined period of time (1-10 minutes) to re-shape the
cornea. The mold is thereafter maintained in position while a UV
light source is positioned above the mold within the staging
device. The mold is preferably fashioned from a material which is
transparent and non-UV absorbing, such as clear acrylic. UV light
is applied to the cornea for a predetermined time wherein the UV
light cross-links, the collagen fibrils and restabilizes the
corneal tissue so that the cornea immediately and retains its new
shape. The stabilization step can also be used for patients having
already undergone long term orthokeratology to eliminate the need
to continue wearing a retainer to maintain the shape of the
cornea.
[0012] Accordingly, among the objects of the instant invention are:
the provision of an accelerated method of orthokeratology including
a means for rapidly restabilizing the cornea tissues after
reshaping; the provision of such a method wherein the cornea is
softened with a softening agent which destabilizes the collagen
fibrils in the cornea; the provision of such a method wherein the
softened cornea is thereafter molded with a mold having a
predetermined curvature and configuration; the provision of such a
method wherein the cornea is stabilized by applying UV light to
cross-link the collagen fibril network; the provision of apparatus
for performing the method including an staging device for limiting
the treatment area of the cornea and preventing leakage of
treatment chemicals outside of the designated area; and the
provision of such a staging device wherein the staging device
guides application of the mold and light energy to the cornea.
[0013] Other objects, features and advantages of the invention
shall become apparent as the description thereof proceeds when
considered in connection with the accompanying illustrative
drawings.
DESCRIPTION OF THE DRAWINGS
[0014] In the drawings which illustrate the best mode presently
contemplated for carrying out the present invention:
[0015] FIG. 1 is a cross-sectional view of a cornea undergoing
treatment according to the teachings of the present invention;
[0016] FIG. 2 is a perspective view of a staging device;
[0017] FIG. 2A is a cross-sectional view of the staging device as
taken along line 2A-2A of FIG. 2;
[0018] FIG. 2B is a cross-sectional view of a second embodiment of
the staging device including a gasket thereon;
[0019] FIG. 2C is a cross-sectional view of a third embodiment of
the staging device;
[0020] FIG. 3 is an elevational view of the sponge assembly;
[0021] FIG. 4 is a perspective view of a mold as used in the method
of the present invention;
[0022] FIG. 5 is a cross-sectional view of the mold as taken along
line 5-5 of FIG. 4;
[0023] FIG. 6 is a perspective view of a mold holder for use in the
method of the present invention;
[0024] FIG. 6A is a cross-sectional view thereof as taken along
line 6A-6A of FIG. 6;
[0025] FIG. 7 is a perspective view of the mold holder and a handle
which can be attached to the mold holder;
[0026] FIG. 8A is a cross-sectional view of an alternative mold
configuration;
[0027] FIG. 8B is a bottom view thereof showing the dimensions of
the various peripheral curve zones;
[0028] FIG. 8C is a bottom view of a similar mold having only a
single mid-peripheral curve;
[0029] FIG. 8D is a cross-section view of a mold for use in
hyperopic and compound hyperopic astigmatism patients;
[0030] FIG. 8E is a cross-sectional view of yet another mold
configuration;
[0031] FIGS. 9-14 are cross-sectional views showing various stages
of the method of the present invention;
[0032] FIG. 15 is a microphotograph of a cross-section of the human
cornea;
[0033] FIG. 16 is an enlargement of the microphotograph showing the
collagen lamella of the stroma; and
[0034] FIG. 17 is a schematic diagram showing a cross-section of
the human cornea.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0035] In accordance with the present invention, there is provided
an improved method for accelerated orthokeratology. The improved
method generally includes the three separate steps of: (1)
softening the cornea so that the cornea can be shaped from a first
configuration to a second emmetropic configuration; (2) reshaping
the cornea by applying a mold to the cornea; and (3) restabilizing
the corneal tissues so that they remain in their new
configuration.
[0036] Referring to FIGS. 15-17, the cornea 10 is made up of 5
distinct layers of tissues, namely the epithelium, Bowman's
Membrane, stroma, Descemet's Membrane, and the endothelium. In
FIGS. 15 and 17, it is obvious that the thickest layer of the
cornea 10 is the stroma 16. The stroma is comprised of alternating
lamellae of collagenous tissue (about 200-250 in number), the
planes of which are parallel to the surface of the cornea.
Referring to FIG. 16, the lamellae are each composed of fine
collagen fibrils and proteoglycans. The collagen fibrils of
alternate lamellae make a right angle with each other. Each
lamellae crosses the whole of the cornea, being about 2 .mu.m
thick. In the methods to be described herein, chemical agents which
soften, degrade or "destabilize" the structural components of the
stroma are topically administered to the cornea 10. The words
soften, degrade, and destabilize are interchangeable for purposes
of this specification, and they are all intended to denote a change
in the corneal tissues which results in the cornea 10 becoming
softer and more pliable so that the cornea can be reshaped from
its' normal configuration to a second "emmetropic" configuration
very quickly.
Chemical and/or Enzymatic Softening Agents
[0037] For purposes of the present invention, any one of a wide
variety of chemical and/or enzymatic softening agents can be
utilized to soften the corneal tissues. As previously described in
the background, the Neefe U.S. Pat. Nos. 3,760,807, 3,776,230 and
3,831,604 collectively describe the use of chemicals such as
proparacaine hydrochloride, dyclonine hydrochloride, chlorine in
solution, and the use of proteolytic enzymes all to soften to
cornea for reshaping. As also described previously herein, the U.S.
patents to Harris describe the use of enzymes, such as
hyalurodinase, for softening of the corneal tissues. Even further
still, the Kelman and DeVore U.S. Pat. Nos. 4,713,446, 4,851,513,
4,969,912, 5,201,764, 5,354,336 and 5,492,135 each describe various
chemical agents for treating and/or softening both natural and
artificial collagen materials for ophthalmic uses. The teachings of
all of these patents with respect to chemical destabilizing agents
are incorporated herein by reference. While incorporated herein,
the teachings of these patents are not intended to limit the scope
of the term destabilizing agent, and the listings recited therein
are not intended to be limiting.
[0038] Despite the multitude of different chemicals which could be
utilized as destabilizing agents, the preferred families of
destabilizing agents include anhydrides, acid chlorides, sulfonyl
chlorides and sulfonic acids. The following lists of chemicals are
intended to be representative of these types of chemicals, and are
not intended to be limiting.
[0039] Suitable, but non-limiting examples of potential anhydrides
include: Dichloroacetic Anhydride; Diglycolic Anhydride;
Chlorodifluoroacetic Anhydride; Dichloroacetic Anhydride; Acetic
Anhydride; Dichloromaleic Anhydride; Maleic Anhydride; Acetic
Anhydride; Trichloroacetic Anhydride; Chloroacetic Anhydride;
Acetic Anhydride; Succinic-D4 Anhydride; Chloroacetic Anhydride;
Dimethyl Pyrocarbonate; (Acetic Anhydride)-D6; Iodoacetic
Anhydride; Hexafluoroglutaric Anhydride; Trifluoroacetic Anhydride;
Succinic Anhydride; 3-Chloro-Glutaric Anhydride; Bromomaleic
Anhydride; Succinic Anhydride; Citraconic Anhydride;
2,3-Dimethylmaleic Anhydride; Diethyl Pyrocarbonate; Itaconic
Anhydride; CIS-1,2-Cyclobutanedicarboxylic Anhydride;
3,4-Pyridinedicarboxylic Anhydride; Glutaric Anhydride;
S-Acetylmercaptosuccinic Anhydride; 1-Cyclopentene-1,2-Dicarboxylic
Anhydride; Methylsuccinic Anhydride; 2-(Acetylthio)succinic
Anhydride; 1,3-Cyclopentanedicarboxylic Anhydride;
1,1-Bis-(2-Hydroxyethyl)-Urea; 2,2-Dimethylsuccinic Anhydride;
2,2-Dimethylglutaric Anhydride; Pentafluoropropionic Anhydride;
3-Methylglutaric Anhydride; 3,3-Dimethylglutaric Anhydride;
(s)-(-)-2-(Trifluoroacetamido)succinic Anhydride; Propionic
Anhydride; Tetrabromophthalic Anhydride; CIS-Aconitico Anhydride;
