U.S. patent application number 15/291527 was filed with the patent office on 2017-02-02 for 1-aminocyclohexane derivatives for the treatment of cochlear tinnitus.
The applicant listed for this patent is MERZ PHARMA GmbH & CO. KGaA. Invention is credited to Michael Althaus, Barbara Ellers-Lenz, Hagen Kruger, Tanja Rosenberg.
Application Number | 20170027885 15/291527 |
Document ID | / |
Family ID | 40451596 |
Filed Date | 2017-02-02 |
United States Patent
Application |
20170027885 |
Kind Code |
A1 |
Ellers-Lenz; Barbara ; et
al. |
February 2, 2017 |
1-AMINOCYCLOHEXANE DERIVATIVES FOR THE TREATMENT OF COCHLEAR
TINNITUS
Abstract
The present invention relates to the treatment of an individual
afflicted with tinnitus associated with hearing loss comprising
administering to the individual an effective amount of a
1-amino-alkylcyclohexane derivative.
Inventors: |
Ellers-Lenz; Barbara;
(Moerfelden-Walldorf, DE) ; Rosenberg; Tanja;
(Frankfurt am Main, DE) ; Kruger; Hagen; (Hamburg,
DE) ; Althaus; Michael; (Schoeneck, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MERZ PHARMA GmbH & CO. KGaA |
FRANKFURT am MAIN |
|
DE |
|
|
Family ID: |
40451596 |
Appl. No.: |
15/291527 |
Filed: |
October 12, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12733646 |
Nov 15, 2010 |
9498450 |
|
|
PCT/EP2008/007421 |
Sep 10, 2008 |
|
|
|
15291527 |
|
|
|
|
60993396 |
Sep 12, 2007 |
|
|
|
61066931 |
Feb 25, 2008 |
|
|
|
61067026 |
Feb 25, 2008 |
|
|
|
61067083 |
Feb 25, 2008 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 31/13 20130101; A61K 9/2054 20130101; A61P 25/00 20180101;
A61K 45/06 20130101; A61P 1/08 20180101; A61P 27/00 20180101; A61P
27/16 20180101 |
International
Class: |
A61K 31/13 20060101
A61K031/13; A61K 45/06 20060101 A61K045/06 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 12, 2007 |
EP |
07253630.3 |
Mar 14, 2008 |
EP |
08004776.4 |
Mar 14, 2008 |
EP |
08004777.2 |
Mar 14, 2008 |
EP |
08004778.0 |
Claims
1. A method of treating or preventing tinnitus associated with
hearing loss in a subject in need thereof, comprising administering
an effective amount of a 1-amino-alkylcyclohexane derivative.
2. The method of claim 1, wherein the tinnitus is associated with
mild hearing loss.
3. The method of claim 1, wherein the 1-amino-alkylcyclohexane
derivative is neramexane or a pharmaceutically acceptable salt
thereof.
4. The method of claim 3, wherein the 1-amino-alkylcyclohexane
derivative is neramexane mesylate.
5. The method of claim 4, wherein neramexane mesylate is
administered in a range from about 5 mg to about 150 mg/day.
6. The method of claim 4, wherein neramexane mesylate is
administered in a range from about 5 mg to about 100 mg/day.
7. The method of claim 4, wherein neramexane mesylate is
administered in a range from about 5 mg to about 75 mg/day.
8. The method of claim 4, wherein neramexane mesylate is
administered at about 50 mg/day.
9. The method of claim 4, wherein neramexane mesylate is
administered at about 75 mg/day.
10. The method of claim 3, wherein neramexane or a pharmaceutically
acceptable salt thereof is administered once a day, twice a day
(b.i.d.), or three times a day.
11. The method of claim 10, wherein neramexane or a
pharmaceutically acceptable salt thereof is administered twice a
day.
12. The method of claim 3, wherein neramexane or a pharmaceutically
acceptable salt thereof is administered in an immediate release
formulation.
13. The method of claim 3, wherein neramexane or a pharmaceutically
acceptable salt thereof is administered in a modified release
formulation.
14. The method of claim 1, wherein an additional pharmaceutical
agent which has been shown to be effective in treating or
preventing tinnitus and, optionally, at least one pharmaceutically
acceptable carrier or excipient is administered.
15. The method of claim 1, wherein an additional pharmaceutical
agent selected from antidepressants or anti-anxiety drugs, dopamine
antagonists, Alpha2Delta ligands, and NK1 antagonists and,
optionally, at least one pharmaceutically acceptable carrier or
excipient is administered.
16. The method of claim 15, wherein the antidepressant or the
anti-anxiety drug is a selective serotonin reuptake inhibitor
(SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), a
noradrenergic and specific serotonergic antidepressant (NASSA), a
norepinephrine (noradrenaline) reuptake inhibitor (NRI), a
norepinephrine-dopamine reuptake inhibitor, or a serotonin 1A
agonist.
17. The method of claim 15, wherein the 1-amino-alkylcyclohexane
derivative is neramexane or a pharmaceutically acceptable salt
thereof.
18. The method of claim 17, wherein neramexane, or a
pharmaceutically acceptable salt thereof, and the additional
pharmaceutical agent are administered conjointly.
19. The method of claim 18, wherein neramexane, or a
pharmaceutically acceptable salt thereof and the additional
pharmaceutical agent are administered in a single formulation.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the treatment of an
individual afflicted with cochlear tinnitus comprising
administering to the individual an effective amount of a
1-amino-alkylcyclohexane derivative.
BACKGROUND OF THE INVENTION
[0002] Tinnitus is commonly referred to as `ringing in the
ears`--the perception of sounds in the absence of an external
source of acoustic signals. Tinnitus has been defined as "the
perception of a sound which results exclusively from the activity
within the nervous system without any corresponding mechanical,
vibratory activity within the cochlea, that is, tinnitus as an
auditory phantom perception" (Jastreboff et al., J Am Acad Audiol
2000; 11(3): 162-177). Tinnitus is frequently associated with a
decreased sound tolerance (i.e. hyperacusis).
[0003] The pathophysiology of subjective tinnitus is poorly
understood and a definitive pathogenesis of tinnitus is unknown.
Many environmental and substance-induced factors may cause
tinnitus. Among the most frequently cited factors are acute
acoustic trauma, occupational noise, and recreational music. In
general, tinnitus seems to be the result of neuronal dysfunction
within the auditory pathway. This dysfunction is misleadingly
perceived as sound by higher auditory centers and can lead to
functional alterations within the auditory nervous system.
Maladaptive functional changes in cortical structures could result
in an altered balance between excitatory and inhibitory
neurotransmission and may lead to more severe tinnitus. In all
cases, a potential malfunction in auditory pathways and auditory
cortex is related to the activity of the prefrontal cortex and
limbic system.
[0004] In most cases (95%), the perceived tinnitus is purely
subjective in nature, e.g. no physical source of acoustic signals
can be identified and, therefore, cannot be heard externally. A
physical examination is performed to exclude objective tinnitus,
e.g. the patient's perception of sound is caused by a real source
of sound waves, e.g. the sound from turbulent flow in blood vessels
reaching the cochlea. Tinnitus may be classified according to
duration of tinnitus and the degree of tinnitus expression (e.g.
severity or annoyance of the tinnitus) (McCombe et al., Clin
Otolaryngol 2001; 26(5): 388-393 and Davis et al., Epidemiology of
Tinnitus. In: Tyler R, editor. Tinnitus Handbook. San Diego:
Singular Publishing Group; 2000. p. 1-23). Regarding the impact of
tinnitus, tinnitus may be severely annoying to the patient and may
be accompanied by social and psychological complications.
[0005] It has also been suggested that tinnitus may be further
classified into two groups, peripheral tinnitus and central
tinnitus, based on differences in how the tinnitus is perceived by
the affected individual. Peripheral (or cochlear) tinnitus is
presumed to originate from the peripheral nervous system and
cochlea, and central tinnitus is presumed to originate in the
auditory cortex.
[0006] Cochlear physiology provides some understanding of the
origins of that form of the disease associated with the cochlea.
Two rows of hair cells are found in the cochlea. Outer hair cells
(OHC) actively contract in the presence of sound, and thus augment
incoming low-oscillation signals and modulate the response of inner
hair cells (IHC). Exposure to noise, including constant, repeated
or even one single "blast trauma", can damage cochlear hair cells,
especially their fragile stereocilia. Since the OHC require
substantially more oxygen than the IHC, they are more sensitive to
noise, ototoxic drugs, trauma, etc. Due to the loss of active
amplification, damage to the OHC can result in reduction of the
dynamic range of the auditory system and impaired frequency
selectivity. Uncontrolled contraction of damaged OHC can lead to
stimulation of IHC and to nerve action potentials that are
interpreted as sounds by the brain. Damage to the IHC can lead to
abnormal deflection of the stereocilia, causing the cells to
depolarize, leading to uncontrolled release of neurotransmitters
which, again, can cause the perception of sound without a real
source (Baguley, Br Med Bull. 2002; 63:195-212).
[0007] With the passage of time, higher levels of the auditory
pathway may be involved, and the perception of tinnitus may not
depend on the cochlear pathology any longer. A massive central
amplification takes place, triggered by pathological cognitive
focussing. Presumably, amplifying feedback mechanisms between the
limbic system and cognitive areas of the CNS are established
(Zenner, Ziel. Dtsch Arztebl. 2001; 37:2361-2365).
[0008] While a large number of afferent, mainly glutamatergic nerve
fibers originate at the IHC (Furness, et al., J Neurosci. 2003 Dec.
