US20110086916A1

US20110086916A1 - Interval therapy for the treatment of tinnitus

Info

Publication number: US20110086916A1
Application number: US12/733,577
Authority: US
Inventors: Barbara Ellers-Lenz; Tanja Rosenberg; Micael Althaus; Herman Russ; Hagen Kruger
Original assignee: Merz Pharma GmbH and Co KGaA
Current assignee: Merz Pharma GmbH and Co KGaA
Priority date: 2007-09-12
Filing date: 2008-09-10
Publication date: 2011-04-14
Also published as: RU2011137131A; EP2548552A3; EP2203163A1; ATE532507T1; EP2386299B1; CA2699210A1; KR20100052557A; MX2010002733A; JP2014221767A; BRPI0816690A2; AR071728A1; ES2604945T3; CN101795679A; BRPI0816712A2; MX2010002735A; ES2562709T3; ES2377253T3; US20110077304A1; CA2699213A1; CN101801366A

Abstract

The present invention relates to interval and/or maintenance therapy employing 1-amino-alkylcyclohexane derivatives (e.g., neramexane or a pharmaceutically acceptable salt thereof) for the treatment of an individual afflicted with tinnitus.

Description

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

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).
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.
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.
There are currently 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 and therapies which are effective in treating or preventing tinnitus. Huynh, et al. (Ann Pharmacother 1995; 29(3): 311-312) also disclose that there is a need for investigating the necessity of a maintenance therapy as well as the role of treatment-free intervals (“drug-holidays’) in the development of new tinnitus medications.
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 α 9/α 10 nicotinic receptor antagonist (Plazas, et al., Eur J. Pharmacol., 2007 Jul. 2; 566 (1-3):11-19).
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.
The instant inventors have discovered that interval and/or maintenance therapy employing 1-amino-alkylcyclohexanes, such as neramexane or a pharmaceutically acceptable salt thereof, may be an effective approach for the treatment of tinnitus.
Maintenance treatment may prevent recurrence of tinnitus in patients with sufficient or stable treatment effects through administering the reduced dose of an 1-amino-alkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate).
A benefit associated with such treatment is a significantly reduced drug exposure while the anti-tinnitus effect is still sufficient.
If tinnitus re-occurs the chance for sufficient treatment effect with 1-amino-alkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate) may be lower than at first onset since irreversible changes in the auditory system may have time to progress and become chronic.
However, if tinnitus symptoms re-occur in patients receiving maintenance treatment (e.g., 20-75% of the therapeutically effective dose) the relapse may be milder and may respond more sensitively to an immediate increase of the 1-amino-alkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate) dose to a therapeutically effective dose (e.g. 25 mg neramexane mesylate b.i.d. or 37.5 mg b.i.d. for subjects heavier then 90 kg bodyweight) than in patients without maintenance treatment.