Propionic Anhydride; Tetrachlorophthalic Anhydride; 6-Chloroisatoic
Anhydride; Isatoic Anhydride; Heptafluorobutyric Anhydride;
5-Nitroisatoic Anhydride; EXO-3,6-Eposy,1,2,3,6-Tetrahydrophthalic
Anhydride; 4,5-Dichlorophthalic Anhydride; 6-Nitorisatoic
Anhydride; CIS-1,2,3,6-Tetrahydrophthalic Anhydride;
3,6-Dichlorophthalic Anhydride; Phthalic Anhydride;
3-Cyclohexene-1,2-Dicarboxylic Anhydride; 3-Chlorophthalic
Anhydride; Phthalic Anhydride; 3,4,5,6-Tetrahydrophthalic
Anhydride; 3-Nitrophthalic Anhydride; 3-Hydroxyphthalic Anhydride;
3,6-Endoxohexahydrophthalic Anhydride; 4-Nitrophthalic Anhydride;
1,2,3,4-Cyclobutanetetracarboxylic Dianhydride;
(+)-Diacetyl-L-Tartaric Anhydride; 5-Chloroisatoic Anhydride;
Tetrahydrofuran-2,3,4,5-Tetracarboxylic Dianhydride;
CIS-1,2-Cyclohexanedicarboxylic Anhydride; Isobutyric Anhydride;
3-Methoxyphthalic Anhydride; Crotonic Anhydride; Butyric Anhydride;
2-Bromo-5-Norbornene-2,3-Dicarboxylic Anhydride;
(+/-)-Trans-1,2-Cyclohex- anedicarboxylic Anhydride;
1,4,5,6,7,7-Hexachloro-5-Norbornene-2,3-Dicarbo- xylic Anhydride;
3-Amino-5-Chloro-N-Methylisatoic Anhydride; Methacrylic Anhydride;
Trimellitic Anhydride Chloride; N-Methylisatoic Anhydride;
(+/-)-Isobutenylsuccinic Anhydride; 1,2,4-Benzenetricarboxylic
Anhydride; CIS-5-Norbornene-Endo-2,3-Dicarboxylic Anhydride;
1,2-Cyclohexanedicarbox- ylic Anhydride; 1-Methyl-6-Nitroisatoic
Anhydride; 3,5-Diacetyltetrahydrop- yran-2,4,6-Trione;
3-Ethyl-3-Methylglutaric Anhydride; Homophthalic Anhydride;
4-Methyl-1,2,3,6-Tetrahydrophthalic Anhydride; Butyric Anhydride;
4-Methylphthalic Anhydride; 5-Methyl-3A,4,7,7A-Tetrahydrophtha- lic
Anhydride; 2-Furoic Anhydride;
3,6-Dimethyl-4-Cyclohexene-1,2-Dicarbox- ylic Anhydride;
Norbornance-2,3-Dicarboxylic Anhydride; 2-Cyonoacetyl
N-(4-Fluorophenyl)Carbamate;
Endo-3,6,Dimethyl-3,6-Endoxohexahydrophthali- c Anhydride;
3,6-Encoso-3-Methylhexahydrophthalic Anhydride; 2-Cyanoacetyl
N-Phenylcarbamate; 2-Methyl-8-Oxaspiro(4.5)Decane-7,9-Dione;
(+/-)-Hexahydro-4-Methylphthalic Anhydride; 3,6-Dimethylphthalic
Anhydride; 8-Methyl-2-Oxaspiro(4.5)Decane-1,3-Dione;
3,3-Tetramethyleneglutaric Anhydride;
Bicyclo(2.2.2)Octa-2,5-Diene-2,3-Di- carboxylic Anhydride;
3-Methoxy-5-Methylhexahydrophthalic Anhydride;
1,2,4,5-Benzenetetracarboxylic Di-Anhydride;
Endo-Bicyclo(2.2.2)Oct-5-Ene- -2,3-Dicarboxylic Anhydride;
Trimethylacetic Anhydride; 1,2,4,5-Benzenetetracarboxylic
Dianhydride; methyl-5-Norbornene-2,3-Dicar- boxylic Anhydride;
Valeric Anhydride; 2-Cyanoacetyl N-(2,3-Dichlorophenyl)Carbamate;
Ethylenediaminetetraacetic Dianhydride; (S)-(+)-2-Methylbutyric
Anhydride; 2-Phenylglutaric Anhydride; 1,8-Naphthalic Anhydride;
Isovaleric Anhydride; 2-Benzylsuccinic Anhydride; 2,3-Naphthalic
Anhydride; Di-Tert-Butyl Dicarbonate;
4,7-Dihydro-4,7A,7B-Trimethyl-4,7-Epoxyisobenzofuran-1,3(7A,7B)-Dione;
4-Mercapto-1,8,Naphthalic Anhydride; Di-Tert-Butyl Dicarbonate;
3-(Tert-Butyldimethylsilyoxy)Glutaric; 4-Sulfo-1,8-Naphthalic
Anhydride; Di-Tert-Butyl Dicarbonate; 4-Bromo-1,8-Naphthalic
Anhydride; 4-Amino-1,8-Naphthalic Anhydride; 2-Cyanocetyl
N-(P-Tolyl)Carbamate; 4-Chloro-1,8-Naphthalic Anhydride;
2-Phthliamidosuccinic Anhydride; 2-Cyanoacetyl
N-(4-Methoxyphenyl)Carbamate; 4-Nitro-1,8-Naphthalic Anhydride;
4-Amino-3,6-Disulfo 1,8-Naphthalic Anhydride; 2-Cyanocetyl
N-(3-Methoxyphenyl)Carbamate; 3-Nitro-1,8-Naphthalic Anhydride;
Bicyclo(2.2.2)Oct-7-Ene-2,3,5,6-Tetracarboxylic Dianhydride;
Hexachlorohexahydro-1,4-Methanonaphthalene-6,7-Dicarboxylic
Anhydride; Diphenic Anhydride; 2-(4-Acetoxyphenyl)Succinic
Anhydride; N-Phthaloyl-Dl-Glutamic Anhydride;
4-methylfuro(3',4':5,6)Naphtho(2,3-D)(-
1,3)Dioxole-1,3(1H,3H)-Dione; Carbobenzyloxy-L-Aspartic Anhydride;
Carbobenzyloxy-L-Glutamic Anhydride;
5-Bromo-1,2,3,4-Tetrahydro-1,4-Ethen- onaphthalene-2,3-Dicarboxylic
Anhydride; Bicyclo(4.2.2)Dec-7-Ene-9,10-Dica- rboxylic Anhydride;
9-Isopropyl-3-Oxaspiro(5.5)Undecane-2,4-Dione;
5-Nitro-1,2,3,4-Tetrahydro-1,4-Ethenonaphthalene-2,3-Dicarboxylic
Anhydride;
3-((Ethoxycarbonyl)oxycarbonyl))-2,2,5,5-Tetramethyl-3-Pyrroli-
n-1-Yloxy, FR; 1,4,5,8-Naphthalenetetracarboxylic Dianhydride;
5-Nitro-10-Oxo-1,2,3,4-Tetrahydro-1,4-Ethanonaphthalene2,3dicarboxylic
Anhydride; 2-(1-Octenyl)Succinic Anhydride; BIS(2,6-Dichlorobenzoic
Anhydride; Benzoic Anhydride;
3-Methoxy-1,2,3,6-Tetrahydro-5-(Trimethylsi- lyoxy)phthalic
Anhydride; 4-Bromobenzoic Anhydride;
4-(2-Hydroxyethylthio)-1,8-Naphthalic Anhydride; Hexanoic
Anhydride; 3,5-Dinitrobenzoyl N-(2-Chlorophenyl)Carbamate; and
Diethylenetriaminepentaacetic Dianhydride.
[0040] Suitable, but non-limiting examples of potential acid
chlorides include: Propionyl Chloride; Methacryloyl Chloride;
Acryloyl Chloride; Methoxyacetyl Chloride; Methacryloyl Chloride;
Methyloxalyl Chloride; Heptafluorobutyrl Chloride;
Cyclopropanecarbonyl Chloride; 2,3 Dichloropropionyl Chloride;
4,4,4-Trifluorocrotonyl Chloride; 3-Bromopropionyl Chloride;
Fumaryl Chloride; Acetoxyacetyl Chloride; (=/-)-2-Bromopropionyl
Chloride; 4,4,4-Trifluorobutyrl Chloride; Ethyl Oxalyl Chloride;
2-Chloropropionyl Chloride; 4-Bromobutyrl Chloride;
3-Chloropropionyl Chloride; Crotonyl Chloride; 4-Chlorobutyrl
Chloride; 5-(Chlorocarbonyl)Uracil; Ethyl Malonyl Chloride;
4-Chlorobutyrl Chloride; 2-Thiophenecarbonyl Chloride;
3-Carbomethoxypropionyl Chloride; Butyrl Chloride; 2-Furoyl
Chloride; 3,3-Dichloropivaloyl Chloride; Isobutyrl Chloride;
Itaconyl Chloride; 2,2-Bis(Chloromethyl)Propionyl Chloride; Butyryl
Chloride; Blutaryl Dichloride; 5-Bromovaleryl Chloride; Butyryl
Chloride; 3,3-Dimethylacryloyl Chloride; 4-Morpholinecarbonyl
Chloride; Cyclobutanecarbonyl Chloride; 5-Chlorovaleryl Chloride;
5-Nitro-2-Furoyl Chloride; Ethyl Malonyl Chloride; 3-Chloropivaloyl
Chloride; Trans-1,2-Cyclobutanedicarbonyl Dichloride; Hexanoyl
Chloride; Valeryl Chloride; Adipoyl Chloride; Hexanoyl Chloride;
Isovaleryl Chloride; Alpha,Alpha-Dimethylsuccinyl Chloride;
Tert-Butylacetyl Chloride; Trimethylacetyl Chloride;
Cyclopentanecarbonyl Chloride; 2-Ethylbutyrl Chloride;
3,4-Dichloro-2,5-Thiophenedicarbonyl Chloride; Ethylsuccinyl
Chloride; Benzoyl-D5 Chloride; Nicontinoyl Chloride Hydrochloride;
1-Chlorocarbonyl-1-Methylethyl Acetate; Pentafluorobenzoyl
Chloride; Isonicotinoyl Chloride Hydrochloride; Methyl
4-(Chloroformyl) Butyrate; Pentachlorobenzoyl Chloride;
2-Thiopheneacetyl Chloride; 6-Bromohexanoyl Chloride;
2,3,4,5-Tetrafluorobenzoyl Chloride; 2,4-Difluorobenzoyl Chloride;
2,6-Dichlorobenzoyl Chloride; 2,3,6-Trifluorobenzoyl Chloride;
3,4-Difluorobenzoyl Chloride; 3,4-Dichlorobenzoyl Chloride;
2,3,4-Trifluorobenzoyl Chloride; 3,5-Difluorobenzoyl Chloride;
3-Bromobenzoyl Chloride; 3,4,5-Tridobenzoyl Chloride;
2,3-Difluorobenzoyl Chloride; 2-Bromobenzoyl Chloride;
2,4-Dichloro-5-Fluorobenzoyl Chloride; 3,5-Dinitorbenzoyl Chloride;
4-Bromobenzoyl Chloride; 2,4,6-Trichloribenzoyl Chloride;
2,6-Pyridnedicarbony Dichloride; 4-Fluorobenzoyl Chloride;
2,6-Difluorobenzoyl Chloride; 2,4-Dichlorobenzoyl Chloride;
2-Flurobenzyol Chloride; 2,5-Difluorobenzoyl Chloride;
3,4-Dichlorobenzoyl Chloride; 3-Fluorobenzoyl Chloride;
2-Nitrobenzoyl Chloride; Benzoyl Chloride;
4-Fluorobenzoyl-Carbonyl-13C Chloride; 2-Chlorobenzoyl Chloride;
(s)-(-)-(Trifluoroacetyl)Prolyl Chlor-Ide, 01.M Solution in
Dichloromethane; 3-(Fluorosulfonyl)Benzoyl Chloride;
4-Chlorobenzoyl Chloride; 3-(2-Furyl)Alany Chloride Hydrochloride;
4-(Fluorosulfonyl)Benzoyl Chloride; 3-Chlorobenzoyl Chloride;
Diethylmalonyl Dichloride; 2-Iodobenzoyl Chloride; Benzoyl
Chloride; 3-Methyladipoyl Chloride; 4-Iodobenzoyl Chloride; Benzoyl
Chloride; Pimeloyl Chloride; 4-Nitrobenzoyl Chloride;
Benzoyl-Carbonyl-13C Chloride; Cyclohexanecarbonyl Chloride;
3-Nitrobenzoyl Chloride; Benzoyl Chloride; 4-Methyl-4-Nitrohexanoyl
Chloride; 4-Cyanobenzoyl Chloride; (+/-)-2-Chloro-2-Phenylacetyl
Chloride; Heptanoyl Chloride; 3-Cyanobenzoyl Chloride;
4-Chlorophenoxyacetyl Chloride; Perfluorooctanoyl Chloride;
Terephthaloyl Chloride; Para-Toluoyl Chloride;
2,3,5,6-Tetrachloroterephthaloyl Chloride; Isophthaloyl Dichloride;
Ortho-Toluoyl Chloride; Pentafluorophenylacetyl Chloride; Phthaloyl
Dichloride; Meta-Toluoyl Chloride; 4-(Trifluoromethly)Benzoyl
Chloride; 1,4-Phenylene BIS(Chloroformate); Pheylacetyl Chloride;
2-(Trifluoromethyl)Benzoyl Chloride; 4-(Trichloromethoxy)Benzoyl
Chloride; Phenoxyacetyl Chloride; 3-(Trifluoromethyl)Benzoyl
Chloride; 2-(2,4,5-Trichlorophenoxy)Acetyl Chloride; and M-Anisoyl
Chloride.
