Note: Descriptions are shown in the official language in which they were submitted.
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DELIVERY OF MODULATORS OF GLUTAMATE-MEDIATED
NEUROTRANSMISSION TO THE INNER EAR
Field of the Invention
The invention relates to devices and methods for the delivery of drugs to the
inner ear for
treatment of inner ear disorders such as tinnitus. In particular, the
invention relates to the use of
modulators of L-glutamate-mediated neurotransmission (MGMN). Specifically, the
invention
relates to delivery of an N-Methyl-D-Aspartate (N1~~A) receptor antagonist to
the round
window niche of the inner ear so as to suppress excessive NMDA receptor-
mediated signals, but
without causing hearing loss associated with suppression of alpha-amino-3-
hydroxy-5-methyl-4-
isoxazolepropionate (AMPA) receptor-mediated signals. In particular, the
invention
encompasses delivering an NMDA receptor antagonist, such as (but not limited
to) D-2-amino-5-
phosphonopentanoate (D-APS), Dizocilpine (MK SO1), 7-chlorokynurenate (7-CIA)
and
Gacyclidine (GK-11) to the round window niche of the inner ear to treat
tinnitus.
Background of the Invention
Any number of insults, such as infections, vascular disorders, or sounds of
sufficient intensity
and duration will damage the ear and result in temporary or permanent hearing
loss. The hearing
loss may range from mild to profound, and may also be associated with
conditions such as
tinnitus, which is the perception of a ringing, roaring, buzzing, or clicking
sound etc that occurs
inside the head when no external sound is present. Repeated sound
overstimulation or other
insults cumulative over a lifetime and can cause permanent damage that is not
currently
treatable. Hearing impairment has a major impact on one's communication
ability and even mild
impairment may adversely affect the quality of life for millions.
Unfortunately, although such
hearing loss is preventable, our increasingly noisy environment places more
and more people at
risk.
L-glutamate (glutamate) is the most important afferent neurotransmitter in the
auditory system,
and is used by the sensory inner hair cells (1HC) of the cochlea to transduce
the mechanical
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displacement of the basilar membrane into activity of the primary auditory
afferent nerve fibers
(for a review, see, e.g., Puel (1995) Neu~obiol 47:449-476). The ionotropic
receptors with which
glutamate interacts during fast excitatory synaptic transmission include three
types of receptors,
which are named for their sensitivity to agonists: N-methyl-D-aspartate
(NMDA), oc-amino-3-
hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and lcainate. Glutamate can
also act through
metabotropic receptors (i.e., receptors having activation coupled to an
intracellular biochemical
cascade). Analysis of glutamate receptors by gene expression,
immunocytochemistry, and ifs situ
hybridization indicates that primary auditory nerve cells express NMDA (NR1
and NR2A-D),
AMPA (GluR2-4), and kainate (GluRS-7) receptor subunits and the high-affinity
kainate-binding
proteins (I~A1 and KA2) (fuel (1995) supra), suggesting that these receptors
all coexist on
primary auditory nerve cells.
In addition to its fast excitatory properties, glutamate also plays a role in
excitotoxicity, a form of
neuronal degeneration in the cochlea, which can occur when, for example,
glutamate is released
in large amounts or when incompletely recycled in the cochlea. Cochlear
excitotoxicity plays a
role in ischemic- or noise-induced sudden deafness, as well as in tinnitus
(Pujol et al. (1999) Ahn
N YAcad Sci. 884:249-54; Pujol et al. (1992) Neu~oRepo~t 3:299-302; Puel et
al. (1994) J.
Co~rzp. Neurol. 341:241-256; Puel (1995), supra).
Excitotoxicity can be generally characterized by a two-step mechanism. In the
first phase,
glutamate causes overactivation of the ionotropic glutamate receptors that are
permeable to
cations, which leads to excessive ion permeation, osmotic swelling, free
radical generation, and
neuronal death. The second phase of glutamate excitotoxicity, which may
develop after strong
and/or repetitive injury, consists of a cascade of metabolic events triggered
by the entry of Ca2+,
which leads to neuronal death in the spiral ganglion. Neo-synaptogenesis and
functional
recovery is accompanied by up-regulation of NMDA and metabotropic glutamate
receptors.
Prevention of excitotoxicity has been studied using various antagonists of the
ionotropic
glutamate receptors. Intracochlear perfusion of the glutamate antagonist
kynurenate protects
against sound-induced synaptic damage in guinea pigs (Fuel et al. (1998)
Neu~oRepo~t 9:2109-
2114). Antagonism of the AMPA receptor, e.g., via intracochlear infusion of a
selective AMPA
receptor antagonist, can block the excitotoxic effect of gultamate in the
cochlea. Intracochlear
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perfusion of 6-7-dinitorquinoxaline-2, 3-dione (DNQX) ten minutes prior to or
concomitant with
AMPA perfusion prevented most of the occurrence of radial dendrite swelling
(Fuel et al.,
(1991), supra). Intracochlear perfusion of both DNQX and D-APS (a D-2-amino-5-
phosphonopentanoate, an NMDA receptor antagonist), provide nearly complete
protection of all
radial dendrites to AMPA perfusion (Fuel et al. (1994) J. Comp Neurol 341:241-
256). However,
use of intracochlear perfusion methods in the clinic is impractical and, on
the whole,
unacceptable in humans as it would cause permanent damage to the cochlea.
Systemic delivery
of compounds that modulate glutamate activity, particularly at dosages
sufficient to provide for
therapy in the inner ear, cause serious aside-effects, such as memory loss and
stupor.
As is evident from the above, there is a great need for devices and methods
for effective and
practical clinical treatment of inner ear disorders such as hearing loss and
related conditions such
as tinnitus. The present invention addresses this problem.
Summary Of The Invention
The invention features methods and devices for local delivery to the inner ear
via the middle ear
and delivery of agents that modify glutamate-mediated neurotransmission to the
inner ear for
treatment of inner ear disorders, such as tinnitus.
In one embodiment, the invention involves delivery of an agent to the inner
ear, that modulates
synaptic transmission either directly, through interaction of the agent upon
the sensory hair cell
to decrease glutamate release or upon the neuron to reduce synaptic
transmission, or indirectly
by modulating an endogenous factor which in turn decrease synaptic
transmission (e.g., by
administration of a dopamine agonist).
In another related embodiment, the invention involves delivery of an agent
that modifies post-
synaptic glutamate-mediated neurotransmission, either directly by interacting
with a glutamate
receptor to decrease glutamate binding (e.g., by decreasing glutamate binding
to one or more
ionotropic receptors or acting as an antagonist to a glutamate receptor such
as an NNmA
receptor) or indirectly by modulating an endogenous factor which in turn
decreases glutamate
binding to a glutamate receptor (e.g., by modulating the glycine site of PCP
site).
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An animal model has been created in which administration of salicylate
produces tinnitus. In
this model, excessive signaling is mediated by NMDA receptors, but not by AMPA
receptors.
The invention uses specific NMDA receptor antagonists to block the excessive
signals thereby
treating tinnitus.
In particular, the invention encompasses delivering an NMDA receptor
antagonist, such as (but
not limited to) D-APS (D-2-amino-5-phosphonopentanoate, a specific NMDA-
antagonist) (Clin
Med J (Engl) 2002 Jan;115(1):89-93), Dizocilpine (MK 801) (J Neurotrauma 2000
Nov;l7(11):1079-93), 7-chlorokynurenate or Gacyclidine (GK-11) (Curr Opin
Investig Arugs
2001 Jun, 2(6):814-9) onto or in the vicinity of the round window niche of the
inner ear to treat
tinnitus. The method suppresses excessive NMDA receptor-mediated signals that
cause tinnitus,
without causing undesired hearing loss associated with suppression of AMPA
receptor-mediated
signals.
One advantage of the invention is that delivery of drug directly to the inner
ear avoids the
potential toxicity and side-effects that can be associated with systemic
delivery of modulators of
glutamate-mediated neurotransmission drug, such as loss of memory or stupor.
In one aspect, the invention features treatment of inner ear disorders by
delivering an agent that
modulates glutamate-mediated neurotransmission in the inner ear, by perfusion
of the agent
across the round window membrane.
Another advantage of the invention is that, where the modulator of glutamate-
mediated
neurotransmission is an NMDA-specific receptor, these drugs have less toxicity
in the form of
hearing loss than other non-NMDA specific receptor modulators glutamate
activity.
Another advantage is that the invention can be used to deliver relatively
small quantities of
modulators of glutamate-mediated neurotransmission accurately and precisely
over a selected
period of time. Use of a long-term drug delivery device obviates the need for
regular dosing by
the patient, thus increasing patient compliance with a prescribed therapeutic
regimen, and in
particular compliance with a prophylactic regimen prescribed prior to the
onset of symptoms.
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This is especially useful in populations in which compliance with such
medications can be more
difficult, e.g., children and the elderly.
Another advantage of the invention is that a modulator of glutamate-mediated
neurotransrriission
can be delivered into the inner ear with such accuracy and precision and at
such low quantities as
to permit long-teen use of such compounds to treat inner ear disorders.
