RU2459618C2 - Neramexane titration kit and using it in treating internal ear disorders - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely otorhinolaryngology and may be used for treating internal ear disorders. That is ensured by using a 1-aminoalkylcyclohexane derivative specified in neramexane or its pharmaceutically acceptable salt. Said derivative is introduced according to the titration schedule which involves increasing a dose of neramexane and gradually increasing a dose by 25 mg or 12.5 mg every week over a period of four to five weeks to achieve an effective daily dose of 50 to 75 mg. What is also presented is using the 1-aminoalkylcyclohexane derivative specified in neramexane or its pharmaceutically acceptable salt, and a method of treating internal ear disorders in an individual in need thereof.

EFFECT: group of inventions enables the fast and safe achievement of the effective dose of neramexane with side effects herewith minimised.

14 cl, 9 dwg, 10 tbl, 8 ex

Description

FIELD OF THE INVENTION

The present invention relates to a dose titration scheme for administering a 1-aminoalkylcyclohexane derivative, which allows for the fast and safe achievement of an effective dose of a 1-aminoalkylcyclohexane derivative while minimizing side effects. The present invention also relates to a titration scheme that allows for a quick and safe dose increase for at least two different and weight-adjusted maintenance doses. The present invention also relates to a titration kit for delivering a 1-aminoalkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof) in at least two different doses. The present titration scheme / titration kit is expected to be useful in treating various disorders of the inner ear, including tinnitus (tinnitus / ringing).

BACKGROUND OF THE INVENTION

Disorders of the inner ear are a growing problem for modern society. The most common of these disorders, tinnitus, usually means “tinnitus” and is a sensation of sounds in the absence of an external source of sound signals. Tinnitus was defined as “a sensation of sound that occurs solely due to activity within the nervous system without any corresponding mechanical, vibrational activity in the cochlea, that is, tinnitus is a phantom auditory sensation” (Jastreboff et al., J Am Acad Audiol 2000; 11 (3): 162-177). For a particular patient, tinnitus may be tolerable or may be a debilitating disease that interferes with sleep and / or work. Tinnitus is often combined with reduced tolerance to sounds (i.e. hyperacusis).

The pathophysiology of tinnitus in subjective cases is obscure, and the specific pathogenesis of tinnitus is unknown. Many environmental factors and factors induced by substances can cause tinnitus. Among the most frequently mentioned factors of this kind are acute acoustic trauma, occupational noise and entertaining music. In general, it appears that tinnitus is the result of neural dysfunction in the conduction pathways of hearing. Higher auditory centers mistakenly perceive this dysfunction as sound, which can lead to functional changes in the auditory department of the nervous system. Functional changes in the cortical structures that are not conducive to adaptation can lead to an imbalance between the exciting and inhibitory neurotransmission and, as a result, to more severe tinnitus. In all cases, a potential dysfunction in the pathways of the hearing and the auditory area of the cerebral cortex is associated with the activity of the prefrontal cortex and limbic system.

In most cases (95%), the sensation of tinnitus is of a purely subjective nature, that is, it is impossible to identify any source of sound signals and, therefore, it is impossible to hear sound from the outside. In such cases, a medical examination is performed to exclude objective tinnitus, that is, the patient's perception of sound caused by a real source of sound waves, for example, sound coming from a turbulent flow in blood vessels and reaching the cochlea. Tinnitus can be classified according to its duration and degree of manifestation (for example, severity or inconvenience) (McCombe et al., Clin Otolaryngol 2001; 26 (5): 388-393 and Davis et al., Epidemiology of Tinnitus. In the book: Tyler R, editor. Tinnitus Handbook. San Diego: Singular Publishing Group; 2000, p. 1-23). As for the effect of tinnitus on life, it can cause severe inconvenience to the patient and be accompanied by social and physiological complications.

Currently, there are no well-grounded and specific medical methods for treating tinnitus that can provide a reproducible decrease in tinnitus and mitigate its vital effects compared with 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).