[0041] Suitable, but non-limiting examples of potential sulfonyl
chlorides include 4-Chlorobenzenesulfonyl Chloride;
4-Chloro-3-(Chlorosulfonyl)-5-N- itrobenzoic Acid;
3-Fluorosulfonylbenzenesulfonyl Chloride; 4-Chlorobenzenesulfonyl
Chloride; 3-(Fluorosulfonyl)benzoyl Chloride;
4-Fluorosulfonylbenzenesuofonyl Chloride;
4-Amino-6-Chloro-1,3-Benzenedis- ulfonyl Chloride;
4-(Fluorosulfonyl)benzoyl Chloride; O-Fluorosulfonylbenzenesulfonyl
Chloride; 3-Amino-4-Chlorobenzenesulfonyl- ;
2-Chloro-5-(Fluorosulfonyl)-Benzoic Acid; Pipsyl Chloride;
Benzenesulfonyl Chloride; 4-(Chlorosulfonyl)phenyl Isocyanate;
4-Nitrobenzenesulfonyl Chloride; Benzenesulfonyl Chloride;
3,5-Dinitro-P-Toluenesulfonyl Chloride; 3-Nitrobenzenesulfonyl
Chloride; 2-Acetamido-4-Methyl-5-Thiazolesulfonyl Chloride;
4-(Chlorosulfonyl)benzo- ic Acid; 2-Nitrobenzenesulfonyl Chloride;
2-Nitro-4-(Trifluoromethyl)Benze- ne-Sulfonyl Chloride;
3-(Chlorosulfonyl)-Benzoic Acid; Methyl 2-(Chlorosulfonyl)benzoate;
8-Quinolinesulfonyl Chloride; Alpha-Toluenesulfonyl Chloride;
3-(Chlorosulfonyl)-P-Anisic Acid;
4-(2,2-Dichlorocyclopropyl)-Benzenesulfonyl Chloride;
P-Toluenesulfonyl Chloride; N-Acetylsulfanilyl Chloride;
2,4-Mesitylenedisulfonyl Chloride; O-Toluenesulfonyl Chloride;
2,5-Dimethoxy-4-Nitrobenzenesulfonyl Chloride; 2-Mesitylenesulfonyl
Chloride; P-Toluenesulfonyl Chloride;
4-Dimethylamino-3-Nitrobenzenesulfonyl Chloride;
6-Diazo-5,6-Dihyrdo-5-Ox- o-1-Naphthalenesulfonyl Chloride;
4-Methoxybenzenesulfonyl Chloride; 2,5-Dimethylbenzenesulfonyl
Chloride; 2,6-Naphthalenedisulfonyl Chloride;
3,5-Dicarboxybenzenesulfonyl Chloride; 2,5-Dimethoxybenzenesulfonyl
Chloride; 2-Naphthalenesulfonyl Chloride; Beta-Styrenesulfonyl
Chloride; 5-Methylsulfonyl-Ortho-Toluenesulfonyl Chloride;
1-Naphthalenesulfonyl Chloride; 2,8,-Dibenzofurandisulfonyl
Chloride; 4-(Dimethyllamino)azobenz- ene-4-Sulfonyl Chloride;
4-Tert-Butylbenzenesulfonyl Chloride;
4-(4-Chloro-5,7-Dibromo-2-Quinolyl)-Benzenesulfonyl Fluoride;
4-Sec-Butylbenzenesulfonyl Chloride; 4,4'-Biphenyldisulfonyl
Chloride; 4-(4-Chloro-6-Nitro-2-Quinolyl)-Benzenesulfonyl Fluoride;
(+)-10-Camphosulfonyl Chloride; 4,4'-Oxybis(Benzenesulfonyl
Chloride); 4-Chloro-6-Fluorosulfonyl-2-(4-Nitrophenyl)quinoline;
(-)-10-Camphorsulfonyl Chloride; 4-(Phenylazo)Benzenesulfonyl
Chloride; 4-Chloro-2-Phenylquinoline-4',6-Disulfonyl Fluoride;
(+/-)-10-Camphorsulfonyl Chloride; Dansyl Chloride;
4-Chloro-2-Phenyl-6-Quinolinesulfonyl Fluoride;
1-Chloro-4-Fluorosulfonyl- -2-Naphthoyl chloride;
4,4'-Methylenebis(Benzenesulfonyl Chloride);
2,4,6-Triisopropylbenzenesulfonyl Chloride;
Pentamethylbenzenesulfonyl Chloride;
2-(Chlorosulfonyl)Anthraquinone; 4-Chloro-2-M-Tolyl)-6-Quinolin-
esolfonyl Fluoride;
4-Chloro-6-Fluorosulfonyl-2-(4-Ethoxy-3-Methoxyphenyl)- Quinoline;
5-(Chlorosulfonyl)-2-(Hexadecycloxy)Benzoic Acid;
4-Chloro-2-({-Tolyl)-6-Quinolinesulfonyl Fluoride;
5,7,7-Trimethyl-2-(1,3,3-Trimethlbutyl)-1-Octancesulfonyl Chloride;
3-Chlorosulfonyl-4-Hexadecycloxybenzoic Acid;
5-Benzoyloxy-1-(3-Chlorosul- fonylphenyl)-3-Methylpyrazole;
4-Chloro-2(4-(N,N-Diethylaminosulfonyl)-Phe-
nyl)-6-Quinolinesulfonyl Fluoride;
5-(Chlorosulfonyl)-2-(Hexadecyclsulfony- l)Benzoic Acid;
1-Hexadecanesulfonyl Chloride; 2-(4-Benzyloxyphenyl)-4-Chl-
oro-6-Quinolinesulfonyl Fluoride; Methyl
3-Chlorosulfonyl-4-(Hexadecyloxy)- Benzoate;
3-(4-Chlorophenylcarbamoyl)-4-Hydroxy-1-Naphthalenesulfonyl
Fluoride; 4-(Hexadecyloxy)Benzenesulfonyl Chloride;
3-Nitro-4-(Octadecylamino)Benzenesulfonyl Chloride; Methyl
4-(4-Chloro-6-Fluorosulfonyl-2-Quinolyl)Benzoate;
4-(2,5-Dichlorophenylaz-
o)-4-Fluorosulfonyl-1-Hydroxy-2-Naphthanilide;
4-(4-Chloro-5,7-Dimethyl-2-- Quinolyl)-Benzenesulfonyl Fluoride;
5-Fluorosulfonyl-2-(Hexadecyloxy)Benzo- yl Chloride; Ethyl
4-Chloro-2-(4-Fluorosulfonylphenyl)-6-Quinolinecarboxyl- ate;
5-Chlorosulfonyl-2-(Hexadecylsulfonyl)Benzoyl Chloride; Oxalyl
Chloride; Acetly-2-13C Chloride; Chlorocarbonylsulfenyl Chloride;
Trichloroacetyl Chloride; Acetyl-1-13C Chloride; Methanesulfonyl
Chloride; Dichloroacetyl Chloride; Acetyl-13C2 Chloride; Acetyl-D3
Chloride; Bromoacetyl Chloride; Acetyl Chloride; Trifluoroacetyl
Chloride; Chloroacetyl Chloride; Trichloroacryloyl Chloride; Oxalyl
Chloride; Chlorosulfonylacetyl Chloride; Pentachloropropionyl
Chloride; Oxalyl Chloride; Acetyl Chloride; Malonyl Cichloride;
Oxalyl Chloride; Acetyl Chloride; and 2,3-Dibromopropionyl
Chloride.
