U.S. patent application number 15/050921 was filed with the patent office on 2016-10-27 for compositions and methods for treating presbyopia, mild hyperopia, and irregular astigmatism.
The applicant listed for this patent is ALLERGAN, INC.. Invention is credited to Juan Carlos Abad.
Application Number | 20160310466 15/050921 |
Document ID | / |
Family ID | 47522725 |
Filed Date | 2016-10-27 |
United States Patent
Application |
20160310466 |
Kind Code |
A1 |
Abad; Juan Carlos |
October 27, 2016 |
COMPOSITIONS AND METHODS FOR TREATING PRESBYOPIA, MILD HYPEROPIA,
AND IRREGULAR ASTIGMATISM
Abstract
The present invention is directed to compositions and methods
for treating ocular conditions, including presbyopia, mild
hyperopia, irregular astigmatism, hyperopic accommodative
esotropia, and glaucoma. The compositions can also be used to
potentiate or enhance interventions that retard, reverse, or modify
the aging process of the crystalline lens and its surrounding
tissues. The compositions include a cholinergic agent, such as a
muscarinic acetylcholine receptor M3 agonist, and an alpha agonist
having an imidazoline group or a non-steroidal anti-inflammatory
agent (NSAID) having COX-2 selectivity. It has been found that an
alpha agonist having an imidazoline group or non-steroidal
anti-inflammatory agent (NSAID) having COX-2 selectivity in
combination with a cholinergic agent, such as pilocarpine, act
synergistically to improve the accommodative and focusing ability
of the eye while minimizing the side effects from each
compound.
Inventors: |
Abad; Juan Carlos;
(Medellin, CO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ALLERGAN, INC. |
Irvine |
CA |
US |
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|
Family ID: |
47522725 |
Appl. No.: |
15/050921 |
Filed: |
February 23, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14140103 |
Dec 24, 2013 |
9301933 |
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15050921 |
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14129012 |
Dec 23, 2013 |
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PCT/IB2012/002335 |
Sep 12, 2012 |
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14140103 |
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61536921 |
Sep 20, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 27/02 20180101;
A61K 31/4178 20130101; A61K 31/4164 20130101; A61K 31/541 20130101;
A61K 9/0048 20130101; A61K 31/4164 20130101; A61P 27/06 20180101;
A61K 31/325 20130101; A61P 43/00 20180101; A61K 31/541 20130101;
A61K 31/16 20130101; A61K 2300/00 20130101; A61K 31/27 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 31/4174 20130101; A61K
2300/00 20130101; A61K 31/5415 20130101; A61K 31/27 20130101; A61P
27/04 20180101; A61K 31/4178 20130101; A61K 31/5415 20130101; A61P
27/10 20180101; A61K 31/4174 20130101; A61K 45/06 20130101 |
International
Class: |
A61K 31/4178 20060101
A61K031/4178; A61K 9/00 20060101 A61K009/00; A61K 31/5415 20060101
A61K031/5415; A61K 31/325 20060101 A61K031/325; A61K 31/4164
20060101 A61K031/4164 |
Claims
1. A composition for treatment of an ocular condition, comprising a
muscarinic acetylcholine receptor M.sub.3 agonist and at least one
of the following: an alpha-stimulant agonist having an imidazoline
group; or a non-steroidal anti-inflammatory agent (NSAID) having
COX-2 selectivity; wherein the ocular condition comprises
presbyopia, mild hyperopia, irregular astigmatism, hyperopic
accommodative esotropia, or glaucoma.
2. The composition of claim 1, wherein the composition comprises:
from about 0.01% to about 4% w/w muscarinic acetylcholine receptor
M.sub.3 agonist; and from about 0.01% to about 0.5% w/w
alpha-stimulant agonist having an imidazoline group or about 0.01%
to about 2% NSAID having COX-2 selectivity, or both.
3. The composition of claim 1, wherein the composition comprises:
from about 0.01% to about 2% w/w muscarinic acetylcholine receptor
M.sub.3 agonist; and from about 0.01% to about 0.2% w/w
alpha-stimulant agonist having an imidazoline group or about 0.01%
to about 1% NSAID having COX-2 selectivity, or both.
4. The composition of claim 1, wherein the composition comprises:
from about 0.5% to about 1.5% w/w muscarinic acetylcholine receptor
M.sub.3 agonist; and from about 0.02% to about 0.1% w/w
alpha-stimulant agonist having an imidazoline group or NSAID having
COX-2 selectivity.
5. The composition of claim 1, wherein the muscarinic acetylcholine
receptor M.sub.3 agonist comprises acetylcholine, bethanechol,
carbachol, oxotremorine, pilocarpidine, or pilocarpine.
6. The composition of claim 1, wherein the muscarinic acetylcholine
receptor M.sub.3 agonist is pilocarpine.
7. The composition of claim 1, wherein the muscarinic acetylcholine
receptor M.sub.3 agonist is carbachol.
8. The composition of claim 1, wherein the alpha-stimulant agonist
comprises oxymetazoline, naphazoline, tetrahydrozoline,
tramazoline, or xylometazoline.
9. The composition of claim 1, wherein the alpha-stimulant agonist
is oxymetazoline.
10. The composition of claim 1, wherein the alpha-stimulant agonist
is naphazoline.
11. The composition of claim 1, wherein the alpha-stimulant agonist
is tetrahydrozoline.
12. The composition of claim 1, wherein the NSAID having COX-2
selectivity comprises meloxicam, celecoxib, rofecoxib, valdecoxib,
parecoxib, etoricoxib, nimesulide, etodolac or nabumetone.
13. The composition of claim 1, wherein the NSAID having COX-2
selectivity is meloxicam.
14. The composition of claim 1, wherein the composition further
comprises an ophthalmically acceptable carrier.
15. The composition of claim 1, wherein the composition further
comprises a cyclodextrin or derivative thereof to enhance ocular
penetration of the composition.
16. The composition of claim 1, wherein the composition is in the
form of an eye drop, suspension, gel, ointment, injectable
solution, or spray.
17. A method of treating presbyopia in a subject, comprising
administering to the subject a therapeutically effective amount of
a composition comprising a therapeutically effective amount of a
muscarinic acetylcholine rececptor M.sub.3 agonist and at least one
of the following: an alpha-stimulant agonist having an imidazoline
group; or a non-steroidal anti-inflammatory agent (NSAID) having
COX-2 selectivity.
18. A method of treating mild hyperopia in a subject, comprising
administering to the subject a therapeutically effective amount of
a composition comprising a therapeutically effective amount of a
muscarinic acetylcholine receptor M.sub.3 agonist and at least one
of the following: an alpha-stimulant agonist having an imidazoline
group; or a non-steroidal anti-inflammatory agent (NSAID) having
COX-2 selectivity.
19. A method of treating irregular astigmatism in a subject,
comprising administering to the subject a therapeutically effective
amount of a composition comprising a therapeutically effective
amount of a muscarinic acetylcholine receptor M.sub.3 agonist and
at least one of the following: an alpha-stimulant agonist having an
imidazoline group; or a non-steroidal anti-inflammatory agent
(NSAID) having COX-2 selectivity.
20. A method of treating hyperopic accommodative esotropia in a
subject, comprising administering to the subject a therapeutically
effective amount of a composition comprising a therapeutically
effective amount of a muscarinic acetylcholine receptor M.sub.3
agonist and at least one of the following: an alpha-stimulant
agonist having an imidazoline group; or a non-steroidal
anti-inflammatory agent (NSAID) having COX-2 selectivity.
21. A method of treating glaucoma in a subject, comprising
administering to the subject a therapeutically effective amount of
a composition comprising a therapeutically effective amount of a
muscarinic acetylcholine receptor M.sub.3 agonist and at least one
of the following: an alpha-stimulant agonist having an imidazoline
group; or a non-steroidal anti-inflammatory agent (NSAID) having
COX-2 selectivity.
22. A method of potentiating or enhancing interventions that
retard, reverse, or modify the aging process of the crystalline
lens and its surrounding tissues, in a subject, comprising
administering to the subject a therapeutically effective amount of
a composition comprising a therapeutically effective amount of a
muscarinic acetylcholine receptor M.sub.3 agonist and at least one
of the following: an alpha-stimulant agonist having an imidazoline
group; or a non-steroidal anti-inflammatory agent (NSAID) having
COX-2 selectivity.
23. The method of claim 27, wherein administering comprises
administering the composition to an eye of the subject.
24. The method of claim 23, wherein the composition is administered
to only one eye of the subject.
25. The method of claim 27, wherein the composition increases
refractive power of an eye of the subject by up to about 4.0
diopters.
26. The method of claim 27, wherein the subject is human.
27. A method of treating an ocular condition in a subject,
comprising administering to the subject a therapeutically effective
amount of a composition comprising a therapeutically effective
amount of pilocarpine and at least one of the following: an
alpha-stimulant agonist having an imidazoline group; or a
non-steroidal anti-inflammatory agent (NSAID) having COX-2
selectivity.
28. The method of claim 27 wherein the ocular condition comprises
presbyopia, mild hyperopia, irregular astigmatism, hyperopic
accommodative esotropia, or glaucoma.
29. The method of claim 27 wherein the ocular condition could
alternatively be corrected with eye glasses having about +0.5D to
about +1.0D lenses and wherein the therapeutically effective amount
comprises from about 0.3% to about 1.0% pilocarpine.
30. The method of claim 27 wherein the ocular condition could
alternatively be corrected with eye glasses having about +1.0D to
about +1.5D lenses and wherein the therapeutically effective amount
comprises from about 0.8% to about 1.6% pilocarpine.
31. The method of claim 27 wherein the ocular condition could
alternatively be corrected with eye glasses having about +1.5D to
about +2.0D lenses and wherein the therapeutically effective amount
comprises from about 1.4% to about 2.2% pilocarpine.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/140,103, filed Dec. 24, 2013, which in turn
is a continuation of U.S. patent application Ser. No. 14/129,012,
filed Dec. 23, 2013, which is a national stage application under 35
U.S.C. .sctn.371of PCT Patent Application Ser. No.