It has been found that 1-aminoalkylcyclohexanes such as neramexane (also known as 1-amino-1,3,3,5,5, pentamethylcyclohexane) are useful in the treatment of various diseases, especially some neurological diseases, including Alzheimer's disease and neuropathic pain. Such 1-aminoalkylcyclohexanes such as neramexane are disclosed in detail, for example, in US Pat. Nos. 6,034,134 and 6,071,966. Thus, the corresponding content of these patents is incorporated herein by reference to the extent that they consider chemical variations of 1-aminoalkylcyclohexanes. The therapeutic effects of 1-aminoalkylcyclohexanes such as neramexane are believed to be associated with the suppression of the effects of excess glutamate in N-methyl-D-aspartate (NMDA) receptors of nerve cells, and, for these reasons, such compounds are also classified as NMDA antagonists or receptor antagonists. NMDA It was also disclosed that neramexane is active at the level of α9 / α10 nicotinic receptors (Plazas, et al., Eur J Pharmacol., 2007 Jul. 2; 566 (1-3): 11-19) and 5-HT3 receptors.

Adverse effects associated with the administration of drugs can be eliminated or minimized using the appropriate titration period with an increase in dose. Thus, there is a need for a convenient titration scheme that will quickly achieve an effective dose, minimizing side effects. In addition, there is also a need for a titration kit that will ensure consistency with the time course of dose adjustment of the 1-aminoalkylcyclohexane derivative. Such titration kits are also known as “matching kits” because they help the patient adhere to the therapeutically indicated dosage regimen.

The authors of the present invention have found that neramexane may be useful in the treatment of tinnitus. The inventors of the present invention also developed a titration scheme for administering a 1-aminoalkylcyclohexane derivative, which allows the rapid achievement of an effective dose of a composition containing a 1-aminoalkylcyclohexane derivative, while minimizing side effects. In addition, the authors of the present invention have developed a titration scheme that allows for a quick and safe dose increase for at least two different and weighted maintenance doses. In addition, the authors of the present invention have developed a titration kit containing at least two different doses of a derivative of 1-aminoalkylcyclohexane, for example, neramexane, which allows a suitable dose increase period to be implemented to produce an acceptably low incidence of drug-related adverse events. Such a titration scheme / titration kit may be suitable for use in the treatment of tinnitus.

SUMMARY OF THE INVENTION

The present invention relates to a derivative of 1-aminoalkylcyclohexane (for example, neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) for treating an inner ear disorder, for example tinnitus, said derivative being administered according to the titration scheme. The specified titration scheme allows for the rapid and safe achievement of an effective dose. Thanks to this mode of administration, the side effects attributed to the administration of 1-aminoalkylcyclohexane derivatives are minimized.

A further aspect of the invention relates to the use of a 1-aminoalkylcyclohexane derivative (for example, neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) for the manufacture of a medicament for the treatment of an inner ear disorder, for example tinnitus, wherein the medicament is administered by a titration scheme that provides rapid and safe achievement of an effective dose. Thanks to this mode of administration, the side effects attributed to the administration of 1-aminoalkylcyclohexane derivatives are minimized. The drug described herein is intended to be administered in accordance with the titration scheme disclosed herein.

A derivative of 1-aminoalkylcyclohexane, as well as the specified drug, is intended for administration in accordance with the above titration scheme. In one embodiment of the invention, the derivative / drug is specifically adapted to provide the patient with relevant titration pattern information. Relevant information about a specific titration scheme can be provided, for example, by appropriate information inside the package or on the package, on the dosage form and / or on the packaging insert, and / or in the patient information sheet. Relevant information on a specific administration schedule can be provided, for example, by appropriate information inside the package or on the package and / or on the package insert and / or in the patient information sheet, as well as the appearance of the dosage forms provided to the patient, for example, tablet form or tablet color.

A further aspect of the invention relates to the aforementioned derivative / method of use thereof, wherein said titration scheme involves increasing a dose of a 1-aminoalkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) over a period of four to five weeks to achieve effective dose.

