NZ623037B2 - Compositions and methods for treating presbyopia, mild hyperopia, and irregular astigmatism - Google Patents
Compositions and methods for treating presbyopia, mild hyperopia, and irregular astigmatism Download PDFInfo
- Publication number
- NZ623037B2 NZ623037B2 NZ623037A NZ62303712A NZ623037B2 NZ 623037 B2 NZ623037 B2 NZ 623037B2 NZ 623037 A NZ623037 A NZ 623037A NZ 62303712 A NZ62303712 A NZ 62303712A NZ 623037 B2 NZ623037 B2 NZ 623037B2
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- New Zealand
- Prior art keywords
- pilocarpine
- composition
- eye
- oxymetazoline
- medicament
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
composition comprising pilocarpine and oxymetazoline which is suitable for treatment of an ocular condition, selected from the group consisting of presbyopia, mild hyperopia, irregular astigmatism, hyperopic accommodative esotropia, and glaucoma.
Description
COMPOSITIONS AND METHODS FOR TREATING PRESBYOPIA, MILD
HYPEROPIA, AND IRREGULAR ASTIGMATISM
This application is being filed on 19 September 2012, as a PCT International
patent application and claims priority to U.S. Provisional Application Serial Number
61/536,921, filed September 20, 2011, the subject matter of which is incorporated by
reference in its entirety.
Background
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.
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.
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.
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.
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.
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.
Patent 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.
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)
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 () 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.
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. It is an object of
the present invention to go someway towards meeting this need and/or to provide
the public with a useful choice.
Summary of the Invention
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.
In a first aspect, the invention provides a composition comprising pilocarpine
and oxymetazoline.
In a second aspect, the invention provides a use of a) pilocarpine and b)
oxymetazoline in the manufacture of a medicament for treating an ocular condition
in a subject in need thereof, wherein the ocular condition is selected from the group
consisting of presbyopia, mild hyperopia, irregular astigmatism, hyperopic
accommodative esotropia, and glaucoma, and wherein the medicament is formulated
for separate, sequential or simultaneous administration of a) and b).
Also described are compositions that include a cholinergic agent, such as a
muscarinic acetylcholine receptor M 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 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.
The compositions described herein 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 compositions described
herein 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 described herein 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
Figure 1 shows the effect of a composition comprising pilocarpine and
oxymetazoline on near vision (Jaeger Equivalent) over time.
Figure 2 shows the effect of a composition comprising pilocarpine and
oxymetazoline on distance vision (LogMAR Equivalent) over time.
Figure 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.
Figure 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.
Figure 5 shows the effect of a composition comprising pilocarpine and
meloxicam on near vision (Jaeger Equivalent) over time.
Figure 6 shows the effect of a composition comprising pilocarpine and
meloxicam on distance vision (LogMAR Equivalent) over time.
Detailed Description of the Invention
Definitions
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.
The term “comprising” as used in this specification and claims means
“consisting at least in part of”. When interpreting statements in this specification,
and claims which include the term “comprising”, it is to be understood that other
features that are additional to the features prefaced by this term in each statement or
claim may also be present. Related terms such as “comprise” and “comprised” are
to be interpreted in similar manner.
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.
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.
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, 1h indicates the condition of the eye 1 hour after
treatment, 4h indicates the condition of the eye 4 hours after treatment, and 6h
indicates the condition of the eye 6 hours after treatment. “Sph Eq” is the spherical
equivalent.
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.
“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
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.
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).
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 GA 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 HE. Corneal stimulation of MMP-1, -9 and uPA by platelet-activating
factor is mediated by cyclooxygenase-2 metabolites. Curr Eye Res. 2001
Aug;23(2):77-85).
The compositions described herein 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 compositions
described herein 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 described herein 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 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 agonist. Additional examples include
acetylcholine, bethanechol, oxotremorine, pilocarpidine, and the like. In an
embodiment, the cholinergic agent is pilocarpine.
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.
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.
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.
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.
The compositions described herein 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.
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.
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.
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.
In one aspect, ophthalmic preparations of the compositions described herein
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 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 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.
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.
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.
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.
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.
In another aspect, ophthalmic preparations of the compositions described
herein 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 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 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.
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.
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
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 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.
The compositions described herein 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.
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.
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 described herein 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 described herein 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.
The compositions described herein 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 ( α-, β-
and γ-) and synthetic (e.g. chemically modified hydroxyethyl- β- or sulfobutylether-
β-) 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- β-cyclodextrin and sulfobutylether- β-cyclodextrin. Cyclodextrins may
also be included in the compositions described herein 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
% β-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 % β-cyclodextrin.