SUMMARY OF THE INVENTION

The present invention relates to a 1-amino-alkylcyclohexane derivative for the treatment of tinnitus, wherein a therapeutically effective amount of the 1-amino-alkylcyclohexane derivative is administered daily for a first period of at least three (3) months, followed by a second period of at least one (1) month wherein the 1-amino-alkylcyclohexane derivative is administered at a dose which is 0-75% of the therapeutically effective dose.
A further aspect the invention relates to the use of a 1-amino-alkylcyclohexane derivative for the manufacture of a medicament for treating tinnitus in a subject in need thereof, wherein a therapeutically effective amount of the 1-amino-alkylcyclohexane derivative is administered daily for a first period of at least three (3) months, followed by a second period of at least one (1) month wherein the 1-amino-alkylcyclohexane derivative is administered at a dose which is 0-75% of the therapeutically effective dose.
A further aspect the invention relates to a 1-amino-alkylcyclohexane derivative for the treatment of a 1-amino-alkylcyclohexane derivative responsive condition in a subject in need thereof wherein a therapeutically effective amount of the 1-amino-alkylcyclohexane derivative is administered to said subject daily for a first period of at least three (3) months, followed by a second period of at least one (1) month wherein the 1-amino-alkylcyclohexane derivative is administered at a dose which is 0-75% of the therapeutically effective dose.
A further aspect the invention relates to the use of a 1-amino-alkylcyclohexane derivative for the manufacture of a medicament for the treatment of a 1-amino-alkylcyclohexane derivative responsive condition in a subject in need thereof wherein a therapeutically effective amount of the 1-amino-alkylcyclohexane derivative is administered to said subject daily for a first period of at least three (3) months, followed by a second period of at least one (1) month wherein the 1-amino-alkylcyclohexane derivative is administered at a dose which is 0-75% of the therapeutically effective dose.
The 1-amino-alkylcyclohexane derivative as well as the medicament specified herein are for the administration according to the above-defined administration scheme. In one embodiment, the derivative/medicament is specifically adapted to provide the respective information regarding the administration scheme to the patient. The respective information regarding the specific administration scheme may be provided via e.g. the respective information in or on the package, the dosage form, such as the appearance thereof, e.g. via tablet color or tablet form, and/or the package leaflet and/or the patient information.
In a further aspect of the invention the therapeutically effective amount of the 1-amino-alkylcyclohexane derivative is administered daily for a period of at least three (3) months, followed by a period of at least one month wherein the 1-amino-alkylcyclohexane derivative is administered at a dose which is above 0 to 75%, such as 20-75% (e.g. 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%), or such as 25-50%, of the therapeutically effective dose.
The reduction of the dose of the 1-amino-alkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate) between the administration of the therapeutically effective dose and the administration of 0-75%, such as above 0-75%, or 20-75%, such as 25-50%, of the therapeutically effective dose may be performed stepwise. The dose of 50 mg neramexane mesylate daily may, for example, be reduced to a dose of 25 mg by 12.5 mg steps, wherein the 37.5 mg dose is, for example, administered for at least one week. The dose of 75 mg neramexane mesylate daily may, for example, be reduced to a dose of 25 mg/day. This may be performed by 12.5 mg steps, wherein the 62.5 mg/day, 50 mg/day, and 37.5 mg/day doses may, for example, be administered for at least one week, respectively. Alternatively, the dose of 75 mg neramexane mesylate daily may, for example, be reduced to a dose of 50 mg/day. This may be performed by 12.5 mg steps, wherein the 62.5 mg/day dose may, for example, be administered for at least one week. In a further embodiment, the dose of 75 mg neramexane mesylate daily may, for example, be reduced to a dose of 12.5 mg/day. This may be performed by 12.5 mg steps, wherein the 62.5 mg/day dose, the 50 mg/day dose, the 37.5 mg/day dose, and the 25 mg/day dose may, respectively, for example, be administered for at least one week.
A further aspect of the invention relates to a treatment regimen for an individual afflicted with tinnitus, comprising administering to the individual a therapeutically effective amount of a 1-amino-alkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate), wherein the therapeutically effective amount of the 1-amino-alkylcyclohexane derivative is administered daily for a period of at least three (3) months, followed by a period of at least one month wherein the 1-amino-alkylcyclohexane derivative is administered at a dose which is 0-75%, such as above 0-75%, or 20-75% or 25-50% of the therapeutically effective dose, with the treatment regimen being repeated after a recurrence of tinnitus.
According to the invention patients who have had a tinnitus relapse continue on the therapeutically effective dose for at least three months, such as for at least one year, before the dose is reduced to a maintenance dose.
Alternatively, the treatment regimen may be repeated after a specific period, such as after administering at a dose which is 0-75%, or above 0-75%, or 20-75%, such as 25-50% of the therapeutically effective dose for a period of from three (3) to six (6) months (e.g. 3, 4, 5, or 6 months).
In a further aspect of the invention the therapeutically effective amount of the 1-amino-alkylcyclohexane derivative is administered daily for a first period of at least three (3) months, followed by a second period of at least one month, such as at least three (3) months, wherein the 1-amino-alkylcyclohexane derivative is not administered, with the treatment regimen being repeated after said (second) period, i.e., in a third period the same treatment as in the first period is performed, while in the fourth period (as in the second period) no 1-amino-alkylcyclohexane derivative is administered. Said order of periods with and without treatment can be repeated several times, usually depending upon the progress of the condition within the subject treated.
The treatment regimen may be repeated after a specific period, such as after a period of from three (3) to six (6) months (e.g. 3, 4, 5, or 6 months).
According to the invention, the dose reduction, as well as the dose increase, may be performed stepwise.
According to the invention, previous to the first period of administering there may be an initial administering of a dose or doses in order to increase the dose(s) to reach the therapeutically effective dose of the first period. If such initial administering is performed, it is usually performed in a stepwise manner (i.e., uptitration).
In a further aspect of the invention a therapeutically effective amount of neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate is administered to the subject, wherein the therapeutically effective amount of said compound is administered daily for a period of at least three (3) months, followed by a period of at least one (1) month wherein said compound is administered at a dose which is 0-75% or above 0-75% of the therapeutically effective dose, with the treatment being repeated as necessary.
In a further aspect of the invention a therapeutically effective amount of neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate is administered to the subject, wherein the therapeutically effective amount of said compound is administered daily for a period of at least three (3) months, followed by a period of at least one (1) month wherein said compound is administered at a dose which is 20-75% of the therapeutically effective dose, with the treatment regimen being repeated as necessary.
In a further aspect of the invention the therapeutically effective amount of neramexane or a pharmaceutically acceptable salt thereof, such as, neramexane mesylate is administered daily for a period of at least three (3) months, followed by a (second) period of at least one (1) month wherein said compound is not administered, with the treatment regimen being repeated after said (second) period. Said order of periods with and without treatment can be repeated several times, usually depending upon the progress of the condition within the subject treated.
A further aspect of the invention relates to a method of treating tinnitus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a 1-amino-alkylcyclohexane derivative, wherein the therapeutically effective amount of the 1-amino-alkylcyclohexane derivative is administered daily for a first period of at least three (3) months, followed by a second period of at least one (1) month wherein the 1-amino-alkylcyclohexane derivative is administered at a dose which is 0-75% of the therapeutically effective dose.
A further aspect of the invention relates to such a method wherein during the second period the 1-amino-alkylcyclohexane derivative is administered at a dose which is above 0-75% of the therapeutically effective dose.
A further aspect of the invention relates to such a method wherein during the second period the 1-amino-alkylcyclohexane derivative is administered at a dose which is 20-75% of the therapeutically effective dose.
A further aspect of the invention relates to such a method wherein during the second period the 1-amino-alkylcyclohexane derivative is administered at a dose which is 25-50% of the therapeutically effective dose.
A further aspect of the invention relates to such a method wherein during the second period the 1-amino-alkylcyclohexane derivative is not administered with treatment being repeated after the second period.
A further aspect of the invention relates to such a method wherein a dose increase to reach a therapeutically effective dose following the second period is performed stepwise.
A further aspect of the invention relates to such a method wherein the second period is followed by administering to the subject a therapeutically effective amount of a 1-amino-alkylcyclohexane derivative after a recurrence of tinnitus.
A further aspect of the invention relates to such a method wherein the administration of the therapeutically effective amount of a 1-amino-alkylcyclohexane derivative after recurrence of tinnitus is continued for at least one year.
A further aspect of the invention relates to such a method wherein the second period is from three (3) to six (6) months.
A further aspect of the invention relates to such a method wherein between the first and second period there is a transition period during which the dose is reduced stepwise.
A further aspect of the invention relates to such a method wherein the 1-amino-alkylcyclohexane derivative is neramexane or a pharmaceutically acceptable salt thereof.
A further aspect of the invention relates to such a method wherein the 1-amino-alkylcyclohexane derivative is neramexane mesylate.
A further aspect of the invention relates to such a method wherein neramexane mesylate is administered in a range from about 5 mg to about 150 mg/day during the first period.
A further aspect of the invention relates to such a method wherein neramexane mesylate is administered in a range from about 5 mg to about 100 mg/day.
A further aspect of the invention relates to such a method wherein neramexane mesylate is administered at about 5 mg to about 75 mg/day.
A further aspect of the invention relates to such a method wherein neramexane mesylate is administered at about 50 mg/day.
A further aspect of the invention relates to such a method wherein neramexane mesylate is administered at about 75 mg/day.
A further aspect of the invention relates to such a method wherein neramexane or a pharmaceutically acceptable salt thereof is administered once a day, twice a day (b.i.d.), or three times a day.
A further aspect of the invention relates to such a method wherein neramexane or a pharmaceutically acceptable salt thereof is administered twice a day.
A further aspect of the invention relates to such a method wherein neramexane or a pharmaceutically acceptable salt thereof is administered in an immediate release formulation.
A further aspect of the invention relates to such a method wherein neramexane or a pharmaceutically acceptable salt thereof is administered in a modified release formulation.
A further aspect of the invention relates to a method of treating a 1-amino-alkylcyclohexane derivative responsive condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a 1-amino-alkylcyclohexane derivative, wherein the therapeutically effective amount of the 1-amino-alkylcyclohexane derivative is administered daily for a first period of at least three (3) months, followed by a second period of at least one (1) month wherein the 1-amino-alkylcyclohexane derivative is administered at a dose which is 0-75% of the therapeutically effective dose.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows data from a tinnitus pilot study with neramexane showing the change in Tinnitus-Beeinträchtigungs-Fragebogen (TBF-12) (i.e., a 12-item the German modified and validated version of the Tinnitus Handicap Inventory or THI) score from baseline to all post-baseline visits.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term tinnitus includes 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.
As used herein, the term hearing loss is synonymous with hearing impairment and includes several grades of hearing loss (such as mild hearing loss, moderate hearing loss, severe hearing loss, profound hearing loss, and deafness) as well as several specific forms, such as acoustic trauma, noise-induced hearing loss, sensorineural hearing loss, mixed hearing loss, unspecified hearing loss, ototoxic hearing loss, drug-induced hearing loss, sudden (idiopathic) hearing loss, auditory processing disorder, presbycusis, environmental chemicals-induced hearing loss, surgery-induced hearing loss, cancer-induced hearing loss, radiation-induced hearing loss, and infection-induced hearing loss.
As used herein, the term subject includes mammals, i.e. animals and humans.
The term 1-amino-alkylcyclohexane derivative is used herein to describe 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.”
The 1-amino-alkylcyclohexane derivatives of the present invention may be represented by the general formula (I):
wherein R* is —(CH₂)_n—(CR⁶R⁷)_m—NR⁸R⁹
wherein n+m=0, 1, or 2
wherein R¹through R⁷are independently selected from the group consisting of hydrogen and C_1-6alkyl, wherein R⁸and R⁹are independently selected from the group consisting of hydrogen and C_1-6alkyl or together represent lower-alkylene —(CH₂)_x— wherein x is 2 to 5, inclusive, and optical isomers, enantiomers, hydrates, and pharmaceutically-acceptable salts thereof.
Non-limiting examples of the 1-amino-alkylcyclohexanes used according to the present invention include:

1-amino-1,3,5-trimethylcyclohexane,
1-amino-1(trans),3(trans),5-trimethylcyclohexane,
1-amino-1(cis),3(cis),5-trimethylcyclohexane,
1-amino-1,3,3,5-tetramethylcyclohexane,
1-amino-1,3,3,5,5-pentamethylcyclohexane (neramexane),
1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane,
1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane,
1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane,
1-amino-(1S,5S)cis-3-ethyl-1,5,5-trimethylcyclohexane,
1-amino-1,5,5-trimethyl-trans-3-ethylcyclohexane,
1-amino-(1R,5S)trans-3-ethyl-1,5,5-trimethylcyclohexane,
1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane,
1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane,
N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,
N-ethyl-1-amino-1,3,3,5,5-pentamethyl-cyclohexane,
N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine,
3,3,5,5-tetramethylcyclohexylmethylamine,
1 amino-1,3,3,5(trans)-tetramethylcyclohexane (axial amino group),
3-propyl-1,3,5,5-tetramethylcyclohexylamine semihydrate,
1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane,
1-amino-1,3,5-trimethylcyclohexane,
1-amino-1,3-dimethyl-3-propylcyclohexane,
1-amino-1,3(trans),5(trans)-trimethyl-3(cis)-propylcyclohexane,
1-amino-1,3-dimethyl-3-ethylcyclohexane,
1-amino-1,3,3-trimethylcyclohexane,
cis-3-ethyl-1(trans)-3(trans)-5-trimethylcyclohexamine,
1-amino-1,3(trans)-dimethylcyclohexane,
1,3,3-trimethyl-5,5-dipropylcyclohexylamine,
1-amino-1-methyl-3(trans)-propylcyclohexane,
1-methyl-3(cis)-propylcyclohexylamine,
1-amino-1-methyl-3(trans)-ethylcyclohexane,
1-amino-1,3,3-trimethyl-5(cis)-ethylcyclohexane,
1-amino-1,3,3-trimethyl-5(trans)-ethylcyclohexane,
cis-3-propyl-1,5,5-trimethylcyclohexylamine,
trans-3-propyl-1,5,5-trimethylcyclohexylamine,
N-ethyl-1,3,3,5,5-pentamethylcyclohexylamine,
N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,
1-amino-1-methylcyclohexane,
N,N-dimethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,
2-(3,3,5,5-tetramethylcyclohexyl)ethylamine,
2-methyl-1-(3,3,5,5-tetramethylcyclohexyl)propyl-2-amine,
2-(1,3,3,5,5-pentamethylcyclohexyl)-ethylamine semihydrate,
N-(1,3,3,5,5-pentamethylcyclohexyl)-pyrrolidine,
1-amino-1,3(trans),5(trans)-trimethylcyclohexane,
1-amino-1,3(cis),5(cis)-trimethylcyclohexane,
1-amino-(1R,5S)trans-5-ethyl-1,3,3-trimethylcyclohexane,
1-amino-(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexane,
1-amino-1,5,5-trimethyl-3(cis)-isopropyl-cyclohexane,
1-amino-1,5,5-trimethyl-3(trans)-isopropyl-cyclohexane,
1-amino-1-methyl-3(cis)-ethyl-cyclohexane,
1-amino-1-methyl-3(cis)-methyl-cyclohexane,
1-amino-5,5-diethyl-1,3,3-trimethyl-cyclohexane,
1-amino-1,3,3,5,5-pentamethylcyclohexane,
1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane,
1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane,
N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,
N-(1,3,5-trimethylcyclohexyl)pyrrolidine or piperidine,
N-[1,3(trans),5(trans)-trimethylcyclohexyl]pyrrolidine or piperidine,
N-[1,3(cis),5(cis)-trimethylcyclohexyl]pyrrolidine or piperidine,
N-(1,3,3,5-tetramethylcyclohexyl)pyrrolidine or piperidine,
N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine or piperidine,
N-(1,3,5,5-tetramethyl-3-ethylcyclohexyl)pyrrolidine or piperidine,
N-(1,5,5-trimethyl-3,3-diethylcyclohexyl)pyrrolidine or piperidine,
N-(1,3,3-trimethyl-cis-5-ethylcyclohexyl)pyrrolidine or piperidine,
N-[(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexyl]pyrrolidine or piperidine,
N-(1,3,3-trimethyl-trans-5-ethylcyclohexyl)pyrrolidine or piperidine,
N-[(1R,5S)trans-5-ethyl,3,3-trimethylcyclohexyl]pyrrolidine or piperidine,
N-(1-ethyl-3,3,5,5-tetramethylyclohexyl)pyrrolidine or piperidine,
N-(1-propyl-3,3,5,5-tetramethylcyclohexyl)pyrrolidine or piperidine,
N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine,
and optical isomers, diastereomers, enantiomers, hydrates, their pharmaceutically acceptable salts, and mixtures thereof.