[0042] Suitable, but non-limiting examples of potential sulfonyl
acids include 4,6-Diamino-2-Methylthiopyrimidine-5-Sulfonic Acid;
4-Pyridylhydroxymethanesulfonic Aceid; Sulfoacetic Acid, Pyridine
Complex; 3,3-Oxetanebis(Methanesulfonic Acid)Disodium Salt;
2,5-Dimethyl-3-Thiophenesulfonic Acid Sodium Salt;
2-Pyrimidinesulfonic Acid, Sodium Sale; 1-Fluoropyridinium
Triflate; Mes Monohydrate; 2-Thiophenesulfonic Acid, Sodium Salt;
3-Sulfoisonicotinic Acid, Barium Salt; 3-Sulfobenzoic Acid;
(+/-)-1-Hyrdoxy-2,5-Dioxo-3-Pyrrolidine-Sulfon- ic Acid, Monosodium
Salt; (1-Methylpyridinium 3-Sulfonate);
6-Acetamido-3-Pyridinesulfonic Acid; 5-Formyl-2-Furansulfonic Acid;
5-Methyl-3-Pyridinesulfonic Acid; 4-Pyridineethanesulfonic Acid;
3-Pyridinesulfonic Acid; 2-Pyridylhydorxymethanesulfonic Acid;
2-Pyridineethanesulfonic Acid; 3-Pyridinesulfonic Acid, Sodium
Salt; 3-Pyridylhydroxymethanesulffonic Acid; Isonicotinic Acid
2-(Sulfomethyl)-Hydrazide, Calcium Salt Dihyrdate; Hepes;
1-(2,5-Dichloro-4-Sulfophenyl)-5-Pyrazolone-3-Carboxylic Acid; Mops
(4-Morpholinepropanesulfonic Acid); Hepes, Sodium Salt;
5-Oxo-1-(4-Sulfophenyl)-2-Pyrazoline-3-Carboxylic Acid; Mops.
Sodium Salt, Monohyrdate, (4-Morpholinepropanesulfonic Acid); Pipes
(1,4-Piperazinebis-(Ethanesulfonic Acid));
5-Oxo-1-(4-Sulfophenyl)-2-Pyra- zoline-3-Carboxylic Acid, Lead
Salt; Mopso, (Beta-Hyroxy-4-Morpholine-Prop- naesulfonic Acid);
Pipes, Disodium Salt Monohyrdate;
4-Chloro-3-(3-Methly-5-Oxo-2-Pyrazolin-1-Yl)-Benzesulfonic Acid;
1-Allylpyridinium 3-Sulfonte; N-(4-Amino-S-Triazin-2-Yl)-Sulfanilic
Acid; 4-(3-Methyl-5-Oxo-2-Pyrazolin-1-Yl)-Benzenesulfonic Acid;
1-(3-Sulfopropyl)Pyridinium Hydroxide; Ethyl 2-Sulfobenzoate,
Sodium Sale; 3-(5-Imino-3-Methyl-2-Pyrazolin-1-Yl) Benzenesulfonic
Acid; 2-Pyridinealdoxime Methyl Methanke-Sulfonate;
2-Methyl-1-(3-Sulfopropyl)P- yridinium Hydroxide, Inner Salt;
Pyridinium 3-Nitrobenzenesulfonate; 1-Piperidinepropanesulfonic
Acid; Epps (4-(2-Hyrdoxyethyl)-1-Piperazine-P- ropanesulfonic
Acid); 2-Ethyl-5-Phenylisoxazolium 3'-Sulfonate;
1-Ethyl-2-Methly-3-(3-Sulfopropyl)Benzimidazole; Acid Orange 74;
2-Ethyl-5-Phenylisoxazolium 4'-Sulfonate Monohydrate;
4-(5-Hyroxy-1-Phenyl-1,2,3-Trizol-4-Ylozo)Benzenesulfonic Acid,
Sodium Salt; Tartrazine; Pyridinium P-Toluenesulfonate;
1,4-Dimethylpyridinium P-Toluenesulfonate; Acid Yellow 34;
Methanesulfonic
(4-Aminophenyl-SulfopropylThizdiasol-2-In-5-Ylidene)Hydrazide;
4-Hyroxy-2-Phenyl-6-Quinolinesulfonic Acid; Mordant Red 19;
4,5-Dihyrdoxy-3-(2-Thiazolylazo)-2,7-Naphthalenedisulfonic Acid,
Sodium Salt; 3-Methoxycarbonyl-1-Methylpyridinium
Para-Toluenesulfonate;
1-Phenyl-3-(3-Sulfobenzamido)-2-Pyrazolin-5-One, Barium Salt;
N-(4-Chlorobenzylideneamino)-Sulfanilic Acid, Pyridinium Salt;
3-(2-Pyridyl)-5,6-Bis(5-Sulfo-2-Furyl)-1,2,4-Triazine Dina
Salt/3H2O; Flavazin L; 2-Fluoro-1-Methylpyridinium
P-Toluene-Sulfonate; Acid Red 183;
5-Tridecyl-1,2-Oxathiolane-2,2-Dioxide;
N-Antipyrinyl-N-Methylaminom- ethanesulfonic Acid, Sodium Salt
Monohydrate; Acid Yellow 17;
4-((4-Chlorobenzylidene)-3-Methly-1-(4-Sulfophenyl)-2-Pyrazolin-5-One;
Reatcie Blue 4; Cibacron Brilliant Yellos 3GP; 2-(3-Sulfobenzoyl)
Pyridine 2-Pyridyl-Hydrazone Dihyrdate; Acid Yellow 40;
2-5,6-Bix-4-Sulfophenyl-1,2,4-Triazin-3-YL-4-Sulfophenyl
Pyridine/3NA/Ind.Grad.;
4-(1-Benzyl-5-Oxo-2-Pyrazolin-3-Ylcarbamoyl)Benze- nesulfonic Acid,
Barium Salt; (Bis)(Cyanoethyl)AminoBenzylidne)-Oxo-Sulfop-
henyl-Pyrazoline-Carboxylic Acid, NA; 1,1'Ethylenedipyridinium
Di-P-Toluenesulfonate;
2,6-Diamino-3-(4-(2-Diethylaminoethoxy)-Phenylazo)- Pyridine
Methanesulfonate; Acid Yellow 76; Merocyanine 540; Palatine Fast
Yellow Bln; Acid Yellow 25; 1-Hexadecanesulfonic (Fluorophenyl)
(Sulfopropyl)Thiadiazol-2-Ylidene)Hydrazide;
3-(2-Pyridyl)-5,6-Diphenyl-1- ,2,4-Triazine-P,P'-Disulfonic Acid,
1-NA XH2O; 2-Hexadecylthio-5-Sulfobenz- oic Acid, Pyridine Salt;
Reative Blue 2; 5-Phenyl-3-(4-Phenyl-2-Pyridyl)-1-
,2,4-Triazine-P,P'-Disulfonic Acid, 2NA Salt;
Trans-4-(4-Dibutylamino)Styr- yl)-1-(3-Sulfopropyl)Pyr Oh/Inner
Salt H2O; 1-Octadecylpyridinium P-Toluenesulfonate; Acid Yellow 29;
4-(5-Oxo-3-Pentadecyl-2-Pyrazolin-1-Y- l) Benzenesulfonic Acid,
Sodium Salt; Direct Orange 31; Sephadex-Sp-C-50, Ion Exchange
Resin; 4-(4-(2-Hexadecyloxyphenyl)-5-Oxo-2-Pyrazolin-1-Yl)Be-
nzenesulfonic Acid Sodium; Acid Yellow 42;
Carboxy-Hexadecyloxybenzenesulf- onic
Methyl-Sulfophenyl-Thiadiazolinylidenehydraz;
2,4-Bis(5,6(4-Sulfophen- yl)-1,2,4-Triazine-3-Yl)Pyridine 4NA Salt
H2O; Acid Orange 63; Reaactive Blue 15; Sephadex-Sp-C-25,
Ion-Exchange Resin; 8-Quinolinesulfonic Acid;
8-Ethoxy-5-Quinolinesulfonic Acid, Sodium Salt Hydrate;
2-Mercaptobenzothiazole-5-Sulfonic Acid, Sodium Salt;
8-Hydroxyquinoline-5-Sulfonic Acid Monohydrate;
8-Ethoxy-5-Quinolinesulfo- nic Acid; Benzothiazole-2,5-Disulfonic
Acid; N-(Methylsulfonyloxy)-Phthali- mide;
6-Methoxy-3-(3-Sulfopropyl)-3H-Benzothiazolin-2-One Hydrazone;
2-Benzofuransolfonic Acid; 1,3-Dioxo-2-Isoindoleneethanesulfonic
Acid, Potassium Salt; 4-Sulfo-1,8-Naphthalic Anhydride, Potassium
Salt, Tech.; 2-Methylthio-5-Benzothiazolesulfonic Acid;
Indole-3-Acetaldeyde Sodium Bisulfite Addition Compound;
8-Bromo-2-Dibenzo-Furansulfonic Acid, Sodium Salt;
2-Methylthiobenzimidazolesulfonic Acid;
3-Methyl-2-Methylthio-6-Nit- ro-5-Sulfobenzothiazolium Methyl
Sulfate; 8-(Chloromercuri)-2-Dibenzofuran- sulfonic Acid, Sodium
Salt; 2-(3-Methly-2-Benzothiazolinyidene)-1-Hydrazin- esulfonic
Acid; 8-Sulfo-2,4-Quinolinedicarboxylic Acid;
8-Nitro-2-Dibenzofiuransulfonic Acid;
8-Hyroxy-7-Iodo-5-Quinoliinesulfoni- c Acid; 6-Norharmansulfonic
Acid; 4-Amino-3,6-Disulfo-1,8-Naphthalic Anhydride Dipotassium
Salt; Harman-N-Sulfonic Acid; Indigo Carmine, Certified;
4-Dibenzofuransulfonic Acid, Sodium Salt Monohyrdate;
4-(2-Benzimidazolyl)-Benzenesulfonic Acid; Potassium
Indigotrisulfonate; 2-Dibenzofuransulfonic Acid; Lucifer Yellow CH,
Dipotassium Salt; Potassium Indigotetrasulfonate;
2-Dibenzofuransulfonic Acid, Sodium Salt; Lucifer Yellow CH;
7-Anilino-1-Naphthol-3-Sulfonic Acid; 2,8-Dibenzofurandisulfinic
Acid, Disodium salt; Harmine-N-Sulfonic Acid, Sodium Salt;
2,3-Dimethyl-6-Nitrobenzothiazolium Para-Toluenesulfonate;
4,6-Dibenzofurandisulfonic Acid;
3-(3-Sulfooxypropyl)-2,5,6-Trimethylbenz- othiasolium Hydroxide,
Inner Salt; 3-Methly-2-(Methylthio)Benzothizolium
P-Toluenesulfonate); 2,8,Dibenzofurandisulfonic Acid, Disodium
Salt; 1-Ethyl-2-Methly-3(3-Sulfooxypropyl)-Benzinudazolium
Hydroxide, Inner Salt; Methanesulfonic Acid
(1-Methly-2-Phenyl-6-Sulfo-4(1H)-Quinolyidene) Hydrazide;
2-Sulfothianthrene-5,5,10,10-Tetraoxide, Sodium Salt;
4-(4-Quinolylazo)Benzenesulfonic Acid; and
2-(Methylthio)Benzothiazole Ethyl P-Toluenesulfonate. All of the
chemicals listed above are available from Aldrich Chemical Company
(Milwaukee, Wis.)