In a further aspect of the invention, the titration scheme comprises increasing the dose of a 1-aminoalkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) over a period of four to five weeks to achieve an effective dose of 5 to 150 mg per day .

In a further aspect of the invention, the titration schedule includes increasing the dose of a 1-aminoalkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) over a period of four to five weeks to achieve an effective dose of 50 to 75 mg per day .

In a further aspect of the invention, the titration scheme comprises increasing the dose of the 1-aminoalkylcyclohexane derivative in incremental increments of the dose of 25 mg or 12.5 mg and at weekly intervals.

In a further aspect of the invention, the 1-aminoalkylcyclohexane derivative is neramexane or a pharmaceutically acceptable salt thereof, for example neramexane mesylate.

In a further aspect of the invention, the titration regimen includes increasing the dose of neramexane or its pharmaceutically acceptable salt (e.g. neramexane mesylate) over a period of four weeks to achieve an effective dose of 50 mg per day while minimizing side effects.

In a further aspect of the invention, neramexane or a pharmaceutically acceptable salt thereof (e.g., neramexane mesylate) is administered as follows: once a day (daily) in the first week at a dose of 12.5 mg, twice a day (daily) in the second week for 12 , 5 mg for each dose, twice a day (daily) in the third week, with the first dose being 12.5 mg and the second dose of 25 mg, as well as twice daily (daily) in the fourth week, 25 mg per every reception.

In a further aspect of the invention, according to the same schedule, neramexane mesylate is administered to a patient. If another pharmaceutically acceptable salt, solvate, isomer, conjugate, prodrug or derivative, for example neramexane hydrochloride, is administered to the patient, an equimolar amount of another pharmaceutically acceptable salt, solvate, isomer, conjugate, prodrug or derivative, for example neramexane hydrochloride, can also be used.

In a further aspect of the invention, neramexane or a pharmaceutically acceptable salt thereof (e.g., neramexane mesylate) is administered as follows: once a day (daily) in the first week at a dose of 12.5 mg, twice a day (daily) in the second week for 12 , 5 mg for each dose, twice a day (daily) in the third week, with the first dose being 12.5 mg and the second dose of 25 mg, as well as twice daily (daily) in the fourth week, 25 mg per each dose, and in those weeks when different doses are used, a dose containing a higher concentration tion of the active substance is administered every second day procedure.

In a further aspect of the invention, according to the same schedule, neramexane mesylate is administered to a patient. If another pharmaceutically acceptable salt, solvate, isomer, conjugate, prodrug or derivative, for example neramexane hydrochloride, is administered to the patient, an equimolar amount of another pharmaceutically acceptable salt, solvate, isomer, conjugate, prodrug or derivative, for example neramexane hydrochloride, can also be used.

In a further aspect of the invention, the titration schedule includes treatment with neramexane or a pharmaceutically acceptable salt thereof (e.g., neramexane mesylate), said titration scheme allowing increasing the dose of neramexane or its pharmaceutically acceptable salt (e.g. neramexane mesylate) for five weeks to achieve an effective dose of 75 mg per day while minimizing side effects.

In a further aspect of the invention, neramexane or a pharmaceutically acceptable salt thereof (e.g., neramexane mesylate) is administered as follows: once a day (daily) in the first week at a dose of 12.5 mg, twice a day (daily) in the second week for 12 , 5 mg for each dose, twice a day (daily) in the third week, with the first dose being 12.5 mg and the second dose of 25 mg, twice a day (daily) in the fourth week 25 mg per dose , and also twice a day (daily) in the fifth week, 37.5 mg per dose.

In a further aspect of the invention, according to the same schedule, neramexane mesylate is administered to a patient. If another pharmaceutically acceptable salt, solvate, isomer, conjugate, prodrug or derivative, for example neramexane hydrochloride, is administered to the patient, an equimolar amount of another pharmaceutically acceptable salt, solvate, isomer, conjugate, prodrug or derivative, for example neramexane hydrochloride, can also be used.