10; 23(36):11296-11304), the OHC are the target of efferent nerve
fibers with acetylcholine being the principal efferent
neurotransmitter in the cochlea (Dallos et al, J Neurosci. 1997
Mar. 15; 17(6):2212-2226). An excess of glutamate in cochlear
neurons is believed to contribute to tinnitus. Therefore, several
approaches to tinnitus treatment have been made by using NMDA
receptor-blocking substances, such as acamprosate or caroverine.
Studies with these substances have shown limited success, possibly
because the treatment target was mainly the afferent part of the
auditory system while efferent neurotransmission was only
marginally influenced.
[0009] Maison et al (J Neurosci. 2002 Dec. 15; 22(24):10838-10846)
also describe efferent protection from acoustic trauma by
overexpression of the .alpha.9/.alpha.10 nicotinic acetylcholine
receptor complex.
[0010] So far, however, there are no well-established, specific
medical treatments for tinnitus that provide replicable reduction
of tinnitus and annoyance due to tinnitus, in excess of placebo
effects (Dobie, Laryngoscope 1999; 109(8): 1202-1211; Eggermont et
al., Trends Neurosci 2004; 27(11): 676-682; and Patterson et al.,
Int Tinnitus J 2006; 12(2): 149-159). Thus, a need exists for
pharmaceutical products which are effective in treating or
preventing tinnitus.
[0011] 1-Amino-alkylcyclohexanes such as neramexane (also known as
1-amino-1,3,3,5,5-pentamethylcyclohexane) have been found to be
useful in the therapy of various diseases especially in certain
neurological diseases, including Alzheimer's disease and
neuropathic pain. 1-Amino-alkylcyclohexanes such as neramexane are
disclosed in detail in U.S. Pat. Nos. 6,034,134 and 6,071,966, the
subject matter of which patents is hereby incorporated by
reference. It is believed that the therapeutic action of
1-amino-alkylcyclohexanes such as neramexane is related to the
inhibition of the effects of excessive glutamate at the
N-methyl-D-aspartate (NMDA) receptors of nerve cells, for which
reason the compounds are also categorized as NMDA antagonists, or
NMDA receptor antagonists. Neramexane has also been disclosed to
exhibit activity as an .alpha.9/.alpha.10 nicotinic receptor
antagonist (Plazas, et al., Eur J Pharmacol., 2007 Jul. 2;
566(1-3):11-19).
[0012] U.S. Pat. No. 6,034,134 discloses that
1-amino-alkylcyclohexanes may be useful in the treatment of
tinnitus due to their activity as NMDA receptor antagonists.
[0013] The instant inventors have discovered that
1-amino-alkylcyclohexanes, such as neramexane, are effective in
treating cochlear tinnitus.
SUMMARY OF THE INVENTION
[0014] The present invention relates to a 1-amino-alkylcyclohexane
derivative for the treatment or the prevention of cochlear tinnitus
in a subject in need thereof.
[0015] In a further aspect the present invention relates to the use
of a 1-amino-alkylcyclohexane derivative for the manufacture of a
medicament for the treatment or prevention of cochlear tinnitus in
a subject in need thereof. The 1-amino-alkylcyclohexane derivative
may be neramexane or a pharmaceutically acceptable salt thereof
such as neramexane mesylate.
[0016] In a further aspect of the invention such treatment occurs
within three (3) to twelve (12) months of onset of tinnitus (e.g.,
treatment is started within three (3) to twelve months (including
three (3) to eight (8) months) after tinnitus first appears). The
1-amino-alkylcyclohexane derivative may be neramexane or a
pharmaceutically acceptable salt thereof such as neramexane
mesylate.
[0017] In a further aspect of the invention within such treatment
the individual is afflicted with tinnitus associated with hearing
loss or tinnitus associated with mild hearing loss.
[0018] In a further aspect the invention relates to a
1-amino-alkylcyclohexane derivative for the treatment or the
prevention of tinnitus associated with hearing loss or mild hearing
loss and the use of a 1-amino-alkylcyclohexane derivative for the
manufacture of a medicament for the treatment or prevention of
tinnitus associated with hearing loss or mild hearing loss in a
subject in need thereof.
[0019] In a further aspect the invention relates to a
1-amino-alkylcyclohexane derivative for the treatment or the
prevention of tinnitus, wherein treatment occurs within three to
twelve months of onset of tinnitus (sub-acute tinnitus), or wherein
treatment occurs within three to eight months of onset of tinnitus
and to the use of 1-amino-alkylcyclohexane derivative for the
manufacture of a medicament for the treatment or prevention of
tinnitus, wherein treatment occurs within three to twelve months of
onset of tinnitus, or wherein treatment occurs within three to
eight months of onset of tinnitus.
[0020] A further aspect of the invention relates to a
1-amino-alkylcyclohexane derivative (e.g., neramexane or a
pharmaceutically acceptable salt thereof such as neramexane
mesylate) in the form of an immediate or a modified release
formulation for the treatment of cochlear tinnitus.
[0021] A further aspect of the invention relates to the above
defined derivative or use, wherein to the individual a
1-amino-alkylcyclohexane derivative (e.g., neramexane or a
pharmaceutically acceptable salt thereof such as neramexane
mesylate) and at least one additional pharmaceutical agent which
has been shown to be effective in treating tinnitus is
administered.
[0022] A further aspect of the invention relates to the
above-defined derivative or use, wherein to the individual a
1-amino-alkylcyclohexane derivative (e.g., neramexane or a
pharmaceutically acceptable salt thereof such as neramexane
mesylate) and at least one additional pharmaceutical agent selected
from antidepressants or anti-anxiety drugs (such as selective
serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine
reuptake inhibitors (SNRIs), noradrenergic and specific
serotonergic antidepressants (NASSAs), norepinephrine
(noradrenaline) reuptake inhibitors (NRIs), norepinephrine-dopamine
reuptake inhibitors, or serotonin 1A agonists), dopamine
antagonists, Alpha2Delta ligands, and NK1 antagonists is
administered.
[0023] A further aspect of the invention relates to a
1-amino-alkylcyclohexane derivative (e.g., neramexane or a
pharmaceutically acceptable salt thereof such as neramexane
mesylate) in combination with other therapies for tinnitus and,
optionally, at least one pharmaceutically acceptable carrier or
excipient.
[0024] A further aspect of the invention relates to a
1-amino-alkylcyclohexane derivative (e.g., neramexane or a
pharmaceutically acceptable salt thereof such as neramexane
mesylate) in combination with an additional pharmaceutical agent
selected from antidepressants or anti-anxiety drugs (such as
selective serotonin reuptake inhibitors (SSRIs),
serotonin-norepinephrine reuptake inhibitors (SNRIs), noradrenergic
and specific serotonergic antidepressants (NASSAs), norepinephrine
(noradrenaline) reuptake inhibitors (NRIs), norepinephrine-dopamine
reuptake inhibitors, or serotonin 1A agonists), dopamine
antagonists, Alpha2Delta ligands, and NK1 antagonists, and,
optionally, at least one pharmaceutically acceptable carrier or
excipient.
[0025] A further aspect of the invention relates to a
1-amino-alkylcyclohexane derivative (e.g., neramexane or a
pharmaceutically acceptable salt thereof such as neramexane
mesylate) in combination with an additional pharmaceutical agent
selected from antidepressants or anti-anxiety drugs (such as
selective serotonin reuptake inhibitors (SSRIs),
serotonin-norepinephrine reuptake inhibitors (SNRIs), noradrenergic
and specific serotonergic antidepressants (NASSAs), norepinephrine
(noradrenaline) reuptake inhibitors (NRIs), norepinephrine-dopamine
reuptake inhibitors, or serotonin 1A agonists), dopamine
antagonists, Alpha2Delta ligands, and NK1 antagonists, and,
optionally, at least one pharmaceutically acceptable carrier or
excipient for the treatment or the prevention of tinnitus.
[0026] The present invention further relates to a method of
treating or preventing cochlear tinnitus in a subject in need
thereof, comprising administering an effective amount of a
1-amino-alkylcyclohexane derivative, or a pharmaceutically
acceptable salt thereof (e.g., neramexane or a pharmaceutically
acceptable salt thereof such as neramexane mesylate), in a
pharmaceutically acceptable carrier.
[0027] A further aspect of the invention relates to such a method
wherein treatment occurs within three to twelve months of onset of
tinnitus.
[0028] A further aspect of the invention relates to such a method
wherein treatment occurs within three to eight months of onset of
tinnitus.
[0029] A further aspect of the invention relates to such a method
wherein the tinnitus is associated with hearing loss, including
mild hearing loss.
[0030] A further aspect of the invention relates to such a method,
wherein the 1-amino-alkylcyclohexane derivative (e.g., neramexane
or a pharmaceutically acceptable salt thereof such as neramexane
mesylate) is administered in a range from about 5 mg to about 150
mg/day, or wherein the 1-amino-alkylcyclohexane derivative (e.g.,
neramexane or a pharmaceutically acceptable salt thereof such as
neramexane mesylate) is administered in a range from about 5 mg to
about 100 mg/day, or wherein the 1-amino-alkylcyclohexane
derivative (e.g., neramexane or a pharmaceutically acceptable salt
thereof such as neramexane mesylate) is administered at about 5 mg
to about 75 mg/day, or wherein the 1-amino-alkylcyclohexane
derivative (e.g., neramexane or a pharmaceutically acceptable salt
thereof such as neramexane mesylate) is administered at about 50
mg/day, or wherein the 1-amino-alkylcyclohexane derivative (e.g.,
neramexane or a pharmaceutically acceptable salt thereof such as
neramexane mesylate) is administered at about 75 mg/day.