PCT/IB2012/002335, filed Sep. 19, 2012, all of which claim the
benefit of U.S. Provisional Patent Application Ser. No. 61/536,921,
filed Sep. 20, 2011, the disclosures of which are hereby
incorporated in their entireties herein by reference.
BACKGROUND
[0002] The normal (emmetropic) eye has a refractive power and axial
length which are balanced with each other. Seeing distant objects
sharply occurs by the light rays passing through the eye's optical
system in a passive way without any active muscular contraction. In
the normal eye, only the focusing of near objects requires an
active muscular increase in the refractive power of the eye. The
hyperopic eye is either shorter or has a weaker refractive power
and hence needs an active muscular mechanism to focus on distant
objects (beyond about 6 meters) that has to be increased even
further to focus on near objects. The myopic eye is either longer
or has a too powerful refractive power, so distant objects appear
blurry but near objects are in perfect focus without any active
muscular intervention.
[0003] The active muscular mechanism of focusing of the human and
primate eye involves the change in shape and position of the
crystalline lens, produced by the contraction of the ciliary muscle
of the eye that increases further the baseline refractive power of
the eye. Starting in childhood, the crystalline lens begins to
gradually lose its malleability and its capacity to change shape
and position in response to the contraction of the ciliary muscle.
From an optical standpoint, hyperopic eyes are generally affected
first by this loss of malleability due to the need to increase the
refractive power of the hyperopic eye to see clearly. Around age
40, the loss of malleability begins to affect normal eyes when they
are unable to focus on near objects (40 centimeters or less from
the eye) in a comfortable manner in a process called
presbyopia.
[0004] In the eye, the ciliary muscle is under the control of the
parasympathetic nervous system via acetylcholine and its muscarinic
receptors. The sympathetic nervous system plays a secondary
(regulatory) role via its alpha and beta receptors. Muscarinic
agonists or stimulants increase the contraction of the ciliary
muscle and hence increase the refractive power of the eye. From the
sympathetic standpoint, alpha-2 and beta-2 stimulants produce the
same contracting action on the ciliary muscle in part by allowing
the parasympathetic system to work in an unopposed manner. If this
stimulation is strong enough, some of the loss of the ability of
the crystalline lens to change shape and position that normally
occurs with age could be overcome while this stimulation is in
place.
[0005] Another mechanism to be taken into account for treating
presbyopia, is the effect on the dilating and sphincter muscles of
the iris that change the diameter of the pupil. The iris sphincter
is mainly under parasympathetic control via muscarinic receptors,
although the sphincter does have some alpha and beta receptors. The
iris dilating muscle is under sympathetic control, mainly alpha-1
and alpha-2 receptors with the alpha-1 stimulants producing
dilation and the alpha-2 stimulants limiting dilation. The depth of
the visual field of the eye could be increased by decreasing the
diameter of the pupil. This is analogous to a photographic camera
in which the depth of field increases as the diaphragm is closed.
Hence the use of a muscarinic agonist (activating the iris
sphincter) or an alpha-2 agonist (relaxing the dilating muscle of
the iris) may constrict the pupil thereby increasing the depth of
focus of the eye.
[0006] The most common way to correct presbyopia is by using
reading glasses or bifocal glasses. There are also special contact
lenses designed for this purpose. Several surgical treatments have
also been devised for the treatment of presbyopia including special
intraocular lenses, laser reshaping of the cornea, and scleral
expansors. Exercises have been proposed as a way to delay the onset
of presbyopia. However, the effectiveness of exercise in treating
or preventing presbyopia has not been demonstrated in medical
research. Pharmacological treatments for presbyopia have been
proposed. However, many of these treatments have proven to be
ineffective and/or have undesirable side effects.
[0007] Pilocarpine is an acetylcholine analog that acts as an
agonist on the muscarinic receptors of the parasympathetic nervous
system. It is a well-known antiglaucoma medication which has been
in use as an ophthalmic preparation for more than 100 years. It is
also used in an oral form to treat dry mouth/eyes. U.S. Pat. Nos.
6,291,466 and 6,410,544 describe one patient that had a decrease in
his/her hyperopia of less than half a diopter after the application
of 0.3% topical pilocarpine. A myopic patient had a decrease in his
myopia after the same dose of pilocarpine which was
counterintuitive.
[0008] U.S. Application No. 2010/0016395 A1 reports being able to
increase the dose of pilocarpine to 1% to 2% by adding the
non-steroidal anti-inflammatory agent diclofenac, but at a
concentration that was five times more concentrated than that
approved by the FDA. Congdon et al. reported that diclofenac is
associated with serious side effects such as persistent epithelial
defects, corneal melting, and corneal perforation. (Congdon et al.,
2001, Corneal complications associated with topical ophthalmic use
of nonsteroidal anti-inflammatory drugs, Ophthalmology,
27:622-631).
[0009] WO 2009/077736 discloses a combination of pilocarpine and
dapiprazole (or thymoxamine) and pilocarpine and brimonidine (or
iopidine) to treat defects of visual acuity, presbyopia, myopia,
hypermetropia, low night vision, and astigmatism. The combinations
listed are pilocarpine and dapiprazole (or thymoxamine), and
pilocarpine and brimonidine (or iopidine). The combination of
pilocarpine and dapiprazole produced red and irritated eyes (WO
2009/077736) and topical administration of brimonidine is known to
those in the art to produce lightheadedness, dizziness, dry mouth,
tachycardia, and stomach upset, among other side effects, which
limits its usage even among patients using it for a severe eye
condition such as glaucoma.
[0010] Although more than 75 molecules have been disclosed for the
medical treatment of presbyopia, no clinically effective
preparations suitable for use by the general public without
unreasonable side effects have been found.
SUMMARY OF THE INVENTION
[0011] Compositions and methods for treating ocular conditions,
including presbyopia and mild hyperopia, up to about 4.00 diopters,
or more in very young patients, irregular astigmatism, hyperopic
accommodative esotropia, and glaucoma, are disclosed. The
compositions of the present invention include a cholinergic agent,
such as a muscarinic acetylcholine receptor M.sub.3 agonist, and an
alpha-stimulant agonist having an imidazoline group or a
non-steroidal anti-inflammatory agent (NSAID) having COX-2
selectivity. Examples of muscarinic acetylcholine receptor M.sub.3
agonists include pilocarpine, acetylcholine, pilocarpidine,
bethanechol, carbachol, and oxotremorine. Examples of
alpha-stimulant agonists having an imidazoline group include
oxymethazoline, naphazoline, tetrahydrozoline, and xylometazoline.
Examples of NSAIDs with COX-2 selectivity include meloxicam,
celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib,
nimesulide, etodolac and nabumetone.
[0012] The compositions of the present invention were surprisingly
and unexpectedly found to potentiate the action of and decrease the
side effects of a cholinergic agent, such as pilocarpine, such that
a cholinergic agent can be effectively used in combination with an
alpha-stimulant agonist having an imidazoline group or a
non-steroidal anti-inflammatory agent (NSAID) having COX-2
selectivity to contract the ciliary and pupillary sphincter muscles
for treating ocular conditions, such as presbyopia, mild hyperopia,
and irregular astigmatism, hyperopic accommodative esotropia and
glaucoma ,without the patient experiencing the undesirable side
effects normally associated with pilocarpine therapy. The present
invention can also be used to potentiate or to enhance
interventions that retard, reverse or modify the aging process of
the crystalline lens and its surrounding tissues. Unlike previous
compositions disclosed in the prior art, it is believed that the
compositions of the present invention can safely be used by
patients for treatment of ocular conditions, including presbyopia,
mild hyperopia, irregular astigmatism, hyperopic accommodative
esotropia, and glaucoma, on a chronic basis.
BRIEF DESCRIPTION OF THE FIGURES
[0013] FIG. 1 shows the effect of a composition comprising
pilocarpine and oxymetazoline on near vision (Jaeger Equivalent)
over time.
[0014] FIG. 2 shows the effect of a composition comprising
pilocarpine and oxymetazoline on distance vision (LogMAR
Equivalent) over time.
[0015] FIG. 3 shows a comparison of the effect of a composition
comprising pilocarpine and oxymetazoline and a composition
comprising pilocarpine alone on near vision (Jaeger Equivalent)
over time.
[0016] FIG. 4 shows a comparison of the effect of a composition
comprising pilocarpine and oxymetazoline and a composition
comprising pilocarpine alone on distance vision (LogMAR Equivalent)
over time.
[0017] FIG. 5 shows the effect of a composition comprising
pilocarpine and meloxicam on near vision (Jaeger Equivalent) over
time.
[0018] FIG. 6 shows the effect of a composition comprising
pilocarpine and meloxicam on distance vision (LogMAR Equivalent)
over time.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0019] The phrase "a" or "an" entity as used herein refers to one
or more of that entity; for example, a compound refers to one or
more compounds or at least one compound. As such, the terms "a" (or
"an"), "one or more", and "at least one" can be used
interchangeably herein.
[0020] As used herein, a "composition" refers to a material
suitable for administration to an eye of a subject. Compositions
may include a polymeric drug delivery system if desired.
Compositions may comprise a liquid carrier. The term can also be
used to refer to materials such as solutions, suspensions,
emulsions, and the like.
[0021] The term "therapeutically effective amount" as used herein,
refers to the level or amount of agent needed to treat an ocular
condition, without causing significant negative or adverse side
effects to the eye or a region of the eye. As used herein, an
"ocular condition" is a disease, ailment or condition which affects
or involves the eye or one of the parts or regions of the eye,
including the eyeball and the tissues and fluids which constitute
the eyeball, the periocular muscles (such as the oblique and rectus
muscles) and the portion of the optic nerve which is within or
adjacent to the eyeball. Examples of an ocular condition include
presbyopia and mild hyperopia, irregular astigmatism, hyperopic
accommodative esotropia, and glaucoma.
[0022] The following terms are ophthalmic terms commonly used by
those of skill in the art. "OD" stands for oculus dexter and means
right eye. "OS" stands for oculus sinister and means left eye.