A further advantage is that a therapeutically effective dose of modulators of
glutamate-mediated
neurotransmission can be delivered at relatively low volume rates, e.g., from
about 0.01 ~,l/day to
2 ml/day so as to minimize disturbance or trauma to the delicate structures of
the middle and/or
firmer ear.
These and other objects, advantages and features of the present invention will
become apparent
to those persons skilled in the art upon reading the details of the
methodology and compositions
as more fully set forth below.
Brief Description Of The Drawings
Fig. 1 is a schematic drawing of the ear showing the outer, middle and inner
ear, and clearly
showing the round window.
Fig. 2 shows two graphs comparing the affect of acute intracochlear perfusion
and chronic round
window perfusion. These graphs represent the mean amplitude of the CAP as. the
function of the
intensity of 8kHz tone burst stimulation. Mean threshold has been calculated
from 5 different
animals. Note that both acute intracochlear and chronic round window
application of riluzole
reduce the CAP amplitude in a dose-dependent manner. However, the effect was
10 times less
potent when the drug was applied onto the round window.
Fig. 3 shows the protective effect of riluzole on intense noise induced
acoustic trauma.
CAP audiograms (threshold shifts as the function of tone frequency) were
measured 2 days after
30 minutes of continuous sound exposure. Threshold shift was calculated as the
difference in the
recording before and 2 days after 6kHz continuous tone exposure. Shown are
threshold shift
recorded after 120 dB SPL exposure during 30 minutes in presence of artificial
perilymph (red
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curve, control). Note the clear protection of 100 ~,M riluzole when either
applied directly into the
cochlea (blue curve, infra) or onto the round window (green curve, RW). "n" is
the number of
tested animals
Fig 4A shows the results of an experiment to determine the ability of perfused
Glutamate
antagonists to suppress salicylate-induced excitation the results from an
original recording from
an auditory nerve fiber coding for 8 kHz with a spontaneous rate of 8 spikes s
1. Intracochlear
perfusion of control artificial periphymph (AP) containing 100 ~M indomethacin
(open bar) did
not change the spontaneous activity of the auditory nerve fiber. In contrast,
application of 5 mM
of sodium-salicylate (Nasal; black bar) reversibly increased spontaneous
firing of the auditory
nerve fibers.
Fig. 4B shows results from a nerve fiber coding for 9 kHz with a spontaneous
rate activity of 7
spikes s 1. Blocking of AMPA receptors with 50 ~,M of the AMPA agonist GYKI
53784
(Neuropharm. 30 1959-1973, 2000) (open bar) blocked both the spontaneous and
the evoked
activity by 5 mM Nasal (black bar).
Fig. 4C shows results from a nerve fiber coding for 7,5 kHz with a spontaneous
rate of 5 spikes
s 1. Sodium-salicylate was continuously applied. Repetitive application (~pen
bars) with the
NMDA antagonist 7 CK (50 ~.M, n = 5) suppressed neural excitation of auditory
nerve induced
by Na Salicylate, but not the spontaneous activity of the fiber.
Fig. 4D shows that repetitive application of the NMDA antagonist gacyclidine
(50 ~M, n = 5)
suppressed neural excitation of auditory nerve induced by Na Salicylate, but
not the spontaneous
activity of the fiber.
Fig SA shows results for the number of positive responses in response to
sound, as a percentage
of the total (Score %) to sound vs. time in days, with salicylate being
delivered between days 2
and 5.
Fig SB shows the results for the number of responses without sound (false
positives), with
salicylate being delivered between days 2 and 5. Using this behavioral
paradigm, treatment with
saline solution (daily injections during 4 days, i.p.) did not change the
score or false positive
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numbers. In contrast, sodium-salicylate treatment (daily injection, 300
mg/kg/day during 4 days,
i.p.) provoked a reversible reduction of the score and a drastic increase of
the number of false
positives.
Fig 5C shows the results for compound action potential (CAP) audiograms in
behavioral trained
animals recorded before (day~0), during (day 3 and day 4) and after salicylate
treatment (day 6).
CAP thresholds were measured using an electrode chronically implanted on round
window in
response to a tone burst of 1 ms rise/fall time and 9 ms duration presented at
a rate of 10 times
per second. Salicylate treatment (daily injection, 300 mg/kg/day during 4
days, i.p.) induced a 30
dB hearing loss across frequency range from 2 to 26 KHz.
Fig 5D shows CAP threshold shift at 10 kHz before, during and after salicylate
treatment. CAP
threshold shifts were calculated as the difference in dB between the auditory
threshold at day 0
and the auditory threshold at each day. To avoid changes due to hearing loss,
the intensity of
sound eliciting behavioral responses was adjusted as a function of CAP
threshold shift.
Fig 5E shows that no significant decrease in the score was observed, with
salicylate being
delivered between days 2 and 5.
Fig 5F shows that false positive responses still remained after salicylate
treatment. This
demonstrates that the increased number of false positive responses during
sodium-salicylate
treatment was due to the occurrence of tinnitus, and not to hearing loss.
Gelfoam placed on the
round window was used to apply drugs into the fluid of the cochlea. (G) Note
that the score
remained unchanged. In contrast, round window application of 50 ~M of 7-CIA
blocked the
occurrence of false positive responses. Findings indicate that tinnitus
induced by sodium-
salicylate requires activation of cochlear NMDA receptors. From this
experiment it can be
concluded that round window perfusion of NMDA antagonists suppresses tinnitus
induced by
salicylate.
Fig. 6 shows the comparative effects on NMDA antagonists on salicylate-induced
tinnitus.
Shown are the number of false positive responses measured at the end
salicylate treatment (day
4) in animals with gelfoams bathed with artificial perilymph alone (AP, n=10)
alone or MK-801
(10 ~M, n=10), 7-chlorokynurenate (7-CK, 50 ~,M, n=10), or gacyclidine (50
~,M, n=10). When
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compared with AP alone, local application of MK-X01, 7-CK, or gacyclidine
drastically reduced
the occurrence of the false positive responses.
Description of the Preferred Embodiments
Before the present device and methods for treatment of an inner ear disorder
are described, it is
to be understood that this invention is not limited to the specific
methodology, devices,
therapeutic formulations, and syndromes described as such may, of course,
vary. It is also to be
understood that the terminology used herein is for the purpose of describing
particular
embodiments only, and is not intended to limit the scope of the present
invention which will be
limited only by the appended claims.
It must be noted that as used herein and in the appended claims, the singular
forms "a", "and",
and "the" include plural referents unless the context clearly dictates
otherwise. Thus, for
example, reference to "a drug delivery device" includes a plurality of such
devices and reference
to "the method of delivery" includes reference to equivalent steps and methods
known to those
skilled in the art, and so forth.
Unless defined otherwise, all technical and scientific terms used herein have
the same meaning
as commonly understood to one of ordinary skill in the art to which this
invention belongs.
Although any methods, devices and materials similar or equivalent to those
described herein can
be used in the practice or testing of the invention, the preferred methods,
devices and materials
are now described.
All publications mentioned herein are incorporated herein by reference for the
purpose of
describing and disclosing the compositions and methodologies which are
described in the
publications which might be used in connection with the presently described
invention. The
publications discussed herein are provided solely for their disclosure prior
to the filing date of
the present application. Nothing herein is to be construed as an admission
that the invention is
not entitled to antedate such a disclosure by virtue of prior invention.
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Definitions
The term "inner ear disorder caused by aberrant glutamate-mediated
neurotransmission" as used
herein refers to conditions that result from overstimulation or
understimulation of glutamate
receptors, e.g., tinnitus, ischemic-induced sudden deafiiess, noise-induced
sudden deafness, and
the like.
The term "subject" is meant any subject, generally a mammal (e.g., human,
canine, feline,
equine, bovine, ungulate, porcine etc.), in which treatment of an inner ear
disorder is desired.
The acronym CAP means Compound Action Potential in microvolts.
The term "implantation site" is used to refer to a site within the body of a
subject at which a drug
delivery device is introduced and positioned.
The terms "agent that modulates glutamate-mediated neurotransmission,"
"modulator of
glutamate-mediated neurotransmission," "glutamate neuromodulatory agent" are
meant to
encompass agents that act either directly or indirectly to increases or
decreases glutamate release
(pre-synaptic modulators of glutamate-mediated neurotransmission) or activity
of glutamate in
binding to glutamate receptors (post-synaptic modulators of glutamate-mediated
neurotransmission).
To call one compound a "derivative" of another compound means that the
derivative has been
made from or could have been made from the original compound, and shares core
structural
components.
An "analogue" is a compound related to another compound structurally and
functionally; the
compound and the analogue share close structural similarity and have a similar
biological
function, and includes isomers.
A "pharmaceutical composition" is a mixture containing a drug (defined below).
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The term "formulation" (or "drug formulation") means any drug together with a
pharmaceutically acceptable excipient or carrier such as a solvent such as
water, phosphate
buffered saline or other acceptable substance. A formulation may comprise one
or more agents
(drugs) that modulate glutamate-mediated neurotransmission e.g.: NMDA receptor
antagonists,
AMPA receptor antagonists, and kainate receptor antagonists or components with
effects on
more than one of said receptor types.
