Note: Descriptions are shown in the official language in which they were submitted.
CA 02368242 2001-08-07
WO 00/54810 PCT/US99/05423
1
COMBINATION THERAPY FOR
TREATING GLAUCOMA
s The present invention relates generally to the field of ophthalmology. In
particular,
the invention relates to the treatment of glaucoma using a combination of a
glutamate
antagonist to preserve visual field and an intraocular pressure lowering
compound.
to Background of the Invention
Although the underlying causes of glaucoma are not well understood at this
time,
glaucoma is characterized by damage to the optic nerve, accompanied by a
decrease in the
normal visual field. One early warning sign of possible glaucomatous visual
field loss is
is elevated intraocular pressure ("IOP"). In fact, glaucoma has historically
been treated by
medically and /or surgically lowering elevated IOP, for example, by the
administration of
IOP-lowering agents such as miotics, oc and a,/(3 adrenergic agonists, beta-
blockers, and
carbonic anhydrase inhibitors. However, factors other than IOP may play a role
in the
occurrence of visual field loss. Degeneration of retinal ganglion cells may be
related to
2o ischemia or mechanical distortion of the nerve fibers as they exit through
the optic nerve head
or from pathological perturbations of the retina.
There has been a growing interest in retinal dysfunction as a contributor to
the
glaucomatous process. Retinal dysfunction, and hence pathology, may be related
to ischemia
2s or excitotoxicity. Excitotoxicity is neuronal injury due to excessive
excitatory amino acid
("EAA") stimulation. In the inner retina, glutamate is the major EAA that
permits the bipolar
and amacrine cells to communicate with the ganglion cell. In the central
nervous system,
excitotoxicity results from hypoxia, ischemia, hypoglycemia or trauma. (See,
for example,
Beal, M.F., "Mechanisms of excitotoxicity in neurologic diseases," FASEB J.,
6:3338-3344
so (1992); and Choi, D.W., "Excitotoxic cell death," J. Neurobiol., 23:1261-
1276 (1992).)
Toxicity to the inner retina has been observed following intravitreal
injection of EAAs
following application of EAAs to the isolated animal retina or from
exogenously applied
glutamate to retinal ganglion cells in culture. See generally, Sattayasai, et
al., "Morphology
of quisqualate-induced neurotoxicity in the chicken retina," Invest.
Ophthalmol Vis Sci ,
ss 28:106-117 (1987); Tung et al., "A quantitative analysis of the effects of
excitatory
neurotoxins on retinal ganglion cells in the chick, Visual Neurosci., 4:217-
223 (1990); Sisk et
al., "Histological changes in the inner retina of albino rats following
intravitreal injection of
CA 02368242 2001-08-07
WO 00/54810 PCT/US99/05423
2
monosodium L-glutamate," Graefe's Arch. Clin Exp Ophthalmol , 223:250-258
(1985);
Siliprandi et al., "N-methyl-D-aspartate-induced neurotoxicity in the adult
rat retina," Visual
Neurosci., 8:567-573 (1992); Reif Lehrer et al., "Effects of monosodium
glutamate on chick
embryo retina in culture," Invest. Ophthalmol. Vis. Sci., 14(2):114-124
(1975); Blanks, J. C.,
s "Effects of monosodium glutamate on the isolated retina of the chick embryo
as a function of
age: A morphological study," Exp. Eye Res., 32:105-124 (1981); Olney et al.,
"The role of
specific ions in glutamate neurotoxicity," Neurosci. Lett., 65:65-71 ( 1986);
Olney et al., "The
anti-excitotoxic effects of certain anesthetics, analgesics and sedative-
hypnotics," Neurosci.
Lett 68:29-34 (1986); Price et al., "CNQX potently and selectively blocks
kainate
io excitotoxicity in the chick embryo retina," Soc. Neurosci. Abst., 14:418
(1988); David et al.,
"Involvement of excitatory neurotransmitters in the damage produced in chick
embryo retinas
by anoxia and extracellular high potassium," Exp. E a Res., 46:657-662 (1988);
Caprioli et
al., "Large retinal ganglion cells are more susceptible to excitotoxic and
hypoxic injury than
small cells Invest. Ophthalmol. Vis. Sci., 34(Suppl):1429 (1993); Cummins et
al.,
is "Electrophysiology of cultured retinal ganglion cells to investigate basic
mechanics of
damage," Glaucoma Update IV, 59-65 (1991); and Sucker et al., "N-methyl-D-
aspartate
antagonists prevent kainate neurotoxicity in rat retinal ganglion cells in
vitro," J. Neurosci.,
11(4):966-971 (1991).