"UDVA" stands for unaided distance visual acuity. "UNVA" stands for
unaided near visual acuity. "Sph" is the sphere, or the amount of
magnification/demagnification that the eye needs to see properly. A
negative sphere indicates myopia, and a positive sphere indicates
hyperopia. "Cyl" is the cylinder, which is a measure of
astigmatism. "Pre" indicates the condition of the eye prior to
treatment, lh indicates the condition of the eye 1 hour after
treatment, 4h indicates the condition of the eye 4 hours after
treatment, and 6 h indicates the condition of the eye 6 hours after
treatment. "Sph Eq" is the spherical equivalent.
[0023] Measurements on the Jaeger scale, a near vision scale, are
used and described herein. Some examples of Jaeger scale values
used herein include the following: J1+is fine "normal" near vision
(equivalent to 20/20 in Snellen terms), which is the ability to
read the bottom line (in 3-point font letters) on a near vision eye
chart; J1 is good near vision (equivalent to 20/25 in Snellen
terms), which is the ability to read the next-to-bottom line (in
4-point font letters) on a near vision eye chart; J2 and J3 are
fair and functional near vision, respectively (equivalent to 20/30
and 20/40, respectively, in Snellen terms), which is the ability to
read lines 3 and 4, respectively, from the bottom on a near vision
eye chart, wherein J3 is "reading vision" for 6-point font
letters.
[0024] "LogMAR" is a commonly used visual acuity scale, expressed
as the (decadic) logarithm of the minimum angle of resolution.
LogMAR scale converts the geometric sequence of a traditional chart
to a linear scale.
Modes for Carrying Out the Invention
[0025] Alpha-stimulant agents having an imidazoline group, such as
oxymetazoline, naphazoline, and tetrahydrozoline, have been used on
a wide scale as self-prescribing medications, available over the
counter in the United States since the 1970's for ocular
redness/irritation with side effects reported very rarely.
Xylometazoline, another derivative of imidazoline, has been used as
a nasal decongestant. Despite widespread use of these agents by the
general public, these agents have not been previously used to treat
ocular conditions, such as presbyopia, because of their lack of a
significant clinical effect when used in isolation.
[0026] Pilocarpine, a cholinergic agent, has been used as an
isolated medication for the treatment of presbyopia and mild
hyperopia, but has not been very effective because topical
concentrations below 0.5% produce minimal effect in the
accommodation of the eye and concentrations above 0.5% are not
tolerated due to side effects such as red eyes, ocular pain, brow
ache, and headache. In addition, at concentrations of pilocarpine
effective enough to improve the reading ability of the presbyopic
patient, the eye is rendered so myopic that there is a significant
decrease in the eye's distance vision (Gilmartin et al., 1995,
Ophthalmic and Physiological Optics, Pergamon Press, Oxford, GB,
15(5):475-479).
[0027] Non-steroidal anti-inflammatory agents (NSAIDs) inhibit the
enzyme cyclooxygenase that produces prostaglandins. This enzyme has
two forms: cyclooxygenase-1 (COX-1) that is supposed to have
"resident" and "housekeeping" functions and cyclooxygenase-2
(COX-2) that is up regulated in cases of inflammation and cancer.
Agents that selectively inhibit COX-2, as opposed to both COX-1 and
COX-2, are believed to block inflammation without affecting the
normal homeostatic body mechanisms. (Fitzgerald G A and Patrono C.
The coxibs, selective inhibitors of cyclooxygenase-2. NEJM 2001;
345:433-442). While this is true for gastrointestinal mucosal
protection, side effects such as thrombotic events or renal damage
have been reported, such as in the case of oral rofecoxib. The
inhibition of COX-2 products at the corneal level decreases
collagenases that increase a known ocular side effect of NSAIDs
such as corneal melting (Ottino P and Bazan H E. Corneal
stimulation of WP-1, -9 and uPA by platelet-activating factor is
mediated by cyclooxygenase-2 metabolites. Curr Eye Res. 2001
August;23(2):77-85).
[0028] The compositions of the present invention have been
surprisingly and unexpectedly found to potentiate the action of and
decrease the side effects of a cholinergic agent, such as
pilocarpine, such that a cholinergic agent can be effectively used
in combination with an alpha-stimulant agonist having an
imidazoline group or a NSAID having COX-2 selectivity to contract
the ciliary and pupillary muscles for treating an ocular condition,
such as presbyopia, mild hyperopia, irregular astigmatism,
hyperopic accommodative esotropia, or glaucoma, without the patient
experiencing the undesirable side effects normally associated with
pilocarpine therapy. In addition, alpha-stimulant agents having an
imidazoline group, which were previously found to lack significant
clinical effect for treating ocular conditions, have a synergistic
effect in combination with a cholinergic agent, such as
pilocarpine. Although not wishing to be bound by any particular
theory, it is believed that the synergistic effect is due
post-receptor cross-talk between muscarinic and adrenergic
receptors, possibly via G proteins, resulting in the observed novel
interaction of imidazole compounds and muscarinic agonists. Unlike
previous compositions disclosed in the prior art, the compositions
of the present invention can safely be used by patients for
treatment of ocular conditions, such as presbyopia, mild hyperopia,
and irregular astigmatism, hyperopic accommodative esotropia, or
glaucoma on a chronic basis. The present invention can also be used
to potentiate or to enhance interventions that retard, reverse or
modify the aging process of the crystalline lens and its
surrounding tissues.
[0029] The compositions of the present invention include a
cholinergic agent in combination with an alpha-stimulant agonist
having an imidazoline group or a NSAID having COX-2 selectivity.
The cholinergic agent can be a muscarinic acetylcholine receptor
M.sub.3 agonist that acts on the ciliary muscle of the eye and
causes it to contract. Pilocarpine and carbachol are examples of a
suitable muscarinic acetylcholine receptor M.sub.3 agonist.
Additional examples include acetylcholine, bethanechol,
oxotremorine, pilocarpidine, and the like. In an embodiment, the
cholinergic agent is pilocarpine.
[0030] Examples of an alpha-stimulant agonist having an imidazoline
group suitable for use in the compositions of the present invention
include oxymetazoline, naphazoline, tetrahydrozoline, tramazoline,
xylometazoline, and the like. In an embodiment, the alpha-stimulant
agonist comprises one or more of oxymetazoline, naphazoline,
tetrahydrozoline, tramazoline, and xylometazoline. In an
embodiment, the alpha-stimulant agonist comprises oxymethazoline.
In another embodiment, the alpha-stimulant agonist comprises
naphazoline. In yet another embodiment, the alpha-stimulant agonist
comprises tetrahydrozoline.
[0031] Examples of a NSAID having COX-2 selectivity include
meloxicam, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib,
nimesulide, etodolac and nabumetone and the like. In an embodiment,
the NSAID comprises one or more of meloxicam, celecoxib, rofecoxib,
valdecoxib, parecoxib, etoricoxib, nimesulide, etodolac and
nabumetone. In another embodiment, the NSAID comprises
meloxicam.
[0032] The cholinergic agent in combination with the
alpha-stimulant agonist having an imidazoline group or the NSAID
having COX-2 selectivity potentiate the effects of the cholinergic
agent and the alpha-stimulant agonist or the NSAID, contracting the
ciliary muscle and reducing the pupillary diameter effectively
treating ocular conditions, such as presbyopia, mild hyperopia, and
irregular astigmatism, hyperopic accommodative esotropia, or
glaucoma. The combinations described herein also decrease the side
effects of the cholinergic agent without adding significant side
effects from the alpha-stimulant agonist or the NSAID, making it
easier for patients to tolerate chronic usage of the compositions
of the invention.
[0033] By administering the cholinergic agent in combination with
the alpha-stimulant agonist or the NSAID, the agents act
simultaneously and precisely on the ocular receptors modulating
each other's effects. When the agents are applied separately on a
sequential basis there is saturation of the receptors by one of the
agents before the other agent is applied leading to erratic
clinical responses. This can be further compounded by the washout
effect of applying one drop of the second agent in the conjunctival
cul-de-sac after the first agent, leading to unknown concentrations
of the active compounds being delivered to the eye.
[0034] The compositions of the invention are suitable for
ophthalmic use. The compositions generally include from about 0.01%
to about 4% w/w cholinergic agent and either from about 0.01% to
about 0.5% w/w alpha-stimulant agonist having an imidazoline group,
or from about 0.01% to about 2% w/w NSAID having COX-2 selectivity,
or both. The compositions can include any of the concentrations of
alpha-stimulant agonist having an imidazoline group and/or NSAID
having COX-2 selectivity as described herein in combination with
any of the concentrations of cholinergic agent as described
herein.
[0035] According to an embodiment, ophthalmic preparations of the
composition comprise from about 0.01% to about 4% w/w cholinergic
agent, such as pilocarpine or carbachol. In another embodiment,
ophthalmic preparations of the composition comprise from about
0.01% to about 3.5% w/w cholinergic agent. In yet another
embodiment, ophthalmic preparations of the composition comprise
from about 0.01% to about 3% w/w cholinergic agent. In yet another
embodiment, ophthalmic preparations of the composition comprise
from about 0.01% to about 2.5% w/w cholinergic agent. In yet
another embodiment, ophthalmic preparations of the composition
comprise from about 0.01% to about 2% w/w cholinergic agent. In yet
another embodiment, ophthalmic preparations of the composition
comprise from about 0.1% to about 2.0% w/w cholinergic agent.
[0036] According to an embodiment, ophthalmic preparations of the
composition comprise from about 0.01% to about 0.5% w/w
alpha-stimulant agonist having an imidazoline group, such as
oxymetazoline. In another embodiment, ophthalmic preparations of
the composition comprise from about 0.01% to about 0.25% w/w
alpha-stimulant agonist having an imidazoline group. According to a
preferred embodiment, ophthalmic preparations of the composition
comprise from about 0.01% to about 0.1% w/w alpha-stimulant agonist
having an imidazoline group. According to another preferred
embodiment, ophthalmic preparations of the composition comprise
from about 0.01% to about 0.05% w/w alpha-stimulant agonist having
an imidazoline group According to another preferred embodiment,
ophthalmic preparations of the composition comprise about 0.025%
w/w alpha-stimulant agonist having an imidazoline group.
