Note: Descriptions are shown in the official language in which they were submitted.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-1-
Compositions and Methods for Treatment of Glaucoma
BACKGROUND OF THE INVENTION
Glaucoma is a multifactorial disease which encompasses a spectrum ranging
from elevated intraocular pressure (10P) to reduced vascular perfusion of the
optic
nerve.
While many factors have been implicated as contributing causes of glaucoma,
currently existing treatments for glaucoma have limited effectiveness in
lowering 10P
and/or are accompanied by a number of side effects, such as fatigue, sedation,
lid
allergy, topical allergy, and/or redness.
0 Because of the side effects, an additional major problem in glaucoma
therapy is
patient compliance in taking medications as prescribed. It is believed that
many of these
side effects and suboptimal efficacy of the existing treatments are unintended
consequences of alpha-1 (a-1) receptor induction from treatment with alpha
agonists.
Over 40% of glaucoma patients require two or more drugs for satisfactory
control
5 of their intraocular pressure. Of these, the prostaglandins/prostanoids,
including
Xalatan (latanoprost), TravatanO (travoprost) and Lumigan (bimatoprost), are
the
leading drugs due to their profound reduction of 10P, typically above 30% in
ocular
hypertensive eyes (21 mm Hg or greater), and long duration improvement in
uveoscleral
outflow. To have the greatest effect, the two drugs should have different
mechanisms
0 of action.
Brimonidine, a known alpha-2 (a-2) adrenergic receptor agonist, typically
causes
moderate peak 10P reduction of about 20 - 25% in ocular hypertensive eyes and
6-18%
in normotensive eyes (less than 21 mm Hg). Its peak effect is within 2-3 hours
of
instillation, its duration of effect is typically less than 12 hours, and its
moderate efficacy
5 usually requires dosing of 2-3 times a day. It is one of the leading
secondary drugs, with
a mechanism of action of aqueous suppression that complements the
prostaglandin/prostanoids uveal scleral outflow enhancement for significant
additive
benefit. Currently, brimonidine is the only commercially available alpha-2
agonist,
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-2-
proving safer and/or more effective than predecessors against which it has
been
compared, including clonidine (fewer instances of systemic hypotension and/or
bradycardia), apraclonidine (fewer instances of tachyphylaxis), and
dexmedetomidine
(less systemic sedation, greater lop reduction efficacy).
However, brimonidine may induce substantial local side effects in 10-25% of
users, such as conjunctival hyperemia (redness), blepharitis, allergy,
conjunctival
edema, conjunctival follicles, foreign body sensation, burning, or blurring.
These side
effects were only modestly improved by recent brimonidine formulations,
resulting in
somewhat reduced concentrations with increased intraocular absorption at more
0 alkaline pH (Alphagan P, Allergan Pharmaceuticals). In general, a-2
agonists,
including brimonidine, clonidine and dexmedetomidine, induce substantial
systemic
effects if absorbed into the circulation, and are specifically known to
decrease blood
pressure (hypotension) and lower the heart rate (bradycardia). Further, many a-
2
agonists, particularly the more lipophilic drugs such as clonidine and
dexmedetomidine
5 readily cross the blood brain barrier and thereby induce potent
sedative effects.
Dexmedetomidine, in particular, is a potent intravenous sedative, and side
effects such
as drowsiness, shortness of breath, dizziness, headache, hypotension,
bradycardia,
and mood depression are common to all a-2 agonists depending on their degree
of
systemic absorption. Brimonidine in particular produces topical lid and
conjunctival
0 allergy, dryness, and redness in well over 10% of patients.These side
effects contribute
to suboptimal compliance with brimonidine, which also negatively affects
treatment.
Dexmedetomidine in phosphate buffer at pH 6.4-6.5 has been studied in
normotensive and artificially elevated eye pressure rabbits.
US 5,304,569
(Lammintausta) describes the use of 0.02% dexmedetomidine in normotensive
rabbits
5 resulted in equal pressure reduction (100%) in the nontreated
(contralateral) eye and
the treated eye, a known side effect indicative of high systemic absorption.
Vartiainen et
al demonstrated that dexmedetomidine at 0.05% in normotensive rabbits results
in a
pressure reduction of 4.75 mm Hg, with a peak effect at about 2 hours. (Inv
Oph. & Vis
Sal., Vol. 33, No. 6, May 1992, Dexmedetomidine-Induced Ocular Hypotension in
0 Rabbits With Normal or Elevated lntraocular Pressures Vartiainen et. al).
The
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-3-
comparison of the use of brimonidine tartrate 0.10% solution vs.
dexmedetomidine in
normotensive rabbits demonstrates a higher peak of about 6.2 mm Hg with
brimonidine,
a longer duration with peak of about 3 hrs vs. 2 hours for dexmedetomidine,
and lower
systemic absorption with brimonidine, with contralateral (nontreated eye) 10P
reduction
of only about 10% vs. about 100% for dexmedetomidine compared to the treated
eye
(Center for Drug Evaluation and Research Number 21-770, Pharmacology Review,
brimonidine tartrate 0.1%, Allergan Pharmaceuticals). For over two decades,
brimonidine has been the only commercially available a-2 agonist, due to its
demonstrated combination of superior 10P reduction with greatly reduced risk
of
0 systemic side effects versus all other a-2 agonists attempted for this
purpose, despite its
less than optimal side effect profile and modest efficacy relative to
prostaglandins/prostanoids.
Accordingly, there is a need for novel formulations of alpha-2 (a-2) agonists
for
the treatment of glaucoma which would have less systemic absorption, minimal,
if any,
5 cross-activation of a-1 receptors, improved intraocular retention with
more effective 10P
lowering and duration, and with significantly reduced or eliminated side
effects of
conventional a-2 agonists, such as burning, stinging, sedation and redness. In
addition,
an improved cosmetic appearance via both reduced redness and a cosmetically
pleasing whiter shading of the eye may be important in reducing the rate of
patients
0 noncompliance.
BRIEF SUMMARY OF THE INVENTION
The present invention provides compositions and methods effective for the
treatment of glaucoma in a patient in need thereof. Preferably, the
compositions of the
5 invention are formulated to prevent sedation, eliminate or reduce
redness, eliminate or
reduce ocular allergy, as well as significantly reduce intraocular pressure.
In some embodiments, the provided compositions may also have an eye
whitening effect. Most preferably, the compositions include all of the above
benefits and
also have neuroprotective benefits and may be used for optic nerve protection,
including
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-4-
the treatment of neurodegenerative conditions, such as ischemic optic
neuropathy,
diabetic retinopathy, optic ischemia, retinal vascular ischemia, and other
optic
neuropathies, particularly those involving retinal ganglion cells and/or axons
at or near
the optic nerve lamina.
The present invention optimizes a-2 agonist corneal permeation utilizing a
highly
selective a-2 agonist which is formulated to optimize intraocular penetration
at a
lipophilicity of preferably Log P 2.5 or greater and range of topical
lipophilicity based on
the pH and optional buffering of the formulation that may range from 0.73 to
3.08
(measured relative to pH as the Log D value). Further, the improved
formulations allow
0 for reduced a-1 agonist activity and reduced systemic absorption,
allowing for a more
lipophilic alpha 2 agonist for topical use.
The preferred compositions of the invention employ selective a-2 adrenergic
receptor agonists.
In a preferred embodiment, the invention provides novel formulations of
5 dexmedetomidine, which are surprisingly found to be much more
effective for the
treatment of glaucoma than brimonidine. These novel inventive formulations
share
some or all of the following characteristics:
a) a high selectivity for a-2 over a-1 adrenergic receptors, such as 1000:1 or
greater; more preferably 1500:1 or greater; and even more preferably 2000:1
LI or greater;
b) a high degree of intraocular lipophilicity as measured by the Log P, the
equilibrated intraocular pH at 7.4, with an octanol-water partition
coefficient
Log P of between about 1.5 and 4.0; and more preferably between about 2.50
and 3.50 at physiologic pH; and
5
c) include a poloxamer at specified concentration range, and one or more
specific viscosity enhancers (also interchangeably referred to as a "gelling
agents").
CA 02863760 2014-08-04
WO 2013/115844 PCT/US2012/050786
-5-
In one embodiment, the invention provides a pharmaceutical composition
comprising:
an a-2 adrenergic receptor agonist at a concentration from between about
0.0125% to about 0.125% weight by volume, wherein said a-2 adrenergic
receptor has a Log P value of 2.0 or greater and has a binding affinity of
950 fold or greater for a-2 over a-1 adrenergic receptors;
ii. a salt;
iii. a poloxamer at a concentration of between 3% and 12% weight by volume
or less; and
iv. a viscosity enhancer,
wherein said pharmaceutical composition has a viscosity of between 50
and 300 cps, and
wherein said pharmaceutical composition is effective for the treatment of
glaucoma in a patient in need thereof.
A preferred a-2 adrenergic receptor agonist is dexmedetomidine.
Preferably, dexmedetomidine is at a concentration from between about 0.035%
and 0.12% weight by volume, and more preferably between about 0.050% and
0.10%.
In one embodiment, the salt selected from the group consisting of sodium
chloride, citrate, mesylate, hydrobromide/bromide, acetate, fumarate,
sulfate/bisulfate,
succinate, phosphate, maleate, nitrate, tartrate, benzoate, carbonate, and
pamoate.
Preferably, the salt is sodium chloride (e.g., a saline solution).
In one embodiment, the viscosity enhancer is selected from carboxymethyl
cellulose, methylcellulose, hydroxymethyl cellulose, hydroxypropylmethyl
cellulose,
hydroxyethyl cellulose, polyethylene glycol, dextran, povidone, alginic acid,
guar gum,
acacia, veegum, gelatin, chitosan, carbopol, locust bean gum, acidic
polycarbophil,
dextran, pectin, povidone, polyvinylpyrridone, polyvinyl alcohol, and
hyaluronic acid.
In a preferred embodiment, the viscosity enhancer is carboxymethyl cellulose.