[0043] Of the above listings, it is likely that the preferred
processes will utilize a simple anhydride to soften the cornea,
i.e. glutaric anhydride, succinic anhydride or maleic anhydride
since each of these anhydrides hydrolyze into rather innocuous
compounds.
Apparatus for Application of the Chemical Agents to the Cornea
[0044] Because it is desired to limit chemical exposure to only the
corneal tissues 10 of the eye, a staging device generally indicated
at 12 has been developed to limit the spreading of the liquid
treatment solutions which will be topically applied to the cornea.
Referring to FIGS. 2, 2A, and 2B, the staging device 12 is
preferably cylindrical in shape having upper and lower ends, 14, 16
respectively, and is preferably manufactured from a plastic
material by injection molding. However, the staging device 12 could
also be formed from metal or fiberglass or any other suitable
material. The staging device 12 is preferably 1.5 to 2.0 inches in
height measured between the upper and lower ends 14, 16, and has an
outer diameter at the lower end 16 of between 10-15 mm. As will be
noted by those skilled in the art, the outer diameter of the lower
end generally corresponds to the diameter of the outer limbic area
17 of the cornea 10 upon which the staging device 12 will rest when
in use. The side wall 18 of the staging device 12 is preferably
between 0.5-2.0 mm thick. The idea is for the staging device to sit
directly on the limbic area to prevent leakage of the drug
solutions beyond the treated surface of the cornea 10 (See FIG. 9).
The staging device 12 further preferably includes an annular
elastomeric gasket 20 (FIG. 2B) which is received around the lower
end 16 of the staging device 12. The elastomeric gasket 20 can be
formed from a variety of non-porous elastomeric materials, such as
synthetic and natural rubbers, non-porous foams, closed cell
sponge, etc. A downwardly facing portion 22 of the gasket 20 will
engage with the surface of the limbic area 17 of the cornea 10 when
positioned to form an annular seal with the surface of the cornea
10. It is contemplated that the lower edges 24 of the lower end 16
of the staging device 12 could be tapered slightly inwardly to
better conform to the sloping surface of the cornea 10. Likewise,
the downwardly facing surfaces 22 of the gasket 20 could also be
tapered inwardly to provide a better fit against the surface of the
cornea.
[0045] The staging apparatus 12 will be used for drug delivery to
the cornea 10 as well as to guide and position the molds during
reshaping. All drugs or solutions used in the methods are
administered into the inside of the staging apparatus 12 after
placement onto the cornea 10 wherein the interface of the gasket 20
with the cornea surface seals off the leakage of the solution from
inside the device 12. To rigidly position the staging device 12
onto the cornea 10, as well as to prevent rotation thereof, a
biological sealant or glue (not shown) may be applied to the
downwardly facing portion 22 of the gasket 20 to adhere the gasket
20 to the limbic area 17 of the cornea 10. Any of the presently
known biological sealants or glues would be acceptable in this
context. Once the staging device 12 is in place, the gasket 20
forms a seal and prevents the leakage of solutions which are
administered into the center of the staging device. In this manner,
the solutions and drugs are applied only to the central area of the
cornea 10 which is to be reshaped.
[0046] Although the preferred embodiment of the staging apparatus
12 is cylindrical it is also contemplated that an alternate staging
apparatus 12A could have a wider diameter at the upper end 14
wherein the outer diameter thereof ranges from 15-35 mm (See FIG.
2C.)
[0047] It is also contemplated that the staging device 12 will have
exterior markings 26 (FIG. 2) which will allow proper rotational
alignment of the staging device 12 with respect to the eye, and
also proper rotational alignment of the mold within the staging
device for correction of astigmatism errors.
Removing Solutions from the Staging Device
[0048] Since the staging device 12 will effectively retain all of
the drug solutions within its interior, it will be necessary to
selectively remove the solutions during the procedure. For example,
it will be necessary to wash the cornea 10 with various buffer
solutions, and to apply different drug solutions at different times
during the procedure. For this purpose, the Applicants have
developed a simple sponge absorbing device (FIG. 3) generally
indicated at 28 comprising a planar disc 30 having a handle portion
32 extending outwardly from an upper side thereof. The disc 32 has
an outer diameter which will allow insertion of the disc 32 into
the interior of the staging device 12. An absorbent sponge material
34 is adhered to the lower side of the disc 30 so that the sponge
material 34 engages with the surface of the cornea 10 to absorb any
solution within the staging device 12 (See also FIG. 10).
Reshaping
[0049] After the cornea 10 is treated with a chemical softening
agent, a mold generally indicated at 36 of predetermined curvature
and configuration is fitted into the staging device (See FIGS. 4-5,
and 11-12). Turning to FIGS. 4-5, the mold 36 is preferably
cylindrical in shape having a mold surface generally indicated at
38 which will engage the anterior surface of the cornea 10, and
further having an opposing rear surface 40. The mold 36 can be
fabricated from any one of a variety of materials, including metal,
glass, plastic, quartz, or epoxy materials. With regard to
preferred materials for fabrication, and as will be described
hereinafter in Example 1, the present preferred method for
restabilizing the cornea 10 after shaping is by means of exposure
to UV light. It is thus preferred that the mold 36 be fabricated
from a UV permeable plastic, such as polymethyl methacrylate. This
plastic material can first be molded in a generic mold shape and
then have the mold surface 38 cut to a predetermined shape by a
lathe.
[0050] The mold surface 38 is provided with a predetermined
geometric configuration which, when engaged with the surface of the
cornea 10, is intended to reshape the cornea to an emmetropic
configuration. The specifics of the geometric curvature of various
portions of the mold surface 38 will be discussed hereinafter. The
mold surface 38 can be formed by any one of a variety of known
methods for forming optical lenses such as lath cutting, molding or
milling depending on the fabrication material of the mold 36.
[0051] The rear surface 49 of the mold 36 is preferably provided
with a key 42 so that the mold 36 can be properly rotationally
oriented on the surface of the cornea 10. Rotation of the mold 36
can be accomplished by a holder tool generally indicated at 44
having a complementary detent 46 on the end thereof (FIGS. 6 and
6A). More specifically, the holder tool 44 has a hollow cylindrical
body portion 48 which is intended to be inserted into the staging
device to engage the mold 36 situated threin. The detent 46 is
located at the distal end of the body portion. At the proximal end
of the body portion 48 there is an enlarged diameter finger grip 50
having a fluted outer surface 52 which can be easily grasped and
rotated by the surgeon. The finger grip is also hollow to provide a
continuous open through the tool holder 44. Referring to FIG. 7,
holder 44 is shown in conjunction with the end of a light rod 54
which will be used to apply light through the mold 36. One end of
the light guide 54 is provided with a reduced diameter portion 56
which fits into the open end of the finger grip 50 of the holder
tool 44. The light guide 54 is maintained in assembled relation
with the holder tool 44 by means a set screw 58 which extends
through the finger grip 50 and engages with the reduced diameter
end 56 of the light guide 54.
[0052] After the mold 36 is oriented in the staging device 12,
downward pressure is applied to the mold 36 for a predetermined
period of time (1-10 minutes) to re-shape the softened cornea 10.
Pressure is preferably applied by pressing downwardly on the holder
tool 44 which is engaged with the mold 36 (See FIG. 12).
Mold Configurations
[0053] Various types of mold configurations can be used to treat
different refractive errors of the eye. Hereinbelow, the
Applicant's will discuss various mold configurations which can be
utilized in the subject process.
[0054] A. Residual Astigmatism (Internal Astigmatism)
[0055] Internal astigmatism is the astigmatism in the eyes optical
system other than that measured on the corneal surface. A patient
with internal astigmatism will require a toric central curve mold
application. When the spectacle refractive astigmatism equals the
corneal astigmatism in a given median, the internal astigmatism is
zero. This is to say that the total astigmatism of the eye is
produced by the corneal toricity. Sphericalizing the cornea with a
mold of the subject invention will result in zero refractive
astigmatism.
[0056] If the refractive astigmatism differs in magnitude but the
same direction as the corneal toricity, the difference is the
internal astigmatism. There are two cases. One where the corneal
astigmatism is greater than the refractive astigmatism, where a
bitoric mold would be used having its steeper curve aligned with
the steeper corneal meridian. The resultant optical outcome would
be an emmetropic with a toric cornea (the axis of corneal
astigmatism would be the same pre-post procedure.) The other case
would be a corneal astigmatism of less magnitude than the
refractive astigmatism along the same meridian. The mold for
treating this condition would have a bitoric central curve. Axis of
astigmatism mold correction 90.degree. from the refractive
astigmatism axis. The mold would have a toric power equal to the
difference between the power of the refraction and corneal
astigmatism. The resultant optical outcome would be an emmetropic
eye with a toric cornea.
EXAMPLE A
[0057] Corneal K's 44/46 at 90 (s diopter of corneal
astigmatism)
[0058] Spectacle refraction -300=-100.times.180 (1 diopter
refractive astigmatism)
[0059] Mold toricity -100.times.180
EXAMPLE B
[0060] Corneal k's 44/45 at 90 (1 diopter of stigmatism)
[0061] Spectacle refraction -300=-200.times.180 (2 diopter of
astigmatism)
[0062] Mold toricity -100.times.90
[0063] The visual optics are fundamental for those skilled in the
art. The resultant internal astigmatism as defined by the formulas
will be corrected for with a bitoric mold having an axis of myopic
correction with the axis of residual myopic astigmatism.
[0064] Where the axis of corneal astigmatism and the axis of
spectacle refraction are not along the same meridian, a new bitoric
mold axis and power can be determined by applying visual optics
formulas known in the art.