In a further aspect of the invention, neramexane or a pharmaceutically acceptable salt thereof (e.g., neramexane mesylate) is administered as follows: once a day (daily) in the first week at a dose of 12.5 mg, twice a day (daily) in the second week for 12 , 5 mg for each dose, twice a day (daily) in the third week, with the first dose being 12.5 mg and the second dose of 25 mg, twice a day (daily) in the fourth week 25 mg per dose , as well as twice a day (daily) in the fifth week, 37.5 mg per dose, and in those weeks when different doses are used, a dose containing a higher concentration of the active substance is administered second in order every day.

In a further aspect of the invention, according to the same schedule, neramexane mesylate is administered to a patient. If another pharmaceutically acceptable salt, solvate, isomer, conjugate, prodrug or derivative, for example neramexane hydrochloride, is administered to the patient, an equimolar amount of another pharmaceutically acceptable salt, solvate, isomer, conjugate, prodrug or derivative, for example neramexane hydrochloride, can also be used.

In a further aspect of the invention, neramexane or a pharmaceutically acceptable salt thereof (e.g., neramexane mesylate) is administered as follows: once a day (daily) in the first week at a dose of 25 mg, once a day (daily) in the second week at a dose of 50 mg , and also, optionally, once a day (daily) in the third week at a dose of 75 mg.

In a further aspect of the invention, neramexane or a pharmaceutically acceptable salt thereof (e.g., neramexane mesylate) is administered in a once-daily modified release dosage form according to the following schedule: once a day (daily) in the first week at a dose of 12.5 mg, once per day (daily) in the second week at a dose of 25 mg, once a day (daily) in the third week at a dose of 37.5 mg, once a day (daily) in the fourth week at a dose of 50 mg for subjects weighing up to 90 kg, and also, in addition to the above, once a day (daily) in 75 mg for subjects weighing more than 90 kg.

A further aspect of the invention relates to a titration scheme in which, according to the same schedule, neramexane mesylate is administered to a patient. If another pharmaceutically acceptable salt, solvate, isomer, conjugate, prodrug or derivative, for example neramexane hydrochloride, is administered to the patient, an equimolar amount of another pharmaceutically acceptable salt, solvate, isomer, conjugate, prodrug or derivative, for example neramexane hydrochloride, can also be used.

In a further aspect of the invention, a composition comprising neramexane or a pharmaceutically acceptable salt thereof (e.g., neramexane mesylate) is administered in a once-daily modified release dosage form according to the following schedule: once a day (daily) in the first week at a dose of 25 mg, once a day (daily) in the second week at a dose of 50 mg for subjects weighing up to 90 kg, and also, in addition to the above, once a day (daily) at a dose of 75 mg for subjects weighing more than 90 kg.

A further aspect of the invention relates to a titration scheme in which, according to the same schedule, neramexane mesylate is administered to a patient. If another pharmaceutically acceptable salt, solvate, isomer, conjugate, prodrug or derivative, for example neramexane hydrochloride, is administered to the patient, an equimolar amount of another pharmaceutically acceptable salt, solvate, isomer, conjugate, prodrug or derivative, for example neramexane hydrochloride, can also be used.

In a further aspect of the invention, the inner ear disorder is at least one pathological condition selected from tinnitus, vertigo (dizziness), such as paroxysmal positional vertigo (BPPV), hearing loss, chronic earache, perilymphatic fistula, secondary endolymphatic edema , labyrinthitis and vestibular neuritis, auditory nerve neuroma, ototoxicity, autoimmune disease of the inner ear (AIED) and Meniere's disease.

The present invention further relates to a titration regimen for treating an inner ear disorder (e.g., tinnitus) which provides for the rapid achievement of an effective dose of a composition containing a 1-aminoalkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate), minimize side effects.

A further aspect of the invention relates to such a titration scheme that includes increasing the dose of a composition containing a 1-aminoalkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) over a period of four to five weeks to achieve an effective dose at minimizing side effects.