CA 02863760 2014-08-04
WO 2013/115844 PCT/US2012/050786
-6-
Preferably, the poloxamer is present at concentration range of 3% to 10% by
weight; and more preferably, at 5% to 6% by weight.
Preferably, the poloxamer is selected from the group consisting of poloxamer
407, poloxamer 188, and combinations thereof.
In one embodiment, the pharmaceutical composition may further comprise a
buffer which may be selected from the group consisting of citrate buffer,
borate buffer,
maleate buffer, succinate buffer, phosphate buffer, acetate buffer, sorbate
buffer and
carbonate buffer.
In one embodiment, the buffer is at a concentration between 1 mM and 100 mM.
In one embodiment, the pharmaceutical composition has an octanol-water
partition coefficient Log D of between about 0.70 and about 2.98, or
preferably between
about 1.25 and 2.50.
Accordingly, in one embodiment the invention provides a pharmaceutical
composition comprising
i. dexmedetomidine is at a concentration from between 0.02% and about
0.12% weight by volume; and more preferably 0.050% to 0.10% weight by
volume.
ii. sodium chloride at a concentration of 0.25% to 0.50%;
iii. a poloxamer at a concentration of between 3 and 12% weight by volume
or more preferably, at 5 to 6%;
iv. carboxymethyl cellulose (CMC), and
wherein said pharmaceutical composition has a viscosity of between 20 and 500
cps and more preferably 50 and 150 cps.
In one embodiment, the pharmaceutical compositions of the invention may
further comprise a mucoadhesive, which may be present at a concentration from
between about 0.5% and about 10% weight by volume.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-7-
In one embodiment, the mucoadhesive is selected from the group consisting of
carbapols, xanthan gums, and cellulose derivatives.
The invention also provides methods of treating glaucoma and/or posterior pole
ocular neurodegenerative conditions and/or dry eye in a patient in need
thereof
comprising administering to said patient the pharmaceutical compositions of
the
invention.
The invention also provides a vehicle formulation for drug delivery, wherein
said
vehicle formulation comprises a poloxamer, hypotonic saline, and a viscosity
enhancer,
at the same concentrations and ranges as previously recited.
The invention also provides an artificial tear solution comprising:
a hypotonic salt or sterile water;
a poloxamer at a concentration of 12% weight by volume or less; and
iii. a viscosity enhancer, and
wherein said pharmaceutical solution has a viscosity of between 25 and 500
cps.
0 DETAILED DESCRIPTION OF THE INVENTION
Definitions
The term "a-1 adrenergic receptor" refers to a G-protein-coupled receptor
(GPCR) associated with the Gq heterotrimeric G-protein.
The term "a-2 adrenergic receptor" refers to a GPCR associated with the Gi
5 heterotrimeric G-protein.
The term "selective a-2 adrenergic receptor agonists" encompasses all a-2
adrenergic receptor agonists which have a binding affinity of 1000 fold or
greater for a-2
over a-1 adrenergic receptors, and more preferably 1500 fold or greater. The
term also
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-8-
encompasses pharmaceutically acceptable salts, esters, prodrugs, and other
derivatives of selective a-2 adrenergic receptor agonists.
The term "dexmedetomidine" encompasses, without limitation, dexmedetomidine
salts, esters, prodrugs and other derivatives.
The term "prodrug" refers to a compound that may be converted under
physiological conditions to a biologically active compound.
As used herein, the term "composition" is intended to encompass a product
comprising the specified ingredients in the specified amounts, as well as any
product
which results, directly or indirectly, from a combination of the specified
ingredients in the
0 specified amounts.
The terms "treating" and "treatment" refer to reversing, alleviating,
inhibiting, or
slowing the progress of the disease, disorder, or condition to which such
terms apply, or
one or more symptoms of such disease, disorder, or condition.
The terms "preventing" and "prevention" refer to prophylactic use to reduce
the
5 likelihood of a disease, disorder, or condition to which such term
applies, or one or more
symptoms of such disease, disorder, or condition, It is not necessary to
achieve a 100%
likelihood of prevention; it is sufficient to achieve at least a partial
effect of reducing the
risk of acquiring such disease, disorder, or condition.
The term "significant side effects" refers to substantial side effects of the
0 treatment which include at least: a) sedation of a patient such that the
patient feels
sedated and becomes impaired or b) visually noticeable increase in redness of
a
patient's eye due to hyperemia.
The term "medicamentosa" refers to the inflammatory sequelae of a-1 agonist
topical medications, particularly following topical ocular or nasal delivery,
such as the
5 development of increased vasodilation and hyperemia, in its less severe
form referred
to as "rebound".
The terms Poloxamer 407 and Pluronic F127 are used interchangeably.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-9-
Embodiments of the Invention
The present invention provides compositions and methods effective for the
treatment of glaucoma in a patient in need thereof. Preferably, the
compositions of the
invention are formulated to prevent sedation, eliminate or reduce redness,
eliminate or
reduce ocular allergy, as well as significantly reduce intraocular pressure.
Specifically, the provided formulations comprise the following ingredients:
a) a selective a-2 agonist, preferably dexmedetomidine, at a concentration
between about 0.0125% to about 0.125% weight by volume;
0 b) a salt (e.g., hypotonic saline, NaCI);
c) a poloxamer (which may be selected from various grades of poloxamer,
including but not limited to 407 and 188) at a concentration at about 12% or
less,
and preferably between about 3% and 10%; and more preferably between about
5% and 6%;
5 d) a viscosity enhancer, preferably carboxymethyl cellulose (CMC) at
0.25-1.0%,
and more preferably at 0.075%;
wherein the viscosity of the provided formulation is between 25 and 500 cps,
and
more preferably about 50 and 200 cps.
In one embodiment, the invention provides a pharmaceutical composition
0 comprising:
dexmedetomidine at a concentration from between about 0.0125% to
about 0.125% weight by volume;
a salt,
iii. a poloxamer at a concentration of 12% weight by volume or less; and
iv. a viscosity enhancer,
wherein said pharmaceutical composition has a viscosity of between 50
and 500 cps, and
wherein said pharmaceutical composition is effective for the treatment of
glaucoma in a patient in need thereof.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-10-
Preferably, dexmedetomidine is at a concentration from between about 0.035%
to 0.10% weight by volume.
Preferably, the pH of the provided compositions is within a range of 4.0 to
8.0,
and more preferably about 5.0 to 6Ø
In one embodiment, the salt selected from the group consisting of sodium
chloride, citrate, mesylate, hydrobromide/bromide, acetate, fumarate,
sulfate/bisulfate,
succinate, phosphate, maleate, nitrate, tartrate, benzoate, carbonate, and
pamoate.
Preferably, the salt is sodium chloride (e.g., a saline solution).
In one embodiment, the viscosity enhancer is selected from carboxymethyl
cellulose, methylcellulose, hydroxymethyl cellulose, hydroxypropylmethyl
cellulose,
hydroxyethyl cellulose, polyethylene glycol, dextran, povidone, alginic acid,
guar gum,
acacia, veegum, gelatin, chitosan, carbopol, locust bean gum, 'acidic
polycarbophil,
dextran, pectin, povidone, polyvinylpyrridone, polyvinyl alcohol, and
hyaluronic acid.
In a preferred embodiment, the viscosity enhancer is carboxymethyl cellulose.
Preferably, the poloxamer is present at concentration range of 3% to 10% by
weight; and more preferably, at 5% to 6% by weight.
Preferably, the poloxamer is selected from the group consisting of poloxamer
407, poloxamer 188. However, other poloxamers and/or combinations of various
poloxamers can be used for the purposes of the present invention.
In a preferred embodiment, the compositions of the invention may include the
following components:
1) dexmedetomidine at a concentration of between 0.0125% and 0.125%, most
preferably 0.035% to 0.10%, weight by volume;
2) sodium chloride at a concentration of between 0 to 0.75%, more preferably
0.25% to 0.50%.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-1 1 -
3) a poloxamer, preferably, Poloxamer 407 (Pluronic F127) or 188 or
combination thereof, at a concentration of between 1% and 10%, more
preferably, 5% to 6%;
4) carboxymethyl cellulose high blend (CMC), at a concentration of between
0.25% and 1%; more preferably 0.62% to 0.75%; and
5) optionally, benzalkonium chloride (BAK) at a concentration of between 0.01%
and 0.02%; preferably at 0.02%.
In one embodiment, the pharmaceutical composition may further comprise a
buffer, which may be selected from the group consisting of citrate buffer,
borate buffer,
maleate buffer, succinate buffer, phosphate buffer, acetate buffer, sorbate
buffer and
carbonate buffer.
In one embodiment, the buffer is at a concentration between 1 mM and 100 mM,
more preferably 4 mM to 10 mM.
In one embodiment, the pharmaceutical composition has an octanol-water
partition coefficient Log D of between about 0.70 and about 2.20, and
preferably
between about 1.25 and 2.00.
In one embodiment, the pharmaceutical compositions of the invention may
further comprise a mucoadhesive, which may be selected from the group
consisting of
carbapols, xanthan gums, and cellulose derivatives. However, other gums and/or
gels,
and/or viscosity enhancers can also be used for the purposes of the present
invention.
In one embodiment, the mucoadhesive is at a concentration from between about
0.5% and about 1.0% weight by volume.
The inventive formulations may also optionally include other ingredients, such
as
corneal penetration enhancers and others.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-12-
The invention also provides a method of treating glaucoma and/or posterior
pole
ocular neurodegenerative conditions in a patient in need thereof comprising
administering to said patient the pharmaceutical compositions of the
invention.
Additionally, the inventive compositions may provide optic nerve protection,
retinal ganglion cell neuroprotection, an increase in a-2 agonist
concentration in the
inner retinal plexiform, and additional neuroprotective benefits. They may
also increase
the outflow at the trabecular meshwork which is populated with endothelial
cells and
believed to be populated with a-2a receptors in humans.