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.
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, cyclohexanesulfamic, 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.
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.
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.
The term “therapeutically effective” applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is appropriate to result in a amelioration of existing tinnitus or tinnitus-related symptoms upon administration to a mammal in need thereof.
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.
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^thEdition.
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.
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.
The 1-amino-alkylcyclohexane derivative (e.g., neramexane, such as neramexane mesylate) or a pharmaceutical composition comprising the same may be used for the treatment of tinnitus according to the administration scheme according to the invention. In one embodiment the derivative and/or pharmaceutical composition (medicament) are adapted to or appropriately prepared for a specific administration as disclosed herein (e.g., intervallic treatment, maintenance therapy, once-a-day, twice-a-day administration, or three times a day administration). For this purpose the package and/or the package leaflet and/or the patient information and/or the dosage form itself may contain corresponding information.
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 tinnitus, wherein the medicament is adapted to or appropriately prepared for a specific administration as disclosed herein (e.g., intervallic treatment, maintenance therapy, 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.
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.
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^thEdition, by A. R. Gennaro).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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®). 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.
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.
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.
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 LD₅₀(the dose lethal to 50% of the population) and the ED₅₀(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 LD₅₀/ED₅₀. Compositions that exhibit large therapeutic indices are preferred.
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 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 50 mg, per day. As a therapeutically effective amount of the present invention a daily dose of neramexane mesylate may be administered within the range from about 20 mg to 150 mg, such as from 25 mg to 100 mg (e.g. 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 95 mg), such as from 50 mg to 75 mg. 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.
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.
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.
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.
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 tinnitus in a mammal.