[0037] According to an embodiment, ophthalmic preparations of the
composition comprise from about 0.01% to about 2% w/w NSAID having
COX-2 selectivity, such as meloxicam. In another embodiment,
ophthalmic preparations of the composition comprise from about
0.01% to about 1% w/w NSAID having COX-2 selectivity. In another
embodiment, ophthalmic preparations of the composition comprise
from about 0.01% to about 0.5% w/w NSAID having COX-2 selectivity.
According to a preferred embodiment, ophthalmic preparations of the
composition comprise from about 0.01% to about 0.2% w/w NSAID
having COX-2 selectivity. According to another preferred
embodiment, ophthalmic preparations of the composition comprise
from about 0.01% to about 0.1% w/w NSAID having COX-2
selectivity.
[0038] In one aspect, ophthalmic preparations of the compositions
of the invention can include from about 0.01% to about 4%, from
about 0.01% to about 3.5%, from about 0.01% to about 3.0%, or from
about 0.01% to about 2.5% w/w cholinergic agent and from about
0.01% to about 0.2% w/w alpha-stimulant agonist having an
imidazoline group. In an embodiment, the composition comprises from
about 0.01% to about 2% w/w cholinergic agent and from about 0.01%
to about 0.2% w/w alpha-stimulant agonist having an imidazoline
group. In an embodiment, the composition comprises from about 0.5%
to about 1.5% w/w cholinergic agent and from about 0.02% to about
0.1% alpha-stimulant agonist. In another embodiment, the
composition comprises from about 0.9% to about 1.1% w/w cholinergic
agent and from about 0.0125% to about 0.5 w/w alpha-stimulant
agonist. The cholinergic agent can be a muscarinic acetylcholine
receptor M.sub.3 agonist that acts on the ciliary muscle of the eye
and causes it to contract. Pilocarpine and carbachol are examples
of a suitable muscarinic acetylcholine receptor M.sub.3 agonist.
Additional examples include acetylcholine, bethanechol,
oxotremorine, pilocarpidine, and the like. Examples of an
alpha-stimulant agonist having an imidazoline group include
oxymetazoline, naphazoline, tetrahydrozoline, tramazoline,
xylometazoline, and the like.
[0039] In embodiments, the composition comprises pilocarpine and
oxymetazoline. The dosage of pilocarpine in these compositions can
range from about 0.01% to about 2% w/w and the dosage of
oxymetazoline can range from about 0.01% to about 0.1% w/w. In an
embodiment, the composition comprises a concentration of
pilocarpine from about 0.5% to about 0.9% w/w and a concentration
of oxymetazoline from about 0.01% to about 0.024% w/w. In another
embodiment, the composition comprises a concentration of
pilocarpine from about 1.1% to about 2% w/w and a concentration of
oxymetazoline from about 0.026% to about 0.1% w/w. In yet another
embodiment, the composition comprises a concentration of
pilocarpine of about 1% w/w and a concentration of oxymetazoline of
about 0.0125% w/w.
[0040] In embodiments, the composition comprises pilocarpine and
naphazoline. The dosage of pilocarpine in these compositions can
range from about 0.01% to about 2% w/w and the dosage of
naphazoline can range from about 0.01% to about 0.2% w/w. In an
embodiment, the composition comprises a concentration of
pilocarpine, from about 0.01% to about 0.9% w/w and a concentration
of naphazoline from about 0.01% to about 0.09% w/w. In another
embodiment, the composition comprises a concentration of
pilocarpine from about 1.1% to about 2% w/w and a concentration of
naphazoline from about 0.11% to about 0.2% w/w. In yet another
embodiment, the composition comprises a concentration of
pilocarpine of about 1% w/w and a concentration of naphazoline of
about 0.1% w/w.
[0041] In embodiments, the composition comprises pilocarpine and
tetrahydrozoline. The dosage of pilocarpine in these compositions
ranges from about 0.01% to about 2% w/w and the dosage of
tetrahydrozoline ranges from about 0.01 to about 0.1% w/w. In an
embodiment, the composition comprises a concentration of
pilocarpine from about 0.01% to about 0.9% w/w and a concentration
of tetrahydrozoline from about 0.01% to about 0.04% w/w. In another
embodiment, the composition comprises a concentration of
pilocarpine from about 1.1% to about 2% w/w and a concentration of
tetrahydrozoline from about 0.06% to about 0.1% w/w. In yet another
embodiment, the composition comprises a concentration of
pilocarpine of about 1% w/w and a concentration of tetrahydrozoline
of about 0.05% w/w.
[0042] Other suitable alpha-stimulant agonists having an
imidazoline group, such as tramazoline and xylometazoline can be
formulated in combination with pilocarpine at the dosages and
concentration ranges disclosed herein for oxymetazoline,
naphazoline, or tetrahydrozoline. In an embodiment, the tramazoline
is present from about 0.03% w/w to about 0.12% w/w. In another
embodiment, pilocarpine, at concentrations disclosed herein, is
combined with tramazoline at a concentration of about 0.06% w/w. In
an embodiment, the xylometazoline is present from about 0.01% w/w
to about 0.10% w/w. In another embodiment, pilocarpine, at
concentrations disclosed herein, is combined with xylometazoline at
a concentration of about 0.025% w/w. Other suitable cholinergic
agents, such as acetylcholine, bethanechol, carbachol,
oxotremorine, and pilocarpidine, can be formulated in combination
with oxymetazoline, naphazoline, tetrahydrozoline, tramazoline, or
xylometazoline at the dosages and concentration ranges disclosed
herein for pilocarpine.
[0043] In another aspect, ophthalmic preparations of the
compositions of the invention can include from about 0.01% to about
4%, from about 0.01% to about 3.5%, from about 0.01% to about 3.0%,
or from about 0.01% to about 2.5% w/w cholinergic agent and from
about 0.001% to about 2% w/w NSAID having COX-2 selectivity. In an
embodiment, the composition comprises from about 0.01% to about 2%
w/w cholinergic agent and from about 0.001% to about 2% w/w NSAID
having COX-2 selectivity. In an embodiment, the composition
comprises from about 0.5% to about 1.5% w/w cholinergic agent and
from about 0.1% to about 1% of the NSAID. In another embodiment,
the composition comprises from about 0.9% to about 1.1% w/w
cholinergic agent and from about 0.01% to about 0.1% w/w of the
NSAID. The cholinergic agent can be a muscarinic acetylcholine
receptor M.sub.3 agonist that acts on the ciliary muscle of the eye
and causes it to contract. Pilocarpine and carbachol are examples
of a suitable muscarinic acetylcholine receptor M.sub.3 agonist.
Additional examples include acetylcholine, bethanechol,
oxotremorine, pilocarpidine, and the like. Examples of a NSAID
having COX-2 selectivity include meloxicam, celecoxib, rofecoxib,
valdecoxib, parecoxib, etoricoxib, nimesulide, etodolac, nabumetone
and the like.
[0044] In embodiments, the composition comprises pilocarpine and
meloxicam. The dosage of pilocarpine in these compositions ranges
from about 0.01% to about 2% w/w and the dosages of meloxicam
ranges from about 0.001% to about 2% w/w. In an embodiment, the
composition comprises a concentration of pilocarpine from about
0.01% to about 0.9% w/w and a concentration of meloxicam from about
0.01% to about 1% w/w. In another embodiment, the composition
comprises a concentration of pilocarpine from about 1.1% to about
2% w/w and a concentration of meloxicam from about 0.1% to about
0.5% w/w. In yet another embodiment, the composition comprises a
concentration of pilocarpine of about 1% w/w and a concentration of
meloxicam of about 0.03% w/w.
[0045] Other suitable NSAIDs having COX-2 selectivity, such as
celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib,
nimesulide, etodolac or nabumetone can be formulated in combination
with pilocarpine at the dosages and concentration ranges disclosed
herein for meloxicam. Other suitable cholinergic agents, such as
acetylcholine, bethanechol, carbachol, oxotremorine, and
pilocarpidine, can be formulated in combination with meloxicam,
celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib,
nimesulide, etodolac or nabumetone at the dosages and concentration
ranges disclosed herein for pilocarpine. In an embodiment, the
M.sub.3 agonist carbachol is present at a concentration of about
0.1% w/w to about 4% w/w or about 0.1% w/w to about 3% w/w in
combination with an alpha-stimulant agonist having an imidazoline
group or a non-steroidal anti-inflammatory agent (NSAID) having
COX-2 selectivity, wherein the alpha-stimulant or NSAID is used at
a concentration as described in one of the above embodiments. In
another embodiment, the M.sub.3 agonist carbachol is present at a
concentration of about 2.5% w/w in combination with an
alpha-stimulant agonist having an imidazoline group or a
non-steroidal anti-inflammatory agent (NSAID) having COX-2
selectivity, wherein the alpha-stimulant or NSAID is used at a
concentration as described in one of the above embodiments.
[0046] The compositions of the invention can be customized for a
patient based on the patient's need for vision correction and the
patient's responsiveness to the composition. For example, patients
with mild forms of hyperopia or presbyopia in need of minor
correction may be provided with a composition with lower a
concentration of cholinergic agent. On the other hand, patients
with more severe hyperopia or presbyopia may be provided with a
composition with a higher concentration of cholinergic agent. In
general, younger patients (e.g. patients less than forty years old)
may experience hyperopia or early symptoms of presbyopia and may
only need minor correction, whereas older patients (e.g. patients
in their fifties and above) may experience more pronounced symptoms
of presbyopia or a combination of hyperopia and presbyopia and may
need more correction. Some patients may need a lower concentration
of cholinergic agent because they respond more strongly to the
medication. For example, very young patients (e.g. children) may
respond more strongly than older patients, and may therefore
benefit from a lower concentration of cholinergic agent.