In addition, the methods and compositions of the invention may be used to
0 reduce eye redness and/or increase eye whiteness in subjects in need
thereof.
Unexpected Results of Using the Specific Combinations of the Ingredients
The presence of these four ingredients at the recited ranges (a selective a-2
agonist, a salt; a poloxamer at 12% or less; and another viscosity enhancer,
preferably
5 CMC) is essential for providing effective pharmaceutical formulations
which provide a
stronger and more durable 10P reduction than prior art brimonidine or
dexmedetomidine
formulations. Unless these ingredients are present, other viscosity enhancers
and other
excipients are ineffective, and/or substantially reduce the a-2 agonist
activity of
dexmedetomidine (and, possibly, of other a-2 agonists), and/or do not reduce
systemic
0 absorption or other side effects of dexmedetomidine formulations, in
particular,
sedation.
It was surprising that the discovered ranges and combinations were found to be
most effective. None of these formulation ingredients by itself provides the
required
sustained release and reduced systemic absorption. Based on prior art, one
would
5 expect that clonidine and dexmedetomidine would be inferior glaucoma
drugs than less
lipophilic brimonidine or apraclonidine.
Further, it has been found that a poloxamer alone, regardless of
concentration, is
not only ineffective for the purposes of the present invention in terms of
increased
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-13-
efficacy, but it also creates severe stinging on topical application, whether
it is buffered
or non-buffered, and regardless of pH.
It would have been expected that the concentration of a poloxamer should be
within the 15% to 25% range, at which gelling effect at room temperature is
known to
occur and/or at the physiologic range of tonicity enhancers; however, it has
been
discovered that a poloxamer is effective in the provided combinations when it
is present
at 12% or less, and preferably at more than 3% but less than 10%. When
poloxamer is
present at a concentration of 15% or greater or less than 2%, the compositions
are
surprisingly less effective or ineffective.
o
It was also surprising and unexpected that other gelling agents, such as
Carbopol0 954 and/or xanthan gums, could not be used instead of a poloxamer.
One
would have expected that these agents be interchangeable.
Further, the use of viscosity enhancers at too low concentrations resulted in
surprisingly more side effects and reduced efficacy. It has also been found
that the use
5 of viscosity enhancers by themselves (i.e., without a poloxamer)
results in much less
effective formulations with more side effects.
Further, it has been surprisingly found that when the tonicity of the provided
formulations is at 0 to 200 mOsm/kg, and preferably at 50 to 150 mOsm/kg, a
sustained
wetting/lubricating effect will result with minimal blurring and the greater
comfort for the
0 patients. Typically, an ophthalmic vehicle requires 280-310 mOsm/kg,
which is achieved
through the use of electrolytes or polyols (e.g. mannitol).
Advantages of the Provided Compositions and Methods
The provided compositions and methods are effective for the treatment of
5 glaucoma. Preferably, the compositions of the invention are
formulated to prevent
sedation, eliminate or reduce redness, may increase duration of therapeutic
action and
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-14-
reduce the incidence of rebound hyperemia and/or other allergic reaction, as
well as
more significantly reduce intraocular pressure than prior art formulations of
a-2 agonists.
It has been surprisingly found that the provided combinations of the
ingredients
result in up to a two-fold increased duration effect, and about a two- fold or
greater peak
10P reduction for dexmedetomidine versus similar dexmedetomidine formulations
(e.g.,
dexmedetomidine in phosphate buffer pH 6.4 ¨ 6.5). They also provide a five to
six-fold
decrease in contra-lateral (non-treated eye) 10P reduction vs. ipsilateral
(treated eye
effect), reflecting greatly reduced systemic absorption affecting the non-
treated eye. In
non-inventive dexmedetomidine formulations (dexmedetomidine at 0.025% to 0.05%
in
0 phosphate buffer at pH 6.4 ¨ 6.5), contra-lateral eye 10P is 90-100% of
the 10P of the
treated eye, due to very high systemic absorption (vs. about 10% systemic
absorption
with the compositions of the present invention).
In a preferred embodiment, the formulations of the present invention provide
the
10P reduction of 40% at 4 hours in a treated eye. The 10P reduction in the
treated eye
5 is greater than that found for the most optimized formulation of
brimonidine (Alphagan
P at 0.1%, pH 7.4 or greater), which is about 20% in a treated eye.
Every 1 mm Hg reduction in 10P may result in substantial prevention of visual
field loss. The longer duration of effect of the present invention creates a
substantial
effect over a 24 hour period, while a single dose of the conventional
brimonidine
0 formulations provides the 10P reduction effect for only about 12 hours or
less.
The provided compositions may also improve cosmetic appearance of the
treated eyes (for example, by increasing whiteness and providing additional
whitening),
resulting in improved patients' compliance. A common side effect of glaucoma
drugs
and, particularly, brimonidine, is eye redness (20-25% rebound redness with
long term
5 use of brimonidine), and compliance is a key problem. For this reason, it
is believed that
reduction of redness, and/or cosmetic whitening achieved with the provided
compositions are likely to substantially improve compliance. The invention
also provides
improved wetting and comfort, lasting up to an hour after instillation.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-15-
In addition, it has been surprisingly discovered that novel formulations
provide a
much greater comfort, a greater eye wetting and lubrication action,
significantly fewer
topical side effects than brimonidine, and result in few, if any, systemic
effects. Thus,
the provided formulations are significantly superior to conventional
brimonidine or
dexmedetomidine formulations. This surprising discovery was contrary to over
20 years
of prior art findings that brimonidine was more effective than
dexmedetomidine.
Thus, in some embodiments, the beneficial effects of the provided compositions
include:
1) onset within one hour;
0 2) peak effects of over 30%, and as great as 40% in normotensive eyes;
3) reduction over normotensive baseline mean 10P of about 15.5 to a mean 10P
of
about 9.3;
4) peak effects at about 3.5 ¨4 hours, compared to 2 to 2.5 hours for
brimonidine;
5) prolonged action with great comfort and minimal to absent stinging, eye
ache, or
5 lid irritation;
6) a strong lubricating-wetting effect for nearly one hour after instillation
with only
transient blurring up to one minute;
7) improved cosmetic appearance via reduction of redness and in some cases
cosmetic whitening;
8) less systemic absorption (only about 16% contralateral (non-treated) eye
lop
reduction with inventive formulations versus much higher systemic absorption
with prior art formulations of dexmedetomidine;
9) reduction of topical and systemic side effects associated with conventional
formulations of a-2 agonists (such as apraclonidine and brimonidine),
including
5 but not limited to reduced incidence of: oral dryness, ocular
hyperemia, burning
and stinging, headache, blurring, foreign body sensation, conjunctival
follicles,
ocular allergic reactions, ocular pruritus, corneal staining/erosion,
photophobia,
eyelid erythema, ocular ache/pain, ocular dryness, tearing, upper respiratory
symptoms, eyelid edema, conjunctival edema, dizziness, blepharitis, ocular
irritation, gastrointestinal symptoms, asthenia, abnormal vision, muscular
pain, lid
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-16-
crusting, conjunctival hemorrhage, abnormal taste, insomnia, conjunctival
discharge, depression, hypertension, anxiety, palpitations/arrhythmias, nasal
dryness and syncope.
Some of the characteristics which are important for the provided compositions
include selectivity for a-2 versus a-1 adrenergic receptors, lipophilicity,
tonicity and
solubility.
Selectivity for a-2 versus a-1 adrenerpic receptors
The selective a-2 adrenergic receptor agonists have binding affinities (K) for
a-2
over a-1 receptors of 1000:1 or greater; more preferably 1500:1 or greater;
and even
more preferably 2000:1 or greater. It is well within a skill in the art to
design an assay to
determine a-2/a-1 functional selectivity. For example, potency, activity or
EC50 at an a-
2A receptor can be determined by assaying for inhibition of adenylate cyclase
activity.
5 Furthermore, inhibition of adenylate cyclase activity can be assayed,
without limitation,
in PC12 cells stably expressing an a-2A receptor such as a human a-2A
receptor.
Additionally, potency, activity or EC50 at an a-1A receptor can be determined
by
assaying for intracellular calcium. Intracellular calcium can be assayed,
without
limitation, in HEK293 cells stably expressing an a-1A receptor, such as a
bovine a-1A
receptor.
For the purposes of the present invention, it is desired to avoid or minimize
triggering of a-1 receptors. Even a small critical threshold achieved of
undesired a-1
receptor recruitment creates sufficient generalized vasoconstriction, micro-
inflammatory
change, and/or pro-inflammatory cytokine release to reduce effectiveness of
the a-2
5 receptor induced positive treatment effects. As all a-2 agonists
known have a relative
affinity for a-2 vs. a-1, this partial affinity is measure by the ratio of a-2
to a-1 receptor
induction, where the multiplied product of the degree of selective a-2
affinity - the a-2/a-
1 ratio x the concentration C% determines that actual total pool of both a-2
and a-1
receptors induced.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-17-
The discovered range of necessary high selectivity, high lipophilicity and
relatively low concentration of induced a-1 effects completely alters the 10P
efficacy and
side effect profile of a-2 agonist drugs. Accordingly, when these a-2 agonists
are used
for the treatment of glaucoma, they greatly reduce 10P and provide eye
whitening
without significant side effects believed to be associated with a-1 receptors,
such as
rebound hyperemia.
In some embodiments, compositions and methods of the invention include
selective a-2 adrenergic receptor agonists which have Ki for a-2 over a-1
receptors of
1500 fold or greater and have an octanol-water partition coefficient of about
Log P 2.50
0 ¨ 3.0 adjusted however for topical pH (Log D) to be between 0.75 and
3.08. Tears and
intraocular fluids are physiologic at pH 7.4, which is equal to pH at Log P
and, according
to the precepts of the present invention, confers 10P reduction benefits.
Corneal
physiology requires a delicate and different octanol-water Log value (called
Log D,
determined by the pH of the formulation), so that the formulations are able to
not only
5 penetrate the lipophilic corneal epithelium and inner endothelium, but
also penetrate the
hydrophilic middle stromal layer.