The term "therapeutically effective amount" means an amount of a therapeutic
agent, or a rate of
delivery of a therapeutic agent, effective to facilitate a desired therapeutic
effect. In general, the
invention involves alleviating symptoms caused by aberrant glutamate-mediated
neurotransmission in the inner ear in a subject suffering from such symptoms
or at risk of a
condition associated with such symptoms (e.g., a subject who is to be exposed
to noise trauma
that may be of a level sufficient to induce temporary or permanent hearing
loss in the subject due
to unacceptably high activity in glutamate-mediated neurotransmission).
The term "sustained release" means release (of a drug) over an extended period
of time, as
contrasted with "bolus" release. Sustained release, for example, may be for a
period of at least
12 hours, at least 24 hours, at least two weeks, at least a month, at least
three months, or longer.
The term "drug delivery device" refers to any means for containing and
releasing a drug wherein
the drug is released into a subject. A drug delivery device may include a
catheter via which a
drug is delivered. The means for containment is not limited to containment in
a walled vessel,
but may be any type of containment device, including non-injectable devices
(pumps etc) and
injectable devices, including a gel, a viscous or semi-solid material or even
a liquid. Drug
delivery devices are split into five major groups: inhaled, oral, transdermal,
parenteral and
suppository. Inhaled devices include gaseous, misting, emulsifying and
nebulizing bronchial
(including nasal) inhalers; oral includes mostly pills; whereas transdermal
includes mostly
patches. Parenteral includes two sub-groups: injectable and non-injectable
devices. Non-
injectable devices are generally referred to as "implants" or "non-injectable
implants" and
include e.g., solid biodegradable polymers and pumps (e.g., osmotic pumps,
biodegradable
implants, electrodiffusion systems, electroosmosis systems, vapor pressure
pumps, electrolytic
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pumps, effervescent pumps, piezoelectric pumps). Injectable devices are split
into bolus
injections, that are injected and dissipate, releasing a drug all at once, and
depots, that remain
discrete at the site of injection, releasing drug over time. Depots include
e.g., oils, gels, liquid
polymers and non-polymers, and microspheres. A drug delivery device of the
invention may be
attached to a catheter to deliver a drug from the device to the target site.
It may also employ a
catheter as a drug delivery device, i.e., a closed catheter, essentially a
tube with at least one
opening at the drug delivery end (but most probably also having an opening at
the other end, to
allow pressure equilibration as drug is discharged) may be filled with a drug,
and inserted into
the ear, for example through the tympanic membrane, with the drug delivery end
resting in the
round window niche, such that the drug will flow out of the catheter into the
round window
niche. This flow may be accomplished by capillary action as drug is absorbed
through the round
window and more drug is drawn from the catheter body through the drug delivery
end. Many
drug delivery devices are described in Encyclopedia of Controlled Drug
Delivery (1999), Edith
Mathiowitz (Ed.), John Wiley & Sons, Inc.
The term "drug" as used herein, refers to any substance meant to alter animal
physiology.
The term "dosage form" refers to a drug plus a drug delivery device.
"Patterned" or "temporal" delivery of drug means delivery of drug in a way
that changes
predictably, e.g., at an increasing, decreasing, substantially constant, or
pulsatile, rate or range of
rates (e.g., amount of drug per unit time, or volume of drug formulation for a
unit time).
The phrase "substantially continuous" means generally uninterrupted for a pre-
selected period of
drug delivery (in contrast to a period associated with, for example, a bolus
injection).
The terms "treat," "treatment," and the like as used herein generally refer to
obtaining a desired
pharmacologic and/or physiologic effect. The effect may be prophylactic in
terms of completely
or partially preventing a condition or symptom thereof and/or may be
therapeutic in terms of a
partial or complete cure for or suppression of a disease and/or adverse
effects attributable to the
disease. "Treatment" as used herein covers any treatment of an inner ear
disorder (including but
not limited to hearing loss, tinnitus, and the like) in an animal,
particularly a human, and
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includes: (a) preventing an inner ear disorder from occurring in a subject
that may be
predisposed but is not at the time displaying symptoms; (b) inhibiting an
inner ear disorder, e.g.,
arresting development of hearing loss or tinnitus or other such disease or
disorder; or (c)
relieving disease, i. e., causing regression and/or amelioration of the
disease.
Overview
The invention is based on the discovery that modulators of glutamate-mediated
neurotransmission can be delivered to the inner ear by diffusion through a
middle-inner ear
membrane (e.g., the round window membrane or the annular ligament of the
stapes footplate),
and further that such delivery is effective in dampening glutamate-mediated
neurotransmission.
In particular, the inventors have discovered that an NMDA receptor antagonist,
such as, but not
limited to, D-APS, MK 801, 7-chlorokynurenate or gacyclidine may be delivered
to the round
window niche of the inner ear in such a way as to suppress excessive NMDA
receptor-mediated
signals, that in certain cases cause tinnitus, but without causing undesired
hearing loss associated
with suppression of AMPA receptor-mediated signals.
Without being held to theory, delivery of modulators of glutamate-mediated
neurotransmission
across the round window membrane is effective to dampen the action potential
and calcium
influx associated with glutamate-mediated neurotransmission. As a result of
the dampening of
glutamate-mediated neurotransmission, overstimulation of the glutamate
receptors is avoided or
diminished, and symptoms normally associated with increased glutamate activity
are decreased,
e.g., hearing can be preserved, tinnitus symptoms are decreased, and the like.
If the drug used to
dampen neurotransmission is a drug that specifically inhibits NMDA receptor-
mediated signals,
then one can avoid unwanted effects, such as hearing loss, that are associated
with inhibition of
AMPA receptor-mediated signals or signals mediated by other receptors.
In view of the above, then, modulation of glutamate-mediated neurotransmission
according to
the invention can be accomplished in a variety of ways. For example, glutamate-
mediated
neurotransmission can be modulated pre-synaptically to decrease glutamate
release, thereby
decreasing stimulation of the glutamate receptors. Pre-synaptic glutamate
neuromodulation can
be accomplished directly, by administration of an agent that acts to decrease
glutamate release.
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Post-synaptic glutamate neuromodulation can be accomplished directly by
administration of an
agent that interacts with one or more glutamate receptors (e.g., to compete
with glutamate for
binding to the receptor, to bind to the receptor in a manner that affects
receptor affinity or avidity
for glutamate, or to otherwise decrease the glutamate receptors available for
glutamate binding
and stimulation). Post-synaptic glutamate neuromodulation can be accomplished
indirectly by
administration of an agent that increase the levels of an endogenous factor
that in turn affects
glutamate binding to a glutamate receptor (e.g., by administration of a
dopamine agonist).
Alternatively, glutamate-mediated neurotransmission can be modulated by
increasing stimulation
of glutamate receptors by, for example, directly or indirectly causing an
increase release of
glutamate (pre-synaptic modulation) or directly or indirectly causing an
increase in stimulation
of glutamate receptors.
It should be noted that the desired effect of the modulator of glutamate-
mediated
neurotransmission need not be complete to be effective. For example, where a
decrease in
glutamate receptor stimulation is desired, the modulator of glutamate-mediated
neurotransmission need not entirely block glutamate activity, but rather only
provide for a
general decrease in glutamate activity in stimulating neurotransmission.
Completely blocking
glutamate-mediated neurotransmission can result in at least temporary hearing
loss (i.e., if there
is no glutamate-mediated neurotransmission, then the auditory nerve is not
stimulated and the
sensation of hearing is lost). Except in instances in which temporary hearing
loss as a result of
blocking of glutamate-mediated neurotransmission may provide a protective
effect against
exposure to a stimulus that would result in permanent hearing loss, completely
blocking
glutamate-mediated neurotransmission is generally undesirable.
Glutamate Neuromodulatory Agents and Formulations
A formulation of the invention will comprise an agent that acts as a direct or
indirect modulator
of glutamate-mediated neurotransmission through activity pre- or post-
glutamate release. Such
agents can include, but are not necessarily limited to, agents that directly
or indirectly decrease
binding of glutamate to an ionotropic glutamate receptor (such as an NMDA
receptor, an AMPA,
receptor, or a kainite receptor) or a metabotropic receptor (such as mGluRl, 3-
5, 7, 8). Further
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agents include agents that directly or indirectly decrease pre-synaptic
release of glutamate. For a
review of glutamate antagonists, steroids, and antioxidants suitable for use
in the invention in the
treatment of inner ear, see Simpson and Davies, (Ti~e~cds Plaa~macol,Sci 20,
12 (1999).
Exemplary agents include, but are not necessarily limited to, NMDA-specific
glutamate
antagonists such as D-2-amino-5-phosphonopentanoate (D-APS), Dizocilpine (MK
SO1), 7-
chlorokynurenate (7-CK) and Gacyclidine (GK-11). Among the Nl~A-antagonists,
Gacyclidine is considered one of the preferred compounds. Agents that could be
used for the
invention may also include drugs that mimic or block the action of the lateral
efferents, including
those that affect neurotransmitters or neuromodulators such as acetylcholine,
GABA, dopamine,
enkephalins, dynorphins and calcitonin gene-related peptide. Additionally, all
drugs that act on
sodium channel activity such as riluzole, dextromethorophan may be used to
treat inner ear
disorders such as tinnitus in accordance with the present invention.