2o EAA receptors have been characterized as metabotropic or ionotropic.
Activation of a
metabotropic receptor affects cellular processes via G-proteins; whereas
ionotropic receptors
affect the translocation of mono- and divalent cations across the cell
membrane. There are at
least three ionotropic receptors that have been named for the agonist that
preferentially
stimulates the receptor. These receptors have been classified as: N-methyl-D-
aspartate
is (NMDA); kainate; and AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)
propanoic
acid). These EAA receptors are differentially distributed to specific cells in
the retina. (See,
for example, Massey, S., "Cell types using glutamate as a neurotransmitter in
the vertebrate
retina," N.N. Osborne and G.J. Chader (Eds.) Progress in Retinal Research, Ch.
9,
Pergammon Press: Oxford, 399-425 (1990); and Miller et al., "Excitatory amino
acid
so receptors in the vertebrate retina," in Retinal Transmitters and
Modulators: Models for the
Brain, (W.W. Morgan, Ed.) CRC Press, Inc., Boca Raton, II:123-160 (1985).) The
localization of such receptors would account for the pathologies associated
with glaucoma or
inner retinal ischemia. For example, death of the retinal ganglion cell has to
a large part been
attributed to the NMDA receptor. (See, for example, Sucker et al., "N-methyl-D-
aspartate
ss antagonists prevent kainate neurotoxicity in retinal ganglion cells in
vitro," J. Neurosci.,
11(4):966-971 (1991).). Thus, antagonists of the NMDA receptor are
neuroprotective;
however, not all antagonists of the diversely distributed EAA receptors are
neuroprotective to
CA 02368242 2001-08-07
WO 00/54810 PCT/US99/05423
3
the inner retina through antagonism of the NMDA receptor, Zeevalk et al.,
"Action of the
anti-ischemic agent ifenprodil on N-methyl-D-aspartate and kainate-mediated
excitotoxicity,"
Brain Res., 522:135-139 (1990)), and many of these EAA antagonists have
significant CNS
side-effects and are therefore not suitable for treating these degenerative
diseases of the eye.
s
Summary of the Invention
The present invention is directed to the use of a glutamate antagonist and an
IOP
io controlling agent, dosed separately or in combination for the treatment of
persons suffering
from glaucoma or ocular hypertension.
Detailed Description of the Invention
is
The present invention involves the use of two types of agents to treat
glaucoma and
ocular hypertension. One agent is an IOP-lowering agent directed at preventing
the damage
to retinal ganglion cells brought on by mechanical, circulatory, and other
poorly understood
factors related to elevated IOP. The second agent is a glutamate antagonist
used to prevent
Zo further damage to ganglion cells and optic nerve fibers from
excitotoxicity.
As used herein the term glutamate antagonist means an antagonist of the NMDA
receptor channel complex. NMDA receptor antagonists include channel Mockers
(agents that
operate uncompetitively to block the NMDA receptor channel); receptor
antagonists (agents
is that compete with NMDA or glutamate at the NMDA binding site); and agents
acting at the
glycine coagonist site or any of several modulation sites (e.g., zinc,
magnesium, redox, or
polyamine sites).
Glutamate antagonists which have been found to be particularly effective have
the
so following structure:
CA 02368242 2001-08-07
WO 00/54810 PCT/US99/05423
4
X
A
Ra
R'
A - R2 \ . ~CH2)" \ . \ .
O
R3 / S R, N R,
~3
R
_ s
n m ~ ~ ~(CH2)" \ s
R3 Y ~(CH2)P Y Jm I /
Y,X = OH, H
s m =0-3
n, p = 1,2
R' = H, halogen, trifluoromethyl, C 1-4 alkyl, OH, C 1-4 alkoxy, benzyloxy, C
1-16
alkanoyloxy, benzoyloxy or when R2 = OH or methoxy in the 4-position and R3 =
H then R'
= hydroxymethyl, carbamoyl, or C 1-4 alkoxycarbonyl;
R2 = H, halogen, C 1-4 alkyl, OH, C 1-4 alkoxyl;
R3, Ra = H, C 1-4 alkyl; and
Rs = H, halogen, trifluoromethyl, C 1-4 alkyl, OH, C 1-4 alkoxy, benzyloxy, C
1-16
alkanoyloxy, benzoyloxy.
is These compounds include all isomers and pharmaceutically acceptable salts.