In yet other embodiments, compositions and methods of the invention include
selective a-2 adrenergic receptor agonists which have Ki for a-2 over a-1
receptors of
1000 fold or greater and are at a concentration from between about 0.0035% to
about
0 0.035% weight by volume.
Brimonidine, guanfacine, guanabenz, dexmedetomidine and fadolmidine are
some of the sufficiently highly selective a-2 agonists to satisfy the
selectivity
requirement. However, of these highly selective a-2 agonists, only
dexmedetomidine
satisfies other additional preferred formulation characteristics of the
present invention,
5 such as lipophilicity. Other a-2 agonists, such as clonidine, may be
sufficiently lipophilic
but lack sufficient selectivity.
It is currently believed that the most preferred selective a-2 adrenergic
receptor
agonist suitable for purposes of the invention is dexmedetomidine as either
the HCI salt,
or as the citrate salt. Other salts may similarly be substituted for the HCI.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-18-
Accordingly, in some embodiments, compositions and methods of the invention
include dexmedetomidine, or another selective a-2 adrenergic receptor agonist,
at a
concentration from between about 0.0125% to about 0.125% weight by volume;
more
preferably, between about 0.025% to about 0.125% weight by volume; and even
more
preferably between about 0.045% and about 0.10% weight by volume.
It is believed that new a-2 agonists can be synthesized to meet the
requirements
of the present invention.
LipophilicitV
0 For any given ophthalmic drug, an optimal lipophilicity exists to
maximize
requisite penetration into the lipophilic cornea surface epithelium and, to a
lesser extent,
inner layer endothelium. If a drug is too hydrophilic, the epithelium becomes
an
impenetrable barrier. If a drug is too lipophilic, the drug cannot pass
through the more
hydrophilic stroma.
5
Lipophilicity may be measured, for example, using known measurements, such
as Log P (log Kow) derivation of the octanol-water partition coefficient
and/or, a closely
related coefficient, XL0gP3-AA. See, for example, Tiejun Cheng et al,
Computation of
Octanol-Water Partition Coefficients by Guiding an Additive Model with
Knowledge, J.
Chem. Inf. Model., 2007, 47 (6), pp 2140-2148. These measurements represent
the
0 intraocular lipophilicity value of topical drugs for intraocular
delivery (i.e., once the drug
permeates into the anterior chamber and is at a pH of 7.4). A person of
ordinary skill in
the art is well familiar with these measurements. Thus, the Log P value is the
octanol-
water coefficient at pH 7.4, i.e., physiologic pH.
It was discovered in prior art that increasing the pH results in a better
lipophilicity
5 profile, making brimonidine mildly lipophilic on topical instillation
and resulting in a better
corneal penetration. For weak base a-2 agonists, such as brimonidine and
dexmedetomidine, the more alkaline pH, the more the equilibrium between
ionized base
releasing H+ and non-ionized base shifts to the left (non-ionized), resulting
in a more
lipophilic compound. This is particularly true for a-2 agonists with pKa
values of near or
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-19-
greater than 7.0, as is the case for brimonidine and dexmedetomidine. This is
because
at a more alkaline pH, more of the compound is present in a non-ionized form,
and
conversely therefore, at more acidic pH more of a drug is ionized and less
lipophilic.
Usually, Log P and/or XLogP3-AA are measured when the formulation at issue is
or will
be at the physiologic pH of about 7.4.
For a majority of drugs a general trend of Log P values from 2.0 to 3.0 is
thought
to be the best range of lipophilicity, though some of the best absorbing drugs
range from
1.00 to about 2.50. Since each drug has its own Log P, and is not always
amenable to
stable Log D/pH manipulation, little is known about how each drug might be
further
0 optimized for topical delivery. The Log P value is highly drug/drug
subclass specific, and
while predictive software algorithms have been developed, there is no
completely
accurate means for determining the ideal Log P value for a proposed drug
formulation
to optimize intraocular penetration.
The range between +2.0 and +3.0 typically allows for the best compromise
5 between: a) the need for a highly lipophilic drug to penetrate the
lipophilic corneal
epithelium, and to a lesser extent, the very thin inner corneal membrane
called
Descemet's membrane, and b) a highly hydrophilic drug to penetrate the stroma,
which
is the middle layer of the corneal "sandwich" that must be penetrated for
effective
ophthalmic absorption.
0 The disclosed combination of a poloxamer, a viscosity enhancer and a
hypotonic
solution at the disclosed concentration ranges provides a delivery vehicle for
dexmedetomidine (and, it is believed, for other mild to highly lipophilic
drugs) that is
independent of pH and largely independent of the individual drug's
lipophilicity.
The optimal pH of the provided formulations (i.e., the topically delivered pH
of
5 the formulation before physiologic equilibration to pH 7.4) is such pH
that results in a
Log "D" value for the drug (the initial topical lipophilicity) of between 0.75
and 3.08, and
more preferably between 0.92 and 2.98, representing the maximum pH range of
4.0 to
8.0, and the preferred pH range of 4.5 to 7.0 for optimal comfort and
stability.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-20-
Noticeably, for some dexmedetomidine formulations, increased stinging has
been observed, particularly at pH of 4.0 to 7.0, and particularly pH 4.0 to
4.5. Further, it
has been discovered that certain buffers added to dexmedetomidine in 0.9% NaCI
render the drug less effective: particularly, phosphate buffer in its pH range
of 6.0 to
about 6.4.
However, it has been discovered that the topical application of the inventive
formulations (i.e., those formulations including all of the required
ingredients at the
required concentrations), is not pH sensitive. Further, the efficacy of the
inventive
formulations no longer appears to be reduced by any particular buffers,
including
0 phosphate buffer. It is believed that the specific combination of the
ingredients in the
inventive formulations confers this pH independence and increased solubility
range on a
variety of active drugs, both for glaucoma and other purposes, as well as
provides
increased absorption and reduced systemic side effects; including but not
limited to
steroidals, nonsteroidals, anti-infectives (antivirals and antimicrobials),
and macular
5 degeneration drug treatments such as anti-VEGF.
The preferred Log P (and XL0gP3-AA) values ¨ those that define intraocular
performance according to the present invention ¨ that are suitable for the
purposes of
the invention are between about 1.00 and 4.50; and more preferably, between
about 2.0
and 3.50. If the selectivity of a specific a-2 agonist is substantially above
1000:1 (for
0 example, 1500:1), additional advantages are believed to be conferred via
greater a-2
agonist binding and reduced a-1 agonist induced ischemia. For example, optic
nerve
damage progression is known to be highly sensitive to circulation change and
ischemia.
Because the drug is used over an extended period of time, even small
reductions in
unintended a-1 agonist-induced ischemia may be beneficial. Thus it is a
discovery of the
5 present invention that the a-2 agonist intraocular lipophilicity as
represented by Log P,
and selectivity as represented by the a-2:a-1 receptor recruitment ratio,
appear to be
very important for greater efficacy of an a-2 agonist glaucoma drug. If the
selectivity is
above, for example, 2000:1, then it is possible that this agonist may be
effective for the
purposes of the invention at slightly reduced lipophilicity, and vice versa.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-21-
Table 1 provides known XL0gP3-AA values (a more accurate Log P) and a2/a1
binding affinities for several a-2 agonists.
TABLE 1
a-2 Agonist XLogP3AA a2 : al
Brimonidine (pH 6.0 ¨ 8.0) 0.6 ¨ 1.8 976
Guanfacine 2.0
Guanabenz 1.7
Dexmedetomidine 3.1 1620
Fadolmidine pivalyl prodrug 1.8
ester
Fadolmidine <1.2
Methoxamine 0.5
Oxymetazoline 2.9 50
Epinephrine -1.4
Clonidine 1.6 200
Apraclondine 1.3 150
Mivazerol 1.1
Xylazine 2.8 160
Methyl Dopa -1.9
Lofexidine 2.6 <300
Table 1 demonstrates that among the listed a-2 agonists, only
dexmedetomidine has an optimal combination of high lipophilicity (XL0gP3-AA)
and
highly selective a2:a1 coefficient. However, it is possible that formulations
including
other a-2 agonists can be achieved which meet the defined requirements of the
present
invention in both selectivity and lipophilicity categories.
0
In some embodiments, dexmedetomidine, or another selective a-2 adrenergic
receptor agonist, has Log P at an intraocular pH 7.4 of about 3.10;
preferably, between
about 2.0 and 5.00; and more preferably between about 2.75 and 3.50
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-22-
As Log D refers to a lipophilicity value at a given pH, this measurement is
especially useful to determine the level of topical lipophilicity and
resultant corneal
permeability of a topical composition through the highly lipophilic corneal
epithelium.
Normally, higher Log P values, such as 3.0 or greater, are constrained by the
highly hydrophilic stroma, and therefore a compromise lipophilicity of 1.0 to
3.0 and
more preferably 1.5 to 2.5 is preferred for most ophthalmic topical drugs.
Corneal
permeability is a complex event, which may be affected by polar surface area,
H+ donor
activity, bond rotation, and active transport phenomenon.
It is a discovery of the present invention that the Log D values of between
about
0 0.75 and about 2.20, and more particularly between about 1.00 and
about 1.50, are
preferred for increased corneal permeation of dexmedetomidine and other
similar a-2
agonists in normal saline, preferably below the pH of 6.4 to 6.5, and that the
"vehicle" of
the present invention including poloxamer, viscosity enhancer and hypotonic
saline or
sterile water greatly reduces and likely totally eliminates such pH
limitations.
5
When the selective a-2 agonist is dexmedetomidine, the optimal Log D value
is
from 0.75 to 2.2, and more preferably is about 1.00 to 2.00 at a topical pH of
about 4.7
to 6Ø
Tonicity
For purposes of comfort topical delivery, ophthalmic drugs typically require
about
0 275 to 320 mOsm/kg tonicity. A variety of tonicity enhancers,
including but not limited to
electrolytes, particularly 0.9% NaCI, and polyols, such as mannitol, may be
used to
achieve the desired range.