Exemplary structures and derivatives or analogues of compounds that may be
used for the
invention are set out below. Derivatives or analogues useful in the invention
may contain
additional or alternative substituent (-R) groups at various locations,
wherein such substituent
groups may be selected from any appropriate group. Substituent groups can be
selected by those
of skill in the art taking into account charge and size and location of the
group to minimize steric
hindrance effects and maintain functionality. For example, substituent groups
may be
individually selected from the group consisting of hydrogen or a halogen and
unsubstituted or
substituted alkyl, alkenyl and alkynyl of up to 6 carbon atoms.
D-2-amino-5-phosphonopentanoate (D-APS), has the following chemical structure:
NHS
H O~
H O-P COO H
O
Derivatives or analogues of D-APS useful in the invention may contain
additional or alternative
substituent (-R) groups at various locations as shown.
14
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WO 2004/022069 PCT/US2002/028519
R$ NH2
HO~
HO-li ~ 'COON
O R7
7-chlorokynurenate (7-CK) has the following chemical structure:
C COON
N
10
Derivatives or analogues of 7-CIA useful in the invention may contain
additional or alternative
substituent (-R) groups at various locations as shown.
Dizocilpine (MK 801), has the following chemical structure:
Derivatives or analogues of MIA 801 useful in the invention may contain
additional or alternative
substituent (-R) groups at various locations as shown.
R6
15
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Gacyclidine (GK-11) has the following chemical structure (two racemic
structures shown):
1 \ 1
s, ~s
~N ''N
'=.
(+) Gacyclidine (GK11) (-) Gacyclidine (GKl l)
Derivatives or analogues of Gacyclidine useful in the invention may contain
additional or
alternative substituent (-R) groups at various locations as shown.
1 jRlo R9 1 jRlo
s\ \ S
S
~N ~~N
..,
R11 R11
15
While the agents above are contemplated for delivery according to the
invention, variations
within the scope of the invention will be readily apparent to the ordinarily
skilled artisan upon
reading the disclosure provided herein.
The modulator of glutamate-mediated neurotransmission delivered can vary
according to a
variety of factors, including but not limited to, concurrent therapy (e.g.,
potential for drug
interactions), age of the subject, severity of the disorder, recurrence of
symptoms in subject, and
the like.
Agents that modulate glutamate-mediated neurotransmission can be provided in
any of a variety
of formulations compatible with delivery across a middle-inner ear membrane,
provided that
such formulation is stable (i.e., not subject to degradation to an
unacceptable amount at body
temperature). The concentration of agent in the formulation may vary from
about 0.1 wt. % to
about 50 or 75 wt.%. The agent can be provided in any form suitable for
delivery and diffusion
of agent across the middle-inner ear membrane structure, e.g., solid, semi-
solid, gel, liquid,
suspension, emulsion, osmotic dosage formulation, diffusion dosage
formulation, erodible
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formulation, etc. In one embodiment, the formulation is suitable for delivery
using an
implantable pump in connection with a catheter inserted near the round window
niche of the
inner ear, e.g., an osmotic pump.
Pharmaceutical grade organic or inorganic carriers, excipients and/or diluents
can be included in
the formulations. The formulations can optionally comprise a buffer such as
sodium phosphate
at physiological pH value, physiological saline or both (i.e., phosphate
buffered saline). Suitable
excipients can comprise dextrose, glycerol, alcohol (e.g., ethanol), and the
like, and
combinations of one or more thereof with vegetable oils, propylene glycol,
polyethylene glycol,
benzyl alcohol, benzyl benzoate, dimethyl sulfoxide (DMSO), organics, and the
like to provide a
suitable composition. In addition, if desired, the composition can comprise
hydrophobic or
aqueous surfactants, dispersing agents, wetting or emulsifying agents,
isotonic agents, pH
buffering agents, dissolution promoting agents, stabilizers, antiseptic agents
and other typical
auxiliary additives employed in the formulation of pharmaceutical
preparations. Exemplary
additional active ingredients that can be present in the formulations useful
with the invention can
include, but are not limited to, D-APS, MK X01, 7-chlorokynurenate or
gacyclidine.
The modulator of glutamate-mediated neurotransmission can be provided in the
formulation as a
solution, a suspension, and/or as a precipitate.
CONDITIONS AMENABLE TO TREATMENT ACCORDING TO THE INVENTION
In general, administration of a formulation according to the invention can be
used to treat (e.g.,
prophylactically or after onset) an inner ear disorder caused by
overstimulation of glutamate
receptors, e.g., due to aberrantly increased release of glutamate and/or due
to defects in
glutamate receptor signaling that lead to aberrantly increased glutamate
receptor activity. Of
particular interest is the management of inner ear disorders that may require
long-terin therapy,
e.g., chronic and/or persistent inner ear disorders (e.g., tinnitus) for which
therapy involves
treatment over a period of several days (e.g., about 3 days to 10 days), to
several weeks (e.g.,
about 2 weeks or 4 weeks to 6 weeks), to several months or years, up to
including the remaining
lifetime of the subject. Subjects who are not presently suffering from a
disease or condition, but
who are susceptible to such, may particularly benefit from prophylactic
management using the
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devices and methods of the invention. Inner ear disorders amenable to therapy
according to the
invention may involve prolonged episodes alternating with relatively symptom-
free intervals, or
substantially unremitting symptoms that vary in severity.
Specific examples of conditions, diseases, disorders, and physiological
responses amenable to
management according to the present invention include, but are not necessarily
limited to
tinnitus, hearing loss due to cochlear ischemia, noise exposure, presbycusis.
DELIVERY OF GLUTAMATE NEUROMODULATORY AGENTS ACCORDING TO THE INVENTION
In general, the glutamate-mediated neurotransmission modulator formulation is
delivered at a
volume rate that is compatible with delivery to the inner ear via the middle
eax, and at a dose that
is therapeutically effective in management of a disorder caused by aberrant
glutamate-mediated
neurotransmission, e.g., overstimulation of glutamate receptors.
In general, administration of a modulator of glutamate-mediated
neurotransmission according to
the invention can be sustained for several hours (e.g., 2 hours, 12 hours, or
24 hours to 48 hours
or more), to several days (e.g., 2 to 5 days or more), to several months or
years. Typically,
delivery can be continued for a period ranging from several days (1, 2, 7, 14
days) to about 1
month to about three months, or 6 month or 9 months or about 12 months or
more. The
modulator of glutamate-mediated neurotransmission may be administered to an
individual for a
period of, for example, from about 2 hours to about 72 hours, from about 4
hours to about 36
hours, from about 12 hours to about 24 hours, from about 2 days to about 30
days, from about 5
days to about 20 days, from about 7 days or more, from about 10 days or more,
from about 100
days or more, from about 1 week to about 4 weeks, from about 1 month to about
24 months,
from about 2 months to about 12 months, from about 3 months to about 9 months,
from about 1
month or more, from about 2 months or more, or from about 6 months or more; or
other ranges
of time, including incremental ranges, within these ranges, as needed. In
particular
embodiments, a formulation is delivered to the subject for a preselected
period without the need
for re-accessing the device and/or without the need for re-filling the device.
In these
embodiments, formulations having a high-concentration of a modulator of
glutamate-mediated
neurotransmission are of particular interest.
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Preferably, delivery of a formulation of the invention is in a patterned
fashion, a substantially
continuous fashion, of at a substantially constant, pre-selected rate or range
of rates (e.g., amount
of agent per unit time, or volume of formulation for a unit time). The agent
is preferably
delivered at a low volume rate of from about 0.01 ~,1/day to about 2 ml/day,
preferably about
0.04 ~1/day to about 1 ml/day, generally about 0.2 ~.1/day to about 0.5
ml/day, typically from
about 2.0 p,l/day to about 0.25 ml/day.
Long-term dosages are convenient for the subject, and administration of the
long-term dose is
simple and can be conducted on an out-patient basis where the patient's health
allows such
(methods for accomplishing delivery are discussed in more detail below). Long-
term delivery
also increases patient compliance, and may provide for more accurate dosing
(e.g., where a
controlled release drug delivery device is used). Implanted drug delivery
devices, e.g., osmotic
pumps, have an added benefit in that they reduce the risk of infection
associated with external
pumps or other methods that require repeated breaking of the skin and/or
maintenance of a port
for administration.
In one embodiment, a drug delivery device provides for substantially
continuous, delivery of
agent at a preselected rate to a middle-inner ear membrane (e.g., to the round
window membrane
or annular ligament of the stapes footplate). In this embodiment, the agent
can be delivered at a
rate of from about 0.1 ~,g/hr to about 200 ~,g/hr, usually from about 0.25
~.g/hr or 3 ~,g/hr to
about 85 ~g/hr, and typically between about 5 ~g/hr to about 100 ~,g/hr. In a
specific exemplary
embodiment, a modulator of glutamate-mediated neurotransmission is delivered
at a rate of from
about 0.1 ~.g/hr, 0.25 ~g/hr, 1 ~,g/hr, generally up to about 200 ~,g/hr.
Appropriate amounts of a particular modulator of glutamate-mediated
neurotransmission can be
readily determined by the ordinarily skilled artisan based upon, for example,
the relative potency
of these drugs, and effectiveness in animal models. The actual dose of drug
delivered will vary
with a variety of factors such as the potency and other properties of the
selected drug used (e.g.,
hydrophilicity, rate of diffusion across the round window membrane, etc.).