Other preferred compounds include: amantadine, budipine, felbamate, cerestat
(CNS-
1102, aptiganel), dextromethorphan, dexanabinol, ADCI, araxins, CNS-5161, B111-
277CL,
WAY-126251 (see Drug News Perspect 11(9), November 1998), memantine, and other
2o compounds disclosed in WO 94/13275 to the extent they are suitable for
chronic
administration.
In general, at least one of the compounds of this invention are administered
orally
CA 02368242 2001-08-07
WO 00/54810 PCT/US99/05423
with daily dosage of these compounds ranging between 0.01 and 500 milligrams.
The
preferred total daily dose ranges between l and 100 milligrams. Non-oral
administration,
such as, intravitreal, topical ocular, transdermal patch, parenteral,
intraocular injection, or
subconjunctival routes may require an adjustment of the total daily dose
necessary to
s provide a therapeutically effect amount of the compound.
The compounds can be incorporated into various types of ophthalmic
formulations for
topical delivery to the eye. They may be combined with ophthalmologically
acceptable
preservatives, surfactants, viscosity enhancers, penetration enhancers,
buffers, sodium
io chloride, and water to form aqueous, sterile ophthalmic suspensions or
solutions. Ophthalmic
solution formulations may be prepared by dissolving the compound in a
physiologically
acceptable isotonic aqueous buffer. Further, the ophthalmic solution may
include an
ophthalmologically acceptable surfactant to assist in dissolving the compound.
The
ophthalmic solutions may contain a thickener, such as, hydroxymethylcellulose,
is hydroxyethylcellulose, hydroxypropylmethylceliulose, methylcellulose,
polyvinyl-
pyrrolidone, or the like, to improve the retention of the formulation in the
conjunctival sac. In
order to prepare sterile ophthalmic ointment formulations, the active
ingredient is combined
with a preservative in an appropriate vehicle, such as, mineral oil, liquid
lanolin, or white
petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending
the active
ingredient in a hydrophilic base prepared from the combination of, for
example,
carbopol-940, or the like, according to the published formulations for
analogous ophthalmic
preparations; preservatives and tonicity agents can be incorporated.
If dosed topically, the compounds are preferably formulated as topical
ophthalmic
zs suspensions or solutions, with a pH of about 4 to 8. The compounds will
normally be
contained in these formulations in an amount .001% to 5% by weight, but
preferably in an
amount of .0l % to 2% by weight. Thus, for topical presentation, 1 to 2 drops
of these
formulations would be delivered to the surface of the eye 1 to 4 times per day
according to the
routine discretion of a skilled clinician.
CA 02368242 2001-08-07
WO 00/54810 PCT/US99/05423
6
The preferred compound, eliprodil, is orally bioavailable, demonstrates a low
incidence of adverse effects upon administration, and effectively crosses the
blood-brain
barner (Drugs of the Future, 1994, 19, 905-909) indicating that effective
concentrations are
expected in the target tissue, the retina. The compound is described in U.S.
Patent No.
s 4,690,931, the contents of which are incorporated herein by reference.
The IOP-lowering agents useful in the present invention include all presently
known
IOP-lowering pharmaceuticals, including, but not limited to, miotics (e.g.,
pilocarpine,
carbachol, and acetylcholinesterase inhibitors); a and a/(3 adrenergic
agonists (e.g.,
io epinephrine, dipivalylepinephrine, para-amino clonidine and brimonidine);
beta-blockers
(e.g., betaxolol, S-betaxolol, levobunolol, carteolol, and timolol);
prostaglandins and their
analogues and derivatives, such as, compounds disclosed in U.S. Patent Nos.
4,599,353;
5,093,329; and 5,321,128 and in European Patent Nos. 0215 860 B 1 and 0 299
914 B 1; and
carbonic anhydrase inhibitors (e.g., acetazolamide, methazolamide, and
ethoxzolamide, and
is compounds disclosed in U.S. Patent Nos. 5,153,192; 5,240,923; 5,378,703;
and 4,797,413)
and ocular hypertensive lipids, such as those compounds (neutral replacement
of the
carboxylic acid group of prostaglandin F2a e.g. AGN 192024) described in IOVS,
March 15,
1998, Vol. 39, No. 4; WO 97/30710, U.S. Patent Nos. 5,238,961; 5,262,437;
5,328,933;
5,352,708; 5,312,842; 5,552,434; 5,545,665; 5,688,819. The preferred IOP-
lowering agents
Zo are: timolol, betaxolol, S-betaxolol levobunolol, carteolol, pilocarpine,
carbachol,
epinephrine, dipivalyl epinephrine-amethyl dipivalylepinephrine, brinzolamide,
dorzolamide,
unoprostone, latanoprost, travoprost, apraclonidine, and brimonidine.