It is a surprising discovery of the present invention that such comfort is
enhanced
when poloxamer at a concentration of about 3% or above is combined with a
viscosity
5 enhancer with no or reduced tonicity enhancement of about 25 ¨ 150
mOsm/kg, and
that poloxamer alone is highly irritating topically at a 3% or greater
concentration.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-23-
Solubility
The solubility of a-2 agonists decreases exponentially at an increased pH.
Table
2 illustrates the relationship between pH and solubility in water for
dexmedetomidine. It
shows that the soluble concentration of dexmedetomidine falls exponentially
with higher
pH. For pH of 4.0 ¨ 6.0 a very high degree of solubility exists.
TABLE 2
pH solution solubility (mg/ml) max soluble
concentration
6.0 1.953 0.195%
6.4 ¨0.60 0.060%
7.0 0.224 0.023%
7.4 ¨0.150 0.015%
8.0 0.134 0.013%
To achieve the greatest solubility while retaining the activity, the inventive
0 compositions should include a salt; a poloxamer at a concentration of 12%
weight by
volume or less; and a viscosity enhancer. For example, using the provided
compositions, dexmedetomidine is rendered soluble up to or beyond 0.15%.
Solubility for dexmedetomidine and other similar drugs in its subclass is
typically
reduced exponentially with increasing pH. For example, dexmedetomidine is only
5 soluble in physiologic saline to about 0.025% at a highly alkaline pH. It
is believed that
the inventive formulations result in enhancement of solubility of
dexmedetomidine, and
by extension other members of its subclass, well above the 0.125% at alkaline
pH.
It is believed the activity of the a-2 agonists, and dexmedetomidine in
particular,
in physiologic saline may be negatively affected by excipients of certain
hydrophilicity or
) polarity, including citrate, various viscosity enhancing agents such as
polyvinyl alcohol,
various buffers such as phosphate buffer, and various gelling agents such as
xanthan
gum.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-24-
Thus, it is inventive and not trivial that only a very limited number of
specific
combinations of the ingredients lead to a greater activity and stability, and
is therefore
unexpectedly superior to other similar formulations. This result was not at
all predictable
and is not likely to be due to simply gelling or enhancing viscosity: for
example, neither
Xanthan gum, Carbopol 954, nor carboxymethylcellulose alone or in combination
conferred the effectiveness equal to that of brimonidine.
It is therefore very unexpected and surprising that the ingredients of the
provided
formulations not only offer an improved efficacy compared to dexmedetomidine
formulations in physiologic saline, but also make the formulations superior to
0 brimonidine formulations. This is surprising because prior art comparisons
of
dexmedetomidine and brimonidine under similar conditions demonstrated
brimonidine
to be the preferred alpha 2 agonist. Such prior art testing demonstrated that
dexmedetomidine (and clonidine) resulted in less 10P reduction with greater
systemic
absorption than brimonidine. It is therefore surprising and unexpected that
under
5 specific and very limited formulation conditions, dexmedetomidine is more
effective than
prior art formulations of dexmedetomidine and more effective than brimonidine
by about
200% (IOP reduction vs. time, which is the key measure of the effectiveness of
10P
reduction).
Other agents that improve solubility which may be used for the purposes of the
0 present invention (as long as a salt, a poloxamer and a viscosity
enhancers are
included in the compositions) include, but are not limited to, polyanionic
(multiple
negatively charged) compounds, such as methylcellulose and derivatives,
particularly
carboxymethyl cellulose (CMC) or other cellulose derivatives; hypotonic
saline; sodium
acetate, calcium salt, methanesulfonate (mesylate), hydrobromide/bromide,
acetate,
5 fumarate, sulfate/bisulfate, succinate, citrate, phosphate, maleate,
nitrate, tartrate,
benzoate, carbonate, pamoate, borate, glycolate, pivylate, sodium citrate
monohydrate,
sodium citrate trihydrate, sodium carbonate, sodium ethylenediaminetetraacetic
acid
(EDTA), phosphoric acid, pentasodium pentetate, tetrasodium etidronate,
tetrasodium
pyrophosphate, diammonium ethylenediamine triacetate, hydroxyethyl-
ethylenediamine
triacetic acid, diethylenetriamine pentaacetic acid, nitriloacetic acid, and
various other
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-25-
alkaline buffering salts, and/or addition of cyclodextrins and/or their
derivatives,
particularly (2-Hydroxypropy1)--beta-cyclodextrin, certain solvents such as
Tween0 20,
Tween 80, polyvinyl alcohol, propylene glycol and analogues or derivatives
thereof;
certain osmotic agents, such as mannitol or sucrose,
hydroxypropylmethylcellulose
(HPMC) or analogues and/or derivatives thereof, or certain chelating agents.
In some preferred embodiments, the composition includes sodium citrate
dehydrate at about 0.17%, and/or sodium acetate at about 0.39%; and/or calcium
salt at
about 0.048%.
0 Compositions and Methods of the Present Invention
Compositions and methods of the inventions encompass all isomeric forms of the
described a-2 adrenergic receptor agonists, their racemic mixtures, enol
forms, solvated
and unsolvated forms, analogs, prodrugs, derivatives, including but not
limited to esters
and ethers, and pharmaceutically acceptable salts, including acid addition
salts.
5 Examples of suitable acids for salt formation are hydrochloric, sulfuric,
phosphoric,
acetic, citric, oxalic, malonic, salicylic, malic, furmaric, succinic,
ascorbic, maleic,
methanesulfonic, tartaric, and other mineral carboxylic acids well known to
those in the
art. The salts may be prepared by contacting the free base form with a
sufficient
amount of the desired acid to produce a salt in the conventional manner. The
free base
0 forms may be regenerated by treating the salt with a suitable dilute
aqueous base
solution such as dilute aqueous hydroxide potassium carbonate, ammonia, and
sodium
bicarbonate. The free base forms differ from their respective salt forms
somewhat in
certain physical properties, such as solubility in polar solvents, but the
acid salts are
equivalent to their respective free base forms for purposes of the invention.
(See, for
5 example S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sc., 66: 1-
19 (1977)
which is incorporated herein by reference).
As long as a particular isomer, salt, analog, prodrug or other derivative of a
suitable selective a-2 adrenergic receptor agonist functions as a suitable
selective a-2
agonist, it may be used for the purposes of the present invention.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-26-
In some embodiments, compositions and methods of the invention include
selective a-2 adrenergic receptor agonists which have binding affinities (K1)
for a-2 over
a-1 receptors of 1000 fold or greater and are highly lipophilic, having an
octanol-water
partition coefficient of about 2.00 or greater. Brimonidine, by comparison,
has a binding
affinity for a-2 over a-1 receptors of about 976 and its lipophilicity range,
even when
optimized by pH, is about three hundred fold less than that of
dexmedetomidine, a
preferred embodiment.
In yet other embodiments, compositions and methods of the invention include
selective a-2 adrenergic receptor agonists which have Ki for a-2 over a-1
receptors of
0 1000 fold or greater and are at a concentration from between about
0.001% to about
0.035% weight by volume.
In some embodiments, compositions and methods of the invention include
selective a-2 adrenergic receptor agonists which have Ki for a-2 over a-1
receptors of
1500 fold or greater, are present at a concentration from between about 0.010%
to
5 about 0.040% weight by volume, and have pH of about 6.2 or less.
In some embodiments, the compositions of the invention may also include other
therapeutic agents; however, the compositions are intended to be effective
without the
need for any other therapeutic agents, specifically including, but not limited
to, a-1
antagonists.
0
The invention also provides methods of treating and/or preventing glaucoma
with
the provided compositions. The provided methods lower 10P in glaucoma
patients,
reduce redness, and provide eye whitening. The provided methods may also treat
ischemic optic neuropathy and other neuropathies of various etiologies due to
neuroprotective effects of the provided compositions.
5
The compositions of the present invention are preferably formulated for a
mammal, and more preferably, for a human. In one embodiment of the invention,
the
compositions are delivered as ophthalmic solutions into the eyes. The
invention also
contemplates topical compositions which include, but are not limited to, gels
and
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-27-
creams. They may also include additional non-therapeutic components, which
include,
but are not limited to, preservatives, delivery vehicles, tonicity adjustors,
buffers, pH
adjustors, antioxidants, tenacity adjusting agents, mucoadhesive agents,
viscosity
adjusting agents, and water.
To make the topical compositions of the present invention, one can simply
dilute
more concentrated solutions of selective a-2 agonists, using methods known in
the art
with diluent of particular gelling agents in solution, being in a preferred
embodiment
Poloxamer 407, Poloxamer 188, or a combination thereof. In addition, the
inventive
formulations may optionally include one or more of electrolytes or tonicity
enhancing
0 agents, and preferably one or more of the weak acids and/or their
salts to achieve a
formulated pH of 4.0 to 8.0, and more preferably 5.5 ¨ 6.5.
One preferred method of carrying out the dilutions involves overnight
refrigeration, solubilizing both the active drug and the other excipients.
This is a well
known technique for solubilizing drugs for use with poloxamers. However, other
5 methods can also be used. The compositions of the invention may
include various
inactive ingredients commonly used in formulating topical compositions and
that may
improve stability of the formulation. For example, the compositions of the
invention may
include alcohols and/or surface active agents, including but not limited to
polyglycol
ether, polyethylene glycol-nonphenol ether, polyethylene glycol sorbitan
monolaurate,
0 polyethylene glycol sorbitan monooleate, polyethylene glycol
sorbitanmonooleate,
polyethylene glycol sterarate, polyethylene glycol polypropylene glycol ether,
polyvinyl
alcohol, polyvinyl pyrrolidine, PEG and its derivatives, including but not
limited to PEG
4000 or PEG 6000, in a total amount of 0.05% to 5% by mass of the composition.