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Delivery of glutamate neuromodulatory agents to the inner ear according to the
invention can be
accomplished in a variety of ways. These include filling the middle ear with a
solution or other
carrier of the agent (see, e.g., Shea (1997) Otolaryngol Clira North Am.
30(6):1051-9. One may
also accomplish delivery of agents by insertion of gelatin or GelfoamTM
comprising the agent,
see, e.g., Silverstein (1984) Ahn Otol Rhinol Laryragol Suppl. 112:44-8;
Lundman et al. (1992)
Otolaryngol 112:524; Nedzelski et al. (1993) Am. J. Otol. 14:278-82;
Silverstein et al. (1996)
Ear Nose Throat J 75:468-88; Ramsay et al. (1996) Otolaryngol. 116:39; Ruan et
al. (1997)
Hear Res 114:169; Wanamaker et al. (1998) Am. J. Otology 19:170; An-iaga et
al. (1998)
Laryngoscope 108:1682-5; and Husmann et al. (1998) Hear Res 125:109). One may
also
accomplish delivery of agents by insertion of hyaluronan or hyaluronic acid
mixed with the
agent, see, e.g., WO 97/38698; Silverstein et al. (1998) Am J Otol. 19(2):196-
201; for use of
fibrin glue or other fibrin-based vehicles in delivery of agents to the inner
ear, see, e.g., Balough
et al. (1998) Otolaryhgol. Head Neck S'urg. 119:427-31; Park et al. (1997)
Lar~~cgoscope
107:1378-81.
Delivery of glutamate neuromodulatory agents to the inner ear according to the
invention can be
accomplished using the IntraEAR~ Round Window ~,-CathTM and Round Window E-
CathTM
products, both of which have received marketing clearance from the FDA and
European CE
Mark approval. The Round Window ~-CathTM and Round Window E-CathTM products
are dual-
and triple-lumen micro-catheters of proprietary design which allow controlled
fluid delivery to
the round window membrane of the middle ear which physicians have used to
treat a variety of
ear disorders. These catheters feature a proprietary tip which is designed to
allow the surgeon to
secure it in the round window niche of the middle ear. These catheters can be
left in place for
many weeks and can be connected to a syringe or pump (such as those
manufactured by
Disetronic Medical Systems) for continuous delivery of therapeutic fluids to
the inner ear. The
dual-lumen design allows the treating physician to add and remove fluid or
flush the device
without a build-up of air or fluid pressure. The E-Cath design incorporates an
additional
electrode to allow physicians to record electrical signals related to
activities in the ear. Such
InnerEar catheters are described in US Patents 6,045,528; 5,421,818; 5,476446;
and 5,474,529,
all expressly incorporated herein by reference. Such catheters can be used in
connection with a
drug delivery device described below.
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Deliver~of dru.~usin 'a controlled release device
In general, the drug release methods or devices suitable for use in the
invention comprise a drug
reservoir for retaining a drug formulation or alternatively some substrate or
matrix which can
hold drug (e.g., polymer, binding solid, etc.). The drug release device can be
selected from any
of a variety of implantable drug delivery systems known in the art and
suitable for delivery of a
drug to the round window, to facilitate perfusion of drug across the round
window or other
middle-inner ear membrane and into the inner ear.
In specific embodiments, the delivery device is one that is adapted for
delivery of a formulation
over extended periods of time. Such delivery devices may be adapted for
administration of a
formulation for several hours to several weeks or longer. Drug delivery
provides treatment or
prophylaxis against hearing loss, tinnitus, or other inner ear disorders.
Generally, the modulator
of glutamate-mediated neurotransmission is administered to an individual for
at least a week, or
at least several weeks, a month, two months, three months, six months a year
or longer.
The drug release device of the invention can be based upon a diffusive system,
a convective
system, or an erodible system (e.g., an erosion-based system). For example,
the drug release
device can be an osmotic pump, an electroosmotic pump, a vapor pressure pump,
or osmotic
bursting matrix, e.g., where the drug is incorporated into a polymer and the
polymer provides for
release of drug formulation concomitant with degradation of a drug-impregnated
polymeric
material (e.g., a biodegradable, drug-impregnated polymeric material). In
other embodiments,
the drug release device is based upon an electrodiffusion system, an
electrolytic pump, an
effervescent pump, a piezoelectric pump, a hydrolytic system, etc.
Where a drug delivery catheter or other delivery device is used in connection
with a controlled
release device, drug can be delivered through the drug delivery catheter from
the reservoir of the
controlled release device to the round window membrane as a result of
capillary action, as a
result of pressure generated from the drug release device, by diffusion, by
electrodiffusion or by
electroosmosis through the device and/or the catheter, e.g., an IntraEAR ~
catheter discussed
above.
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The drug delivery device is generally capable of carrying the drug formulation
in such quantities
and concentration as therapeutically required, and must provide sufficient
protection to the
formulation from attack by body processes for the duration of implantation and
delivery. The
exterior is thus preferably made of a material that has properties to dimiiush
the risk of leakage,
cracking, breakage, or distortion so as to prevent expelling of its contents
in an uncontrolled
manner under stresses it would be subj ected to during use. The drug reservoir
must be
biocompatible (e.g., substantially non-reactive with respect to a subject's
body or body fluids).
Suitable materials are well known in the art. For example, the reservoir
material may comprise a
non-reactive polymer or a biocompatible metal or alloy. Suitable polymers
include, but are not
necessarily limited to, acrylonitrile polymers such as acrylonitrile-butadiene
polymer, and the
like; halogenated polymers such as polytetrafluoroethylene, polyurethane,
polychlorotrifluoroethylene, copolymer tetrafiuoroethylene and
hexafluoropropylene;
polyethylene vinylacetate (EVA), polyimide; polysulfone; polycarbonate;
polyethylene;
polypropylene; polyvinylchloride-acrylic copolymer; polycarbonate-
acrylonitrile-butadiene-
styRemy; polystyRemy; cellulosic polymers; and the like. Further exemplary
polymers are
described in The Handbook of Common Polymers, Scott and Roff, CRC Press,
Cleveland
Rubber Co., Cleveland, Ohio.
Metallic materials suitable for use in the reservoir of the drug release
device include stainless
steel, titanium, platinum, tantalum, gold and their alloys; gold-plated
ferrous alloys;
platinum-plated titanium, stainless steel, tantalum, gold and their alloys as
well as other ferrous
alloys; cobalt-chromium alloys; and titanium nitride-coated stainless steel,
titanium, platinum,
tantalum, gold, and their alloys.
Exemplary materials for use in polymeric matrices include, but are not
necessarily limited to,
biocompatible polymers, including biostable polymers and biodegradable
polymers. Exemplary
biostable polymers include, but are not necessarily limited to silicone,
polyurethane, polyether
urethane, polyether urethane urea, polyamide, polyacetal, polyester, poly
ethylene-
chlorotrifluoroethylene, polytetrafluoroethylene (PTFE or "Teflon"), styRemy
butadiene
rubber, polyethylene, polypropylene, polyphenylene oxide-polystyRemy, poly-a-
chloro-p-
xylene, polymethylpentene, polysulfone and other related biostable polymers.
Exemplary
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WO 2004/022069 PCT/US2002/028519
biodegradable polymers include, but are not necessarily limited to,
polyanhydrides,
cyclodestrans, polylactic-glycolic acid, polyorthoesters, n-vinyl alcohol,
polyethylene
oxide/polyethylene terephthalate, polyglycolic acid, polylactic acid and other
related
bioabsorbable polymers.
Another well-known drug delivery device is a "depot" which is an injectable
biodegradable
sustained release device that is generally non-containerized and that may act
as a reservoir for a
drug, and from which a drug is released. Depots include polymeric and non-
polymeric materials,
and may be solid, liquid or semi-solid in form. For example, a depot as used
in the present
invention may be a high viscosity liquid, such as a non-polymeric non-water-
soluble liquid
carrier material, e.g., Sucrose Acetate Isobutyrate (SAIB) or another compound
described in U.S.
Patent Nos. 5,747,058 and 5,968,542, both expressly incorporated by reference
herein. For
reference, please refer generally to "Encyclopedia of Controlled Drug
Delivery" 1999, published
by John Wiley & Sons Inc, edited by Edith Mathiowitz. SAIB may be formulated,
for example,
with one or more solvents, including but not limited to, nonhydroxylic
solvents such as benzyl
benzoate, N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), or mixtures
thereof. In
certain embodiments, it may be desirable to use a solvent such as ethanol,
methanol, or glycerol.
Where the formulation is to be administered as a spray, a propellant may be
added. The solvent
can be added to SAIB in a ratio of from about 5°1° to about 50%
solvent.
An exemplary device for controlled delivery of drug to the inner ear according
to the invention is
described in PCT Publication No. WO 00/33775. This device generally comprises
a drug
delivery unit comprising a carrier media material comprising one or more
therapeutic agents.
The carrier media material is designed to release the agent in a controlled
manner over time, and
is shaped and sized for placement of at least portion of the device in the
round window niche.