EXAMPLES OF REPRESENTATIVE FORMULATIONS

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

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 1

Neramexane mesylate, 12.5 mg film coated tablets

	Amount
Component	[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	5.00	Coating
or Sepifilm
Coat weight	5.00
coated tablet total	130.00
weight

TABLE 2

Neramexane mesylate, 25.0 mg film coated tablets

	Amount
Component	[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	10.00	Coating
or Sepifilm
Coat weight	10.00
coated tablet total	260.00
weight

TABLE 3

Neramexane mesylate, 37.5 mg film coated tablets

	Amount
Component	[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	15.00	Coating
or Sepifilm
Coat weight	15.00
coated tablet total	390.00
weight

TABLE 4

Neramexane mesylate, 50.0 mg film coated tablets

	Amount
Component	[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	20.00	Coating
or Sepifilm
Coat weight	20.00
coated tablet total	520.00
weight

EXAMPLES

The following examples illustrate the invention without limiting its scope.

Example 1

Double Blind Placebo Controlled Pilot Trial of Neramexane for Treatment of Tinnitus

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

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.
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. (Participants received either neramexane mesylate (e.g. 50 mg, as 25 mg immediate release tablets given twice daily) or placebo twice daily for 16 weeks. Neramexane mesylate was uptitrated in weekly steps of 12.5 or 25 mg during a 4-week uptitration period preceding the fixed-dose 12-week treatment period. Treatment was followed by a four week follow-up period.)
The scheduled visits for evaluation of each patient were as follows:
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-Beeinträchtigungs-Fragebogen (TBF-12) (i.e., a 12-item German modified and validated version (Greimel K V et al., Tinnitus-Beeinträchtigungs-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 Inventory. 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 (Geräuschüberempfindlichkeit-Fragenbogen (GÜF)) Questionnaire (if applicable).
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 GÜF Questionnaire (if applicable). The subject was enrolled in the study and study medication (placebo or neramexane) was dispensed as described below.
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 GÜF Questionnaire (if applicable). Medication compliance was assessed, and medication for the next 4 weeks was dispensed as described below.
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 GÜF Questionnaire (if applicable). Medication compliance was assessed and, medication for the next 4 weeks was dispensed as described below.
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 GÜF Questionnaire (if applicable). Medication compliance was assessed and, medication for the next 4 weeks was dispensed as described below.
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 GÜF Questionnaire (if applicable). Pure-tone audiometry (air conduction) was also conducted.
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 GÜF Questionnaire (if applicable).

Administration of Neramexane

Neramexane mesylate immediate release tablets (12.5 mg and 25 mg) and matching placebo tablets were administered as film coated tablets.
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 (7×4 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.
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 neramexane mesylate/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.
Throughout the double-blind treatment period, patients were to continue to take 2×2 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 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	25/12.5	25/25	37.5/37.5	(75 mg/d)	—
Medium-dose	12.5/0	12.5/0	12.5/12.5	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

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.
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

Primary Outcome

- 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.

Secondary Outcomes

- TBF-12 total score (values and absolute change from baseline) at all post-baseline visits except the endpoint visit.
- Change in the TBF-12 total score from Week 16 to Week 20 (values and absolute changes).
- TBF-12 factorial scores (values and absolute change from baseline, including the change from Week 16 to Week 20) at all post-baseline visits.
- Hyperacusis questionnaire GÜF (“Geräuschüberempfindlichkeits-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.
- 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).
- 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.
- 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

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.
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.
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.

Discussion

This clinical study showed promising results in terms of efficacy and safety. After a 16-week double-blind treatment (Visit 6) with final daily doses of 50 or 75 mg neramexane mesylate, patients reported a clear improvement of their tinnitus, as measured by the TBF-12, which was distinct from the groups treated with placebo or low-dose (25 mg) neramexane mesylate. The treatment period was followed by a 4-week wash-out period without any medication. Remarkably, subjects previously treated with either 50 or 75 mg neramexane mesylate reported a further relevant improvement of their tinnitus which was not reported by subjects who had received placebo or low-dose neramexane. This was an entirely unexpected clinical observation. At the end of the 4-week wash-out (Week 20, Visit 7), differences in TBF-12 improvement between the 50 mg and the placebo group reached statistical significance. These results are shown in Table 6 below and in FIG. 1.