In some embodiments, the compositions of the invention may include acids or
5 monoglycerides of fatty acids having 8 to 12 carbon atoms, which when
in 0.5 ¨ 1.5 M,
and preferably equimolar concentration to the alpha 2 agonist may improve
corneal
permeation via ion pair formation; or antioxidants such as ion-
exchange/photooxidation
stabilizing agents, including but not limited to citric acid, sorbic acid,
boric acid, caprylic
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-28-
acid, glyceryl monocaprylate, glyceryl monocaproate, glycerol monolaurate,
sodium
metabisulfite.
In some embodiments, the compositions and methods of the present invention
may include chelating agents that further improve stability, including but not
limited to
ethylenediaminetetraacetic acid (EDTA) and structurally related acids and even
more
preferably citric acid or its salt. In some embodiments, the chelating agents
are present
at a concentration of between 0.005% and 0.2% weight/vol.
Preservatives include, but are not limited to, benzalkonium chloride (BAK),
methylparaben, polypropylparaben, chlorobutanol, thimerosal, phenylmercuric
acetate,
0 perborate, or phenylmercuric nitrate. BAK, in particular, has been found
to be effective
with preferred embodiments.
Delivery vehicles include, but are not limited to, polyvinyl alcohol,
polyethyleneglycol (PEG) and its analogues, povidone, hydroxypropyl methyl
cellulose,
poloxamers, carboxymethyl cellulose (CMC), hydroxyethyl cellulose and purified
water.
5 It is also possible to use a physiological saline solution as a major
vehicle.
Tonicity adjustors include, but are not limited to, a salt such as sodium
chloride,
potassium chloride, dextran, cyclodextrins, mannitol, dextrose, glycerin, or
another
pharmaceutically or ophthalmically acceptable tonicity adjustor. In some
embodiments,
the tonicity modifying agents are present at a concentration of between 0.1%
and 1%
0 weight by volume.
The compositions of the present invention may comprise corneal permeation
enhancing agents which include, but are not limited to, preservatives,
cyclodextrins,
viscosity enhancers, and ion-channel enhancing agents. In some embodiments,
corneal
permeation enhancing agents include citrate, a citrate salt and/or other salts
which
5 increase solubility, chelating agents such as EDTA, preservatives, ion-
channeling
agents, cyclodextrin, or other additives which increase corneal permeability.
In some embodiments of the invention, a corneal permeation enhancing agent
may be selected from the group consisting of BAK at 0.01% to 0.02% weight by
volume,
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-29-
EDTA at 0.005% weight by volume, caprylic acid, citric acid, boric acid,
sorbic acid
and/or salts, derivatives, and analogues thereof, where citric acid or its
salt is a
preferred embodiment.
In some embodiments, the compositions and methods of the present invention
may include additional viscosity enhancers and/or agents increasing solubility
and/or
stability, including but not limited to polyvinylpyrrolidone, polyethylene
glycol (PEG),
cellulose or cellulose derivatives of various molecular weights, including
methylcellulose, cellulose glycolate, hydroxypropylcellulose, CMC and its
salts, gelatin,
sorbitol, alpha-cyclodextrin and/or other cyclodextrin derivatives,
niacinamide,
o carbomers of various molecular weights including carbomer 934 P and 974
P, xanthan
gums, alginic acid, guar gums, locust bean gum, chitosan, propylene glycol,
polyvinyl
alcohol, polysorbate including polysorbate 80, glycerin, mannitol, benzyl
alcohol,
phenylethyl alcohol, povidone, borate, acetate, phosphate or other similar
buffering salts
or agents, BAK, methyl paraben, sodium bisulfite, or peroxide preservative
systems,
5 surfactants, etc. In some embodiments, these agents are present at a
total amount of
0.05% to 5% by w/v.
Many of the listed additives (for example, BAK, EDTA, etc) may serve more than
one purpose: for example, they can serve as both preservatives and corneal
permeation
enhancing agents (e.g. BAK), or solubilizing, preservative, and corneal
permeation
0 enhancing agents (e.g. citrate).
Buffers and pH adjustors include, but are not limited to, acetate buffers,
carbonate buffers, citrate buffers, phosphate buffers and borate buffers. It
is understood
that various acids or bases can be used to adjust the pH of the composition as
needed.
pH adjusting agents include, but are not limited to, sodium hydroxide and
hydrochloric
5 acid. Antioxidants include, but are not limited to, sodium metabisulfite,
sodium
thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated
hydroxytoluene.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-30-
Use of Provided Formulations as Vehicles For Drug Delivery
Dryness is a common problem with topical use of alpha 2 agonists for glaucoma
as well as many other topical eye medications. For example, more than 10% of
brimonidine users complain of dryness. The formulations of the present
invention were
tested as a vehicle without the active agent (dexmedetomidine) after
substantial wetting
and comfort was observed with its use.
Thus, in one embodiment, the invention provides a vehicle formulation for drug
delivery, wherein said vehicle formulation comprises a poloxamer, hypotonic
saline, and
a viscosity enhancer, at the same concentrations and ranges as previously
recited.
0
The provided vehicle formulations may intraocularaly deliver
dexmedetomidine
and other drugs, particularly lipophilic drugs, with improved efficacy and
reduced
systemic absorption. The drugs which can be delivered with vehicle
formulations of the
present invention include Ketoralac0 and other non-steroidal agents,
prednisone and
other steroidal agents, latanaprost and other prostaglandins, prostanoids and
other
5 prostaglandin analogues, a-1 antagonists such as phentolamine, anti-
viral drugs, anti-
microbial drugs, anti-fungal drugs, anti-VEGF drugs, and/or other drugs.
These vehicle formulations dramatically enhanced the comfort and wetting
effect
after application. Wetting was appreciably improved with extended tear breakup
times
for up to about 55 minutes after application, and with initial blurring of
vision resolving
0 after only about 15-40 seconds. These effects allowed for a more
prolonged duration in
which eyes could be kept open for several seconds longer between blinks (up
until
about 55 minutes after instillation (a measure of improved tear "wetability"
of the cornea.
In contrast, the longest duration artificial tear gels currently available,
such as
Celluvisc , which provides similar improved tear breakup time up to about 60
minutes
5 after instillaiton, causes significant blurring for about 5 to 10
minutes after instillation,
reducing the effectiveness of prior art formulations vs. the vehicle of the
present
invention as both an artificial tear and as a possible vehicle for ophthalmic
drug delivery.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-31-
Thus, in one embodiment, the invention provides an artificial tear solution
comprising:
i. a hypotonic salt or sterile water;
a poloxamer at a concentration of 12% weight by volume or less; and
iii. a viscosity enhancer, and
wherein said pharmaceutical solution has a viscosity of between 25 and 500
cps.
The following Examples are provided solely for illustrative purposes and are
not
0 meant to limit the invention in any way.
EXAMPLE 1
Intraocular Pressure (10P), Redness and Burnino/Stinqina
5 Experimental Design
Various formulations of a-2 agonists were unilaterally administered to a
normotensive (<21 mm Hg) human subject. The subject first underwent baseline
10P
testing using standard applanation tonometry via slit lamp. After fluorescein
instillation,
the drug was instilled as a morning dose at between about 7:00 and 9:00 AM.
0 Preliminary measurements at 2, 3, 3.5, 4 and 4.5 hours demonstrated a
substantial
peak effect between about 3.45 and 4.15 hours for a preferred formulation of
the
invention. Follow up 10P checks were designed to be about 4 hours after
initial
instillation, where instillation consisted of 1-2 drops.
5 Experimental Results
The comparative human studies of: a) a preferred embodiment of the present
invention versus; b) a dexmedetomidine formulation without poloxamer; and c)
brimonidine demonstrate significant therapeutic advantages of the inventive
composition over prior art.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-32-
In particular, testing of prior art formulations of dexmedetomidine (in
phosphate
buffer 6.4) and brimonidine (Alphagan Pe) were consistent with published data
showing
30-35% 10P reduction in normotensive rabbits (equivalent to about 20%
reduction in
normotensive human eyes which have thicker corneas and less intraocular
penetration).
In contrast, the present invention demonstrates a surprising increase in 10P
reduction,
peaking at about 4 hours (versus, 2 hours for brimonidine), nearly two-fold
greater 10P
reduction versus brimonidine, greater topical comfort, greater redness
reduction,
reduced topical side effects, and reduced systemic side effects.
Table 3 demonstrates the results of this experiment.