Drug release devices based upon a mechanical or electromechanical infusion
pump, can also be
suitable for use with the present invention, generally with an operably
connected catheter which
is implanted for delivery of drug to the round window membrane. Examples of
such devices
include those described in, for example, U.S. Pat. Nos. 4,692,147; 4,360,019;
4,487,603;
4,360,019; 4,725,852, and the like. In general, the present methods of drug
delivery can be
accomplished using any of a variety of refillable, non-exchangeable pump
systems. Pumps and
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WO 2004/022069 PCT/US2002/028519
other convective systems are generally preferred due to their generally more
consistent,
controlled release over time. Osmotic pumps are particularly preferred due to
their combined
advantages of more consistent controlled release and relatively small size. Of
the osmotic
pumps, the DUROSTM osmotic pump is particularly preferred (see, e.g., WO
97/27840 and U.S.
Pat. Nos. 5,985,305 acid 5,728,396)).
In one embodiment, the drug release device is a continuous drug release device
in the form of an
osmotically-driven device. Preferred osmotically-driven drug release systems
are those that can
provide for release of drug in a range of rates of from about 0.1 ~,g/hr to
about 200 ~,g/hr, and
which can be delivered at a volume rate of from about 0.25 ~,l/day to about
100 ~,1/day (i.e., from
about 0.0004 ~1/hr to about 4 ~,1/hr), preferably from about 0.04 p,l/day to
about 10 ~,1/day,
generally from about 0.2 ~.l/day to about 5 ~,1/day, typically from about 0.5
p,l/day to about
1 ~,l/day. In one embodiment, the volume/time delivery rate is substantially
constant (e.g.,
delivery is generally at a rate ~ about 5% to 10% of the cited volume over the
cited time period,
e.g., a volume rate of about
In general, the drug delivery devices suitable for use in the invention are
those that can deliver
drug at a low dose, e.g., from about 0.1 ~,g/hr to about 200 ~g/hr, and
preferably at a low volume
rate e.g., on the order of nanoliters to microliters per day. In one
embodiment, a volume rate of
from about 0.01 ~,1/day to about 2 ml/day is accomplished by delivery of about
80 ~,l/hour over a
period of 24 hours, with the delivery rate over that 24 hours period
fluctuating over that period
by about ~ S% to 10%. Exemplary osmotically-driven devices suitable for use in
the invention
include, but are not necessarily limited to, those described in U.S. Pat. Nos.
3,760,984;
3,845,770; 3,916,899; 3,923,426; 3,987,790; 3,995,631; 3,916,899; 4,016,880;
4,036,228;
4,111,202; 4,111,203; 4,203,440; 4,203,442; 4,210,139; 4,327,725; 4,627,850;
4,865,845;
5,057,318; 5,059,423; 5,112,614; 5,137,727; 5,234,692; 5,234,693; 5,728,396;
and the like.
Delivery Using Delivery Catheter
In some embodiments it may be desirable to provide a drug delivery catheter
with the drug
delivery device, e.g., where the implantation site and the desired delivery
site are not the same.
The drug delivery catheter is generally a substantially hollow elongate member
having a first end
(or "proximal" end) associated with the drug release device of the drug
delivery device, and a
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WO 2004/022069 PCT/US2002/028519
second end'(or "distal" end) for delivery of the drug-comprising formulation
to a desired delivery
site. Where a drug delivery catheter is used, a first end of the drug delivery
catheter can be
operably connected to a drug delivery device so that the lumen of the drug
delivery catheter is in
communication with the drug reservoir in the drug delivery device, so that a
formulation
contained in a drug reservoir can move into the drug delivery catheter, and
out a delivery outlet
of the catheter which is positioned for delivery of agent to the round window
membrane. In one
embodiment, the catheter is positioned at least partially within the round
window niche so as to
provide for deliver of agent to the round window membrane.
The body of the catheter defines a lumen, which lumen is to have a diameter
compatible with
providing leak-proof delivery of drug formulation. Where the drug delivery
device dispenses
drug by convection (as in, e.g., osmotic drug delivery systems), the size of
the catheter lumen
leading from the reservoir of the drug release system can be designed as
described by Theeuwes
(1975) J. Pharnz. Sci. 64:1987-91.
The body of the catheter can be of any shape (e.g., curved, substantially
straight, tapered, etc.).
The distal end of the drug delivery catheter can have one or a plurality of
openings.
The drug delivery catheter may be produced from any of a variety of suitable
materials.
Impermeable materials suitable for use in production of the controlled drug
release device as
described above are generally suitable for use in the production of the drug
delivery catheter.
Exemplary materials include, polymers; metals; glasses; polyolefins (high
density polyethylene
(HDPE), low density polyethylene (LDPE), linear low density polyethylene
(LLDPE),
polypropylene (PP), and the like); nylons; polyethylene terephtholate;
silicones; urethanes; liquid
crystal polymers; PEBAX°; HYTREL°; TEFLON~; perflouroethylene
(PFE) perflouroalkoxy
resins (PFA); poly(methyl methacrylate) (PMMA); multilaminates of polymer,
metals, and/or
glass; nitinol; and the like.
The drug delivery catheter can comprise additional materials or agents (e.g.,
coatings on the
external or internal catheter body surface(s)) to facilitate placement of the
drug delivery catheter
and/or to provide other desirable characteristics to the catheter. For
example, the drug delivery
catheter inner and/or outer walls can be coated with silver or otherwise
coated or treated with
CA 02497867 2005-03-04
WO 2004/022069 PCT/US2002/028519
antimicrobial agents, thus further reducing the risk of infection at the site
of implantation and
drug delivery.
In one embodiment, the drug delivery catheter is primed with a drug-comprising
formulation,
e.g., is substantially pre-filled with drug prior to implantation. Priming of
the drug delivery
catheter reduces delivery start-up time, i.e., time related to movement of the
drug from the drug
delivery device to the distal end of the drug delivery catheter.
Devices for Use in the Invention
Delivery of a glutamate neuromodulatory agent to a middle-inner ear membrane
(e.g., the round
window niche for perfusion across the round window membrane or annular
ligament of the
stapes footplate) can be accomplished through use of a delivery device such as
those described in
described in U.S. Pat. Nos. 5,421,818, which describe various treatment
systems comprising a
reservoir for a therapeutic agent and, in various embodiments, a fluid
transfer means (e.g., pores,
a semi-permeable membrane, and the like) which allows fluid materials to be
delivered to, for
example, the round window membrane for subsequent diffusion into the inner
ear. In another
embodiment, the device comprises a plurality of reservoir portions and
multiple stem portions
designed for implantation into, for example, the endolymphatic sac and duct
using standard
microsurgical techniques. In still another embodiment, the apparatus comprises
a reservoir
portion for retaining liquid medicine materials therein, and first and second
stems. The second
stem can reside within the patient's external auditory canal lateral to the
ear drum, with the first
stem residing within, for example, an opening formed in the stapes
footplate/annular ligament so
that medicine materials can be delivered to the inner ear from the reservoir
portion.
Another device suitable for use in the invention is described in U.S. Pat. No.
6,045,528. The
device described in this patent comprises one or more fluid transfer conduits
connected to a
cover member that can be placed over or at least partially within the round
window niche, and in
some embodiments forms a liquid resistant fluid-receiving zone within the
round window niche.
The cover member can be a plate-like structure or can comprise a compressible
material.
PCT Publication No. WO 00/04854 describes another device suitable for use in
the invention,
which device comprises a fluid transfer conduit comprising one or more
passageways
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therethrough. An inflatable bladder attached to the conduit, and is sized for
insertion at least
partially within an internal cavity of the ear (e.g., the round window niche).
When inflated, the
bladder engages the internal side wall of the internal cavity to secure the
bladder and part of the
conduit within the internal cavity, thus allowing transfer of fluids to and
from the internal cavity.
Implantation and Deliver~Sites
In a particular embodiment, a drug delivery device can be implanted at any
suitable implantation
site using methods and devices well known in the art. Implantation sites
include, but are not
necessarily limited to a subdermal, subcutaneous, intramuscular, or other
suitable site within a
subject's body, e.g., at a subcutaneous site near the ear, e.g., behind the
external auditory meatus
of the ear. Subcutaneous implantation sites are preferred because of
convenience in implantation
and removal of the drug delivery device. Delivery of drug from a drug delivery
device at an
implantation site that is distant from a delivery site can be accomplished by
providing the drug
delivery device with a catheter.
The drug delivery device can be entirely or at least partially within an
internal cavity of the ear,
and, in a preferred embodiment, at least partially within the round window
niche, e.g., either
spaced apart from the round window membrane or positioned against and/or
adjacent the
membrane.
Many different methods may be used to insert the agent, or device comprising
the agent, into the
ear for delivery of agent to a middle-inner ear membrane. For example, agent
formulation can be
injected into the middle ear through the tympanic membrane, and may be
specifically placed
within, for example, the round window nice to facilitate contact of the agent
formulation with a
middle-inner ear membrane. Alternatively a drug delivery device can be
inserted into the middle
ear for delivery of agent to the middle ear, or more directly to the round
window membrane
structure. In another embodiment, a drug delivery device is positioned
external to the middle
ear, and a catheter or other drug delivery conduit operably attached to the
drug delivery device
provides for delivery of drug from a reservoir of the device and to the middle
ear, e.g., to the
round window membrane.