[0031] A further aspect of the invention relates to such a method
wherein the 1-amino-alkylcyclohexane derivative (e.g., neramexane
or a pharmaceutically acceptable salt thereof such as neramexane
mesylate) is administered once a day, twice a day (b.i.d.), or
three times a day.
[0032] A further aspect of the invention relates to such a method
wherein the 1-amino-alkylcyclohexane derivative (e.g., neramexane
or a pharmaceutically acceptable salt thereof such as neramexane
mesylate) is administered twice a day (b.i.d.).
[0033] A further aspect of the invention relates to such a method
wherein the 1-amino-alkylcyclohexane derivative (e.g., neramexane
or a pharmaceutically acceptable salt thereof such as neramexane
mesylate) is administered in an immediate release formulation.
[0034] A further aspect of the invention relates to such a method
wherein the 1-amino-alkylcyclohexane derivative (e.g., neramexane
or a pharmaceutically acceptable salt thereof such as neramexane
mesylate) is administered in a modified release formulation.
[0035] The present invention further relates to a method of
treating or preventing cochlear tinnitus in a subject in need
thereof, comprising administering an effective amount of a
1-amino-alkylcyclohexane derivative, or a pharmaceutically
acceptable salt thereof (e.g., neramexane or a pharmaceutically
acceptable salt thereof such as neramexane mesylate), and an
additional pharmaceutical agent which has been shown to be
effective in treating or preventing tinnitus.
[0036] A further aspect of the invention relates to a method of
treating or preventing tinnitus such as cochlear tinnitus in a
subject in need thereof, comprising administering an effective
amount of a 1-amino-alkylcyclohexane derivative, or a
pharmaceutically acceptable salt thereof (e.g., neramexane or a
pharmaceutically acceptable salt thereof such as neramexane
mesylate), and an additional pharmaceutical agent, wherein the
additional pharmaceutical agent is selected from antidepressants or
anti-anxiety drugs (such as selective serotonin reuptake inhibitors
(SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs),
noradrenergic and specific serotonergic antidepressants (NASSAs),
norepinephrine (noradrenaline) reuptake inhibitors (NRIs),
norepinephrine-dopamine reuptake inhibitors, or serotonin 1A
agonists), dopamine antagonists, Alpha2Delta ligands, and NK1
antagonists
[0037] A further aspect of the invention relates to such a method
wherein the 1-amino-alkylcyclohexane derivative (e.g., neramexane
or a pharmaceutically acceptable salt thereof such as neramexane
mesylate) and the additional pharmaceutical agent are administered
conjointly.
[0038] A further aspect of the invention relates to such a method
wherein the 1-amino-alkylcyclohexane derivative (e.g., neramexane
or a pharmaceutically acceptable salt thereof such as neramexane
mesylate) and the additional pharmaceutical agent are administered
in a single formulation.
[0039] The present invention further relates to a method of
treating tinnitus in a subject in need thereof, comprising
administering an effective amount of a 1-amino-alkylcyclohexane
derivative, or a pharmaceutically acceptable salt thereof (e.g.,
neramexane or a pharmaceutically acceptable salt thereof such as
neramexane mesylate), in a pharmaceutically acceptable carrier,
wherein treatment occurs within three to twelve months of onset of
tinnitus.
[0040] A further aspect of the invention relates to such a method
wherein treatment occurs within three to eight months of onset of
tinnitus.
[0041] The present invention further relates to a method of
treating or preventing tinnitus associated with hearing loss
(including mild hearing loss) in a subject in need thereof,
comprising administering an effective amount of a
1-amino-alkylcyclohexane derivative, or a pharmaceutically
acceptable salt thereof (e.g., neramexane or a pharmaceutically
acceptable salt thereof such as neramexane mesylate), in a
pharmaceutically acceptable carrier.
[0042] The present invention further relates to a pharmaceutical
composition for the treatment or the prevention of cochlear
tinnitus comprising a therapeutically effective amount a
1-amino-alkylcyclohexane derivative, or a pharmaceutically
acceptable salt thereof (e.g., neramexane or a pharmaceutically
acceptable salt thereof such as neramexane mesylate), and at least
one pharmaceutically acceptable carrier or excipient.
[0043] The present invention further relates to a pharmaceutical
composition comprising a therapeutically effective amount of a
1-amino-alkylcyclohexane derivative, or a pharmaceutically
acceptable salt thereof (e.g., neramexane or a pharmaceutically
acceptable salt thereof such as neramexane mesylate), in
combination with an additional pharmaceutical agent which has been
shown to be effective for the treatment or the prevention of
tinnitus and, optionally, at least one pharmaceutically acceptable
carrier or excipient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0044] FIG. 1 shows data from a tinnitus pilot study with
neramexane showing the change in
Tinnitus-Beeintrachtigungs-Fragebogen (TBF-12) (i.e., the German
version of the Tinnitus Handicap Inventory or THI) score at the end
of treatment for the 50 mg dose group compared to placebo.
DETAILED DESCRIPTION OF THE INVENTION
[0045] As used herein, the term "tinnitus" includes, but is not
limited to, all manifestations of subjective and objective tinnitus
as well a acute, subacute and chronic forms. It also includes
cochlear tinnitus as well as tinnitus associated with hearing loss
or mild hearing loss.
[0046] As used herein, the term "cochlear tinnitus" refers to
tinnitus in a frequency range of hearing loss. The term cochlear
tinnitus includes motor tinnitus, cochlear motor tinnitus or hair
cell tinnitus. Cochlear tinnitus may be caused by toxic drugs (e.g.
loop diuretics such as frusemide, aminoglycosides such as
gentamicin) or loud sound exposure (e.g. acoustic trauma, chronic
occupational noise).
[0047] As used herein the term "sub-acute tinnitus" includes
tinnitus of a duration of three (3) to twelve (12) months.
[0048] As used herein the term "hearing loss" (or "hearing
impairment") is a full or partial loss of the ability to detect
sounds or to distinguish among different sounds. Hearing loss is
diagnosed clinically by an increased hearing threshold level in a
pure tone audiogram. The hearing threshold level of left/right ear
in decibel (dB) may be calculated as the average of the actual
numbers at different frequencies on a pure tone audiogram, ie. as
the average hearing level threshold levels at 0.25, 0.5, 1, 2 and 4
kHz. There are different degrees of hearing loss. Hearing loss is
defined herein as "mild hearing loss" (or "mild hearing
impairment") if the hearing threshold level is within 20-40 decibel
(dB). Noise-induced tinnitus associated with hearing loss may be
caused by acute or chronic conditions. Long-term exposure to
excessive noise is the more common cause of noise-induced tinnitus
associated with hearing loss; however, such tinnitus associated
with hearing loss may also be caused by extremely loud sounds.
Sensorineural tinnitus associated with hearing loss is due to
insensitivity of the inner ear or to impairment of function in the
auditory nervous system. Sensorineural tinnitus associated with
hearing loss may be caused by abnormalities in the hair cells of
the organ of the Corti in the cochlea.
[0049] Within the present application the term "subject"
encompasses mammals including animals and humans.
[0050] The term 1-amino-alkylcyclohexane derivative is used herein
to describe a compound which is a 1-amino-alkylcyclohexane or a
compound derived from 1-amino-alkylcyclohexane, e.g.
pharmaceutically acceptable salts of 1-amino-alkylcyclohexanes. The
present 1-amino-alkylcyclohexane derivatives may also be described
as "1-aminocyclohexane derivatives."
[0051] The 1-amino-alkylcyclohexane derivatives of the present
invention may be represented by the general formula (I):
##STR00001##
wherein R* is
--(CH.sub.2).sub.n--(CR.sup.6R.sup.7).sub.m--NR.sup.8R.sup.9
wherein n+m=0, 1, or 2 wherein R.sup.1 through R.sup.7 are
independently selected from the group consisting of hydrogen and
C.sub.1-6alkyl, wherein R.sup.8 and R.sup.9 are independently
selected from the group consisting of hydrogen and C.sub.1-6alkyl
or together represent lower-alkylene --(CH.sub.2).sub.x-- wherein x
is 2 to 5, inclusive, and optical isomers, enantiomers, hydrates,
and pharmaceutically-acceptable salts thereof.