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 described herein 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.
In certain embodiments, the carrier used herein 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.
In embodiments, the compositions described herein 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 described herein
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.
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
polyethylene glycol (PEG), and PLURONICS .
The compositions described herein can include one or more preservatives
such as phenol, cresol, paraaminobenzoic acid, BDSA, sorbitrate, chlorhexidine,
benzalkonium chloride, sorbic and boric acids, Purite (oxychloride compounds),
Polyquad (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.
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.
Compositions described herein 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 compositions described herein 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
described herein 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 described herein in both eyes of a
presbyopic patient may result in optimum enhancement of near vision, but may
slightly decrease distant vision. The compositions described herein 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 described herein is administered only to the dominant eye of the patient
to improve reading ability.
The compositions described herein 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 described herein 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 described herein 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.
Also described are kits for treating an ocular condition. 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
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
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.
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 1. (Pilocarpine + Oxymetazoline)
Pre 1h 4h 6h Pre 1h 4h 6h
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
M 48 OD J3 J1+ J1+ J3 20/20 20/30 20/30 20/20
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
F 56 OD J16 J5 J5 J7 20/30 20/30 20/30 20/25
OS J10 J5 J5 J7 20/30 20/30 20/30 20/30
Table 1 Continued. (Pilocarpine + Oxymetazoline)
ID Pre Sph 1h Sph 4h Sph 6h Sph Pre Cyl 1h Cyl 4h Cyl 6h 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
OD 0.25 -0.50 -0.50 0.00 -0.25 -0.50 -0.25 -0.25
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
OD 0.75 -0.25 -0.25 0.00 -0.25 -0.25 0.00 -0.25
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
Table 1 Continued. (Pilocarpine + Oxymetazoline)
Pre Sph 1h Sph 4h Sph 6h Sph Pre
ID Eq Eq Eq Eq Pupil 1h Pupil 4h Pupil 6h 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
OD 0.13 -0.75 -0.63 -0.13 5.4 2 2.1 3
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
OD 0.63 -0.38 -0.25 -0.13 4.1 1.9 2 2.9
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
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:
1) potentiated the observed increase in refractive power of the
eye to improve near vision in emmetropes, myopes and hyperopes;
2) potentiated the observed increase in refractive power of the
eye to improve distance visual acuity in mild hyperopes; and
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
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
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.
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 FIGURES 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 2. [Pilocarpine + Oxymetazoline(OD) vs. Pilocarpine alone (OS)]
Pre 4h 6h Pre 1h 4h 6h
ID Sex Age UNVA 1h UNVA UNVA UNVA UDVA UDVA UDVA UDVA
1 M 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 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 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 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
M OD J3 J1+ J1 J1 20/25 20/40 20/30 20/25
OS J5 J1+ J1 J2 20/25 20/30 20/30 20/25
6 F 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 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 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 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
F OD J7 J3 J3 J3 20/25 20/30 20/30 20/25
OS J7 J3 J5 J5 20/20 20/30 20/25 20/25
Table 2 Continued. [Pilocarpine + Oxymetazoline (OD) vs. Pilocarpine alone
(OS)]
ID Pre Sph 1h Sph 4h Sph 6h Sph Pre Cyl 1h Cyl 4h Cyl 6h 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
OD 0.25 -0.50 -0.50 0.00 -0.25 -0.50 -0.25 -0.25
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
OD 0.75 -0.25 -0.25 0.00 -0.25 -0.25 0.00 -0.25
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
Table 2 Continued. [Pilocarpine + Oxymetazoline (OD) vs. Pilocarpine alone
(OS)]
Pre Sph 1h Sph 4h Sph 6h Sph Pre
ID Eq Eq Eq Eq Pupil 1h Pupil 4h Pupil 6h 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
OD 0.50 -1.00 -0.75 0.25 4.1 2.1 2.7 4
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
OD -0.13 -0.50 -0.50 -0.13 4.7 2.1 2.9 4.7
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
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.
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.
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.