TABLE 6

Change in the TBF-12 total score from baseline to all post-baseline visits (ITT-LOCF)

Neramexane - Placebo

	Actual	Change	Change	LSMean
n	Mean ± SD	Mean ± SD	LSMean	Diff. ± SE	95% CI	p-value

Week 4

Placebo	111	13.6 ± 4.1	−0.8 ± 2.7	−0.8	n.a.	n.a.	n.a.
25 mg/d	106	13.4 ± 4.5	−1.0 ± 2.6	−0.8	−0.1 ± 0.4	[−0.8, 0.7]	0.875
Neramexane
50 mg/d	106	13.0 ± 4.7	−1.4 ± 3.2	−1.4	−0.6 ± 0.4	[−1.3, 0.1]	0.110
Neramexane
75 mg/d	99	12.2 ± 4.3	−1.7 ± 2.7	−1.6	−0.9 ± 0.4	[−1.6, −0.1]	0.026
Neramexane

Week 8

Placebo	111	12.5 ± 4.2	−1.9 ± 3.0	−1.8	n.a.	n.a.	n.a.
25 mg/d	106	12.7 ± 4.9	−1.7 ± 2.9	−1.5	0.3 ± 0.4	[−0.5, 1.2]	0.429
Neramexane
50 mg/d	106	12.3 ± 4.8	−2.2 ± 3.3	−2.1	−0.3 ± 0.4	[−1.1, 0.5]	0.488
Neramexane
75 mg/d	99	11.9 ± 4.5	−2.0 ± 3.3	−1.9	−0.1 ± 0.4	[−1.0, 0.7]	0.813
Neramexane

Week

12

Placebo	111	12.3 ± 4.8	−2.2 ± 3.5	−2.1	n.a.	n.a.	n.a.
25 mg/d	106	12.8 ± 5.0	−1.6 ± 3.4	−1.4	0.6 ± 0.5	[−0.3, 1.6]	0.182
Neramexane
50 mg/d	106	11.8 ± 4.9	−2.6 ± 3.8	−2.5	−0.4 ± 0.5	[−1.4, 0.5]	0.357
Neramexane
75 mg/d	99	11.4 ± 4.9	−2.5 ± 3.5	−2.4	−0.4 ± 0.5	[−1.3, 0.6]	0.457
Neramexane

Week

16

Placebo	111	12.0 ± 4.9	−2.4 ± 3.6	−2.3	n.a.	n.a.	n.a.
25 mg/d	106	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	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	11.0 ± 5.1	−2.9 ± 3.9	−2.8	−0.5 ± 0.5	[−1.6, 0.5]	0.289
Neramexane

Week 20 (Follow-up)

Placebo	101	12.0 ± 5.1	−2.6 ± 4.2	−2.5	n.a.	n.a.	n.a.
25 mg/d	100	12.3 ± 5.5	−2.1 ± 3.4	−2.0	0.5 ± 0.6	[−0.6, 1.6]	0.336
Neramexane
50 mg/d	95	10.4 ± 5.3	−3.9 ± 4.4	−3.8	−1.3 ± 0.6	[−2.4, −0.2]	0.021
Neramexane
75 mg/d	89	10.5 ± 4.9	−3.3 ± 3.6	−3.2	−0.7 ± 0.6	[−1.8, 0.5]	0.244
Neramexane

* LSmeans and p-values derived from an ANCOVA model with treatment and center as factors and baseline TBF-12 as covariate

These findings demonstrate that neramexane has the capability for a sustained improvement of tinnitus even after the drug is withdrawn. Thus, neramexane may be useful as an interval therapy in the treatment of tinnitus which allows for medication-free intervals without patients experiencing a deterioration of their tinnitus or as maintenance therapy in the treatment of tinnitus to prevent recurrence of tinnitus in patients through administering a reduced dose of neramexane.

Example 2

Double Blind Placebo Controlled Trial of Neramexane for Treatment of Tinnitus

The objective of this project is to conduct a clinical trial to further assess the sustained effects of neramexane as a treatment for tinnitus. The primary objective of this study is to compare the efficacy, tolerability and safety of neramexane with placebo in subjects with first onset, persistent, unilateral or bilateral subjective tinnitus.