0
TABLE 3
Dru lop Reduction @ 4
Induced Redness Burning ¨ Stinging
g
hrs post instillation on
instillation
Brimonidine 0.20% (prior 20% 25% incidence >10%
incidence
art formulation)
Dexmedetomidine
0.10% in phosphate
buffer pH 6.4; BAK
0.02% (Prior art 20% Whitens None
formulation)
Dexmedetomidine
0.10% in poloxamer gel
5-6%; CMC high blend
0.72%; 0.25% saline; 40% Whitens None,
prolonged
BAK 0.02%, pH 5.5 ¨
lubricating action of
6.0 about 55
minutes
(Preferred embodiment)
Tables 4-8 summarize studies of various formulations and excipients with
5 dexmedetomidine. In particular, Table 4 demonstrates that there are
significant side
effects, such as sedation, when dexmedetomidine concentration is at or greater
than
about 0.02%, Table 5 demonstrates substantial and surprising improvements over
Table 4 and prior art studies with the preferred embodiment of
dexmedetomidine.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-33-
TABLE 4
Poloxamer, Normal Saline
Formulations
Components __________ 1 2 3 4 5 6 7
Dexmedetomidine 0.02%
0.02% 0.05% 0.05% 0.05% 0.05% 0.07%
CMC high viscosity
blend - - - - - - -
NaC1 0.90%
0.90% 0.90% 0.90% 0.90% 0.90% 0.90%
Poloxamer 407 - - - - 2-3% - -
Poloxamer 407 * - - - - - 2-3% -
Xanthan Gum - - - - - - -
BAK 0.01%
0.01% 0.01% 0.01% 0.01% 0.01% 0.01%
EDTA - - - - - - -
PVA - - - - - - -
PVP - - - - - - _ -
citric acid - - - - - -
4.5 -
pH 7 4.5-5.2 5.2 7.0-7.5 4.5-5.5 4.5-5.5 4.5-5.5
Effects
Peak IOP reduction 18% 20% 22% 20%
20-22% 20-22% 25%
Side effects (0-4)
Bradycardia 0 0 1 1 1 1 2.5
Stinging 0 1 1 1 1 1 1
Dry Mouth 0 0 2 2 2 2 2.5
Sedation 0 0.5 1.5 1.5 1.5 1.5 2
Rate ("-" bad,
"+++++" best) - +- - - - - - - - -
* different source
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-34-
TABLE 5
CMC, Poloxamer, Normal Saline
Formulations
Components 8 9 10 11 12 13 14
Dexmedetomidine
0.07% 0.07% 0.07% 0.07% 0.07% 0.07% 0.07%
CMC high viscosity
blend 0.50% 0.92% 0.62%
0.92% 0.62% 0.62%
NaCI
0.90% 0.90% 0.90% 0.90% 0.90% 0.90% 0.25%
Poloxamer 407 - - -
Poloxamer 407 * - - - 2-3% 2-3% 2-3% 2-
3%
Xanthan Gum - - -
BAK
0.01% 0.01% 0.02% 0.02% 0.02% 0.02% 0.02%
EDTA - - - -
PVA- - - - - - -
PVP - - - - - - -
citric acid
pH 4.5-
5.5 4.5-5.5 4.5-5.5 4.5-5.5 4.5-5.5 4.5-5.5 4.5-5.5
Effects
Peak TOP reduction 20-
22% 20-25% 25-30% 25-30% 25-30% 25-30% 25-30%
Side effects (0-4)
Bradycardia 1 0 0 2 0 0 0
Stinging 1 1 1 1 1 1 1
Dry Mouth 2 0 1 1 0 1 I
Sedation I 0 0 0 0 0 0
Rate ("-" bad,
"+++++" best) + + + ++ + ++ +++
* phosphate buffered
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-35-
TABLE 6
Poloxamer, CMC, Hypotonic NaCI, pH
Formulations
Components 15 16 16A 16b 16b2 17 18
19
Dexmedetomidine 0.075% 0.07% 0.085% 0.100% 0.100% 0.07% 0.07% 0.07%
CMC high viscosity
blend -
0.62% 0.62% 0.62% 0.75% 0.62% 0.62% 0.62%
NaC1
0.90% 0.25% 0.23% 0.2.3% 0.23% 0.23% 0.23% 0.23%
Poloxamer 407
Poloxamer 407 * 5% 5-6% 5-6%
5-6% 5-6% 5-6% 5-6% 5-6%
Xanthan Gum
BAK
0.02% 0.02% 0.02% 0.02% 0.02% 0.02% 0.02% 0.02%
EDTA
PVA
- 0.30% - 0.30%
PVP -
0.30% 0.30%
citric acid
4.5 - 4.5 - 4.5 -
4.5 -
pH 5.5 4.5 4.5 4.5 5.5-7.0 5.5 5.5
5.5
Effects
Peak TOP reduction 30% 40% 40% 40% 40% 40% 35% 35%
Side effects (0-4)
Bradycardia 0 0 0 0.5 0.5 0 0
0
Stinging 2 0.5 0.5 0.5 0 0.5 0.5
0.5
Dry Mouth 1.5 0.5 0.5 0.5 0.5 0.5 0.5
0.5
Sedation 0 0 0 1 0-1* 0 0
0
"+++++" best) +++1/2 +++1/2 +++1/2 ++++ ++++1/2 +++ +++
+++
* alternate source
** 0 with 30 sec punctal occlusion
TABLE 7
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-36-
Other Viscosity Enhancers, Xanthan Gums, Poloxamer, pH
Formulations
20 21 22 23 24
Components
Dexmedetomidine 0.07% 0.075% 0.075% 0.075%
0.075%
CMC high viscosity blend - - - - -
NaC1 <0.25% 0.50% 0.50% 0.50%
0.50%
Poloxamer 407 - - - - -
Poloxamer 407 * 5-6% - - -
-
Xanthan Gum- 0.100% 0.100% 0.120%
0.120%
BAK 0.01% 0.01% 0.01% 0.01%
0.01%
EDTA 0.01% - _ 0.01%
0.01%
PVA 0.30% - - - -
,
PVP 0.30% - - -
-
citric acid 0.03%- -
, - -
pH 7.0-7.5 4.5 5.2 4.5
5.2
Effects
IOP ,peak 20-25% 15% 20% 25%
25%
Side effects (0-4)
Bradycardia 1 1 1 1
1
Stinging 0-1 0-1 0-1 0-1
0-1
Dry Mouth 1.5x 0 0 0
0
Sedation
Rate ("-" bad, "+++++"
best) +IA 1/2 1/2 V2
1/2
* phosphate buffered
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-37-
TABLE 8
Xanthan Gums, NaCI, Polysorbate 80
Formulations
Components 25 26 27 28 29 30 31 32
Dexmedetomidine 0.100% 0.100% 0.120% 0.120% 0.120% 0.120% 0.150% 0.150%
Xanthan Gum **
0.075% 0.075% 0.085% 0.085% 0.100% 0.100% 0.100% 0.100%
NaC1
0.250% 0.250% 0.250% 0.250% 0.250% 0.250% 0.250% 0.250%
Polysorbate 80
0.050% 0.050% 0.050% 0.050% 0.050% 0.050% 0.050% 0.050%
BAK
0.010% 0.010% 0.010% 0.010% 0.010% 0.010% 0.010% 0.010%
mannitol
EDTA
- 0.01% 0.01% 0.01% 0.01%
citric acid
pH 5.2 4.5 5.2 4.5 5.2 4.5 4.5
4.5
Effects
20% 18% 25% 22% 28% 25% 25% 25%
10P Reduction
Sedation 2.00 2.00 2.50 2.50 2.75 2.75 2.75
2.75
Rate ("-" bad,
"+++++" best)
As Tables 4-8 demonstrate, the most effective compositions with lowest side
effect profile are those which contain poloxamer at about 5-6%, CMC, sodium
chloride
and BAK. The peak dose response 10P reduction for preferred embodiments of the
present invention appeared to be between about 0.070% - 0.10%.
EXAMPLE 3
Effect of Topical Administration of Dexmedetomidine at on Cosmetic Appearance
of the
0 Eyes
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-38-
Experimental Design
The purpose of this experiment was to evaluate effect of dexmedetomidine on
cosmetic appearance (i.e., whiteness) of the treated eyes at concentrations of
0.010%;
0.022%: 0.050%; and 0.10% within a pH range of 4.5 ¨ 6Ø The tested
dexmedetomidine solution contained poloxamer at 6%; NaCI at 0.25%; CMC high
blend
at 0.50-0.75%; and BAK at 0.02%. The experiment was designed as follows:
1-2 drops of dexmedetomidine were topically applied to one eye of an
individual.
Eye whiteness prior to and after the application was visually measured by the
patient on
a scale of 0 (white eye, no hyperemia) to 4 (significantly reddened eye,
strong
0 hyperemia), with measurements taken at about 30 min to 3 hours after
instillation.
Experimental Results
TABLE 9
Dexmedetomidine Redness Eye White Shade
Concentration
-- -
Baseline 1.5 1
0.010% 1.25 1
0.022% 1.25 1.25
0.050% 1.0 1.5
0.075% 1.0 1.5
0.10% 0.75 1.75
*Poloxamer 6%; NaCl 0.25; CMC Hi blend 0.50-0.75%; BAK 0.02%
5
Conventional Redness Scale: 0 (none) - 4
(reddest + chemosis),
Eye White Shade: 4 (whitest)- 1
off-white-gray/yellow
The decrease in hyperemia and increase in whiteness started about 2 minutes
0 after the application. The maximum whiteness was reached in about 10
minutes, with a
gradual and slow decline over a period of several hours thereafter. The total
duration of
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-39-
the effect both in terms of reduced hyperemia and increase in whiteness was
about 3-5
hours. Although the effect both in terms of decreased redness and whitening
was
modest, it was nevertheless noticeable and cosmetically beneficial to the
subject,
particularly at dexmedetomidine concentrations of 0.050% and above.
The experiment has demonstrated that dexmedetomidine at 0.010% provides
noticeable hyperemia reduction and 0.050% and above effects modest but
noticeable
cosmetic improvement via eye whitening.
EXAMPLE 4
0 Effects on Intraocular Pressure (10P) and Side Effects
Experimental Design
First, baseline 10P measurements were performed on a subject using
applanation slit lamp tonometry following instillation of fluorescein. Then,
two drops of
the topical agent to be tested were applied seconds apart to the left eye, and
the
5 punctum occluded for 30 seconds. Approximately four hours later, lOP
testing was
again performed. Three initial readings were taken and discarded to ensure
minimal
patient blepharospasm, following which the next three readings were recorded
and
averaged. There was a washout period of several days ¨ 1 week between tests.
All
baseline 10P measurements were between 15.0¨ 15.5 mm Hg at 8:00 AM ¨ 9:00 AM
at
0 the time of instillation.
Side effects were qualitatively graded from 0-4 (0 ¨ no side effects; 4- high
degree of side effects (stinging on instillation, eye dryness, pharyngeal
dryness, fatigue,
sedation)) for the two tested dexmedetomidine formulations.
5 Experimental Results
The comparative human studies of: a) a preferred embodiment of the present
invention versus; b) a dexmedetomidine formulation at 0.10% in a buffered
phosphate
at pH 6.4-6.5 without poloxamer; and c) brimonidine, demonstrated significant
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-40-
therapeutic advantages of the inventive composition over prior aft
formulations of
brimonidine or dexmedetomidine.