A further aspect of the invention relates to such a titration scheme that includes increasing the dose of a composition containing a 1-aminoalkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) over a period of four to five weeks to achieve an effective dose of 5 to 150 mg per day while minimizing side effects.

A further aspect of the invention relates to such a titration scheme that includes increasing the dose of a composition containing a 1-aminoalkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) over a period of four to five weeks to achieve an effective dose of 50 to 75 mg per day while minimizing side effects.

A further aspect of the invention relates to such a titration regimen that includes treatment with a composition containing neramexane or a pharmaceutically acceptable salt thereof (for example, neramexane mesylate), and which includes increasing the dose of a composition containing neramexane or its pharmaceutically acceptable salt for four weeks to achieve an effective doses of 50 mg per day while minimizing side effects.

A further aspect of the invention relates to a titration scheme in which a composition containing neramexane or a pharmaceutically acceptable salt thereof (eg, neramexane mesylate) is administered as follows: once a day (daily) in the first week at a dose of 12.5 mg, two once a day (daily) in the second week, 12.5 mg per dose, twice a day (daily) in the third week, the first dose being 12.5 mg and the second dose 25 mg, and also twice day (daily) in the fourth week, 25 mg per dose.

A further aspect of the invention relates to a titration scheme in which, in the weeks when different doses are used, a dose containing a higher concentration of the active substance is administered second in order every day.

A further aspect of the invention relates to such a titration regimen that includes treatment with a composition containing neramexane or a pharmaceutically acceptable salt thereof (for example, neramexane mesylate), and which includes increasing the dose of a composition containing neramexane or its pharmaceutically acceptable salt for five weeks to achieve an effective doses of 75 mg per day while minimizing side effects.

A further aspect of the invention relates to a titration scheme in which a composition containing neramexane or a pharmaceutically acceptable salt thereof (eg, neramexane mesylate) is administered as follows: once a day (daily) in the first week at a dose of 12.5 mg, two once a day (daily) in the second week, 12.5 mg per dose, twice a day (daily) in the third week, the first dose being 12.5 mg and the second dose 25 mg, twice a day ( daily) in the fourth week, 25 mg per dose, and also twice a day (daily) n and in the fifth week, 37.5 mg per dose.

A further aspect of the invention relates to a titration scheme in which, in the weeks when different doses are used, a dose containing a higher concentration of the active substance is administered second in order every day.

The present invention further relates to a titration regimen for treating a pathological condition responsive to a 1-aminoalkylcyclohexane derivative, which provides for the rapid achievement of an effective dose of a composition containing a 1-aminoalkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate), to minimize side effects.

The present invention further relates to a titration kit for the delivery of a 1-aminoalkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate), in which the 1-aminoalkylcyclohexane derivative is presented, for example, in at least two different doses. The specified titration kit can be used in the treatment of diseases of the inner ear according to the titration scheme disclosed herein.

A further aspect of the invention relates to a titration kit for delivering a 1-aminoalkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate), in at least two different dosages, the titration kit containing at least two sets of drug forms with the same dosage, each set contains at least three individually accessible address zones, and each address zone contains or is represented by a derivative of 1-aminoalkylcyclohexane (on for example, neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate), including a tablet.

A further aspect of the invention relates to a titration kit for delivering a pharmaceutical composition comprising a derivative of 1-aminoalkylcyclohexane (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate), in at least two different dosages, the titration kit containing at least , two sets of dosage forms with the same dosage, each set contains at least three individually accessible address zones, and each address zone contains or is represented armatsevticheskoy composition including a tablet.

A further aspect of the invention relates to such a titration kit in which at least three individually accessible address zones in each set are ordered in essentially at least one horizontal line (defining a “row”), or in essentially at least one vertical line (defining a "column").

An additional embodiment of the invention relates to such a titration kit in which at least three address zones in at least two sets of dosage forms with the same dosage differ from each other by at least one feature selected from the following group, or any combination of these signs: highlighting and / or painting and / or embossing, making blister packs in the position of the address zone, making a notch / elevation, making from different materials or with radienta material manufacturing pockets or blister or other possible insulating compartment of a 1-aminoalkylcyclohexane derivatives (e.g., neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate).