Study Design

In a double-blind, multicenter, randomized, placebo-controlled, parallel-group study, the efficacy of neramexane in subjects suffering from tinnitus is assessed. Patients who fulfill particular inclusion criteria and meet none of particular exclusion criteria are randomized into double-blind treatment groups.
Subjects are treated for 17 weeks with neramexane or placebo including a four-resp. five-week up-titration period, depending on study drug dose, followed by a 12-week treatment-free observational period to investigate the sustained effects of the drug after cessation of the treatment.
Subjects with a target daily dose of 50 mg neramexane mesylate (<90 kg body weight) will reach steady state after four weeks, patients with a target total daily dose of 75 mg neramexane mesylate (≧90 kg body weight) will reach steady state after five weeks of treatment. For patients experiencing dose limiting adverse events with the 75 mg dose, the dosage may be reduced by switching the patient to 50 mg/day. Patients unable to tolerate a minimum dosage of 50 mg/day will be discontinued.
The scheduled visits for evaluation of each patient are as follows:
Visit 1 (screening): After signing the consent form, the subject undergoes a physical examination and clinical laboratory testing. Patient eligibility for the study was evaluated via a check of inclusion/exclusion criteria.
Visit 2 (baseline): The subject is asked about adverse events and changes in concomitant medication/disease, which events/changes are documented. The subject is evaluated for study eligibility based on a review of the inclusion/exclusion criteria. Trial procedures as well as allowed and forbidden concomitant medications are reviewed with the subject. Safety and efficacy parameters are evaluated. The subject is enrolled in the study and study medication (placebo or neramexane) is dispensed as described below.
Visit 3 (Week 5): This visit occurs at the end of the up-titration sequence. The subject is asked about adverse events and changes in concomitant medication/disease, which events/changes are documented. Safety and efficacy parameters are evaluated. Medication is dispensed as described below.
Visit 4 (Week 9): This visit occurs at the end of the first 4-week fixed-dose double-blind treatment period. The subject is asked about adverse events and changes in concomitant medication/disease, which changes are documented. Safety and efficacy parameters are evaluated. Medication is dispensed as described below.
Visit 5 (Week 13): This visit occurs at the end of the second 4-week fixed-dose double-blind treatment period. The subject is asked about adverse events and changes in concomitant medication/disease, which changes are documented. Safety and efficacy parameters are evaluated. Medication is dispensed as described below.
Visit 6 (Week 17, end of treatment): This visit occurs at the end of the 12-week fixed-dose double-blind treatment period. The subject is asked about adverse events and changes in concomitant medication/disease, which changes are documented. A clinical laboratory evaluation is performed. Safety and efficacy parameters are evaluated.
Visit 7 (Week 21): This visit occurs 4 weeks 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. Safety and efficacy parameters are evaluated.
Visit 8 (Week 25): This visit occurs 8 weeks 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. Safety and efficacy parameters are evaluated.
Visit 9 (Week 29): This visit occurs at the end of the 12-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. Safety and efficacy parameters are evaluated.

Administration of Neramexane

Neramexane mesylate immediate release tablets (12.5 mg and 25 mg) and matching placebo tablets are administered as film coated tablets.
Medication is dispensed from Visit 2 to Visit 5. Study medication for each study day consists of 4 separate tablets. The dosing schedule is shown in Table 7.
Throughout the double-blind treatment period, patients are to continue to take 2×2 tablets of medication daily at a constant interval of 12 hours.

TABLE 7

Administration of Neramexane mesylate

			12-week
	5-week double-blind	12-week fixed-dose	follow-up
Treatment	up-titration period	double-blind period	Weeks

group	Week 1	Week 2	Week 3	Week 4	Week 5	Weeks 6-17	18-29

75 mg/d dose	0/12.5	12.5/12.5	12.5/25	25/25	37.5/37.5	37.5/37.5	(75 mg/d)	—
50 mg/d dose	0/12.5	12.5/12.5	12.5/25	25/25	25/25	25/25	(50 mg/d)	—

Placebo	0/0	0/0	0/0	0/0	0/0	0/0	—

xx/xx refers to the morning/evening dose in mg, respectively

In case of dose limiting adverse events, the investigator could consider a dose reduction of 25 mg/d only in the 75 mg/d group. Subjects unable to tolerate a minimum dosage of 50 mg/d are discontinued.
Subjects are 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).

Efficacy

Primary Outcome

- The change in TBF-12 total score from baseline (Visit 2) to end of treatment is the primary efficacy endpoint in this study.

Secondary Outcomes

- TBF-12 and TBF-12 factorial scores (values and absolute change from baseline) at all post-baseline visits.
- Tinnitus loudness (11-point Likert scale).
- Tinnitus annoyance (11-point Likert scale).
- Tinnitus impact on life (11-point Likert scale).
- Sum score of Tinnitus loudness, Tinnitus annoyance and Tinnitus impact on life (T-Score).

Data Analysis

All efficacy analyses are performed on the ITT population using the last-observation-carried-forward (LOCF) approach. All statistical tests used for testing the primary efficacy (confirmatory testing) and secondary efficacy criteria (exploratory), and all statistical tests used for exploratory analyses are two-sided hypothesis tests performed at the 5% significance level.

Discussion

This clinical study is expected to further demonstrate that neramexane has the capability for a sustained improvement of tinnitus even after the drug is withdrawn and that, therefore, neramexane may be useful as an interval therapy in the treatment of tinnitus which allows for medication-free intervals without patients experiencing a deterioration of their tinnitus, or as maintenance therapy in the treatment of tinnitus to prevent recurrence of tinnitus in patients through administering a reduced dose of neramexane.