[0065] The spherical mold is fit flatter than the corneal
astigmatic meridian by the magnitude of the spectacle refraction.
The mold should have a power equal to the power of the flat corneal
astigmatic meridian with a refractive power along that meridian.
This method works only if there is no residual astigmatism.
[0066] When a residual astigmatism exists, a bitoric mold is used
which has a minus cylinder axis at the same axis as the residual
astigmatism. The power difference between bitoric curves is equal
to the magnitude of the residual astigmatism. The spherical
component of the mold is determined by the aforementioned
method.
[0067] B. Spherical Base Curves for Mold Design
[0068] The spherical mold is fit flatter than the flat corneal
astigmatic meridian by the magnitude of the spectacle refraction
along that flat meridian. The mold base curve should have a power
equal to the power of the flat corneal astigmatic meridian minus
the refractive power along that meridian. This method works only if
there is no residual astigmatism.
[0069] (1) Simple Myopia
[0070] a. -300 sph spectacle refraction
[0071] b. 44 sph corneal power
[0072] c. 44-3=41 diopters=mold base curve power
[0073] (2) Simple Astigmatism
[0074] a. pl=-100.times.180
[0075] b. 43/44 at 90 corneal powers
[0076] c. 44 (flat corneal power)-plane (0)=44 diopter mold base
curve power. The mold is aligned on the flat corneal meridian
[0077] (3) Compound Myopic Astigmatism
[0078] a. -200=-100.times.180
[0079] b. 43/44 at 90 corneal powers
[0080] c. 44-43=1 diopters=mold base curve power
[0081] C. Base Curve Mold Configuration for Hyperopia, Compound
Hyperopic Astigmatism, and Presbyopia are Computed Using the Same
Formulas.
[0082] The base curve of the mold is steeper than the flat corneal
meridian by the magnitude of the spectacle refraction along that
flat corneal meridian. The base curve can be spherical or
aspherical or bitoric and the optic zone diameter will vary
depending on the magnitude of the power correction required. The
mid-peripheral curve will be flatter, preferably aspherical, but
may be spherical and will in general be flatter and wider as the
central refractive power/corneal power ratio increases. This is to
say that the more hyperopic refractive correction, the steeper the
central base curve and the flatter the mid-peripheral curve
becomes.
[0083] The concept of the mold (for all refractive errors) is to
reconfigure a given square mm surface area of the cornea by
flattening the optic zone (in myopes) and displacing the tissue
laterally into the relief zone pocket, without changing the overall
square mm surface area of the cornea.
[0084] The overall configuration is a smooth spherical optic zone
(unless a bitoric curve is necessary for residual astigmatism) with
a gradual relief zone that gradually flattens out to the natural
peripheral corneal curvature.
Mold Dimensions
[0085] Referring to FIGS. 5 and 8C, there is shown a mold
configuration 36 of the general type which will be used in the
processes of the present invention. The mold 36 is particularly
suited for treating a myopic cornea wherein the object is to
flatten out the central portion of the cornea 10. In this regard,
the mold surface 38 includes a central curve zone 60, a single
mid-peripheral (relief) curve 62, and a large base curve 64. The
width of the central curve 60 is about 4 mm, and the width of the
mid-peripheral (relief) curve 62 is between 1 mm and 1.5 mm,
spherical or aspherical. The configuration of the base curve was
discussed generally hereinabove. The mid-peripheral curve 62 is
2-15 diopters steeper than the central base curve 60 for myopic
corrections. The larger the base curve/k relationship (increased
myopia, the steeper and wider the mid-peripheral (relief) curve 62.
The same holds true for hyperopia wherein the rule is that the
larger the base curve/k relationship, the flatter and wider the
mid-peripheral curve 62. The mid-peripheral curve 62 in hyperopic
molds are between 2-15 diopters flatter than the central base curve
60.
[0086] The type and magnitude of corneal astigmatism will influence
the width and curvature of the mid-peripheral (relief) curve 62 in
this and likely all mold designs. Larger magnitudes of compound
hyperopic astigmatism (CHA) will require flatter and wider
mid-peripheral curves and larger magnitudes of CMA will require
steeper and wider relief mid-peripheral curves. Small degrees of
total corneal astigmatism and small spherical emmetropics will
require less of a difference in curvature between the central base
curve and mid-peripheral relief curve. Aspheric mid-peripheral
curves will optimally be used for astigmatic corneas with reverse
geometry mold designs. If an outer peripheral curve is utilized in
the mold, it should have a width of about 0.25 mm-2.0 mm. The
curvature of the peripheral curve is somewhere near cornea
alignment.
[0087] Referring now to FIGS. 8A-8B, a mold 36A incorporating
multiple mid-peripheral curves is shown. The width of the central
curve 66 is between about 4-9 mm. The configuration of the central
base curvature was discussed generaly hereinabove. The first
mid-peripheral relief curve 68 (innermost curve) has a diameter of
0.3 mm to about 4.0 mm. This curve is 3-9 diopters steeper than the
central optic zone 66. The second mid-peripheral relief curve 70
has a width of 0.3-1.5 mm and is flatter than the first relief
curve 68. If an outer peripheral curve 72 is used, it should have a
width of between about 0.25 mm and 1.0 mm. This peripheral curve 72
is nearer to the corneal alignment than the first mid-peripheral
relief curve. The function of the peripheral curve 72 is to block
the cornea from structural flow outside of the periphery of the
mold 36A.
[0088] Referring now to FIG. 8D, a mold 36B for use in treating
hyperopic and compound hyperopic astigmatism is illustrated. The
mold 36B is first divided into two zone, a central optic zone 74,
and a mid-peripheral zone generally indicated at 76. The
mid-peripheral zone is divided into three separate curvatures
areas, namely a transition zone 78, an apex 80 of the
mid-peripheral curvature 76 and an outer curve portion 82.
Generally speaking, the central optic zone 74 is steeper than the
corneal curvature (spherical, aspherical or bitoric). The
transition zone 78 is flatter than the optical zone 74, but not as
flat as the apex zone 80. The apex 80 of the mid-peripheral
curvature 76 bears on the corneal surface and may move laterally or
medially on the curvature zone 76. The outer curve 82 is stepper
than the apex area curve 80 and aligned more with the surface of
the cornea 10.
[0089] Referring to FIG. 8E, yet another mold configuration 36C is
illustrated for use in treating myopia or mixed myopic astigmatism.
The mold surface 38 is provided with a central optic curve zone 84,
and a mid-peripheral relief zone generally indicated at 86. The
central optic curve zone 84 can be spherical, aspherical or
bitoric, and is approximately 6.0-10 mm is diameter, with an
optimal diameter of about 7 mm. The relief zone 86 is preferably
divided into three areas, namely, an inner portion 88, an apex
portion 90 and outer peripheral portion 92. The mid-peripheral
relief zone 86 is a concave surface which is approximately 1.5-3.0
mm in width having a variable apex location within the curve 86.
The inner portion 88 of the mid-peripheral relief curve 86 is
preferably flatter than the optical zone 84 (spherical or
aspherical). The apex portion 90 of the relief curve 86 is
approximately 0.3-0.4 mm in width and the apex thereof may be
skewed to medial or lateral locations of the relief curae 86. The
outer peripheral portion 92 of the relief curve 86 is approximately
0.25-1.5 mm in width, and maybe steeper than the optical zone 84
and also steeper than the corneal curvature under the mold 36 at
that location. The radius of curvature of each of the portions of
the mid-peripheral relief zone 86 is off alignment with the line of
sight. The preferred embodiment of the mold 36C will not have an
outer peripheral curve zone 92.
[0090] All of the above-described mold information is of the
general type known in the art of fitting orthokeratology contact
lenses. The information has been provided as a means for
explanation of the various molds used during the processes
described, but it is not intended to limit the scope of the
disclosure to any particular type or design of mold structure as
many different mold design will work to produce the same effect of
shaping the corneal tissues to the curvature of the mold to alter
the refractive power of the eye.
Stabilization of the Cornea After Shaping
[0091] The last and most crucial step in the process comprises
restabilizing the corneal tissues after reshaping into the new
"emmetropic" configuration. For purposes of the present disclosure
the Applicant has adopted the term "stabilizing agent" as a means
to refer to all of the potential agents for restabilizing the
collagen matrix of the eye. Included among the stabling agents to
be described hereinafter are chemical stabilizing agents, light
energy including UV and visible light, thermal radiation, microwave
energy, and radio waves.
Crosslinking Using UV Light
[0092] It is well known that UV radiation and UVC is effective in
crosslinking collagen. (See the Kelman and DeVore U.S. Pat. Nos.
4,969,912; 5,201,764; 5,219,895; 5,354,336; and 5,492,135 regarding
UV crosslinking of collagen materials). While the exact mechanism
is not well understood, it is thought that UVC acts primarily on
tyrosine residues in the collagen molecule. Accordingly, the
polymerization or crosslinking of the reshaped corneal tissues may
be carried out simply by exposing the cornea to short wave UV light
(e.g. 254 nm). However, the rate of polymerization is not practical
for use because of the potential damage to the corneal tissues
caused by long term exposures to UV light. The rate of
polymerization may be significantly increased by applying
appropriate redox initiators to the cornea prior to the UV light
exposure. Without such an initiator, UV polymerization, would
require at least 10 minutes of exposure.
[0093] Suitable, but non-limiting, examples of some initiators
include sodium persulfate, sodium thiosulfate, ferrous chloride
tetrahydrate, sodium bisulfate, and oxidative enzymes such as
peroxidase or catechol oxidase.
[0094] A suitable dosage of the chemical initiator is one that
sufficiently promoted the polymerization of the corneal matrix
within between about 30 seconds and about 2 minutes, preferably
between about 30 second and 1 minute, but insufficient to cause
oxidative damage to the corneal tissues.
[0095] Polymerization by UV irradiation may be accomplished in the
short wave length range by using a standard 254 nm source of
between about 4 and 12 watts. Polymerization generally occurs in
between about 30 seconds and about two minutes, preferably no
longer than 1 minute, at an exposure distance of between about 1.5
and 5 cm distance. Because excess UV exposure will begin to
depolymerize the collagen polymers ad cause eye damage, it is
important to limit UV irradiation for short periods. At 254 nm, the
penetration depth is very limited.