A further embodiment of the invention relates to such a titration kit in which a 1-aminoalkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) is presented as a solid.

An additional embodiment of the invention relates to such a titration kit in which a 1-aminoalkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) is presented in the form of a solid dosage form selected from tablets, tabloids, pills, troches, lozenges, capsules, granules, fine granules, pressed bodies or balls.

An additional embodiment of the invention relates to such a titration kit in which three or more doses are presented in three or more different sets of dosage forms with the same dosage, including four or more different doses in four or more different sets of dosage forms with the same same dosage.

An additional embodiment of the invention relates to such a titration kit in which each set of dosage forms with the same dosage contains at least five address zones (for example, seven address zones or fourteen address zones).

An additional embodiment of the invention relates to such a titration kit which contains two or more different doses / dosages of a 1-aminoalkylcyclohexane derivative (for example, neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate), the chemical nature of the derivative being the same, at least for two different dosages, along with the fact that the amount of derivative varies between two different dosages.

An additional embodiment of the invention relates to such a titration kit that allows for increasing and / or lowering the dose of a derivative of 1-aminoalkylcyclohexane (for example, neramexane or its pharmaceutically acceptable salt, such as neramexane mesylate) until a certain final dose level is reached .

An additional embodiment of the invention relates to a titration kit containing at least one set of dosage forms with the same dosage of a 1-aminoalkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) and at least one (second) set containing a placebo.

An additional embodiment of the invention relates to a titration kit, as defined above, wherein said titration kit is intended for treating a pathological condition responsive to a 1-aminoalkylcyclohexane derivative, and ensures the rapid achievement of an effective dose of a composition containing a 1-aminoalkylcyclohexane derivative (e.g., neramexane or its pharmaceutically acceptable salt, such as neramexane mesylate), while minimizing side effects.

Brief Description of the Drawings

Figure 1-4 show the titration kit described in example 3.

5-6 show the titration kit described in example 4.

7 shows a titration kit described in example 5.

Fig. 8 shows a titration kit described in Example 6.

Fig.9 shows the titration kit described in example 7.

DETAILED DESCRIPTION OF THE INVENTION

When used in the context of the present invention, the term “inner ear disorder” includes, but is not limited to, tinnitus, vertigo, in particular paroxysmal positional vertigo (BPPV), hearing loss, including contributing factors such as acoustic trauma, noise-induced hearing loss , Sensorineural hearing loss, hearing loss of mixed origin, hearing loss of unknown origin, ototoxic hearing loss (ototoxicity), drug-induced hearing loss, exo-induced hearing loss genetic chemicals, cancer-induced hearing loss, surgical-induced hearing loss, radiation-induced hearing loss, infection-induced hearing loss, sudden (idiopathic) hearing loss, hearing impairment, and presbyakusis (senile hearing loss) perilymphatic fistula, secondary endolymphatic edema, labyrinthitis and vestibular neuritis, auditory nerve neuroma, autoimmune disease of the inner ear (AIED), chronic pain in the ears and Meniere's disease.

Noise-induced hearing loss can be caused by acute or chronic effects. The most common cause of noise-induced hearing loss is prolonged exposure to excess noise, but extremely loud sounds can also cause such hearing loss.

Sensorineural hearing loss develops due to insensitivity of the inner ear or functional impairment in the auditory nervous system. Sensorineural hearing loss can be caused by abnormalities in the hair cells of the cochlear organ of the cochlea.

Ototoxic hearing loss can be caused by medications that damage the ear (i.e., medication-induced hearing loss is implied). Such medication effects include chemotherapeutic (i.e., antineoplastic or anti-cancer) agents (e.g., cisplatin), aminoglycosides (e.g., gentamicin), diuretics (e.g., bumetanide), salicylates (e.g., aspirin), quinines, NSAIDs (NSAIDs - non-steroidal anti-inflammatory drugs) ) and macrolide antibiotics.