[0052] Non-limiting examples of the 1-amino-alkylcyclohexanes used
according to the present invention include: [0053]
1-amino-1,3,5-trimethylcyclohexane, [0054]
1-amino-1(trans),3(trans),5-trimethylcyclohexane, [0055]
1-amino-1(cis),3(cis),5-trimethylcyclohexane, [0056]
1-amino-1,3,3,5-tetramethylcyclohexane, [0057]
1-amino-1,3,3,5,5-pentamethylcyclohexane (neramexane), [0058]
1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane, [0059]
1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane, [0060]
1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane, [0061]
1-amino-(1S,5S)cis-3-ethyl-1,5,5-trimethylcyclohexane, [0062]
1-amino-1,5,5-trimethyl-trans-3-ethylcyclohexane, [0063]
1-amino-(1R,5S)trans-3-ethyl-1,5,5-trimethylcyclohexane, [0064]
1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane, [0065]
1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane, [0066]
N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, [0067]
N-ethyl-1-amino-1,3,3,5,5-pentamethyl-cyclohexane, [0068]
N-(1,3,3,5,5-pentamethylcyclohexyl) pyrrolidine, [0069]
3,3,5,5-tetramethylcyclohexylmethylamine, [0070] 1
amino-1,3,3,5(trans)-tetramethylcyclohexane (axial amino group),
[0071] 3-propyl-1,3,5,5-tetramethylcyclohexylamine semihydrate,
[0072] 1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane, [0073]
1-amino-1,3,5-trimethylcyclohexane, [0074]
1-amino-1,3-dimethyl-3-propylcyclohexane, [0075]
1-amino-1,3(trans),5(trans)-trimethyl-3(cis)-propylcyclohexane,
[0076] 1-amino-1,3-dimethyl-3-ethylcyclohexane, [0077]
1-amino-1,3,3-trimethylcyclohexane, [0078]
cis-3-ethyl-1(trans)-3(trans)-5-trimethylcyclohexamine, [0079]
1-amino-1,3(trans)-dimethylcyclohexane, [0080]
1,3,3-trimethyl-5,5-dipropylcyclohexylamine, [0081]
1-amino-1-methyl-3(trans)-propylcyclohexane, [0082]
1-methyl-3(cis)-propylcyclohexylamine, [0083]
1-amino-1-methyl-3(trans)-ethylcyclohexane, [0084]
1-amino-1,3,3-trimethyl-5(cis)-ethylcyclohexane, [0085]
1-amino-1,3,3-trimethyl-5(trans)-ethylcyclohexane, [0086]
cis-3-propyl-1,5,5-trimethylcyclohexylamine, [0087]
trans-3-propyl-1,5,5-trimethylcyclohexylamine, [0088]
N-ethyl-1,3,3,5,5-pentamethylcyclohexylamine, [0089]
N-methyl-1-amino-1,3,3,5.5-pentamethylcyclohexane, [0090]
1-amino-1-methylcyclohexane, [0091]
N,N-dimethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, [0092]
2-(3,3,5,5-tetramethylcyclohexyl)ethylamine, [0093]
2-methyl-1-(3,3,5,5-tetramethylcyclohexyl)propyl-2-amine, [0094]
2-(1,3,3,5,5-pentamethylcyclohexyl)-ethylamine semihydrate, [0095]
N-(1,3,3,5,5-pentamethylcyclohexyl)-pyrrolidine, [0096]
1-amino-1,3(trans),5(trans)-trimethylcyclohexane, [0097]
1-amino-1,3(cis),5(cis)-trimethylcyclohexane, [0098]
1-amino-(1R,5S)trans-5-ethyl-1,3,3-trimethylcyclohexane, [0099]
1-amino-(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexane, [0100]
1-amino-1,5, 5-trimethyl-3(cis)-isopropyl-cyclohexane, [0101]
1-amino-1,5,5-trimethyl-3(trans)-isopropyl-cyclohexane, [0102]
1-amino-1-methyl-3(cis)-ethyl-cyclohexane, [0103]
1-amino-1-methyl-3(cis)-methyl-cyclohexane, [0104]
1-amino-5,5-diethyl-1,3,3-trimethyl-cyclohexane, [0105]
1-amino-1,3,3,5,5-pentamethylcyclohexane, [0106]
1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane, [0107]
1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane, [0108]
N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, [0109]
N-(1,3,5-trimethylcyclohexyl)pyrrolidine or piperidine, [0110]
N-[1,3(trans),5(trans)-trimethylcyclohexyl]pyrrolidine or
piperidine, [0111]
N-[1,3(cis),5(cis)-trimethylcyclohexyl]pyrrolidine or piperidine,
[0112] N-(1,3,3,5-tetramethylcyclohexyl)pyrrolidine or piperidine,
[0113] N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine or
piperidine, [0114]
N-(1,3,5,5-tetramethyl-3-ethylcyclohexyl)pyrrolidine or piperidine,
[0115] N-(1,5,5-trimethyl-3,3-diethylcyclohexyl)pyrrolidine or
piperidine, [0116]
N-(1,3,3-trimethyl-cis-5-ethylcyclohexyl)pyrrolidine or piperidine,
[0117] N-[(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexyl]pyrrolidine
or piperidine, [0118]
N-(1,3,3-trimethyl-trans-5-ethylcyclohexyl)pyrrolidine or
piperidine, [0119]
N-[(1R,5S)trans-5-ethyl,3,3-trimethylcyclohexyl]pyrrolidine or
piperidine, [0120]
N-(1-ethyl-3,3,5,5-tetramethylyclohexyl)pyrrolidine or piperidine,
[0121] N-(1-propyl-3,3,5,5-tetramethylcyclohexyl)pyrrolidine or
piperidine, [0122] N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine,
and optical isomers, diastereomers, enantiomers, hydrates, their
pharmaceutically acceptable salts, and mixtures thereof.
[0123] 1-Amino-alkylcyclohexane derivatives (e.g., neramexane,
1-amino-1,3,3,5,5-pentamethylcyclohexane) are disclosed in U.S.
Pat. Nos. 6,034,134 and 6,071,966. 1-Amino-alkylcyclohexane
derivatives (e.g., neramexane) may be used according to the
invention in the form of any of pharmaceutically acceptable salts,
solvates, isomers, conjugates, and prodrugs, any references to
1-amino-alkylcyclohexane derivatives (e.g., neramexane) in this
description should be understood as also referring to such salts,
solvates, isomers, conjugates, and prodrugs.
[0124] As used herein the term antidepressants or anti-anxiety
drugs (such as selective serotonin reuptake inhibitors (SSRIs),
serotonin-norepinephrine reuptake inhibitors (SNRIs), noradrenergic
and specific serotonergic antidepressants (NASSAs), norepinephrine
(noradrenaline) reuptake inhibitors (NRIs), norepinephrine-dopamine
reuptake inhibitors, or serotonin 1A agonists) includes:
fluoxetine, fluvoxamine paroxetine, citalopram, escitalopram,
sertraline, bupropion, desipramine, reboxetine, viloxazine,
amirtazapine, milnacipran, nefazodone, venlafaxine, desvenlafaxine,
duloxetine, mirtazapine, atomoxetine, buspirone and
pharmaceutically acceptable salts thereof
[0125] As used herein the term dopamine antagonist includes
trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}--
3,3-dimethyl-urea and pharmaceutically acceptable salts
thereof.
[0126] As used herein the term Alpha2Delta ligand includes
gabapentin, pregabalin, phenibut, PF-2393296, and PF-293765 and
pharmaceutically acceptable salts thereof.
[0127] As used herein the term NK1 antagonist includes aprepitant,
fosaprepitant, vestipitant, casopitant, AV-608, dilopetine, and
LY-686017 and pharmaceutically acceptable salts thereof.
[0128] Pharmaceutically acceptable salts include, but are not
limited to, acid addition salts, such as those made with
hydrochloric, methylsulfonic, hydrobromic, hydroiodic, perchloric,
sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic,
pyruvic, malonic, succinic, fumaric, tartaric, citric, benzoic,
carbonic, cinnamic, mandelic, methanesulfonic, ethanesulfonic,
hydroxyethanesulfonic, benezenesulfonic, p-toluene sulfonic,
cyclohexane-sulfamic, salicyclic, p-aminosalicylic,
2-phenoxybenzoic, and 2-acetoxybenzoic acid. All of these salts (or
other similar salts) may be prepared by conventional means. The
nature of the salt is not critical, provided that it is non-toxic
and does not substantially interfere with the desired
pharmacological activity.
[0129] The term "analog" or "derivative" is used herein in the
conventional pharmaceutical sense, to refer to a molecule that
structurally resembles a reference molecule (such as neramexane),
but has been modified in a targeted and controlled manner to
replace one or more specific substituents of the referent molecule
with an alternate substituent, thereby generating a molecule which
is structurally similar to the reference molecule. Synthesis and
screening of analogs (e.g., using structural and/or biochemical
analysis), to identify slightly modified versions of a known
compound which may have improved or biased traits (such as higher
potency and/or selectivity at a specific targeted receptor type,
greater ability to penetrate mammalian blood-brain barriers, fewer
side effects, etc.) is a drug design approach that is well known in
pharmaceutical chemistry.
[0130] The term "treat" is used herein to mean to relieve or
alleviate at least one symptom of a disease in a subject. Within
the meaning of the present invention, the term "treat" also denotes
to arrest, delay the onset (i.e., the period prior to clinical
manifestation of a disease) and/or reduce the risk of developing or
worsening a disease.
[0131] The term "therapeutically effective" applied to dose or
amount refers to that quantity of a compound or pharmaceutical
composition that is sufficient to result in a desired activity upon
administration to a mammal in need thereof.
[0132] The phrase "pharmaceutically acceptable", as used in
connection with compositions of the invention, refers to molecular
entities and other ingredients of such compositions that are
physiologically tolerable and do not typically produce untoward
reactions when administered to a mammal (e.g., human). Typically,
the term "pharmaceutically acceptable" means approved by a
regulatory agency of the Federal or a state government or listed in
the U.S. Pharmacopeia or other generally recognized pharmacopeia
for use in mammals, and more particularly in humans.
[0133] The term "carrier" applied to pharmaceutical compositions of
the invention refers to a diluent, excipient, or vehicle with which
an active compound (e.g., neramexane) is administered. Such
pharmaceutical carriers can be sterile liquids, such as water,
saline solutions, aqueous dextrose solutions, aqueous glycerol
solutions, and oils, including those of petroleum, animal,
vegetable or synthetic origin, such as peanut oil, soybean oil,
mineral oil, sesame oil and the like. Suitable pharmaceutical
carriers are described in "Remington's Pharmaceutical Sciences" by
A. R. Gennaro, 20.sup.th Edition.
[0134] The term "about" or "approximately" usually means within
20%, alternatively within 10%, including within 5% of a given value
or range. Alternatively, especially in biological systems, the term
"about" means within about a log (i.e., an order of magnitude),
including within a factor of two of a given value.