[0096] While short wave UV in the range of 254 nm is disclosed, it
is to be understood that other wavelengths of UV would also be
suitable depending on application of a suitable photoinitiator
matched to the particular wavelength. In the experiments outlined
below, the UV exposure was conducted with no filter, thereby
providing broadband UV irradiation. Filters will provide a more
specific wavelength, which will be matched to an appropriate
photochemical or redox initiator. Filters also reduce the
temperature elevation at the exposure site. Sodium persulfate which
is listed as the preferred initiator in Example 1 exhibits a
maximum absorption at 254 nm, but appears to be effective at much
higher wavelengths. For maximum efficiency, it is preferred to
match the UV wavelength to a specific redox or photochemical
initiator.
Gamma Irradiation
[0097] Polymerization, or crosslinking, can also be accomplished
using Gamma irradiation between 0.5 to 2.5 Mrads. However, excess
Gamma exposure will also depolymerize collagen polymers.
Chemical Crosslinking
[0098] There are many potential chemical "stabilizing" agents for
use in chemically crosslinking the collagen matrix.
[0099] The historical collagen cross-linking technique utilizes
glutaraldehyde. Glutaraldehyde and other aldehydes, such as
glyoxal, acrolein, acetaldehyde, butyraldehyde, propionaldehyde,
and formaldehyde create lateral bridges between polypeptide chains
and between collagen fibers. Other suitable, but non-limiting,
chemical cross-linkers include periodates, acyl azides,
Denacol.RTM. ethers, i.e. Sorbitol Polyglycidyl Ether, Polyglycerol
Polyglycidyl Ether, Pentaerythritol Polyglycidyl Ether, Diglycerol
Polyglycidyl Ether, Triglycidyl Tris Isocyanurate and Glycerol
Polyglycidyl Ether, bifunctional acylation agents, including
anhydrides, acid chlorides, and sulfonyl chlorides, e.g.
1,2,3,4-cyclobutanetetracarboxylic dianhydride,
Tetrahydrofuran-2,3,4,5-t- etracarboxylic dianhydride,
1,2,4,5-benzenetetracarboxylic di-anhydride,
ethylenediaminetetraacetic dianhydride,
bicyclo(2,2,2)oct-7-ene-2,3,5,6-t- etracarboxylic dianhydride,
glutaryl dichloride, adipoyl chloride, 3-methyladipoyl chloride,
pimeloyl chloride, terephthaloyl chloride, isophthaloyol
dichloride, phthaloyl dichloride, 1,4-phenylene bis(chloroformate),
2,4-mesitylenedisulfonyl chloride, 2,6 naphthalenedisulfonyl
chloride, malonyl dichloride, and homobifunctional amine
cross-reactive cross-linkers such as homobifunctional imidoesters
and homobifunctional N-hydroxysuccinimidyl are also suitable.
[0100] Unfortunately, many of these agent elicit adverse tissue
reactions, and therefore their use must be carefully controlled and
directed to a specific site. In this regard, chemical cross-linking
is not discussed herein as the preferred method of stabilization.
However, such agents would be highly useful in the present method
should appropriate delivery systems become available in the
future.
Thermal Radiation
[0101] Heat is another possible means of cross-linking, or
"stabilizing" the corneal tissues after reshaping. It is generally
known that the application of heat speeds up tissue metabolism and
will help stabilize the tissue faster than if no heat were applied.
Laser thermal keratoplasty (LTK) is the use of heat produced at
specified points in the cornea stroma by absorption of laser light
to modify the structure and mechanical properties of stromal
collagen. Typically, in LTK, the laser is directed to a particular
spot on the eye. As the spot absorbs light and heat up to about
55-60 degrees centigrade, the collagen will shrink. Rings of spots
are used to tighten the tissues to create a change in the anterior
curvature of the cornea. As a final step in the present
methodology, the reshaped cornea could be exposed to laser light
wherein the corneal tissues would be heated and stabilized in the
new emmetropic configuration. The treatment parameters at this
point in development are purely speculative.
Microwave Energy
[0102] Microwave energy is also currently being investigated as a
means of treating myopia. The treatment has been called microwave
thermokeratoplasty, and has been previously documented by D. X.
Pang, B. S. Trembly, L. R. Bartholomew, P. J. Hoopes, and D. G.
Campbell, Microwave Thermokeratoplasty, Investigational
Ophthamology and Visual Science, 36:s988, 1995, and D. X. Pang, B.
S. Trembly, L. R. Bartholomew, and P. J. Hoopes, Microwave
Thermokeratoplasty: Reshaping Corneal Contour (Corneal
Microwave-TKP), Accepted for Publication, International Journal of
Hyperkeratoplasty, (1998). See also U.S. Pat. No. 4,881,543 to
Trembly entitled Combined Microwave Heating and Surface Cooling of
the Cornea (1989), and U.S. Pat. No. 5,618,284 to Sand, Collagen
Treatment Apparatus, (1997). The mechanism for cross-linking
appears to be via the creation of heat at specific sites in the
stroma. As stated above for thermal radiation, it is generally
known that the application of heat speeds up tissue metabolism and
will help stabilize the tissue faster than if no heat were applied.
It is contemplated that microwave energy could be used to generate
heat in the stroma to stabilize the corneal tissues after softening
and molding as described in the present invention. As a final step
in the present methodology, the reshaped cornea could be exposed to
microwave energy wherein the corneal tissues would be heated,
either at specific points or throughout the whole cornea, and
stabilized in the new emmetropic configuration. The treatment
parameters at this point in development are purely speculative.
Application of Heat Through the Mold
[0103] Another possible technique of applying heat to the cornea
would be through direct contact with the mold. In this regard, the
mold could be provided with a controlled heating element to heat
the mold body to a predetermined temperature. Such heating could be
accomplished by electric elements or by a heated fluid flow through
the mold.
Radio Waves
[0104] It is still further contemplated that radio frequency energy
could be used to generate heat in the stroma to stabilize the
coreal tissues' after softening and molding as described in the
present invention. As a final step in the present methodology, the
reshaped cornea could be exposed to radio frequency (RF) energy
wherein the corneal tissues would be heated, either at specific
points or throughout the whole cornea, and stabilized in the new
emmetropic configuration. The treatment parameters at this point in
development are purely speculative. See U.S. Pat. No. 5,638,384 to
Gough et al entitled Multiple antenna ablation apparatus, (1997)
describing the use of RF energy in surgical ablation
techniques.
Visible Light
[0105] It is also possible to crosslink collagen using visible
light. However, this method will require a photochemical initiator
to transfer photoenergy into a free radical chemical reaction.
Suitable, but non-limiting, photochemical dye initiators include
Pheno-safranin, methyl red, bromphenol blue, crocein scarlet,
phenol red, alcian blue, Rose Bengal, Methylene blue, A zure A,
Toluidine blue, Eosin Y, Evans blue, Methylene green, Amythest
violet, Lumazine, Thionine, Xanthopterin,
2,3,5-triphenyl-tetrazolium Cl., Acridine red, Acridine orange,
Proflavine, Rosazurin, Azure B, Bindschedler's green, Primuline,
Acridine yellow, Neutral red, Erythrosine, Fluorescein, Indo-oxine,
and Malachite green. Of these chromophores, Fluorescein, Eosin,
Indo-oxine and Rose bengal appear to be best suited for corneal
use. It is noted that the exposure times for these chromophores are
excessive and therefore, the use of these chemical may not be
practical in actual usage. However, use is being tested for optimum
performance times.
[0106] It is thought that Redox initiators will work much faster.
Suitable but non-limiting, redox initiators include Diphenylamine,
Erioglaucin A, 2,2'-Dipyridyl ferrous ion, and N-Phenylanthranilic
acid.
Visible Light Stabiization following Destabilization using a
Sulfonic Acid Chromophore
[0107] An alternative technique for reshaping the cornea may
comprise destabilizing the cornea with a sulfonic acid dye,
followed by reshaping the cornea, and stabilizing the cornea by
exposure to a specific wavelength of visible light corresponding to
a maximum absorbance of the chromophore attached to amines reacted
in the softening process.
[0108] Suitable, but non-limiting sulfonic acid dyes include:
lucifer yellow vs, direct yellow 8, 2,2'-azinobis
(3-ethylbenzothiazoline-6-sulfo- nic acid),
4,5-dihydroxy-3-(4-sulfolnapthylazo)27napthalenedisulfonic acid,
2-dibenzofuransulfonic acid, 1-(2-hydroxyethyl)quinolinium
p-toluenesulfonate, brilliant sulphaflavine, thiazine red r,
pyrogallol red, papaverine sulfonic acid, direct yellow 27,
napthylazoxine a, 1-ethyl-2undecyl-5-benzamidazolesulfonic acid,
hoechst 2495,
8-hydroxy-7-(4-sulfo-1-napthylazo)-5-quinolinesulfonic acid,
3-hydroxy-4(2-hydroxy-4-sulfo-1-napthyl-azo)-2-napthalenecarboxylic
acid, 1-hexadecanesulfonic
(methyl-sulfo-benzothiazolinylidene)hydrazid, sulfobromophthalein
sodium hydrate, prmulin, sulforhodamine g,
8-hydroxy-5-(1-napthylazo)-2-naphthyalenesulfonic acid,
2-methylthio-3-phenylbenzothiazolium para-toluenesulfonate,
2-(m-aminophenyl)-1-dodecylbenzimidazole-5-sulfonic acid,
2-(4-bromobenzyl)isothiothiouronium
8-(4-hydroxy-1-naphthylazo)2naphthale- nesulfonate,
(hexadecyl-methylsulfamoyl)benzenesulfonic
(me-sulfo-bz-thiazolinyliden)hydrazid, merocyanine 540, fast
sulphon black f,
2-(3-amino-3-methylpentyl)-1-octadecyl-5-benzimidazolesulfonic
acid, sulforhodamine b,
3,6-bis-(4-solfo-1-naphthylazo)-4,5-di-oh-2,7-nap-
hthyalenedisulfonic acid, copper
phthalocyanine-3,4',4",4.sup.111-tetrasul- fonic acid,
1-hexadecanesesulfonic acid, 4-(hexadecylsulfamoyl)bezenesulfo- nic
acid, nickel phthalocyaninetetrasulfonic acid, azocarmine g,
sulforhodamine 101 hydrate,
6,6'-(1,1'-biphenyl44'diylbisazo)bis(4amino5h-
ydroxyl13naphthalenedi-so3h2ona salt), azocarmine b,
carboxy-hexadecyloxybenzenesulfonic acid, 1-hexadecanesesulfonic
acid, thiazol yellow g, carboxy-hexadecylsulfonylbenzenesulfonic
acid, 1-hexadecanesesulfonic acid, chlorazol azurine,
3-methyl-2-benzothiazolin- one azine, methylthymol blue, reactive
blue 15, acetamidohexadecylsulfonyl- benzenesulfonic acid, owens
blue, direct yellow 29, indocyanine green
EXAMPLE 1
Preferred Methodology
[0109] (1) Apply the staging apparatus 12 to the eye (FIG. 9);
[0110] (2) Pretreat the cornea (10--shown in solid line) with 0.02M
disodium phosphate buffer solution (94), pH 8.5 for 1 minute (FIG.