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Insertion of a drug delivery device can be accomplished by passing the device
or a portion of the
device (using an appropriate microsurgical instrument of conventional design)
through or under
the tympanic membrane. The tympanic membrane preferably has an incision that
allows the
drug delivery device, or a portion thereof, to pass through. Alternatively,
the device or a portion
thereof can be inserted into the middle ear beneath a tympanomeatal flap.
Proper orientation
and/or insertion of a drug delivery device can be accomplished through the use
of a conventional
operating microscope or otologic endoscope apparatus for example of the type
disclosed in U.S.
Patent No. 5,419,312 to Arenberg et al.
Placement of the drug delivery device is in a manner so that drug from the
device will come in
contact with at least a portion of a middle-inner ear membrane. Packing
materials of the type
normally used for medical applications can be employed within the ear to
secure the drug
delivery device in its desired position within an internal cavity of the ear.
Agent is released from
the drug delivery device upon reaching the round window membrane, and travels
through a
membrane or other structure that provides an interface between the middle and
inner ear, and
into the inner ear.
In general, the drug delivery systems and methods provide numerous benefits
and capabilities
including: (1) the repeatable and sustained delivery of therapeutic agents
into the inner ear
through the round window membrane; (2) the delivery of many different
therapeutic agents (e.g.
pharmaceutical preparations) to the inner ear in a safe and direct manner; (3)
the accomplishment
of effective drug delivery without overly invasive surgical procedures; and
(4) the use of a
simplified method to deliver therapeutic agents into the inner ear of a
patient without complex
medical procedures, monitoring, and patient discomfort.
E~~AMPLES
Methods and Materials
Animal Model of Human Inner Ear.
Experiments were performed on adult guinea pigs weighing from about 250g to
300g. The
animals were anaesthetized with urethane (1.4 glkg, i.p.) and artificially
respired. Supplemental
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doses of urethane (0.35 g/kg, i.p.) were administered every 2 hr, or more
often if the animal
withdrew its paw in response to pressure applied to the paw. The rectal
temperature was
maintained at about 38.5 ~ 1 °C, and heart rate (normal range 260 - 330
beats/min) monitored
using EI~G electrodes. The external auditory canal was opened near the
tympanic annulus,
exposing the tympanic membrane and allowing sound to reach the drum without
any obstruction.
At the end of the experiment, the animals were euthanized by intracardiac
injection of an
overdose of sodium pentobarbitone.
Intracochlear perfusion.
Methods for intracochlear perfusion were generally performed as described in
Puel 1995
Neurobiology 47:449-476. Briefly, after the cochlea was exposed ventrally and
the middle ear
muscles severed, 10-min perfizsions of a selected drug were performed through
a hole made in
the scale tympani, at the rate of 2.5 microlitres/min, and the drug was
allowed to flow out of the
cochlea through a hole made in the scala vestibuli. Measurements were taken
before and after
perfusion of placebo, and after cumulative perfusion of increasing
concentrations of agent. At
the end of each experiment, the cannula was flushed with artificial perilymph
to evaluate the
reversibility of the agent's effect. The artificial perilymph solution had the
following
compositions: 1.37 xnM NaCl; 5 mM ICI; 2 mM CaCl2; 1 mM MgCl2; 1 mM NaHC03; 11
mM
glucose, pH 7.4, osmolarity (302 ~ 4.2 mosmol/kg HZO). Five to ten guinea pigs
were used in
each experimental group.
D-APS and MIA 801 was formulated by dissolution in water to a final
concentration varying from
to 1000 micromolar, 7-chlorokinurenate and gacyclidine was dissolved in 100%
DMSO to
final concentrations of from 1 to 100 micromolar.
Perfusion Across The Round Window Membrane.
Drugs were delivered to the round window membrane at the rate of 1 ~,1 drug
solution per hour
using an animal RWE-CathT"" attached to an AlzetT"" Osmotic Pump for up to 14
days, providing
a model of chronic delivery to the inner ear. The AlzetT"" Osmotic Pump was
primed with the
highest concentration that did not cause change in the CAP amplitude, increase
in CAP latency
or decrease in CM amplitude in intracochlear perfusion experiments.
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Experiments were performed in order to determine the highest concentration of
agent that
provides a significant beneficial effect, but does not cause a change in the
CAP amplitude, CAP
latency, or decrease CM amplitude. If the concentration of drug did change the
CAP amplitude,
increase the CAP latency, or decrease the CM amplitude, lower concentrations
(not lower flow
rates) were tested. If the concentration of drug did not change the CAP
amplitude, increase the
CAP latency, or decrease the CM amplitude, higher concentrations (not higher
flow rates) were
tested. Five guinea pigs were used in each experimental group.
Stimulation And Recording Technidue.
Tone bursts (1 ms rise/fall time, 9 ms duration) were generated by an
arbitrary function generator
(LeCroy Instrument type 9100R) at a rate of 10 times per second. Acoustic
stimuli were
amplified and delivered in a closed system via a Bruel and Kjaer microphone
(type 4134).
Intensity amplitude-functions were obtained by varying tone burst intensities
(0-100 dB SPL
(Sound Pressure Level) in 5 dB steps). The compound action potential of the
auditory nerve
(CAP: Nl-P1), Nl latency, cochlear microphonic (CM) and summating potential
(SP) were
recorded from a silver electrode coated with Teflon (except for the tip)
placed in a third hole
made in the scala vestibuli of the basal turn of to choclea. The potentials
were amplified
(Tektronic TM 503, gain 1000) averaged (256 samples) and stored on a Pentium
PC computer.
The sampling rate of the A/D converter was 50 kHz with a dynamic range of 12
bits and 1024
samples per record. The threshold of the CAP was defined as the dB SPL needed
to elicit a
measurable response (>_ 1 microVolt).
Statistical analysis. Analysis of variances (ANQVA) and Newmann-Keuls multiple
range test
were used to determine the significance (p < 0,05) of agent effects. Data is
expressed as the
mean ~ standard error.
Salicylate Tinnitus Model. Salicylate, the active component of aspirin, is of
special concern in
auditory science because it induces tinnitus in humans. The efficacy of agents
to treat tinnitus
was tested by measuring firing rate of the auditory nerve fibers in presence
of salicylate.
The method of recording single unit responses from the auditory nerve during
direct application
of drugs into the cochlea has been already described elsewhere (J. Ruel, C.
Chen, R. Pujol, R. P.
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Bobbin, J. L. Puel, JPhysiol. 518, 667, 1999). Briefly, the test solutions
were applied into the
cochlea using a mufti-barrel perfusion pipette (ASI Instruments) placed into a
hole made in the
basal turn scala tympani and allowed to flow out of the cochlea through a hole
(0.2 mm
diameter) made at the apex . The cochlear nerve was exposed using a posterior
fossa approach.
Extracellular action potentials from single auditory nerve fibers were
recorded with glass
microelectrodes. Once a single unit was isolated, spontaneous activity was
averaged over 10
seconds. The unit's tuning curves were then determined by a computer-
controlled, threshold-
tracking program using a 200 ms tone burst presented at 3/s. The threshold
criterion was a
difference of 10 spikes/s, i.e., 2 spikes difference between the tone (200 ms)
and non-tone (200
ms) counting intervals. The program determined the characteristic frequency
(CF) and the
frequency tuning of the fiber by measuring the QloaB defined as the CF divided
by the bandwidth
at 10 dB above the CF threshold.
A critical step in the initiation of the action potential is the activation of
the postsynaptic
receptors by the glutamate (Glu), the endogenous neurotransmitter released by
the sensory inner
hair cells (elsewhere (J. Ruel, C. Chen, R. Pujol, R. P. Bobbin, J. L. Puel,
JPlaysiol. 518, 667,
1999). The hypothesis that sodium-salicylate modulates fast cochlear synaptic
neurotransmission by acting on alpha-amino-3-hydroxy-5-methyl-4-isoxasole-
propionate
(AMPA) receptors was proposed. As shown in Fig. lb, blocking AMPA receptors
with 50 pM
the AMPA agonist GYKI 53784 (Neuropharm. 30 1959-1973, 2000) blocked both
spontaneous
activity and those evoked induced by sodium-salicylate or sound. Another
possibility was an
action of salicylate on N-Methy-D-Aspartate (NMDA) receptors. Although
intracochlear
perfusion of 10 ~M MK-801, 50 ~.M gacyclidine or 50 pM 7-chlorokynurenic acid
(7-CK) had
no effect on spontaneous activity of the auditory fibers, NMDA antagonists
suppressed neural
excitation induced by sodium-salicylate (Fig. 1 c). Thus, excitatory action of
sodium-salicylate
on auditory nerve activity requires the activation of cochlear NMDA.
Example 1: The Comparative Effect Of Acute Intracochlear Perfusion And Chronic
Round
Window Perfusion of Riluzole
Because acute intracochlear perfusion (AICP) is not practical in humans, the
inventors
investigated whether a safe and therapeutic effect could be achieved via round
window choclear
perfusion (RWCP).
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The comparative effect of acute intracochlear perfusion and chronic round
window perfusion
was investigated. Results are shown in Fig. 2, in which the graphs represent
the mean amplitude
of the CAP as the function of the intensity of 8kHz tone burst stimulation.
Mean threshold was
calculated from 5 different animals. Note that both acute intracochlear and
chronic round
window application of Riluzole reduce the CAP amplitude in a dose-dependent
manner.