[0135] In conjunction with the methods of the present invention,
also provided are pharmaceutical compositions comprising a
therapeutically effective amount of a 1-amino-alkylcyclohexane
derivative (e.g., neramexane). The compositions of the invention
may further comprise a carrier or excipient (all pharmaceutically
acceptable). The compositions may be formulated for once-a-day
administration, twice-a-day administration, or three times a day
administration.
[0136] The active ingredient (e.g., neramexane, such as neramexane
mesylate) or the composition of the present invention may be used
for the treatment of at least one of the mentioned disorders,
wherein the medicament is adapted to or appropriately prepared for
a specific administration as disclosed herein (e.g., to once-a-day,
twice-a-day administration, or three times a day administration).
For this purpose the package leaflet and/or the patient information
contains corresponding information.
[0137] The active ingredient (e.g., neramexane, such as neramexane
mesylate) or the composition of the present invention may be used
for the manufacture of a medicament for the treatment of at least
one of the mentioned disorders, wherein the medicament is adapted
to or appropriately prepared for a specific administration as
disclosed herein (e.g., to once-a-day, twice-a-day administration,
or three times a day administration). For this purpose the package
leaflet and/or the patient information contains corresponding
information.
[0138] According to the present invention, the dosage form of the
1-amino-alkylcyclohexane derivative (e.g., neramexane) may be a
solid, semisolid, or liquid formulation according to the
following.
[0139] The 1-amino-alkylcyclohexane derivatives of the present
invention (e.g., neramexane) may be administered orally, topically,
parenterally, or mucosally (e.g., buccally, by inhalation, or
rectally) in dosage unit formulations containing conventional
non-toxic pharmaceutically acceptable carriers. In another
embodiment for administration to pediatric subjects, the
1-amino-alkylcyclohexane derivative may be formulated as a flavored
liquid (e.g., peppermint flavor). The 1-amino-alkylcyclohexane
derivatives of the present invention may be administered orally in
the form of a capsule, a tablet, or the like, or as a semi-solid,
or liquid formulation (see Remington's Pharmaceutical Sciences,
20.sup.th Edition, by A. R. Gennaro).
[0140] For oral administration in the form of a tablet or capsule,
the 1-amino-alkylcyclohexane derivatives of the present invention
(e.g., neramexane) may be combined with a non-toxic,
pharmaceutically acceptable excipients such as binding agents
(e.g., pregelatinized maize starch, polyvinylpyrrolidone or
hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose,
glucose, mannitol, sorbitol and other reducing and non-reducing
sugars, microcrystalline cellulose, calcium sulfate, or calcium
hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or
silica, steric acid, sodium stearyl fumarate, glyceryl behenate,
calcium stearate, and the like); disintegrants (e.g., potato starch
or sodium starch glycolate); or wetting agents (e.g., sodium lauryl
sulphate), coloring and flavoring agents, gelatin, sweeteners,
natural and synthetic gums (such as acacia, tragacanth or
alginates), buffer salts, carboxymethylcellulose,
polyethyleneglycol, waxes, and the like.
[0141] The tablets may be coated with a concentrated sugar solution
which may contain e.g., gum arabic, gelatine, talcum, titanium
dioxide, and the like. Alternatively, the tablets can be coated
with a polymer that dissolves in a readily volatile organic solvent
or mixture of organic solvents. In specific embodiments, neramexane
is formulated in immediate-release (IR) or modified-release (MR)
tablets. Immediate release solid dosage forms permit the release of
most or all of the active ingredient over a short period of time,
such as 60 minutes or less, and make rapid absorption of the drug
possible (immediate release formulations of
1-amino-alkylcyclohexanes such as neramexane are disclosed in US
Published Application Nos. 2006/0002999 and 2006/0198884, the
subject matter of which is hereby incorporated by reference).
Modified release solid oral dosage forms permit the sustained
release of the active ingredient over an extended period of time in
an effort to maintain therapeutically effective plasma levels over
similarly extended time intervals and/or to modify other
pharmacokinetic properties of the active ingredient (modified
release formulations of neramexane are disclosed in US Published
Application No. 2007/0141148, the subject matter of which is hereby
incorporated by reference). For example, neramexane mesylate may be
formulated in a modified release dosage form (including modified
release tablets) to provide a 50 mg dose of neramexane
mesylate.
[0142] For the formulation of soft gelatin capsules, the
1-amino-alkylcyclohexane derivatives of the present invention
(e.g., neramexane) may be admixed with e.g., a vegetable oil or
poly-ethylene glycol. Hard gelatin capsules may contain granules of
the active substances using either the above mentioned excipients
for tablets e.g., lactose, saccharose, sorbitol, mannitol, starches
(e.g., potato starch, corn starch or amylopectin), cellulose
derivatives or gelatine. Also liquids or semisolids of the drug can
be filled into hard gelatine capsules.
[0143] The 1-amino-alkylcyclohexane derivatives of the present
invention (e.g., neramexane) can also be introduced in microspheres
or microcapsules, e.g., fabricated from polyglycolic acid/lactic
acid (PGLA) (see, e.g., U.S. Pat. Nos. 5,814,344; 5,100,669 and
4,849,222; PCT Publications No. WO 95/11010 and WO 93/07861).
Biocompatible polymers may be used in achieving controlled release
of a drug, include for example, polylactic acid, polyglycolic acid,
copolymers of polylactic and polyglycolic acid, polyepsilon
caprolactone, polyhydroxybutyric acid, polyorthoesters,
polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked
or amphipathic block copolymers of hydrogels.
[0144] Formulation of the 1-amino-alkylcyclohexane derivatives of
the present invention in a semi-solid or liquid form may also be
used. The 1-amino-alkylcyclohexane derivative (e.g., neramexane)
may constitute between 0.1 and 99% by weight of the formulation,
more specifically between 0.5 and 20% by weight for formulations
intended for injection and between 0.2 and 50% by weight for
formulations suitable for oral administration.
[0145] In one embodiment of the invention, the
1-amino-alkylcyclohexane derivative (e.g., neramexane) is
administered in a modified release formulation. Modified release
dosage forms provide a means for improving patient compliance and
for ensuring effective and safe therapy by reducing the incidence
of adverse drug reactions. Compared to immediate release dosage
forms, modified release dosage forms can be used to prolong
pharmacologic action after administration, and to reduce
variability in the plasma concentration of a drug throughout the
dosage interval, thereby eliminating or reducing sharp peaks.
[0146] A modified release form dosage may comprise a core either
coated with or containing a drug. The core being is then coated
with a release modifying polymer within which the drug is
dispersed. The release modifying polymer disintegrates gradually,
releasing the drug over time. Thus, the outer-most layer of the
composition effectively slows down and thereby regulates the
diffusion of the drug across the coating layer when the composition
is exposed to an aqueous environment, i.e. the gastrointestinal
tract. The net rate of diffusion of the drug is mainly dependent on
the ability of the gastric fluid to penetrate the coating layer or
matrix and on the solubility of the drug itself.
[0147] In another embodiment of the invention, the
1-amino-alkylcyclohexane derivative (e.g., neramexane) is
formulated in an oral, liquid formulation. Liquid preparations for
oral administration can take the form of, for example, solutions,
syrups, emulsions or suspensions, or they can be presented as a dry
product for reconstitution with water or other suitable vehicle
before use. Preparations for oral administration can be suitably
formulated to give controlled or postponed release of the active
compound. Oral liquid formulations of 1-amino-alkylcyclohexanes,
such as neramexane, are described in PCT International Application
No. PCT/US2004/037026, the subject matter of which is hereby
incorporated by reference.
[0148] For oral administration in liquid form,
1-amino-alkylcyclohexane derivatives of the present invention
(e.g., neramexane) may be combined with non-toxic, pharmaceutically
acceptable inert carriers (e.g., ethanol, glycerol, water),
suspending agents (e.g., sorbitol syrup, cellulose derivatives or
hydrogenated edible fats), emulsifying agents (e.g., lecithin or
acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl
alcohol or fractionated vegetable oils), preservatives (e.g.,
methyl or propyl-p-hydroxybenzoates or sorbic acid), and the like.
Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate,
sodium ascorbate, citric acid) can also be added to stabilize the
dosage forms. For example, solutions may contain from about 0.2% to
about 20% by weight of neramexane, with the balance being sugar and
mixture of ethanol, water, glycerol and propylene glycol.
Optionally, such liquid formulations may contain coloring agents,
flavoring agents, saccharine and carboxymethyl-cellulose as a
thickening agent or other excipients.
[0149] In another embodiment, a therapeutically effective amount of
a 1-amino-alkylcyclohexane derivative (e.g., neramexane) is
administered in an oral solution containing a preservative, a
sweetener, a solubilizer, and a solvent. The oral solution may
include one or more buffers, flavorings, or additional excipients.
In a further embodiment, a peppermint or other flavoring is added
to the neramexane derivative oral liquid formulation.
[0150] For administration by inhalation, 1-amino-alkylcyclohexane
derivatives (e.g., neramexane) of the present invention may be
conveniently delivered in the form of an aerosol spray presentation
from pressurized packs or a nebulizer, with the use of a suitable
propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
In the case of a pressurized aerosol, the dosage unit can be
determined by providing a valve to deliver a metered amount.
Capsules and cartridges of, e.g., gelatin for use in an inhaler or
insufflator can be formulated containing a powder mix of the
compound and a suitable powder base such as lactose or starch.
[0151] Solutions for parenteral applications by injection may be
prepared in an aqueous solution of a water-soluble pharmaceutically
acceptable salt of the active substances, e.g., in a concentration
of from about 0.5% to about 10% by weight. These solutions may also
contain stabilizing agents and/or buffering agents and may
conveniently be provided in various dosage unit ampoules.