Hearing loss induced by exogenous chemicals can be caused by agents (i.e. chemicals from the environment) that damage the ear (such as butyl nitrite, mercury, or toluene).

Cancer-induced hearing loss can be caused by tumors in the middle ear, as well as other cancers affecting the ear and / or brain.

Hearing loss induced by surgery can be observed after otological or neotological surgery, however, the mechanism (s) for the development of such hearing loss is unclear (unclear).

Hearing loss induced by radioactive radiation can cause intentional (for example, radiation therapy) or unintentional contact with radiation.

Infection-induced hearing loss can be caused by infections affecting the inner ear and auditory nerve, as well as infections affecting the middle ear. In addition, there are many other types of infections (for example, mumps, Lyme disease, meningitis, herpes virus infections, fungal infections, bacterial infections, AIDS and tuberculosis) that can lead to hearing loss.

Presbyakusis, apparently, is partly associated with the influence of noise and is characterized by an increase in the rigidity of the basement membrane, as well as damage / deterioration of hair cells, vascular strips, ganglia cells and cochlear nuclei.

When used in the context of the invention, the term “tinnitus” includes, but is not limited to all manifestations of subjective and objective tinnitus, as well as its acute, subacute and chronic forms. It also includes cochlear tinnitus and tinnitus, combined with hearing loss or mild hearing loss.

The term "subject" as used in the context of the present invention encompasses mammals, including both animals and humans.

The term 1-aminoalkylcyclohexane derivative is used in the context of the present invention to describe 1-aminoalkylcyclohexane or a compound derived from 1-aminoalkylcyclohexane, for example, pharmaceutically acceptable salts of 1-aminoalkylcyclohexanes. Existing derivatives of 1-aminoalkylcyclohexane can also be described as "derivatives of 1-aminocyclohexane".

Derivatives of 1-aminoalkylcyclohexane proposed by the present invention can be described by the general formula (I):

(I)

where R * means - (CH ₂ ) _n - (CR ⁶ R ⁷ ) _m -NR ⁸ R ⁹ ,

where n + m = 0, 1 or 2,

where the radicals from R ¹ to R ⁷ independently selected from the group consisting of hydrogen and C _1-6 alkyl, where R ⁸ and R ⁹ independently from each other can be selected from the group consisting of hydrogen and C _1-6 alkyl, or together represent lower alkylene - (CH ₂ ) _x- , where x is from 2 to 5, inclusive, as well as their optical isomers, enantiomers, hydrates and pharmaceutically acceptable salts.

Non-limiting examples of 1-aminoalkylcyclohexanes available for use in accordance with 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-pentamethylcyclohexane,

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 hemihydrate,

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 hemihydrate,

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) isopropylcyclohexane,

1-amino-1,5,5-trimethyl-3 (trans) isopropylcyclohexane,

1-amino-1-methyl-3 (cis) ethylcyclohexane,

1-amino-1-methyl-3 (cis) methylcyclohexane,

1-amino-5,5-diethyl-1,3,3-trimethylcyclohexane,

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-tetramethylcyclohexyl) pyrrolidine or piperidine,

N- (1-propyl-3,3,5,5-tetramethylcyclohexyl) pyrrolidine or piperidine,

N- (1,3,3,5,5-pentamethylcyclohexyl) pyrrolidine,

as well as their optical isomers, diastereomers, enantiomers, hydrates, pharmaceutically acceptable salts and mixtures.

Derivatives of 1-aminoalkylcyclohexane (eg, neramexane, 1-amino-1,3,3,5,5-pentamethylcyclohexane) are disclosed in US patent No. 6034134 and 6071966. Derivatives of 1-aminoalkylcyclohexane (eg, neramexane) in accordance with the invention can be used in the form of any pharmaceutically acceptable salts, solvates, isomers, conjugates and prodrugs, and any references to derivatives of 1-aminoalkylcyclohexane (e.g. neramexane) in the present description should be construed as also referring to these salts, solvates, isomers, conjugates and n on Medicine.