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
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 3. (Pilocarpine + Meloxicam)
Pre 1h 4h 6h Pre 1h 4h 6h
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
F 55 OD J10 J5 J7 J7 20/25 20/40 20/30 20/30
OS J10 J5 J5 J7 20/25 20/30 20/40 20/25
Table 3 Continued. (Pilocarpine + Meloxicam)
ID Pre Sph 1h Sph 4h Sph 6h Sph Pre Cyl 1h Cyl 4h Cyl 6h 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
OD 0.25 -0.50 -0.25 0.00 -0.75 -0.50 -0.50 -0.75
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
Table 3 Continued. (Pilocarpine + Meloxicam)
Pre Sph 1h Sph 4h Sph 6h Sph
ID Eq Eq Eq Eq Pre Pupil 1h Pupil 4h Pupil 6h 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
OD -0.13 -0.75 -0.50 -0.38 4 2.2 2.4 3
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
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
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.
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.
In this specification where reference has been made to patent specifications,
other external documents, or other sources of information, this is generally for the
purpose of providing a context for discussing the features of the invention. Unless
specifically stated otherwise, reference to such external documents is not to be
construed as an admission that such documents, or such sources of information, in
any jurisdiction, are prior art, or form part of the common general knowledge in the
art.
In the description in this specification reference may be made to subject
matter that is not within the scope of the claims of the current application. That
subject matter should be readily identifiable by a person skilled in the art and may
assist in putting into practice the invention as defined in the claims of this
application.
Claims (17)
1. A composition comprising pilocarpine and oxymetazoline.
2. A composition as claimed in claim 1, suitable for treatment of an ocular condition, selected from the group consisting of presbyopia, mild hyperopia, irregular astigmatism, hyperopic accommodative esotropia, and glaucoma.
3. The composition of claim 1 or claim 2, wherein the composition comprises: from about 0.01% to about 10% w/w pilocarpine; and from about 0.01% to about 0.5% w/w oxymetazoline.
4. The composition of claim 1 or claim 2, wherein the composition comprises: from about 0.01% to about 2% w/w pilocarpine; and from about 0.01% to about 0.2% w/w oxymetazoline.
5. The composition of claim 1 or claim 2, wherein the composition comprises: from about 0.5% to about 1.5% w/w pilocarpine; and from about 0.02% to about 0.125% w/woxymetazoline.
6. The composition of any one of claims 1 to 5, wherein the composition further comprises an ophthalmically acceptable carrier.
7. The composition of any one of claims 1 to 6, wherein the composition further comprises a cyclodextrin or derivative thereof to enhance ocular penetration of the composition.
8. The composition of any one of claims 1 to 7, wherein the composition is in the form of an eye drop, suspension, gel, ointment, injectable solution, or spray.
9. A use of a) pilocarpine and b) oxymetazoline in the manufacture of a medicament for treating an ocular condition in a subject in need thereof, wherein the ocular condition is selected from the group consisting of presbyopia, mild hyperopia, irregular astigmatism, hyperopic accommodative esotropia, and glaucoma, and wherein the medicament is formulated for separate, sequential or simultaneous administration of a) and b).
10. The use of claim 9, wherein the medicament is formulated for administration to an eye of the subject.
11. The use of claim 10, wherein the medicament is to be administered to only one eye of the subject.
12. The use of any one of claims 9 to 11, wherein the medicament increases refractive power of an eye of the subject by up to about 4.0 diopters.
13. The use of any one of claims 9 to 12, wherein the subject is human.
14. The use of claim 9 wherein the ocular condition could alternatively be corrected with eye glasses having about +0.5D to about +1.0D lenses and wherein the medicament comprises a therapeutically effective amount of from about 0.3% to about 1.0% pilocarpine.
15. The use of claim 9 wherein the ocular condition could alternatively be corrected with eye glasses having about +1.0D to about +1.5D lenses and wherein the medicament comprises a therapeutically effective amount of from about 0.8% to about 1.6% pilocarpine.
16. The use of claim 9 wherein the ocular condition could alternatively be corrected with eye glasses having about +1.5D to about +2.0D lenses and wherein the medicament comprises a therapeutically effective amount of from about 1.4 % to about 2.2% pilocarpine.
17. The use of claim 9, wherein the medicament comprises from about 0.01% to about 10% w/w pilocarpine and from about 0.01% to about 0.5% w/w oxymetazoline.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161536921P | 2011-09-20 | 2011-09-20 | |
US61/536,921 | 2011-09-20 | ||
PCT/IB2012/002335 WO2013041967A2 (en) | 2011-09-20 | 2012-09-19 | Compositions and methods for treating presbyopia, mild hyperopia, and irregular astigmatism |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ623037A NZ623037A (en) | 2016-07-29 |
NZ623037B2 true NZ623037B2 (en) | 2016-11-01 |
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