[0152] The formulations of the invention may be delivered
parenterally, i.e., by intravenous (i.v.), intracerebroventricular
(i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.),
intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.)
administration, by direct injection, via, for example, bolus
injection or continuous infusion. Formulations for injection can be
presented in unit dosage form, e.g., in ampoules or in multi-dose
containers, with an added preservative. Alternatively, the active
ingredient may be in powder form for reconstitution with a suitable
vehicle, e.g., sterile pyrogen-free water, before use.
[0153] The invention also provides a pharmaceutical pack or kit
comprising one or more containers containing a
1-amino-alkylcyclohexane derivative (e.g., neramexane) and,
optionally, more of the ingredients of the formulation. In a
specific embodiment, neramexane is provided as an oral solution (2
mg/ml) for administration with the use of a 2 teaspoon capacity
syringe (dosage KORC.RTM.). Each oral syringe has blue hatch marks
for measurement, with lines on the right side of the syringe (tip
down) representing tsp units, and those on the left representing ml
units.
[0154] The optimal therapeutically effective amount may be
determined experimentally, taking into consideration the exact mode
of administration, from in which the drug is administered, the
indication toward which the administration is directed, the subject
involved (e.g., body weight, health, age, sex, etc.), and the
preference and experience of the physician or veterinarian in
charge.
[0155] Dosage units for rectal application may be solutions or
suspensions or may be prepared in the form of suppositories or
retention enemas comprising neramexane in a mixture with a neutral
fatty base, or gelatin rectal capsules comprising the active
substances in admixture with vegetable oil or paraffin oil.
[0156] Toxicity and therapeutic efficacy of the compositions of the
invention may be determined by standard pharmaceutical procedures
in experimental animals, e.g., by determining the LD.sub.50 (the
dose lethal to 50% of the population) and the ED.sub.50 (the dose
therapeutically effective in 50% of the population). The dose ratio
between therapeutic and toxic effects is the therapeutic index and
it may be expressed as the ratio LD.sub.50/ED.sub.50. Compositions
that exhibit large therapeutic indices are preferred.
[0157] Suitable daily doses of the active compounds of the
invention in therapeutic treatment of humans are about 0.01-10
mg/kg bodyweight on peroral administration and 0.001-10 mg/kg
bodyweight on parenteral administration. For example, for adults,
suitable daily doses of neramexane (e.g. neramexane mesylate) are
within the range from about 5 mg to about 150 mg per day, such as
from about 5 mg to about 120 mg, from about 5 mg to about 100 mg,
or from about 5 mg to about 75 mg, or from about 5 mg to about 50
mg, such as 25 mg or 37.5 mg or 50 mg, per day. For example the
daily dose may be body weight-adjusted such as 50 mg/day up to 90
kg body weight or 75 mg/day for patients with a body weight of
.gtoreq.90 kg. An equimolar amount of another pharmaceutically
acceptable salt, a solvate, an isomer, a conjugate, a prodrug or a
derivative thereof, such as neramexane hydrochloride, is also
suitable. For pediatric subjects aged 4-14, neramexane (e.g.
neramexane mesylate) may be administered as an oral, liquid dosage
form, at about 0.5 mg/day, up to a maximum dose of 10 mg/day.
[0158] The daily doses indicated herein may be administered, for
example, as one or two dosing units once, twice or three times per
day. Suitable doses per dosage unit may therefore be the daily dose
divided (for example, equally) between the number of dosage units
administered per day, and will thus typically be about equal to the
daily dose or one half, one third, one quarter or one sixth
thereof. Dosages per dosage unit may thus be calculated from each
daily dosage indicated herein. A daily dose of 5 mg, for example
may be seen as providing a dose per dosage unit of, for example,
about 5 mg, 2.5 mg, 1.67 mg, 1.25 mg and 0.83 mg, depending upon
the dosing regimen chosen. Correspondingly, a dosage of 150 mg per
day corresponds to dosages per dosing unit of, for example, about
150 mg, 75 mg, 50 mg, 37.5 mg, and 25 mg for corresponding dosing
regimens.
[0159] Treatment duration may be short-term, e.g., several weeks
(for example 8-14 weeks), or long-term until the attending
physician deems further administration no longer is necessary.
[0160] The 1-amino-alkylcyclohexane derivatives of the present
invention (e.g., neramexane) may be administered as a monotherapy,
or in combination with another agent prescribed for the treatment
of tinnitus.
[0161] The term "combination" applied to active ingredients is used
herein to define a single pharmaceutical composition (formulation)
comprising two active agents (e.g., a pharmaceutical composition
comprising a 1-amino-alkylcyclohexane derivative, such as
neramexane, and another agent prescribed for the treatment of
tinnitus) or two separate pharmaceutical compositions, each
comprising an active agent (e.g. a pharmaceutical composition
comprising a 1-amino-alkylcyclohexane derivative, such as
neramexane, or another agent prescribed for the treatment of
tinnitus), to be administered conjointly.
[0162] Within the meaning of the present invention, the term
"conjoint administration" is used to refer to administration of
1-amino-alkylcyclohexane derivative, such as neramexane, and a
second active agent (e.g. another agent prescribed for the
treatment of cochlear tinnitus) simultaneously in one composition,
or simultaneously in different compositions, or sequentially. For
the sequential administration to be considered "conjoint", however,
1-amino-alkylcyclohexane derivative, such as neramexane, and the
second active agent must be administered separated by a time
interval which still permits the resultant beneficial effect for
treating cochlear tinnitus in a mammal.
EXAMPLES OF REPRESENTATIVE FORMULATIONS
[0163] With the aid of commonly used solvents, auxiliary agents and
carriers, active ingredients may be processed into tablets, coated
tablets, capsules, drip solutions, suppositories, injection and
infusion preparations, and the like and can be therapeutically
applied by the oral, rectal, parenteral, and additional routes.
Tablets suitable for oral administration may be prepared by
conventional tabletting techniques. The following example is given
by way of illustration only and is not to be construed as
limiting.
Formulation Example 1
Neramexane Mesylate Immediate Release Tablets
[0164] The following tables provide the make-up of neramexane
immediate release tablets in 12.5, 25.0, 37.5, and 50.0 mg dosages,
including active components, coating agents, and other
excipients.
TABLE-US-00001 TABLE 1 Neramexane mesylate, 12.5 mg film coated
tablets Component Amount [mg] Function Neramexane mesylate 12.50
Active pharmaceutical ingredient Cellulose microcrystalline 103.25
Binder Croscarmellose sodium 6.25 Disintegrant Silicon dioxide,
colloidal 1.25 Flow promoter Talc 1.25 Glident Magnesium stearate
0.50 Lubricant core weight 125.00 Coating (HPMC), Opadry or 5.00
Coating Sepifilm Coat weight 5.00 coated tablet total weight
130.00
TABLE-US-00002 TABLE 2 Neramexane mesylate, 25.0 mg film coated
tablets Component Amount [mg] Function Neramexane mesylate 25.00
Active pharmaceutical ingredient Cellulose microcrystalline 206.50
Binder Croscarmellose sodium 12.5 Disintegrant Silicon dioxide,
colloidal 2.50 Flow promoter Talc 2.50 Glident Magnesium stearate
1.00 Lubricant core weight 250.00 Coating (HPMC), Opadry or 10.00
Coating Sepifilm Coat weight 10.00 coated tablet total weight
260.00
TABLE-US-00003 TABLE 3 Neramexane mesylate, 37.5 mg film coated
tablets Component Amount [mg] Function Neramexane mesylate 37.50
Active pharmaceutical ingredient Cellulose microcrystalline 309.75
Binder Croscarmellose sodium 18.75 Disintegrant Silicon dioxide,
colloidal 3.75 Flow promoter Talc 3.75 Glident Magnesium stearate
1.50 Lubricant core weight 375.00 Coating (HPMC), Opadry or 15.00
Coating Sepifilm Coat weight 15.00 coated tablet total weight
390.00
TABLE-US-00004 TABLE 4 Neramexane mesylate, 50.0 mg film coated
tablets Component Amount [mg] Function Neramexane mesylate 50.00
Active pharmaceutical ingredient Cellulose microcrystalline 413.00
Binder Croscarmellose sodium 25.00 Disintegrant Silicon dioxide,
colloidal 5.00 Flow promoter Talc 5.00 Glident Magnesium stearate
2.00 Lubricant core weight 500.00 Coating (HPMC), Opadry or 20.00
Coating Sepifilm Coat weight 20.00 coated tablet total weight
520.00
[0165] The following example illustrates the invention without
limiting its scope.
Example 1
Double Blind Placebo Controlled Pilot Trial of Neramexane for
Treatment of Tinnitus
[0166] The objective of this pilot project was to conduct a
clinical trial to assess the efficacy of neramexane as a treatment
for tinnitus. The primary objective of this study was to compare
the efficacy, tolerability and safety of neramexane mesylate at
three different dosages (25, 50 or 75 mg/d) with placebo in
subjects with subjective tinnitus of at least moderate
severity.
Study Design
[0167] In a double-blind, multicenter, randomized,
placebo-controlled, parallel-group study, the efficacy of
neramexane in subjects suffering from tinnitus of at least moderate
severity was assessed. Approximately 100 patients, who fulfilled
particular inclusion criteria and met none of particular exclusion
criteria, were randomized to each of four double-blind treatment
groups (neramexane mesylate 25, 50, 75 mg/d or placebo), resulting
in approximately 400 patients in total.