[0047] According to exemplary embodiments, a composition for
treating patients with very mild conditions or who respond strongly
comprises from about 0.1% to about 0.5% w/w cholinergic agent, such
as pilocarpine, or from about 0.2% to about 0.4% w/w cholinergic
agent, or about 0.3% w/w cholinergic agent. A composition for
treating patients with mild conditions or whose vision could
alternatively be corrected with eye glasses having about +0.5D to
about +1.0D, or about +0.75D lenses may comprise from about 0.3% to
about 1.0% w/w cholinergic agent, such as pilocarpine, or from
about 0.4% to about 0.8% w/w cholinergic agent, or from about 0.5%
to about 0.7% w/w cholinergic agent, or about 0.6% w/w cholinergic
agent. A composition for treating patients whose vision could
alternatively be corrected with eye glasses having about +1.0D to
about +1.5D lenses or about +1.2D to +1.3D lenses may comprise from
about 0.8% to about 1.6% w/w cholinergic agent, such as
pilocarpine, or from about 1.0% to about 1.4% w/w cholinergic
agent, or from about 1.1% to about 1.3% w/w cholinergic agent, or
about 1.2% w/w cholinergic agent. A composition for treating
patients whose vision could alternatively be corrected with eye
glasses having about +1.5D to about +2.0D or about +1.75D lenses
may comprise from about 1.4% to about 2.2% w/w cholinergic agent,
such as pilocarpine, or from about 1.6% to about 2.0% w/w
cholinergic agent, or from about 1.7% to about 1.9% w/w cholinergic
agent, or about 1.8% w/w cholinergic agent.
[0048] Very young patients (e.g. children) may particularly benefit
from the use of the compositions disclosed herein. Very young
patients may respond more strongly to the composition, and may thus
need a lower concentration of the cholinergic agent. The
compositions of the invention may also be used to treat more severe
conditions in very young patients than in older patients; for
example, the composition may be used to treat moderate hyperopia
(up to +4.0D) in children. The compositions of the invention may
also be customized for a patient based on the patient's sensitivity
to irritation or side effects. For example, a patient with more
sensitivity may be provided with a composition having a higher
concentration of agents that reduce redness and irritation, such as
alpha-stimulant agonist having an imidazoline group or NSAID having
COX-2 selectivity. According to an embodiment, a composition for
treating patients with more sensitivity may comprise from about
0.05% to about 0.2% w/w alpha-stimulant agonist having an
imidazoline group or NSAID having COX-2 selectivity, or a
combination of both.
[0049] The compositions of the invention can further include a
cyclodextrin or derivative thereof. Cyclodextrins are cyclic
oligosaccharides that have less hydrophilic inner cavities and
hydrophilic outer surfaces and are capable of forming non-covalent
complexes with a variety of molecules. Both naturally occurring
(.alpha.-, .beta.- and .gamma.-) and synthetic (e.g. chemically
modified hydroxyethyl-.beta.- or sulfobutylether-(.beta.-)
cyclodextrins are available. Cyclodextrins and their derivatives
can be used to enhance ocular penetration of the cholinergic agent,
alpha-stimulant agonist, and/or NSAID having COX-2 selectivity and
decrease discomfort of the patient and ameliorate irritation upon
instillation of the compositions of the invention into the eye.
Examples of suitable cyclodextrins include hydrophilic
cyclodextrins, such as hydroxyethyl-.beta.-cyclodextrin and
sulfobutylether-.beta.-cyclodextrin. Cyclodextrins may also be
included in the compositions of the invention to improve the
solubility, bioavailability and shelf-life of the active
ingredients of the compositions. According to an exemplary
embodiment, the composition comprises from about 0.1% to about 4.0%
of pilocarpine, from about 0.01% to about 0.1% oxymetazoline or
from about 0.01% to about 0.2% meloxicam, and from about 0.1% to
about 2.0% .beta.-cyclodextrin. According to another exemplary
embodiment, the composition comprises from about 0.75% to about 4%
of carbachol, from about 0.01% to about 0.1% oxymetazoline or from
about 0.01% to about 0.2% meloxicam, and from about 0.1% to about
2.0% .beta.-cyclodextrin.
[0050] The compositions described herein include, without
limitation, liquid-containing compositions, such as formulations,
and polymeric drug delivery systems. The compositions may be
understood to include solutions, suspensions, emulsions, and the
like, such as other liquid-containing compositions used in
ophthalmic therapies. The compositions of the invention can be
incorporated into polymeric drug delivery systems including a
polymeric component, and may be understood to include biodegradable
polymers, biodegradable implants, non-biodegradable implants,
biodegradable microparticles, such as biodegradable microspheres,
nanoparticles and the like. The biodegradable polymers degrade in
vivo wherein degradation or erosion of the polymer or polymers over
time occurs concurrent with or subsequent to release of the
compositions of the invention incorporated into and loaded onto the
polymers. Substances of the composition with different half-lives
may be incorporated in different types (size, form, composition or
number) of nanoparticles, resulting in appropriate rates of release
for and concentrations of each component in the treated tissue. A
biodegradable polymer may be a homopolymer, a copolymer, or a
polymer comprising more than two different polymeric units. The
drug delivery systems disclosed herein may encompass elements in
the form of tablets, wafers, rods, sheets, threads, filaments, and
the like. The polymeric drug delivery systems may be solid,
semisolid, or viscoelastic.
[0051] In certain embodiments, the carrier used in the present
invention may be a solid support, including a polymer bead or a
resin, such as a Wang resin. Supports can be solids having a degree
of rigidity such as silicon, plastic, and the like. Support can
also be flexible materials such as plastic or otherwise synthetic
materials (such as nylon), materials made of natural polymers (such
as cellulose or silk) or derivatives thereof (such as
nitrocellulose) and the like. In certain embodiments the support is
a porous material which can be rigid or flexible, intermeshed
fibers including woven fabrics, and the like. In some embodiments,
the solid support is a bead or pellet, which can be porous. In
certain embodiments, the carrier or carriers may be optimized for
slow or timed release of the active agents. Formulations including
a polymer bead carrier, or other such carrier or carriers as
described above, may be injected subconjuctivally, injected
directly into the eye or the tissues surrounding the eye, may be
applied topically to the eye or surrounding tissues, or may be
applied in the form of a plug that is located at the nasolacrimal
punctum.
[0052] In embodiments, the compositions of the invention are
formulated for delivery to the eye or the tissues or fluids
surrounding the eye. The compositions can be in the form of a
suspension, eye drop, ointment, gel, spray, powder, slow release
preparation for administration either subconjunctivally or in any
other eye location, or other suitable form for administering the
compositions of the invention to the eye or fluids and/or tissues
surrounding the eye. The use of buffers, stabilizers, reducing
agents, anti-oxidants and chelating agents in the preparation of
pharmaceutical compositions is well known in the art. See, Wang et
al., "Review of Excipients and pHs for Parenteral Products Used in
the United States." J. Parent. Drug Assn., 34(6):452-462 (1980);
Wang et al., "Parenteral Formulations of Proteins and Peptides:
Stability and Stabilizers," J. Parent. Sci. and Tech., 42: S4-S26
(Supplement 1988); Lachman, et al., "Antioxidants and Chelating
Agents as Stabilizers in Liquid Dosage Forms Part 1," Drug and
Cosmetic Industry, 102(1): 36-38, 40 and 146-148 (1968); Akers, M.
J., "Antioxidants in Pharmaceutical Products," J. Parent. Sci. and
Tech., 36(5):222-228 (1988); and Methods in Enzymology, Vol. XXV,
Colowick and Kaplan eds., "Reduction of Disulfide Bonds in Proteins
with Dithiothreitol," by Konigsberg, pages 185-188.
[0053] Suitable carriers include pharmaceutically acceptable
carriers, excipients, or stabilizers which are nontoxic to the cell
or mammal being exposed thereto at the dosages and concentrations
employed. Often the physiologically acceptable carrier is sterile
water or an aqueous pH buffered solution. pH regulatory agents
include boric, phosphoric, acetic, carbonic, citric, sorbic acids,
and the like. pH adjusting agents include acids such as
hydrochloric acid or bases such as sodium or potassium hydroxide,
sodium bicarbonate, and the like. Suitable physiologically or
ophthalmically acceptable carriers include buffers such as
phosphate, citrate, and other organic acids; antioxidants including
ascorbic acid; low molecular weight (less than about 10 residues)
polypeptide; proteins, such as serum albumin, gelatin, or
immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone;
amino acids such as glycine, glutamine, asparagine, arginine or
lysine; monosaccharides, disaccharides, and other carbohydrates
including glucose, mannose, or dextrins; chelating agents such as
EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming
counterions such as sodium; and/or nonionic surfactants such as
TWEEN.TM. polyethylene glycol (PEG), and PLURONICS.TM..
[0054] The compositions of the invention can include one or more
preservatives such as phenol, cresol, paraaminobenzoic acid, BDSA,
sorbitrate, chlorhexidine, benzalkonium chloride, sorbic and boric
acids, Purite.RTM. (oxychloride compounds), Polyquad.RTM.
(quaternary ammonium), polyhexamethylen biguanide, sodium
perborate, and the like. Compositions intended for long-term use in
chronic conditions can be formulated and packaged to minimize the
use of preservatives that may irritate the eye. For example, the
composition may be packaged in single-dose containers, or in
containers utilizing alternative means for minimizing microbial
contamination, such as membranes, valve mechanisms or silver.
[0055] The compositions can include stabilizer and viscosant agents
such as one or more of microcrystalline cellulose, magnesium
stearate, mannitol, sucrose, EDTA, sodium hydrogen sulfite, methyl
cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose,
hyaluronic acid, alginate, chonodroitin sulfate, dextran,
maltodextrin, dextran sulfate, polyvinyl pyrrolidone, polyvinyl
alcohol, and the like. The composition can include an emulsifier
such as polysorbate 20, polysorbate 80, pluronic, triolein, soybean
oil, lecithins, squalene and squalanes, sorbitan treioleate, and
the like. The composition can include an antimicrobial such as
phenylethyl alcohol, phenol, cresol, benzalkonim chloride,
phenoxyethanol, chlorhexidine, thimerosol, and the like. Suitable
thickeners include natural polysaccharides such as mannans,
arabinans, alginate, hyaluronic acid, dextrose, and the like; and
synthetic ones like the PEG hydrogels of low molecular weight and
aforementioned suspending agents. The composition can include also
osmotic agents, such as sodium chloride, potassium chloride,
magnesium sulfate, calcium chloride, sodium hydrogen phosphate and
the like, and humectants, such as propylene glycol, glycerine,
sorbitol, mannitol, and the like.