However, the effect was 10 times less potent when the drug was applied onto
the round window.
The aim of the study was to compare the effect of acute intracochlear
perfusion (AICP) with
chronic round window perfusion (CRWP) on the normal functioning of the
cochlea. These
graphs (Fig. 2) represent the mean amplitude of the CAP as the function of the
intensity of 8kHz
tone burst stimulation. Mean threshold has been calculated from 5 different
animals. Graph A
shows acute intracochlear window application of Riluzole reduced the CAP
amplitude. Graph B
shows chronic round window application of Riluzole also reduced the CAP
amplitude in the dose
dependent manner. Note the need to increase concentration by 10 times to get
the same effect on
CAP. From this experiment it can be concluded that Riluzole retains its
activity in the inner ear
following chronic perfusion across the round window membrane.
Example 2: The Protective Effect Of Riluzole On Intense Noise Induced Acoustic
Trauma
As has already been shown, acute cochlear perfusion of Riluzole rescues
hearing after noise
induced hearing loss (Wang et al., Neuroscience 2002, 111,635-648). An
experiment was done to
determine the protective effect of Riluzole on intense noise induced acoustic
trauma. The results
are shown in Fig. 3, which shows CAP (Compound Action Potential) audiograms
(threshold
shifts as the fiuiction of tone frequency) were measured 2 days after 30
rr~inutes of continuous
sound exposure. Threshold shift was calculated as the difference in the
recording before and 2
days after 6kHz continuous tone exposure. Shown are threshold shift recorded
after 120 dB SPL
exposure during 30 minutes in presence of artificial perilymph (red curve,
control). Note the clear
protection of 100 ~M Riluzole when either applied directly into the cochlea
(blue curve, intra) or
onto the round window (green curve, RW). The letter "n" represents the number
of tested animals
The goal of this experiment was to prove that Riluzole is effective in
protecting the inner ear
from noise trauma when applied onto the round window membrane. Control animals
were
implanted with an osmotic mini-pump containing artificial perilymph alone.
Exposure to 120 dB
SPL pure tone (6 kHz, for 30 min.) immediately (within 20 min) resulted in 50-
60 dB permanent
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threshold shift 2 days after sound exposure (see Wang et al., Neuf~osciehce,
if2 press). When 100
~M Riluzole was applied into the cochlea, a clear recovery of threshold was
observed. The same
effect was obtained when Riluzole was applied onto the round window. From this
experiment it
can be concluded that perfusion of Riluzole onto the round window membrane is
effective in
protecting the inner ear from noise trauma.
Example 3 ~ Effect of Perfusion Of Glutamate Antagonists On Salicylate-Induced
Excitation
An experiment was carried out to determine the ability of perfused Glutamate
antagonists to
suppress salicylate-induced excitation. The results are shown in Fig. 4.
Fig 4A shows the results from an original recording from an auditory nerve
fiber coding for 8
kHz with a spontaneous rate of 8 spikes s 1. Intracochlear perfusion of
control artificial
periphymph (AP) containing 100 ~M indomethacin (open bar) did not change the
spontaneous
activity of the auditory nerve fiber. In contrast, application of 5 mM of
sodium-salicylate
(Nasal; black bar) reversibly increased spontaneous firing of the auditory
nerve fibers.
Fig. 4B shows results from a nerve fiber coding for 9 kHz with a spontaneous
rate activity of 7
spikes s 1. Blocking of AMPA receptors with 50 ~,M the AMPA agonist GYKI 53784
(Neuropharm. 30 1959-1973, 2000) (open bar) blocked both the spontaneous and
the evoked
activity by 5 mM Nasal (black bar).
Fig. 4C shows results from a nerve fiber coding for 7,5 kHz with a spontaneous
rate of 5 spikes
s 1. Sodium-salicylate was continuously applied. Repetitive application (Open
bars) with the
NMDA antagonist 7 CK (50 ~M, n = 5) suppressed neural excitation of auditory
nerve induced
by Nasal, but not the spontaneous activity of the fiber
Similar results were obtained with 10~M MK 801 and GK-11. Thus, excitatory
action of
sodium-salicylate on auditory nerve activity requires the activation of
cochlear NMDA, but not
AMPA receptors. From this experiment it can be concluded that perfusion of
glutamate
antagonists suppressed excitation of the auditory nerve induced by salicylate
Examt~le 4' Effect of NMDA antagonists on salicylate-induced tinnitus
To verify that the excitatory action of sodium-salicylate on the auditory
nerve fibers results in
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perception of tinnitus, a behavioral model was designed in rats based upon an
active avoidance
task. Animals were trained to respond to a conditioned stimulus consisting of
a 10 kHz tone burst
of 3 s duration. Experiments were carried out and the results are shown in
Fig. 5.
Fig SA shows results for the number of positive responses in response to
sound, as a percentage
of the total (Score %) to sound vs. time in days, with salicylate being
delivered between days 2
and 5.
Fig SB shows the results for the number of responses without sound (false
positives), with
salicylate being delivered between days 2 and 5. Using this behavioral
paradigm, treatment with
saline solution (daily injections during 4 days, i.p.) did not change the
score or false positive
numbers. In contrast, sodium-salicylate treatment (daily injection, 300
mg/kg/day during 4 days,
i.p.) provoked a reversible reduction of the score and a drastic increase of
the number of false
positives.
Fig SC shows the results for compound action potential (CAP) audiograms in
behavioral trained
animals recorded before (day 0), during (day 3 and day 4) and after salicylate
treatment (day 6).
CAP thresholds were measured using an electrode chronically implanted on round
window in
response to a tone burst of 1 ms rise/fall time and 9 ms duration presented at
a rate of 10 times
per second. Salicylate treatment (daily injection, 300 mg/kg/day during 4
days, i.p.) induced a 30
dB hearing loss across frequency range from 2 to 26 I~HHz.
Fig SD shows CAP threshold shift at 10 kHz before, during and after salicylate
treatment. CAP
threshold shifts were calculated as the difference in dB between the auditory
threshold at day 0
and the auditory threshold at each day. To avoid changes due to hearing loss,
the intensity of
sound eliciting behavioral responses was adjusted as a function of CAP
threshold shift.
Fig SE shows that no significant decrease in the score was observed, with
salicylate being
delivered between days 2 and 5.
Fig SF shows that false positive responses still remained after salicylate
treatment. This
demonstrates that the increased number of false positive responses during
sodium-salicylate
treatment was due to the occurrence of tinnitus, and not to hearing loss.
Gelfoam placed on the
round window was used to apply drugs into the fluid of the cochlea. (G) Note
that the score
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remained unchanged. In contrast, round window application of 50 ~.M of 7-CK
blocked the
occurrence of false positive responses. Findings indicate that tinnitus
induced by sodium-
salicylate requires activation of cochlear NMDA receptors. From this
experiment it can be
concluded that round window perfusion of NMDA antagonists suppresses tinnitus
induced by
salicylate.
Example 4~ Comparative effect of I~A antagonists on salicylate-induced
tinnitus
To support the hypothesis that salicylate induced false positive via cochlear
NMDA receptors,
we applied other NMDA antagonists into the perilyrnphatic fluids using gelfoam
placed on the
round window of both ears. Local application of control artificial perilymph
did not influence
the decrease of the score (Fig 6) or the increase of the number of false
positive responses induced
by salicylate (Fig 6). In contrast, local application of 10 ~M of MK 801; 50
~M of 7-CK or 50
~M of gacyclidine strongly reduced the occurrence of false positive responses
induced by
salicylate, the reduction of the score still been unchanged (Fig 6). When
compared with the
control artificial perilymph animals at day 4 (6.2 false positives ~ 0.86),
the number of false
positive responses fell to 0.7 ~ 0.21; 0.7 ~ 0.26 and 1 ~ 0.21 for MK 801, 7-
CK and gacyclidine
respectively (Fig SC). Altogether, these results provides evidence salicylate
acts on cochlear fast
synaptic transmission via the activation of NMDA receptors, accounting for the
occurrence of
tinnitus
Conclusion
From the above experiments It can be concluded that human tinnitus is produced
by aberrant
glutamate-mediated neurotransmission mediated by NMDA receptors, and that I~A
receptor
antagonist may be used to treat such tinnitus. The current disclosure suggests
that specific
NMDA receptor antagonists block salicylate-induced tinnitus without causing
undesired hearing
loss associated with suppression of AMPA receptor-mediated signals. Such NMDA
antagonists
may be include (but are not limited to) D-APS (D-2-amino-5-
phosphonopentanoate), Dizocilpine
(MK 801), 7-chlorokynurenate or Gacyclidine (GK-11). Such treatment includes
delivery onto
or in the vicinity of the round window niche of the inner ear, for example to
the middle-inner
membrane or to the annular ligament of the stapes footplate. Analogues and
derivatives of such
drugs may equally be used.
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Having herein described preferred embodiments of the invention, it is
anticipated that suitable
modifications may be made thereto by individuals skilled in the art, which
nonetheless remain
within the scope of the invention. For example, the invention shall not be
limited with respect to
the exemplary compositions used or construction materials being employed. In
this regard, the
invention shall only be construed in accordance with the following claims:
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