[0168] The double-blind, 16-week treatment period consisted of a
4-week uptitration period and a 12-week fixed-dose treatment period
at unchanged maintenance b.i.d. dosing. In case of poor
tolerability, however, the investigator could consider a dose
reduction by 25 mg/d (or placebo, respectively). After the
treatment phase, there was a 4-week follow-up period with no active
treatment and concomitant therapy restrictions. In total, this
study involved seven study visits: screening, baseline, and at the
end of weeks 4, 8, 12, 16, and 20.
[0169] The scheduled visits for evaluation of each patient were as
follows:
[0170] Visit 1 (screening): After signing the consent form, the
subject underwent a physical examination and clinical laboratory
testing. Patient eligibility for the study was evaluated via a
check of inclusion/exclusion criteria. An initial Tinnitus
Interview was conducted. The subject also completed a
Tinnitus-Beeintrachtigungs-Fragebogen (TBF-12) (i.e., a 12-item
German modified and validated version (Greimel K V et al.,
Tinnitus-Beeintrachtigungs-Fragebogen (TBF-12). Manual. Frankfurt
am Main: Swets & Zeitlinger B. V.; 2000) of the 25-item
Tinnitus Handicap Inventory or THI (Newman C W, et al. Development
of the Tinnitus Handicap Inven-tory. Arch Otolaryngol Head Neck
Surg 1996; 122(2): 143-148; Newman C W, et al. Psychometric
adequacy of the Tinnitus Handicap Inventory (THI) for evaluating
treatment outcome. J Am Acad Audiol 1998; 9(2): 153-160)), a
Hospital Anxiety and Depression Scale--Depression Subscale (HADS-D)
Questionnaire and a Hyperacusis
(Gerauschuberempfindlichkeit-Fragenbogen (GUF)) Questionnaire (if
applicable).
[0171] Visit 2 (baseline): The subject was asked about adverse
events and changes in concomitant medication/disease, which
events/changes were documented. The subject was evaluated for study
eligibility based on a review of the inclusion/exclusion criteria.
Trial procedures as well as allowed and forbidden concomitant
medications were reviewed with the subject. An initial Tinnitus
Interview was conducted. The subject also completed a TBF-12,
HADS-D Questionnaire and GUF Questionnaire (if applicable). The
subject was enrolled in the study and study medication (placebo or
neramexane) was dispensed as described below.
[0172] Visit 3 (Week 4): This visit occurred at the end of the
4-week up-titration sequence. The subject was asked about adverse
events and changes in concomitant medication/disease, which
events/changes were documented. A follow-up Tinnitus Interview was
conducted. The subject also completed a TBF-12, HADS-D
Questionnaire and GUF Questionnaire (if applicable). Medication
compliance was assessed, and medication for the next 4 weeks was
dispensed as described below.
[0173] Visit 4 (Week 8): This visit occurred at the end of the
first 4-week fixed-dose double-blind treatment period. The subject
was asked about adverse events and changes in concomitant
medication/disease, which changes are documented. Blood samples
were collected in order to determine neramexane pre-dose
concentration. A follow-up Tinnitus Interview was conducted. The
subject also completed a TBF-12, HADS-D Questionnaire and GUF
Questionnaire (if applicable). Medication compliance was assessed
and, medication for the next 4 weeks was dispensed as described
below.
[0174] Visit 5 (Week 12): This visit occurred at the end of the
second 4-week fixed-dose double-blind treatment period. The subject
was asked about adverse events and changes in concomitant
medication/disease, which changes are documented. A follow-up
Tinnitus Interview was conducted. The subject also completed a
TBF-12, HADS-D Questionnaire and GUF Questionnaire (if applicable).
Medication compliance was assessed and, medication for the next 4
weeks was dispensed as described below.
[0175] Visit 6 (Week 16, end of treatment): This visit occurred at
the end of the 12-week fixed-dose double-blind treatment period.
The subject was asked about adverse events and changes in
concomitant medication/disease, which changes are documented. A
clinical laboratory evaluation was performed. A follow-up Tinnitus
Interview was conducted, and the subject completed a TBF-12, HADS-D
Questionnaire and GUF Questionnaire (if applicable). Pure-tone
audiometry (air conduction) was also conducted.
[0176] Visit 7 (Week 20): This visit occurred at the end of the
4-week follow-up period after the last study medication dose.
Review of concomitant medications as well as the occurrence of
adverse events since the last visit is conducted with subject. A
follow-up Tinnitus Interview was conducted, and the subject
completed a TBF-12, HADS-D Questionnaire and GUF Questionnaire (if
applicable).
Administration of Neramexane
[0177] Neramexane mesylate immediate release tablets (12.5 mg and
25 mg) and matching placebo tablets were administered as film
coated tablets.
[0178] Medication was supplied in blister boxes that were dispensed
from Visit 2 to Visit 5. Each blister box contained 4 blister cards
for 4 treatment weeks and 1 blister card as reserve. Blister cards
were identified by treatment weeks. Daily medication within the
blister cards were identified per day. Study medication for each
study day consisted of 4 separate tablets. One blister card
contained of 32 tablets (7.times.4 tablets, 4 tablets per day, and
a reserve of 4 tablets for one day). One package of medication per
patient consisted of 5 boxes. Box 2 was added as reserve medication
for box 1 (uptitration period) and was only to be dispensed if the
subject lost a blister card of box 1 or the whole box.
[0179] Study medication was dispensed at Visit 2 (baseline, day 0).
Each patient received one blister box containing 5 blister cards
(including one reserve blister) of double-blind study medication
(i.e., 32 tablets). Subjects were instructed to take 2 tablets
twice daily (4 tablets/d), beginning the day after dispensing of
the study medication, until they returned for their next study
visit (Visit 3). For those subjects assigned to receive active
medication, some placebo tablets were incorporated into the dosing
regimen to ensure blinding during the uptitration period. The
target fixed-maintenance dose of 25, 50, or 75 mg/d was
administered starting with the fifth week of double-blind treatment
and was continued throughout the study. At each of the subsequent
visits (Visits 3, 4, and 5, corresponding to end of week 4, 8 and
12) patients received another blister box containing 5 blister
cards for the 4 week intervals, with double-blind medication for
the intervening treatment period until the next study visit. The
dosing schedule is shown in Table 5.
[0180] Throughout the double-blind treatment period, patients were
to continue to take 2.times.2 tablets of medication daily at a
constant interval of 12 hours. In case the patient had already
taken the morning dose of study medication on the day of Visits 4
and 6 (Week 8 and Week 16), no scheduled blood sampling was to be
done. The investigator had to re-dispense a sufficient amount of
study medication. The patient should continue to take 2 by 2
tablets at a constant interval of 12 hours and had return for
pre-dose Neramexane blood sampling within the time window of Visits
4 and 6.
TABLE-US-00005 TABLE 5 Administration of Neramexane mesylate 4-week
double-blind 12-week fixed-dose 4-week Treatment up-titration
period double-blind period follow-up group Week 1 Week 2 Week 3
Week 4 Weeks 5-16 Weeks 17-20 High-dose 12.5/0 12.5/12.5 .sup.
25/12.5 25/25 37.5/37.5 (75 mg/d) -- Medium-dose 12.5/0 12.5/0
12.5/12.5 .sup. 25/12.5 25/25 (50 mg/d) -- Low-dose 12.5/0 12.5/0
12.5/0 12.5/0 12.5/12.5 (25 mg/d) -- Placebo 0/0 0/0 0/0 0/0 0/0 --
(xx/xx) refers to the morning/evening dose in mg, respectively
[0181] In case of poor tolerability the investigator could consider
a dose reduction of 25 mg/d by omitting the bigger tablet in the
morning which constituted an effective dose reduction only in the
75 mg/d and 50 mg/d neramexane mesylate groups. After omitting the
bigger tablet (25 mg or placebo, respectively) of the morning dose,
these patients could then continue the course of the study as
scheduled, while receiving only one smaller tablet as the morning
dose (12.5 mg or placebo, respectively) and 2 tablets of different
sizes (12.5 mg, 25 mg or placebo, respectively) as the evening
dose. The dose was to be kept stable until the end of the
study.
[0182] Subjects were instructed to take study medication always at
an individually convenient, but stable time point throughout the
study course and at a constant dosing interval of 12 hours whenever
possible (e.g. 6:00 h and 18:00 h or 8:00 h and 20:00 h). At each
study visit, the investigator enquired the time points of study
medication intake on the preceding day. At the end of week 4, 8,
12, and 16 (or upon early termination), patients returned to the
study site bringing their blister boxes containing 5 blister cards
with them for an assessment of medication compliance.
Efficacy
[0183] Primary Outcome [0184] The change in TBF-12 total score from
baseline (Visit 2) to the endpoint visit (Visit 6, i.e. Week 16)
was the primary efficacy endpoint in this study.
[0185] Secondary Outcomes [0186] TBF-12 total score (values and
absolute change from baseline) at all post-baseline visits except
the endpoint visit. [0187] Change in the TBF-12 total score from
Week 16 to Week 20 (values and absolute changes). [0188] TBF-12
factorial scores (values and absolute change from baseline,
including the change from Week 16 to Week 20) at all post-baseline
visits. [0189] Hyperacusis questionnaire GUF
("Gerauschuberempfindlichkeits-Fragebogen"), values and absolute
change from baseline, including the change from Week 16 to Week 20,
total and factorial scores at all post-baseline visits if
hyperacusis was present. [0190] Clinical global impression of
change: item 27 of the tinnitus follow-up interview was summarized
after dichotomization of the responses in any improvement (values
1, 2, 3) versus no improvement (values 4, 5, 6, 7) and in marked
improvement (values 1, 2) versus no marked improvement (values 3,
4, 5, 6, 7). [0191] Total score of HADS-D as well as the depression
and anxiety subscale scores (values and absolute change from
baseline, also the change from week 16 to week 20) at all
post-baseline visits. [0192] Values of tinnitus interview (initial
and follow-up) at all post-baseline visits; absolute change from
baseline and change from Week 16 to Week 20 for items 8, 9, 10, 19,
20, 21, 24, 25 and 26 of the follow-up interview.