[0056] Compositions of the invention can be used to treat an ocular
condition. Preferred ocular conditions include presbyopia, mild
hyperopia, irregular astigmatism (increased high order optical
aberrations in the front part of the eye), hyperopic accommodative
esotropia, and glaucoma (open angle; acute, subacute and chronic
narrow angle; iris plateau, etc.). The present invention can also
be used to potentiate or to enhance interventions that retard,
reverse or modify the aging process of the crystalline lens and its
surrounding tissues. The compositions of the invention are
generally administered to an "ocular region" or "ocular site" of
the subject undergoing treat. The subject is generally human, but
can include other mammals such as dogs, cats, horses, etc. The
terms "ocular region" and "ocular site" refer generally to any area
of the eyeball, including the anterior and posterior segment of the
eye, and which generally includes, but is not limited to, any
functional (e.g., for vision) or structural tissues found in the
eyeball, or tissues or cellular layers that partly or completely
line the interior or exterior of the eyeball. Specific examples of
ocular sites include the crystalline lens, the zonules, the ciliary
muscle, the iris, and the pupil. Specific examples of areas of the
eyeball in an ocular region include the anterior chamber, the
posterior chamber, the vitreous cavity, the choroid, the
suprachoroidal space, the subretinal space, the conjunctiva, the
subconjunctival space, the episcleral space, the intracorneal
space, the epicorneal space, the sclera, the pars plana,
surgically-induced avascular regions, the macula, and the retina.
The use of the compositions of the invention in both eyes of a
presbyopic patient may result in optimum enhancement of near
vision, but may slightly decrease distant vision. The compositions
of the invention may also be used only in one eye, typically the
non-dominant eye, thus improving near vision in that eye and
conserving distance vision in the untreated eye. In an embodiment,
a composition of the invention is administered only to the dominant
eye of the patient to improve reading ability.
[0057] The compositions of the invention can increase the
refractive power of the eye by up to about 4 diopters, or even more
in very young patients (e.g. children). In an embodiment, the
compositions of the invention increase the refractive power of the
eye by up to about 0.5 diopters, about 0.75 diopters, about 1.0
diopters, about 1.25 diopters, about 1.50 diopters, about 1.75
diopters, about 2.0 diopters, about 2.5 diopters, about 3.0
diopters, about 3.5 diopters, or about 4.0 diopters. In an
embodiment, the compositions of the invention increase the
refractive power of the eye from about 0.5 to about 0.75 diopters,
about 0.5 to about 1.0 diopters, about 0.5 to about 1.25 diopters,
about 0.5 to about 1.5 diopters, about 0.5 to about 1.75 diopters,
about 0.5 diopters to about 2.0 diopters, about 0.5 diopters to
about 2.5 diopters, about 0.5 diopters to about 3.0 diopters, about
0.5 diopters to about 3.5 diopters, or about 0.5 diopters to about
4.0 diopters. In an embodiment, the increase in refractive power of
the eye occurs without substantially affecting the cylindrical
(astigmatic) component of the eye. In an embodiment, the effect on
the cylindrical component of the eye is less than 0.5 diopters. In
an embodiment, the effect on astigmatismo is less than about 2.0
diopters.
[0058] In another aspect of the invention, kits for treating an
ocular condition are provided. The kits generally include: a) a
container, such as a syringe, tube, vial, dropper (such as would be
used for eye drops), or other applicator, comprising a composition
as described herein; and b) instructions for use, which may include
diagrams, drawings, or photographs, in addition to text. The
instructions may include steps of how to handle the material (which
may include storage conditions, such as temperature ranges for
storage), how to insert the material into an ocular region
(optionally including diagrams, drawings, or photographs), how
often to apply the composition, and what to expect from using the
composition. The container may contain a single dose of the
composition or multiple doses of the composition. The container may
deliver the composition drop wise. The container may include tamper
evident features, such as a foil or plastic seal.
EXAMPLES
[0059] For the following examples, the terms "a/an/the" include
plural alternatives (at least one). The disclosed information is
illustrative, and other embodiments exist and are within the scope
of the present invention.
Example 1
[0060] A group of 10 patients (20 eyes) considered emmetropes or
slightly hyperopic (Spherical equivalent from +0.88 D to -0.50 D
with less than 1.00 D of astigmatism) was treated with a
composition of the invention. Each patient had an extensive ocular
examination prior to treatment that included: 1) refractive power
of each eye; 2) the unaided distance visual acuity (UDVA) measured
using an Snellen chart; 3) the unaided near vision (UNVA) measured
at 40 centimeters using a hand-held Rosembaum chart and the Jaeger
notation; and 4) the pupillary diameter measured in medium lighting
(mesopic) conditions with a special infrared camera device.
[0061] Three drops containing 1% pilocarpine and 0.125%
oxymetazoline w/w dissolved in a solution of 0.5% sodium chloride,
with carboxymethyl cellulose as a viscosant and benzalkonium
chloride as preservative were instilled into each eye three times
separated 5 minutes each, and the same measurements were taken one
hour, four hours and six hours later (Table 1). As shown in Table 1
and FIGS. 1-2, there was an average gain of 3.7 units of unaided
near visual acuity while losing 0.7 lines of uncorrected distance
visual acuity at one hour after instillation. As shown in FIG. 1,
there was some decay of the effect at 4 hours and it decreased to
almost half at six hours. The improvement in near vision was more
pronounced in younger patients and the lack of detriment of the
distance vision (FIG. 2) was more marked in hyperopic patients. The
refractive change was related to the sphere mostly with the
cylinder remaining almost unchanged.
TABLE-US-00001 TABLE 1 (Pilocarpine + Oxymetazoline) Pre 1 h 4 h 6
h Pre 1 h 4 h 6 h ID Sex Age UNVA UNVA UNVA UNVA UDVA UDVA UDVA
UDVA 1 M 42 OD J2 J1+ J1+ J1 20/20 20/25 20/25 20/20 1 OS J2 J1+
J1+ J2 20/20 20/25 20/25 20/20 2 F 44 OD J2 J1+ J1+ J2 20/20 20/30
20/25 20/20 2 OS J2 J1+ J1+ J1 20/20 20/30 20/25 20/20 3 F 45 OD J3
J1+ J1+ J1 20/20 20/25 20/30 20/25 3 OS J3 J1+ J1+ J2 20/20 20/30
20/30 20/20 4 M 46 OD J5 J1 J2 J3 20/25 20/20 20/20 20/25 4 OS J5
J2 J2 J3 20/25 20/20 20/20 20/20 5 M 48 OD J3 J1+ J1+ J3 20/20
20/30 20/30 20/20 5 OS J3 J2 J1 J2 20/20 20/20 20/25 20/20 6 F 49
OD J5 J1 J1 J3 20/25 20/30 20/30 20/25 6 OS J5 J2 J3 J5 20/25 20/30
20/25 20/25 7 M 50 OD J3 J1+ J1+ J1 20/30 20/40 20/40 20/40 7 OS J3
J1+ J1+ J1 20/30 20/40 20/40 20/30 8 F 52 OD J5 J2 J2 J3 20/20
20/25 20/25 20/20 8 OS J5 J2 J2 J3 20/20 20/25 20/25 20/20 9 M 54
OD J10 J3 J3 J5 20/25 20/20 20/20 20/20 9 OS J10 J3 J3 J5 20/25
20/20 20/25 20/25 10 F 56 OD J16 J5 J5 J7 20/30 20/30 20/30 20/25
10 OS J10 J5 J5 J7 20/30 20/30 20/30 20/30 ID Pre Sph 1 h Sph 4 h
Sph 6 h Sph Pre Cyl 1 h Cyl 4 h Cyl 6 h Cyl 1 OD 1.00 -0.25 0.00
0.50 -0.25 -0.50 -0.50 -0.25 1 OS 1.00 -0.50 -0.50 -0.25 -0.25
-0.25 -0.25 -0.25 2 OD 0.00 -0.75 -0.50 0.00 -0.25 -0.50 -0.25
-0.25 2 OS 0.00 -0.50 -0.25 0.00 -0.75 -1.00 -0.75 -0.75 3 OD 0.00
-0.25 -0.50 -0.25 -0.25 -0.25 -0.50 -0.25 3 OS 0.25 -0.25 0.00 0.25
-0.50 -0.50 -0.50 -0.25 4 OD 0.75 0.00 0.25 0.50 -0.50 -0.50 -0.25
-0.50 4 OS 0.75 0.00 0.00 0.25 -0.25 -0.25 -0.25 -0.25 5 OD 0.25
-0.50 -0.50 0.00 -0.25 -0.50 -0.25 -0.25 5 OS 0.50 0.00 -0.25 0.00
0.00 -0.25 -0.25 0.00 6 OD 0.25 -0.25 -0.25 0.00 -0.75 -0.50 -0.50
-0.50 6 OS 0.50 -0.25 0.00 0.25 -0.50 -0.50 -0.50 -0.50 7 OD -0.25
-0.50 -0.50 -0.25 -0.50 -0.50 -0.75 -0.75 7 OS 0.00 -0.50 -0.25
-0.25 -0.75 -0.75 -0.75 -0.75 8 OD 0.25 -0.25 -0.25 0.00 -0.25
-0.25 -0.25 -0.25 8 OS 0.25 -0.25 -0.25 0.00 0.00 -0.25 -0.25 0.00
9 OD 0.75 0.00 0.25 0.50 -0.25 -0.25 -0.25 -0.25 9 OS 0.75 0.00
0.25 0.50 -0.50 -0.25 -0.50 -0.50 10 OD 0.75 -0.25 -0.25 0.00 -0.25
-0.25 0.00 -0.25 10 OS 0.50 0.00 0.00 0.00 -0.50 -0.75 -0.75 -0.50
AVERAGE 0.41 -0.26 -0.18 0.09 -0.38 -0.44 -0.41 -0.36 Pre Sph 1 h
Sph 4 h Sph 6 h Sph Pre 1 h 4 h 6 h ID Eq Eq Eq Eq Pupil Pupil
Pupil Pupil 1 OD 0.88 -0.50 -0.25 0.38 5.1 1.9 2.2 3.1 1 OS 0.88
-0.63 -0.63 -0.38 5.4 2 2.3 3.2 2 OD -0.13 -1.00 -0.63 -0.13 5.2
2.2 2.2 3.6 2 OS -0.38 -1.00 -0.63 -0.38 5.3 2.1 2.3 3.5 3 OD -0.13
-0.38 -0.75 -0.38 5.1 2.3 2.5 3.2 3 OS 0.00 -0.50 -0.25 0.13 5.2
2.4 2.5 3.3 4 OD 0.50 -0.25 0.13 0.25 6.1 2.3 2.6 3.9 4 OS 0.63
-0.13 -0.13 0.13 6 2.2 2.7 3.8 5 OD 0.13 -0.75 -0.63 -0.13 5.4 2
2.1 3 5 OS 0.50 -0.13 -0.38 0.00 5.5 2 2.1 3 6 OD -0.13 -0.50 -0.50
-0.25 4.7 2.3 2.2 3.1 6 OS 0.25 -0.50 -0.25 0.00 4.8 2.4 2.3 3 7 OD
-0.50 -0.75 -0.88 -0.63 4.3 2.2 2.4 3.3 7 OS -0.38 -0.88 -0.63
-0.63 4.4 2 2.3 3.2 8 OD 0.13 -0.38 -0.38 -0.13 4.6 2.1 2.2 3.7 8
OS 0.25 -0.38 -0.38 0.00 4.5 2 2.1 3.6 9 OD 0.63 -0.13 0.13 0.38
4.2 2.2 2.4 3.2 9 OS 0.50 -0.13 0.00 0.25 4.3 2.1 2.3 3.3 10 OD
0.63 -0.38 -0.25 -0.13 4.1 1.9 2 2.9 10 OS 0.25 -0.38 -0.38 -0.25
4.1 2 2 2.8 AVERAGE 0.23 -0.48 -0.38 -0.09 4.92 2.13 2.29 3.29
[0062] The observed improvement in the near vision is believed to
have occurred for at least two reasons. First, an increase in the
refractive power of the eye of roughly +0.70 diopters was observed
following treatment that could compensate presbyopia and mild
degrees of hyperopia. Second, the depth of visual field of the eye
was increased by 0.50 to 0.75 diopters following treatment
(probably related to the decrease in pupillary diameter to about
2.0 mm) This observed increase in depth of field is believed to
have: [0063] 1) potentiated the observed increase in refractive
power of the eye to improve near vision in emmetropes, myopes and
hyperopes; [0064] 2) potentiated the observed increase in
refractive power of the eye to improve distance visual acuity in
mild hyperopes; and [0065] 3) compensated any loss in distance
vision in emmetropic or myopic patients caused by the observed
change in refractive power of the eye.