The present invention demonstrates a surprising increase in lop reduction,
nearly two-fold greater lOP reduction versus brimonidine, greater topical
comfort,
greater redness reduction, reduced topical side effects, and reduced systemic
side
effects.
Table 10 demonstrates the results of this experiment.
TABLE 10
Drug 10P 10P%.1 Pharynx Stinging Redness Eye Comfort
Sedation
# Dryness Dryness
Alphagan 11.7 23.3% 10-30%* 10-30%* 10-30%* 3-9%* 2 of 4
10-30%*
Dexmedetomidine 12.0 21.4% 2 of 4 0 of 4 0 of 4 0 of 4 3 of 4
2 of 4
0.10% w
phosphate buffer
Preferred 9.2 39.6% 0.5 of 4 0 of 4 0 of 4 0 of 4 4 of 4
0 of 4
Embodiment**
*Published data
**Dexmedetomidine 0.10%, Poloxamer gel 5-6%. CMC high blend 0.75%. BAK 0.02%,
pH
6.0
0
This experiment demonstrated that the provided inventive compositions result
in
a substantially greater therapeutic benefit than prior art formulations of
brimonidine or
dexmedetomidine with improved systemic and topical side effect profile.
5 EXAMPLE 5
Effect of Carbopol 954 and Poloxamer 407 on dexmedetomidine, with and without
Viscosity Agent Enhancement, with and without NaCl
Experimental Design
The goal of this experiment was to investigate the effects of adding Carbopol
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-41-
954 (C) and Poloxamer 407 (P) (both separately and in combination) on the
effectiveness of topical dexmedetomidine at 0.025% weight by volume in normal
saline.
The concentrations of CarbopolO 954P and Poloxamer 407 ranged from 1% to 8%.
Experimental Results
Table 11 demonstrates the results of this experiment.
TABLE 11
Formulation pH Stinging 0-4 Color IOP Effect
Observation
C I% 4.5 ¨6.5 1-2 + Turbid <= prior art Cloudy
solution
C 2% - 5% 4.5 ¨ 6.5 Too thick at
all pH
levels tested
P 1-2% 4.5 ¨6.5 1 + Clear <= prior art
P 4%-6% 4.5 ¨ 6.5 2+ Clear Not tested Hi
pharyngeal
dryness, sedation
risk
P 8% 4.5 ¨ 6.5 4+ Clear Not tested Poorly
tolerated
P2% + C 1% 4.5 ¨ 6.5 1.5 + Turbid Not tested
Uncomfortable
P l-10%+ high 4.5 ¨ 6.5 1 + Clear >25%
Moderately
blend CMC
uncomfortable.
0.25% Mod ¨ hi
pharyngeal dryness
P 1-10% + high 4.5 ¨7.0 0 ¨ 0.25 Clear >30% with Great
comfort,
blend CMC 0.50- (slight,transient high of 40% at barely
noticeable
0.75% + Nacl <=15 seconds) 5-6% no pH pharyngeal
dryness
0.025% effect
P 1-10% + high 6.5 0-0.25 Clear Not tested Tear
break up time
blend CMC 0.50- (slight,transient improvement
30 ¨
0.75% + Nacl 55 minutes;
initial
<=15 seconds)
0.025% w/o blurring 30-
60
dexmedetomidine seconds.
C: Carbomer 934P
P: Poloxamer 407
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-42-
As Table 14 demonstrates, neither Poloxamer 407 alone nor Carbomer 934P
alone provided satisfactory topical comfort for human use. However, a
combination of
specific concentrations of Poloxamer 407 and a viscosity agent (such as CMC)
provided
improved comfort and 10P reduction. There was an additional comfort and even
stronger !OP reduction effect at more hypotonic solutions.
In particular, a combination of Poloxamer 1-10%, a viscosity agent and reduced
salinity provided excellent comfort. The best formulation contained Poloxamer
5-6% +
high blend CMC 0.62-0.75% + NaCI 0.025%. It provided best comfort, lop effect
treated
eye and least local-systemic effect (pharyngeal dryness).
0 EXAMPLE 6
Comparison of Treated and Non-Treated Eye lntraocular Pressure With
Brimonidine
0.20%, Dexmedetomidine 0.010% in phosphate buffered saline vs. Dexmedetomidine
Preferred Embodiment*
5 Experimental Design
The following formulations were compared:
a) brimonidine (Alphagan P) (Composition B)
b) dexmedetomidine at 0.01%, phosphate buffered to pH 6.4 (Composition C);
and
c) dexmedetomidine at 0.1% with 5% Poloxamer 407 (F127), 0.25% NaCl, CMC
high blend 0.75%, and BAK 0.02% at pH 6.1 (Composition A) (preferred
embodiment).
Two drops of each of the tested formulations were placed in the left eye of a
subject without punctual occlusion on separate days with a washout (break)
(between
5 several days to a week) between the administrations.
Intraocular pressure
measurements were taken 2.5 and 3.75 hours later in both the treated and non-
treated
eye.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-43-
Experimental Results
Table 12 demonstrates the results of this experiment.
TABLE 12
MP %
Non
IOP KW 2.5 KW 4 Baseline 101) 2.5 IOP 4
Treated Eye
Baseline hours hours (Non- Hours Hours
to Treated
(Non - Eye
(IOP
(Treated (Treated (Treated Treated (Non -
Drug
Eye) Eye) Eye) Eye) Treated TreatedMax
Eye) Eye)
mm Hg mm Hg mm Hg mm Hg
Reduction)
mm Hg mm Hg
mm Hg
9.3 14 14
Composition A (33% (40% 15.5 (6.6% (6.6%
16.5%
reduction) reduction) reduction) reduction)
12 12.5 14 14
Composition B (20% (16.6% 15 (6.6% (6.6% 33%
reduction) reduction) reduction) reduction)
12 12 12.5 13
15 15
Composition C (20% (20% (16.6% (13.4% 83%
reduction) reduction) reduction) reduction)
5 As Table 12 demonstrates, this experiment showed the following:
1) two-fold greater 10P peak % reduction in the treated eye with the inventive
formulation (Composition A) vs. brimonidine (Composition B);
2) two-fold less 10P % reduction in the non-treated eye with the inventive
formulation
(Composition A) vs. brimonidine (Composition B);
0 3) two-fold greater lOP reduction in the treated eye after 4 hours with
the inventive
formulation (Composition A) vs. alternative dexmedetomidine formulation
(Composition
C); and
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-44-
4) Longer duration of action to peak 10P reduction for the inventive
formulation
(Composition A) increasing from 2.5 hours to 4 hours vs. brimonidine
(Composition B).
These results demonstrate improved efficacy and systemic absorption reduction
of the inventive compositions as compared with similar dexmedetomidine
compositions
and conventional brimonidine compositions.
A greater differential of 10P reduction between treated and non-treated eye
using
the inventive compositions represents a lower systemic side effect profile as
it is
interpreted to correlate with reduced systemic absorption of drug reaching the
non-
treated eye.
0
EXAMPLE 7
Effect of Composition A on !OP vs. baseline over a 24 hour period
Experimental Design
Three subjects with normo-tensive baseline 10P (<21 mm Hg) were treated with
5 a single instillation of two drops of the composition A (as described in
Example 6) per
eye at 8:30 AM, followed by 30 seconds of punctual occlusion with application
on days
1, 3, and 5.
10P was measured at one or more of 4 hrs, 8 hrs, 12 hrs, 24 hrs, 32 hrs and
comfort and side effect profile were qualitatively assessed.
0 Experimental Results
Table 13 demonstrates the results of this experiment.
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-45-
TABLE 13
PATIENT NO. 1
Day right eye left eye
Time IOP mm Hg Reduction in
Reduction
mean % I 0 P in % IOP
8 am 17 Baseline 17 Baseline
1
am 15 11.8% 15 11.8%
12 pm 7 58.8% 8 52.9%
4 pm 7 58.8% 8 52.9%
8 am 12 29.4% 12 29.4%
2
4 pm 15 11.8% 16 5.9%
8 am 15 Baseline 16 Baseline
5
4 pm 9 40.0% 9 43.8%
TABLE 13 (continued)
PATIENT NO. 2
Day right eye left eye
Time IOP mm Hg Reduction in Reduction
mean % lop in % IOP
8 am 14 Baseline 12 Baseline
1
10 am 11 21.4% 10 16.7%
12 pm 9 35.7% 9 25.0%
4 pm 8 42.9% 9 25.0%
8 am 9 35.7% 10 16.7%
2
4 pm 13 7.1% 13 N/A
8 am 16 Baseline 16 Baseline
5
4 pm 11 12
CA 02863760 2014-08-04
WO 2013/115844
PCT/US2012/050786
-46-
TABLE 13 (continued)
PATIENT NO. 3
Day right eye left eye
Time IOP mm Hg Reduction in Reduction
mean % IOP in 'A tOP
8 am 12 Baseline 12 Baseline
1
am 10 16.7% 10 16.7%
12 pm N/A N/A
4 pm 7 41.7% 8 33.3%
8 am 12 0% 12 0%
2
4 pm 12 0% 11 8.3%
8 am 11 Baseline 11 Baseline
5
4 pm 7 36.4% 8 27.3%
As Table 13 demonstrates, the tested inventive formulation achieved a peak 10P
reduction effect at about 4 to 8 hours after instillation. Furthermore, in two
out of three
5 patients the 10P remained below the baseline 24 hours after instillation.
Typically,
conventional brimonidine formulations achieve a peak 10P reduction effect of
only about
15-18% in normotensive eyes about 2-3 hours after instillation. The 10P
reduction effect
of the inventive formulation was much stronger: from 41.7% to 58.8% at 8 hours
after
instillation.
0 Therefore, the formulations of the invention demonstrate improved
performance
over brimonidine as well as other known glaucoma drugs under similar
conditions of
testing (1-2 days of use, normotensive eyes).
No significant local or systemic side effects were observed.