Data Analysis
[0193] All efficacy analyses were performed on the ITT population
using the last-observation-carried-forward (LOCF) approach. For
sensitivity purposes an analysis of the per-protocol set and of
observed cases was performed additionally. All statistical tests
used for testing the primary efficacy (confirmatory testing) and
secondary efficacy criteria (exploratory), and all other
statistical tests used for exploratory analyses were two-sided
hypothesis tests performed at the 5% significance level. For all
variables standard descriptive statistics were calculated.
[0194] Change from baseline (Visit 2) to Week 16 in TBF-12 total
score was analyzed using a two-way ANCOVA model with treatment
group and study centers as factors and baseline TBF-12 total score
as covariate.
[0195] For secondary efficacy parameters, the comparison between
neramexane and placebo was performed, if appropriate, by visit
using a two-way ANCOVA with treatment group and study center as
factors and the corresponding baseline value of the efficacy
parameter as covariate.
[0196] This clinical study showed promising results in terms of
efficacy and safety. Moreover, subgroup analyses indicated that
subjects who were classified by the respective investigators as
suffering from cochlear tinnitus (i.e. tinnitus in the frequency
region of the patient's sensorineural hearing loss and a tinnitus
sensation level between 3 and 12 dB) responded well to treatment
with neramexane. FIG. 1 shows the change in TBF-12 score at the end
of treatment for the 50 mg dose group compared to placebo. In the
same trial, patients who were treated within three (3) to eight (8)
months of onset of tinnitus (Table 6) and patients with mild
hearing loss (Table 7) showed a better response (effect in treating
tinnitus) to neramexane as compared to the total study population
(Table 8). Especially in the 50 mg dose group, the improvement (as
compared to placebo treatment) in patients whose onset of tinnitus
was three to eight months before treatment or who showed a mild
hearing loss was markedly higher (-1.9 points difference in each
group) and reached statistical significance in the post-hoc
analyses (p=0.019 and 0.024), whereas the difference to placebo in
the total study population was only 0.8 point and failed to reach
statistical significance (p=0.098).
[0197] In patients presenting at baseline with clinical symptoms of
anxiety or depression, as indicated by a total score of 10 or more
measured on the Hospital anxiety and depression scale (HADS),
treatment with a 50 or 75 mg daily dose of neramexane monotherapy
produced a weaker benefit compared to such treatment in patients
with a score below 10 at baseline (Table 9). Since anxiety and
depression are common medical problems in tinnitus patients
(Reynolds et al., Clin. Otolaryngol., 2004, 29, 628-634), a
combination of anti-depressants and anti-anxiety drugs with
neramexane may offer additional benefits for the treatment of this
subgroup of tinnitus patients.
TABLE-US-00006 TABLE 6 Subjects with tinnitus duration 3 to <8
months Change in the TBF-12 total score (range 0-24) from baseline
to week 16 (ITT-LOCF) Week 16 Week 16 Neramexane - Placebo Baseline
Actual Change Change LSMean ITT-LOCF n Mean .+-. SD Mean .+-. SD
Mean .+-. SD LSMean Diff. .+-. SE 95% CI p-value.sup.1 Placebo 50
14.1 .+-. 3.4 11.8 .+-. 4.6 -2.3 .+-. 3.3 -2.2 n.a. n.a. n.a. 25
mg/d 45 14.9 .+-. 3.8 12.3 .+-. 4.9 -2.5 .+-. 3.0 -2.2 0.0 .+-. 0.8
[-1.6, 1.5] 0.983 Neramexane 50 mg/d 45 14.2 .+-. 3.4 10.0 .+-. 5.1
-4.2 .+-. 3.9 -4.0 -1.9 .+-. 0.8 [-3.4, -0.3] 0.019 Neramexane 75
mg/d 41 14.0 .+-. 3.3 10.6 .+-. 5.0 -3.4 .+-. 4.0 -3.3 -1.1 .+-.
0.8 [-2.7, 0.5] 0.173 Neramexane .sup.1p-values are derived from an
ANCOVA model including baseline as covariate and treatment as well
as pooled center as factors. CI = confidence interval, Diff. =
difference, ITT = intent-to-treat, LOCF = last observation carried
forward, LSMean = least square mean (mean adjusted for covariates),
n = number of patients with data, n.a. = not applicable, SD =
standard deviation, SE = standard error
TABLE-US-00007 TABLE 7 Subjects with mild hearing loss Change in
the TBF-12 total score (range 0-24) from baseline to week 16
(ITT-LOCF) Week 16 Week 16 Neramexane - Placebo Baseline Actual
Change Change LSMean ITT-LOCF n Mean .+-. SD Mean .+-. SD Mean .+-.
SD LSMean Diff. .+-. SE 95% CI p-value.sup.1 Placebo 42 14.8 .+-.
3.9 12.8 .+-. 5.2 -2.0 .+-. 4.3 -2.0 n.a. n.a. n.a. 25 mg/d 33 14.6
.+-. 4.2 13.1 .+-. 5.8 -1.5 .+-. 3.4 -1.3 0.7 .+-. 0.9 [-1.2, 2.5]
0.474 Neramexane 50 mg/d 43 15.3 .+-. 3.5 11.5 .+-. 5.2 -3.8 .+-.
3.9 -3.9 -1.9 .+-. 0.8 [-3.6, -0.3] 0.024 Neramexane 75 mg/d 30
13.9 .+-. 3.1 12.0 .+-. 4.6 -1.9 .+-. 3.2 -1.8 -0.2 .+-. 0.9 [-1.6,
2.1] 0.797 Neramexane .sup.1p-values are derived from an ANCOVA
model including baseline as covariate and treatment as well as
pooled center as factors. CI = confidence interval, Diff. =
difference, ITT = intent-to-treat, LOCF = last observation carried
forward, LSMean = least square mean (mean adjusted for covariates),
n = number of patients with data, n.a. = not applicable, SD =
standard deviation, SE = standard error
TABLE-US-00008 TABLE 8 Total study population Change in the TBF-12
total score from baseline to week 16 (ITT-LOCF) Week 16 Week 16
Neramexane - Placebo Baseline Actual Change Change LSMean ITT-LOCF
n Mean .+-. SD Mean .+-. SD Mean .+-. SD LSMean Diff. .+-. SE 95%
CI p-value.sup.1 Placebo 111 14.4 .+-. 3.7 12.0 .+-. 4.9 -2.4 .+-.
3.6 -2.3 n.a. n.a. n.a. 25 mg/d 106 14.4 .+-. 3.9 12.4 .+-. 5.3
-2.0 .+-. 3.4 -1.8 0.5 .+-. 0.5 [-0.5, 1.5] 0.359 Neramexane 50
mg/d 106 14.5 .+-. 3.3 11.2 .+-. 5.1 -3.2 .+-. 4.1 -3.1 -0.8 .+-.
0.5 [-1.8, 0.2] 0.098 Neramexane 75 mg/d 99 13.9 .+-. 3.7 11.0 .+-.
5.1 -2.9 .+-. 3.9 -2.8 -0.5 .+-. 0.5 [-1.6, 0.5] 0.289 Neramexane
.sup.1p-values are derived from an ANCOVA model including baseline
as covariate and treatment as well as pooled center as factors. CI
= confidence interval, Diff. = difference, ITT = intent-to-treat,
LOCF = last observation carried forward, LSMean = least square mean
(mean adjusted for covariates), n = number of patients with data,
n.a. = not applicable, SD = standard deviation, SE = standard
error
TABLE-US-00009 TABLE 9 Change in TBF-12 total score from baseline
to week 16 - stratified by grouped HADS-D subscales at baseline
(ITT-LOCF) 25 mg/d Neramexane 50 mg/d Neramexane 75 mg/d Neramexane
(N = 106) (N = 106) (N = 99) Week 16 Neramexane - Placebo n LSMean
p-value n LSMean p-value n LSMean p-value Depression subscale 0-7
69 -0.3 0.634 76 -1.3 0.039 69 -0.9 0.153 8-10 22 0.6 0.600 18 -1.1
0.353 18 0.0 0.984 >10 15 3.9 0.043* 12 3.3 0.155 12 0.4 0.847
Anxiety subscale 0-7 47 0.2 0.835 55 -0.5 0.472 51 0.1 0.892 8-10
30 -2.3 0.022 24 -2.9 0.008 30 -3.1 0.003 >10 29 2.3 0.020* 27
0.6 0.573 18 0.3 0.802 *= in favor of placebo ITT =
intent-to-treat, LOCF = last observation carried forward, LSMean =
least square mean (mean adjusted for covariates), N = number of
patients in respective treatment group, n = number of patients with
data
[0198] These findings demonstrate that neramexane is effective in
treating subjects with tinnitus originating in the cochlea and
before the stage of centralisation, and that, therefore, neramexane
may be useful in treating patients with cochlear tinnitus.
[0199] The present invention is not to be limited in scope by the
specific embodiments described herein. Indeed, various
modifications of the invention in addition to those described
herein will become apparent to those skilled in the art from the
foregoing description. Such modifications are intended to fall
within the scope of the appended claims.
[0200] All patents, applications, publications, test methods,
literature, and other materials cited herein are hereby
incorporated by reference.
* * * * *