Example 2
[0066] Five patients (ten eyes) from 30 to 55 years-old with "mild
hyperopia" (i.e., eyes having a spherical equivalent from +0.50 to
+2.00 D) were treated with three drops of 1% pilocarpine and 0.125%
oxymetazoline separated 5 minutes. Following treatment, all of the
patients were able to improve their unaided distance visual acuity
at one and four hours. Thirty-five percent had an improvement in
one line of distance vision at 6 hours
Example 3
[0067] A group of 10 patients (20 eyes) considered emmetropes or
slightly hyperopic (Spherical equivalent from +0.88 D to -0.13 D
with less than 1.00 D of astigmatism) was treated with a
composition of the invention. Each patient had an extensive ocular
examination prior to treatment that included: 1) refractive power
of each eye; 2) the unaided distance visual acuity (UDVA) measured
using an Snellen chart; 3) the unaided near vision (UNVA) measured
at 40 centimeters using a hand-held Rosembaum chart and the Jaeger
notation; and 4) the pupillary diameter measured in medium lighting
(mesopic) conditions with a special infrared camera device.
[0068] One drop containing 1% pilocarpine and 0.025% oxymetazoline
w/w dissolved in a solution of 0.5% sodium chloride, with
carboxymethyl cellulose as a viscosant and benzalkonium chloride as
preservative were instilled once into the right eye, and the same
solution containing 1% pilocarpine without oxymetazoline was
instilled once into the left eye and the same measurements were
taken one hour, four hours and six hours later. (Each patient acted
as its own control) (Table 2). As shown in Table 2 and FIGS. 3 and
4, it could be seen that when using pilocarpine alone the
improvement in near vision was smaller and tended to wear out
earlier, also there was more decrease in distance vision at the 1
and 4 hour time points. From the refractive standpoint, pilocarpine
alone seemed to induce more astigmatism. This result was likely due
to crystalline lens changes, whereas when pilocarpine was
administered with oxymetazoline less astigmatism was induced. The
addition of oxymetazoline improved pilocarpine's effect over the
pupillary contraction thereby enhancing optical performance. Some
discrepancy was noted in both groups between the obtained
refractions and the unaided distance and near acuities, which may
indicate that other factors are involved with the improvement in
vision, for example increased high order optical measurements
(aberrations) such as spherical aberration, coma, trefoil, etc.
TABLE-US-00002 TABLE 2 [Pilocarpine + Oxymetazoline(OD) vs.
Pilocarpine alone (OS)] Pre 1 h 4 h 6 h Pre 1 h 4 h 6 h ID Sex Age
UNVA UNVA UNVA UNVA UDVA UDVA UDVA UDVA 1 M 43 OD J1 J1+ J1 J1
20/25 20/30 20/20 20/25 1 OS J1 J1+ J1 J1 20/30 20/40 20/50 20/30 2
F 45 OD J2 J1+ J1 J1 20/30 20/40 20/30 20/30 2 OS J3 J1 J3 J3 20/30
20/50 20/40 20/30 3 M 45 OD J3 J1+ J1 J2 20/20 20/30 20/40 20/20 3
OS J3 J1+ J1 J2 20/20 20/30 20/20 20/20 4 M 46 OD J5 J1+ J2 J3
20/20 20/30 20/30 20/25 4 OS J3 J1 J1 J3 20/20 20/40 20/40 20/20 5
M 48 OD J3 J1+ J1 J1 20/25 20/40 20/30 20/25 5 OS J5 J1+ J1 J2
20/25 20/30 20/30 20/25 6 F 48 OD J7 J1 J2 J3 20/40 20/30 20/25
20/30 6 OS J7 J2 J3 J7 20/30 20/30 20/30 20/30 7 M 50 OD J5 J2 J3
J5 20/25 20/30 20/25 20/25 7 OS J5 J1 J3 J5 20/25 20/40 20/30 20/25
8 M 51 OD J5 J2 J3 J3 20/20 20/40 20/40 20/20 8 OS J5 J3 J3 J5
20/20 20/30 20/30 20/20 9 F 52 OD J7 J3 J3 J5 20/30 20/40 20/40
20/30 9 OS J5 J3 J3 J5 20/30 20/50 20/40 20/30 10 F 54 OD J7 J3 J3
J3 20/25 20/30 20/30 20/25 10 OS J7 J3 J5 J5 20/20 20/30 20/25
20/25 ID Pre Sph 1 h Sph 4 h Sph 6 h Sph Pre Cyl 1 h Cyl 4 h Cyl 6
h Cyl 1 OD 1.00 -0.25 0.00 0.50 -0.25 -0.50 -0.50 -0.25 1 OS 1.00
-0.50 -0.25 0.00 -0.25 -0.75 -0.25 -0.25 2 OD 0.00 -0.75 -0.50 0.00
-0.25 -0.50 -0.25 -0.25 2 OS 0.00 -0.50 -0.25 0.00 -0.75 -1.00
-0.75 -0.75 3 OD 0.00 -0.25 -0.50 -0.25 -0.25 -0.25 -0.50 -0.25 3
OS 0.25 0.00 0.00 0.25 -0.50 -0.50 -0.50 -0.25 4 OD 0.75 -0.50
-0.25 -0.25 -0.50 -0.50 -0.25 -0.50 4 OS 0.75 -0.25 -0.25 0.00
-0.25 -0.75 -0.50 -0.25 5 OD 0.25 -0.50 -0.50 0.00 -0.25 -0.50
-0.25 -0.25 5 OS 0.50 0.00 -0.25 0.25 0.00 -0.25 -0.25 0.00 6 OD
0.25 -0.25 -0.25 0.00 -0.75 -0.50 -0.50 -0.50 6 OS 0.50 0.00 0.00
0.25 -0.50 -0.50 -0.50 -0.50 7 OD 0.25 -0.25 -0.50 0.25 -0.50 -0.50
-0.75 -0.75 7 OS 0.00 -0.50 -0.25 -0.25 -0.75 -0.75 -0.75 -0.75 8
OD 0.25 -0.25 -0.25 0.00 -0.25 -0.25 -0.25 -0.25 8 OS 0.25 -0.25
-0.25 0.00 0.00 -0.25 -0.25 0.00 9 OD 0.75 0.00 0.25 0.50 -0.25
-0.25 -0.25 -0.25 9 OS 0.75 0.25 0.50 0.50 -0.50 -0.25 -0.50 -0.50
10 OD 0.75 -0.25 -0.25 0.00 -0.25 -0.25 0.00 -0.25 10 OS 0.50 0.00
0.25 0.50 -0.50 -0.75 -0.75 -0.50 AVERAGE Pilo + Oxy 0.61 -0.48
-0.25 0.43 -0.39 -0.41 -0.39 -0.36 Pilo + NaCl 0.59 -0.32 -0.14
0.57 -0.36 -0.59 -0.59 -0.43 Pre Sph 1 h Sph 4 h Sph 6 h Sph Pre 1
h 4 h 6 h ID Eq Eq Eq Eq Pupil Pupil Pupil Pupil 1 OD 1.00 -0.50
-0.13 0.25 5.5 2 2.5 4.7 1 OS 0.63 -1.00 -0.88 0.25 5.6 2.1 2.7 4.9
2 OD 0.50 -1.13 -0.75 0.38 5.2 2.2 2.6 4.8 2 OS 0.13 -1.00 -0.75
0.38 5.3 2.3 2.8 4.9 3 OD 0.38 -0.75 -0.75 0.13 4.8 2.1 2.5 4.7 3
OS 0.50 -0.25 -0.13 0.38 4.7 2.2 2.5 4.7 4 OD 0.50 -1.00 -0.63 0.25
4.9 2.3 2.7 4.5 4 OS 0.63 -0.88 -0.63 0.63 4.8 2.3 2.9 4.4 5 OD
0.50 -1.00 -0.75 0.25 4.1 2.1 2.7 4 5 OS 0.63 -0.63 -0.50 0.50 4
2.2 2.8 4.2 6 OD 0.88 -0.63 -0.25 0.63 4.7 1.9 2.2 4.8 6 OS 0.75
-0.50 -0.38 0.50 4.7 2.1 2.4 4.9 7 OD 0.50 -0.50 -0.13 0.38 4.3 2.3
2.5 3.9 7 OS 0.38 -0.75 -0.50 0.38 4.2 2.4 3 4.1 8 OD 0.13 -0.88
-0.50 0.25 4.1 2.2 2.4 4 8 OS 0.13 -0.50 -0.50 0.13 4.2 2.4 2.9 4.2
9 OD 0.38 -0.63 -0.50 0.38 4.5 2 2.6 4.4 9 OS 0.50 -0.75 -0.38 0.25
4.4 2.5 2.6 4.4 10 OD -0.13 -0.50 -0.50 -0.13 4.7 2.1 2.9 4.7 10 OS
0.25 -0.50 -0.13 0.50 4.8 2.1 3.1 4.7 AVERAGE Pilo + Oxy 0.42 -0.68
-0.44 0.25 4.25 1.93 2.33 4.05 Pilo + NaCl 0.41 -0.61 -0.43 0.35
4.25 2.05 2.52 4.13
Example 4
[0069] A larger number of patients (n=65) from 40 to 56 years-old
with refractions from +0.50 D to -0.25 D (spherical equivalent)
with less than -1.00 D of astigmatism were given eye drops to use
three times a day. The eye drops contained 1% pilocarpine and
0.0125% oxymetazoline. The patients were seen one week after the
start of treatment and then monthly to refill the drop prescription
for six months.