9);
[0111] (3) Remove excess buffer (94) with the sponge apparatus (28)
(See FIG. 10);
[0112] (4) Treat cornea (10) with a solution containing 5-50 mg of
glutaric anhydride dissolved immediately before application in 1 ml
of 0.02M disodium phosphate, pH 8.5. The preferred concentration of
glutaric anhydride is 10-30 mg pre ml of disodium phosphate;
[0113] (5) Remove the anhydride solution with sponge apparatus;
[0114] (6) Place a shaping mold (36) into the staging apparatus 12,
rotate to the desired position using the tool holder 44, and apply
appropriate pressure to attain the desired anterior curvature of
the cornea (10) (See FIG. 12) (the original corneal shape is now
shown in broken line and the new second configuration is shown in
solid line);
[0115] (7) With the mold 36 in place, treat the cornea with a Redox
initiator in a slightly alkaline buffer. For sodium persulfate,
preferably use 0.1M to 0.5M sodium persulfate in 0.02M phosphate
buffer pH 8.0. The preferred concentration of sodium persulfate is
0.2M to 0.4M;
[0116] (8) With the mold 36 still in place, expose the corneal
surface to UV irradiation in the 250-390 nm range. Preferably an
EFOS Novacure unit is utilized and set at 3000 mW/cm.sup.2 for
10-120 seconds, preferably 30-60 seconds. The EFOS light guide 96
is positioned within the staging apparatus 12 at a distance of
0.25-3.0 inches from the cornea, optimally 0.25-1.0 inches.
Exposures may range from 2500 mW.times.120 seconds to 4500
mW.times.45 seconds, preferably 2500 mW.times.75 seconds to 4500
mW.times.30 seconds (FIG. 13);
[0117] (9) Following the UV exposure, the cornea is thoroughly
washed with 0.02M phosphate buffer at pH 7.2; and
[0118] (10) The mold 36 and staging apparatus 12 are then removed
from the eye and the eye is examined using slit lamp and corneal
topography methods to determine the degree of change of curvature
and to determine if additional shaping may be required (FIG. 14).
The original curvature of the cornea is shown in FIG. 14 in broken
line, while the new "emmetropic" curvature is shown in solid
line.
Stabilization of Long Term Orthokeratology Patients
[0119] One of the anticipated benefits of the stabilization process
is that it can be used to stabilize the corneas of patients having
already undergone long term orthokeratology. The stabilization
procedures will eliminate the need to continue wearing retainer
lenses to maintain the shape of the cornea. While it may be
possible to simply utilize the stabilization step for these
patients, it is anticipated that the cornea will have to be
destabilized before it can be restabilized to take on the new
configuration. In such a method, the eye would be destabilized
using the methodology as described above. Because the eye was
already preshaped, very little shaping will be necessary to reshape
the eye to the proper configuration. A mold would however be used
to maintain the proper shape during the restabilization process.
With the mold in place, the eye would then be exposed to a
photoinitiator and exposed to UV light to restabilize the cornea in
the new configuration.
Experiment 1
[0120] Experiments conducted using enucleated pig eyes.
Pre-treatment and post-treatment evaluations of eyes were made by
slit-lamp examination and by taking K-readings. In a control
portion of the experiment, several pig eyes were treated with
contact lenses only. Neither destabilization nor stabilization were
performed on the control eyes. As expected, there was no change in
the corneal curvature as determined by slit-lamp examination and
measurement of K-readings. In a second part of the experiment,
contact lenses were applied to two eyes without destablization,
followed by treatment with sodium persulfate solution
(photochemical initiator) and exposure to UV light using an
Ultracure 100SS Plus UV light source manufactured by EFOS of
Williamsville, N.Y. The dosage of light was approximately 1500
mWatts for about 30 seconds (broad wavelength of 25-390 nm).
Pretreatment measurements of the two eyes were 36.75/37.5. After
treatment measurements were 43/41.5 and 40.5/44. The eyes were
clear and the ridge created by the contact lens was visible after 1
hour. In a third part of the experiment, an eye was treated with a
pH 8.76 phosphate buffer for 1 minute followed by exposure to 10
mg/ml glutaric anhydride in phosphate buffer for 1 minute to
destabilize the cornea. A contact lens was applied. The eye was
then flushed with phosphate buffer, pH 7.2 to remove residual
glutaric acid and then soaked with phosphate buffer (0.02M), pH 8.0
containing 0.3M sodium persulfate. UV light was applied for 20
seconds, the lens removed and the eye again flushed with phosphate
buffer, pH 7.2. The pretreatment measurements of the eye were
36.75/37.5. The pig eye was examined after the glutaric anhydride
treatment and measurements were 40.5/39.0. After UV treatment,
measurements were too steep to read and rather distorted.
Indentations and ridges created by the lens were observed
immediately post-treatment and 1 hour after treatment. Results
showed definite curvature changes and very obvious ridges created
by the lens.
Experiment 2
[0121] Second set of experiments also using enucleated pig eyes. an
EYESYS topographical system was available to perform topographical
mapping of the eyes before and after treatment. In addition, the
EFOS Ultracure 100SS was available for UV light treatment. In a
control part of the experiment, an eye was examined using a slit
lamp and using the EYESYS system. Neither glutaric anhydride nor
sodium persulfate were administered prior to application of UV
light exposure. However, buffers were administered to simulate full
treatment. EYESYS evaluation demonstrated that the surface
characteristics following treatment remained the same as before
treatment. In a second part of the experiment, a second pig eye was
examined by slit lamp, and EYESYS. Topographical profiles were
printed. The eye was them soaked in phosphate buffer at pH 8.5 for
2 minutes. Glutaric anhydride at 10 mg/ml was prepared in an
alcohol solution and immediately administered to the eye. A contact
lens was applied to the eye and held in place for 1 minute. The eye
was then soaked in a sodium persulfate solution (0.3M sodium
persulfate in pH 8.5 buffer) with the lens still in place. After
several one (1) minute soaks in the sodium persulfate solution, the
eye was exposed to UV light for about 30 seconds. The lens was
removed and the eye washed with phosphate buffer, pH 7.2. The eye
was then examined by slit lamp and EYESYS. Slit lamp examination
showed that the eye had developed some cloudiness (probably due to
the alcohol solution containing the glutaric anhydride). EYESYS
examination demonstrated that the eye topography had been changed.
In a third part of the experiment, a third eye was treated the same
as above, expect that the glutaric anhydride was delivered in a
phosphate buffer, pH 8.5, in an attempt to prevent the clouding
observed using alcohol. Slit lamp examinations showed much less
corneal clouding. EYESYS examinations demonstrated topographical
changes appearing to match the curvature of the applied contact
lens. The experiments show that the described techniques could
alter the shape of the anterior curvature of the cornea.
Experiment 3
[0122] Third set of experiments using a live rabbit. Both the
EYESYS topographical system and EFOS Ultracure 100SS were
available. The rabbit's eyes were examined by slit-lamp and EYESYS.
Topographical profiles were printed. The control eye was left
untreated. The experimental eye was exposed to 0.02M phosphate
buffer, pH 8.5, and treated with glutaric anhydride at 20 mg/ml in
pH 8.5 phosphate buffer followed by application of a contact lens.
The eye was then washed with 0.02M phosphate buffer, pH 8.5 to
remove residual glutaric acid, soaked with buffer containing 0.3M
sodium persulfate and exposed to UV light for two 30 second bursts
with the contact lens in place. Both the control and treated eyes
were examined by slit-lamp and EYESYS. Topographical profiles were
printed. The treated eye showed and obvious change in surface
topography. Slit-lamp examination indicated some corneal haze,
which cleared in about 1 hour. The experiment, in a live animal,
demonstrated that the anterior corneal curvature could be altered
in a live subject using the described techniques.
[0123] It can therefore be seen that the instant invention provides
a unique and effective method for quickly modifying the anterior
curvature of the cornea with non-invasive surgical techniques. The
three step process of destabilizing, shaping and restabilizing will
allow potential patients to have the refractive vision errors
corrected in a matter of hours, without a recovery period, rather
than endure the lengthy and oftentimes painful procedures which
currently exist. The unique method of restabilizing the cornea
significantly decreases treatment time, and stabilizes the cornea
in a corrected emmetropic configuration that will eliminate the
need for retainer lenses or any other corrective lenses for that
matter. As stated above, the unique aspects of the method are
believed to reside in the unique three steps, destabilization,
reshaping and stabilization and in the apparatus used to achieve
the method. There has not been provided in the art a simple,
non-surgical, non-invasive, and rapid treatment for refractive
errors of the eyes, and the present invention is believed to have
solved the problems of the prior art. For these reasons, the
instant invention is believed to represent a significant
advancement in the art which has substantial commercial merit.
[0124] While there is shown and described herein certain specific
structure embodying the invention, it will be manifest to those
skilled in the art that various modifications and rearrangements of
the parts may be made without departing from the spirit and scope
of the underlying inventive concept and that the same is not
limited to the particular forms herein shown and described except
insofar as indicated by the scope of the appended claims.
* * * * *