One or more IOP-lowering agents will be administered systemically, or if in a
topical
2s formulation, at a concentration of between 0.001 and 5.0 wt%, preferably,
0.01 to 2.5 wt%,
but preferably 0.001 - 0.005 for prostaglandins.
The IOP-lowering compositions of the present invention may additionally
include
components to provide sustained release and/or comfort. Such components
include high
so molecular weight, anionic mucomimetic polymers, gelling polysaccharides and
finely-divided
drug carrier substrates. These components are discussed in greater detail in
U.S. Patent Nos.
4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these
patents are
incorporated herein by reference.
3s In addition to the above-described principal ingredients, the IOP-lowering
compositions of the present invention may further comprise various formulatory
ingredients,
CA 02368242 2001-08-07
WO 00/54810 PCT/US99/05423
7
such as antimicrobial preservatives and tonicity agents. Examples of suitable
antimicrobial
preservatives include: benzalkonium chloride, thimerosal, chlorobutanol,
methyl paraben,
propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, Polyquad~
and other
agents equally well-known to those skilled in the art. Such preservatives, if
utilized, will
s typically be employed in an amount between about 0.001 and about 1.0 wt%.
Examples of
suitable agents which may be used to adjust the tonicity or osmolality of the
formulations
include: sodium chloride, potassium chloride, mannitol, dextrose, glycerin,
and propylene
glycol. Such agents, if utilized, will typically be employed in an amount
between about 0.1
and about 10.0 wt%.
io
As will be appreciated by those skilled in the art, the compositions may be
formulated
in various dosage forms suitable for topical ophthalmic delivery, including
solutions,
suspensions, emulsions, gels, and erodible solid ocular inserts. The
compositions are
preferably aqueous suspensions or solutions.
is
The compositions of the present invention may also comprise non-aqueous
formulations such as: substantially non-aqueous liquids substantially non-
aqueous semi-solid
compositions and solid compositions or devices.
2o The first class, substantially non-aqueous liquids, comprise an IOP-
lowering agent and
a second agent ("drug combination") dissolved or suspended in one or more of
the following:
vegetable and mineral oils, such as, liquid petrolatum, corn oil, castor oil,
sesame oil, and
peanut oil; triglycerides, such as the capric/caprylic triglycerides commonly
used in foods and
cosmetics; liquid lanolin and lanolin derivatives; and perfluorohydrocarbons.
2s
The second class, semi-solid compositions, comprise an IOP-lowering agent
dissolved
or suspended in one or more of the following: various types of petrolatum,
such as white,
yellow, red and so on; lanolin and lanolin derivatives; gelled mineral oil
having a
hydrocarbon base, such as Plastibase~; petrolatum and ethylene carbonate
mixtures;
so petrolatum in combination with surfactants and polyglycol, such as polyoxyl
40 stearate and
polyethylene glycol.
The third class, solid compositions or devices, include non-erodible devices
which are
inserted into the conjunctiva) sac of the eye and later removed, such as the
Alza-type
ss diffusion or osmotic pressure controlled polymer membranes; and bioerodible
polymers
which do not have to be removed from the conjunctiva) sac, such as essentially
anhydrous but
water soluble polymers and resins (e.g., celluloses, polycarboxylic acids, and
so on).
CA 02368242 2001-08-07
WO 00/54810 PCT/US99/05423
8
Especially preferred are the bioerodible inserts described and detailed in US
4,540,408
(Lloyd) and US 4,730,013 (Bondi et al.), wherein drug combinations of the
present invention
would be entrained in a non-aqueous matrix consisting essentially of polyvinyl
alcohol. The
entire contents of these two patents are incorporated herein by reference.
s
The present invention is also directed to methods of treating persons with
glaucoma or
ocular hypertension. At least one glutamate antagonist will be administered
systemically and
at least one IOP-lowering composition described above is applied topically to
the affected
eyes) of the patient. The frequency and amount of dosage will be determined by
the clinician
~o based on various clinical factors. The methods will typically comprise
topical application of
one or two drops (or an equivalent amount of a solid or semi-solid dosage
form) to the
affected eye one to four times per day.
The invention has been described by reference to certain preferred
embodiments;
is however, it should be understood that it may be embodied in other specific
forms or
variations thereof without departing from its spirit or essential
characteristics. The
embodiments described above are therefore considered to be illustrative in all
respects and
not restrictive, the scope of the invention being indicated by the appended
claims rather than
by the foregoing description.