[0070] Only four patients discontinued use of the eye drops due to
lack of effect (one patient) or side effects such as brow ache or
ocular pain (three patients). The rest of the patients continued
using the medication to improve their near vision in lieu of
reading glasses. No significant side effects were reported from
this cohort of real life patients. Minor side effects including a
sense of decreased illumination (likely associated with the
pupillary constriction) and ocular floaters (the pinhole effect
improves vision not only for the objects outside the eye but also
for the minor irregularities floating inside the eye) were reported
by patients in several instances.
[0071] In another group of patients with higher degrees of myopia,
hyperopia or astigmatism, the eye drops were used over their
contact lenses or distance glasses to avoid using bifocal
glasses.
[0072] The refractive improvement was very similar to example 1,
where there was an increase in the refractive power of the eye of
about 0.50 diopters on the average without affecting the
cylindrical (astigmatic) component. In the patients with higher
degrees of myopia, hyperopia or astigmatism, there was usually a 2
to 4 line gain in near visual acuity with the distance visual
acuity either improving one line, remaining unchanged or dropping
one to two lines according to the baseline refraction. The effect
lasted over time and patients noticed that as they used the drops
on a regular basis, there was a cumulative effect where the effect
of the drops seemed to last longer. Also, these patients noted a
decrease in any mild irritation/redness that the drops might have
caused initially. Two-thirds of the patients were using the herein
mentioned drops exclusively and the other third used them most of
the time, but also used reading glasses occasionally (at night at
home, etc.) in lieu of the drops.
Example 5
[0073] After a two-week washout period, five of the patients from
example 1 were treated with a combination of 1% pilocarpine and
0.015% meloxicam dissolved in a solution of 0.5% sodium chloride in
water plus carboxymethyl cellulose as viscosant and benzalkonium
chloride as a preservative, and the same measurements in example 1
were taken at one hour, four hours, and eight hours later.
TABLE-US-00003 TABLE 3 (Pilocarpine + Meloxicam) Pre 1 h 4 h 6 h
Pre 1 h 4 h 6 h ID Sex Age UNVA UNVA UNVA UNVA UDVA UDVA UDVA UDVA
1 M 43 OD J2 J1 J1 J2 20/20 20/20 20/20 20/20 1 OS J1 J1+ J1+ J1
20/20 20/20 20/20 20/20 2 M 46 OD J2 J1 J2 J2 20/25 20/40 20/40
20/30 2 OS J3 J2 J2 J2 20/25 20/30 20/25 20/25 3 F 49 OD J5 J2 J2
J3 20/25 20/40 20/40 20/30 3 OS J7 J2 J5 J5 20/25 20/40 20/30 20/40
4 F 52 OD J7 J5 J5 J5 20/30 20/25 20/25 20/20 4 OS J5 J3 J3 J5
20/30 20/20 20/25 20/25 5 F 55 OD J10 J5 J7 J7 20/25 20/40 20/30
20/30 5 OS J10 J5 J5 J7 20/25 20/30 20/40 20/25 ID Pre Sph 1 h Sph
4 h Sph 6 h Sph Pre Cyl 1 h Cyl 4 h Cyl 6 h Cyl 1 OD 0.75 0.25 0.50
0.50 -0.25 -0.50 -0.50 -0.25 1 OS 0.75 0.25 0.25 0.25 -0.50 -0.50
-0.50 -0.50 2 OD -0.25 -0.75 -0.50 -0.50 -0.25 -0.50 -0.25 -0.25 2
OS -0.25 -0.50 -0.25 -0.25 0.00 0.00 -0.25 -0.25 3 OD 0.25 -0.50
-0.50 -0.25 -0.75 -0.50 -0.50 -0.50 3 OS 0.25 -0.50 -0.25 -0.25
-0.50 -0.25 -0.25 -0.50 4 OD 0.75 0.00 0.25 0.00 0.00 -0.25 -0.25
-0.25 4 OS 0.75 0.25 0.25 0.25 -0.50 -0.25 -0.50 -0.50 5 OD 0.25
-0.50 -0.25 0.00 -0.75 -0.50 -0.50 -0.75 5 OS 0.25 -0.25 -0.25 0.00
-0.50 -0.50 -0.75 -0.50 AVERAGE 0.35 -0.23 -0.08 -0.03 -0.38 -0.38
-0.43 -0.43 Pre Sph 1 h Sph 4 h Sph 6 h Sph Pre 1 h 4 h 6 h ID Eq
Eq Eq Eq Pupil Pupil Pupil Pupil 1 OD 0.63 0.00 0.25 0.38 5.3 2.1
2.2 3.2 1 OS 0.50 0.00 0.00 0.00 5.4 2.2 2.3 3.4 2 OD -0.38 -1.00
-0.63 -0.63 5.8 2.3 2.6 3.9 2 OS -0.25 -0.50 -0.63 -0.38 5.6 2.2
2.7 3.7 3 OD -0.13 -0.75 -0.75 -0.50 4.9 2.4 2.6 3.2 3 OS 0.00
-0.63 -0.38 -0.50 4.7 2.3 2.4 3.2 4 OD 0.75 -0.13 0.13 -0.13 4.5
2.2 2.2 3.8 4 OS 0.50 0.13 0.00 0.00 4.5 2 2.1 3.8 5 OD -0.13 -0.75
-0.50 -0.38 4 2.2 2.4 3 5 OS 0.00 -0.50 -0.63 -0.25 4.1 2.1 2.2 3.1
AVERAGE 0.15 -0.41 -0.31 -0.24 4.88 2.2 2.37 3.43
[0074] As shown in Table 3 and FIG. 5, when using the combination
of pilocarpine and meloxicam there was a myopization of around 0.57
diopters and an improvement in unaided near acuity of 2.6 lines at
one hour which is less than that obtained by the pharmacological
combination presented in example 1 but still of good clinical
usage. The drop in distance visual acuity was 0.6 lines at one hour
(FIG. 6). Overall the pilocarpine/meloxicam results could be
interpreted as the latter having a mitigating effect on the side
effects of pilocarpine since it is not known to affect any of the
receptors involved in near vision. This is in contrast with the
preparation in example 1 where there seems to be a synergistic
effect between the two described compounds.
Example 6
[0075] After a two-week washout period, the patients from example 5
were treated with a combination of 1% pilocarpine and 0.1%
naphazoline dissolved in a solution of 0.5% sodium chloride in
water plus carboxymethyl cellulose as viscosant and benzalkonium
chloride as preservative. Both eyes in the patients were treated
and the same measurements as in example 5 were taken at one hour,
four hours, and eight hours later. After another two week washout
period, the patients were treated with a combination of 1%
pilocarpine and 0.05% tetrahydrozoline dissolved in a solution of
0.5% sodium chloride in water plus carboxymethyl cellulose as
viscosant and benzalkonium chloride as preservative. Both eyes in
the patients were treated and the same measurements as in example 5
were taken at one hour, four hours, and eight hours later. In both
treatment groups, an improvement in near vision with a very modest
decrease in unaided distance vision was observed. These results are
similar to the observed results in example 5 and demonstrate a
mitigation of the side effects of pilocarpine by naphazoline and
tetrahydrozoline with modest potentiation of the therapeutic
effects of pilocarpine.
[0076] While certain embodiments of the invention have been
described, other embodiments may exist. While the specification
includes a detailed description, the invention's scope is indicated
by the following claims. Furthermore, while the specification has
been described in language specific to structural features and/or
methodological acts, the claims are not limited to the features or
acts described above. Rather, the specific features and acts
described above are disclosed as illustrative aspects and
embodiments of the invention. Various other aspects, embodiments,
modifications, and equivalents thereof which, after reading the
description herein, may suggest themselves to one of ordinary skill
in the art without departing from the spirit of the present
invention or the scope of the claimed subject matter.
* * * * *