Example 3

Placebo Controlled Trial of Neramexane for Treatment of Hearing Loss

Study Design

The primary objective of this study is to investigate the safety and efficacy of neramexane mesylate at daily doses of up to 75 mg in the treatment of hearing loss in comparison to placebo.

Administration of Neramexane

Neramexane mesylate 25 mg modified release tablets and matching placebo tablets are administered as film coated tablets.
Neramexane mesylate (or placebo) is uptitrated to a maximum daily dose of 75 mg, starting with a daily dose of 25 mg for one week, and increasing dosage in 25 mg steps at weekly intervals.
Treatment is started in the evening of study day 1. The daily starting dose is 25 mg neramexane mesylate per dose to be taken for 7 days at bedtime. At day 8, the daily neramexane mesylate dose is increased to 50 mg for another 7 days (two tablets in the evening for one week). At day 15, patients are uptitrated to 75 mg neramexane mesylate. Patients continue to take neramexane for 13 weeks (three tablets once daily in the evening for 13). Patients who do not tolerate 75 mg per day may reduce the neramexane mesylate dose by 25 mg to 50 mg for the remainder of the total scheduled treatment duration. For example, patients who do not tolerate a 75 mg dose are allowed to step back to a 50 mg dose. Patients are then asked to stay on the 50 mg dose for the remainder of the total scheduled treatment duration of 7 weeks. This dosing regimen is shown in Table 8.

TABLE 8

Administration of Neramexane mesylate

	2-week double-blind	14-week fixed-dose	4-week
Treatment	uptitration period	double-blind period	follow-up

group	1	2	3-16	17-20

Neramexane	0/25	0/50	0/75 mg/d	—
mesylate
Placebo	0/0	0/0	0/0	—

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.
All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference.

Claims

1-17. (canceled)

18. A method of treating tinnitus in a subject in need thereof, comprising administering a therapeutically effective amount of a 1-amino-alkylcyclohexane derivative, wherein the therapeutically effective amount of the 1-amino-alkylcyclohexane derivative is administered daily for a first period of at least three (3) months, followed by a second period of at least one (1) month wherein the 1-amino-alkylcyclohexane derivative is administered at a dose which is 0-75% of the therapeutically effective dose.

19. The method of claim 18, wherein during the second period the 1-amino-alkylcyclohexane derivative is administered at a dose which is above 0-75% of the therapeutically effective dose.

20. The method of claim 18, wherein during the second period the 1-amino-alkylcyclohexane derivative is administered at a dose which is 20-75% of the therapeutically effective dose.

21. The method of claim 18, wherein during the second period the 1-amino-alkylcyclohexane derivative is administered at a dose which is 25-50% of the therapeutically effective dose.

22. The method of claim 18, wherein during the second period the 1-amino-alkylcyclohexane derivative is not administered with treatment being repeated after the second period.

23. The method of claim 18, wherein a dose increase to reach a therapeutically effective dose following the second period is performed stepwise.

24. The method of claim 18, wherein the second period is followed by administering to the subject a therapeutically effective amount of a 1-amino-alkylcyclohexane derivative after a recurrence of tinnitus.

25. The method of claim 24, wherein the administration of the therapeutically effective amount of a 1-amino-alkylcyclohexane derivative after recurrence of tinnitus is continued for at least one year.

26. The method of claim 18, wherein the second period is from three (3) to six (6) months.

27. The method of claim 18, wherein between the first and second period there is a transition period during which the dose is reduced stepwise.

28. The method of claim 18, wherein the 1-amino-alkylcyclohexane derivative is neramexane or a pharmaceutically acceptable salt thereof.

29. The method of claim 28, wherein the 1-amino-alkylcyclohexane derivative is neramexane mesylate.

30. The method of claim 29, wherein neramexane mesylate is administered in a range from about 5 mg to about 150 mg/day during the first period.

31. The method of claim 29, wherein neramexane mesylate is administered in a range from about 5 mg to about 100 mg/day during the first period.

32. The method of claim 29, wherein neramexane mesylate is administered in a range from about 5 mg to about 75 mg/day during the first period.

33. The method of claim 29, wherein neramexane mesylate is administered at about 50 mg/day during the first period.

34. The method of claim 29, wherein neramexane mesylate is administered at about 75 mg/day during the first period.

35. The method of claim 28, wherein neramexane or a pharmaceutically acceptable salt thereof is administered once a day, twice a day (b.i.d.), or three times a day.

36. The method of claim 35, wherein neramexane or a pharmaceutically acceptable salt thereof is administered twice a day.

37. The method of claim 28, wherein neramexane or a pharmaceutically acceptable salt thereof is administered in an immediate release formulation.

38. The method of claim 28, wherein neramexane or a pharmaceutically acceptable salt thereof is administered in a modified release formulation.

39. A method of treating a 1-amino-alkylcyclohexane derivative responsive condition in a subject in need thereof, comprising administering a therapeutically effective amount of a 1-amino-alkylcyclohexane derivative, wherein the therapeutically effective amount of the 1-amino-alkylcyclohexane derivative is administered daily for a first period of at least three (3) months, followed by a second period of at least one (1) month wherein the 1-amino-alkylcyclohexane derivative is administered at a dose which is 0-75% of the therapeutically effective dose.