Pharmaceutically acceptable salts include, but are not limited to, acid addition salts, in particular salts obtained by the addition of hydrochloric, methylsulfonic, hydrobromic, hydrogen iodide, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, dairy, pyruvic, malonic, succinic, fumaric, tartaric, citric, benzoic, charcoal, cinnamon, almond, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamine, salicylic, p-amine salicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acid. All of these salts (or other similar salts) can be obtained by conventional methods. The nature of the salt is uncritical, provided that it is not toxic and does not substantially interfere with the manifestation of the desired pharmacological activity.

The term “analogue” or “derivative” is used in the context of the present invention in the generally accepted pharmaceutical sense to refer to a molecule that is similar in structure to a reference molecule (such as neramexane) but has been modified in a targeted and controlled manner to replace one or more specific substituents the reference molecule with an alternative substituent, thereby creating a molecule that is similar in structure to the reference molecule. Synthesis and screening of analogues (for example, using structural and / or biochemical analysis) to identify slightly modified variants of a known compound that may have improved or biased properties (such as increased power and / or selectivity for a specific target receptor type, greater ability penetrate the blood-brain barriers of mammals, fewer side effects and so on) are an approach to drug development that is well known en in pharmaceutical chemistry.

The term “treat” means amelioration or alleviation of at least one symptom of a disease or disease state in a subject. Within the meaning of the present invention, the term "treat" also means to suspend, delay the onset (that is, the period preceding the clinical manifestations of the disease) and / or reduce the risk of developing or worsening the disease.

The term “therapeutically effective (s, s)” as applied to a dose or amount refers to an amount of a compound or pharmaceutical composition sufficient to produce a result such as a desired activity when introduced into the body of a mammal in need thereof.

The phrase "pharmaceutically acceptable (s)" when used in relation to the 1-aminoalkylcyclohexane derivative of the invention refers to molecular objects and other components, for example, pharmaceutical compositions that are physiologically tolerable and typically do not cause adverse reactions when administered to a mammal ( for example, to a person). In a typical case, when used in the context of the present invention, the term "pharmaceutically acceptable (s)" means an official approval for use by a regulatory body or inclusion in a generally recognized pharmacopeia for use in mammals and, especially, humans.

The term “carrier” as applied to the pharmaceutical compositions of the invention refers to a diluent, excipient or carrier with which the active compound (for example, neramexane) is administered. Sterile fluids such as water, saline solutions, aqueous dextrose solutions, aqueous solutions of glycerol and oils, including oils of petroleum, animal, vegetable or synthetic origin, in particular peanut oil, soybean oil, mineral oil, sesame oil, can be used as pharmaceutical carriers. oil and the like. Such carriers may also be solids, for example fillers, as described below. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences", A. R. by Gennaro, 20th Edition.

The term "about" or "approximately" usually means a deviation within 20%,

alternatively, within 10%, including a deviation within 5% of the specified value or range.

The term "titration scheme" means the treatment method discussed in the description, which consists in the fact that patients receive treatment for a disease or pathological condition when they are administered at least two different dosages (doses) of one or more derivatives of 1-aminoalkylcyclohexane , for example, in the form of pharmaceutical compositions useful for treating such a disease / condition, in which they are administered in a phased manner once a day or several times a day (daily), with lower doses being administered at the start of treatment, and large doses are administered in subsequent weeks of treatment. Optionally, in those weeks of treatment when patients are administered different doses over the course of a single day, the titration scheme implies the introduction of a lower dose in the morning and a larger dose in the evening, which minimizes the side effects induced by the drug in the most productive hours of the day.

A 1-aminoalkylcyclohexane derivative (e.g., neramexane / neramexane mesylate) or a pharmaceutical composition containing this substance can be used to treat an inner ear disorder according to the titration scheme of the invention. In one embodiment of the invention, said derivative and / or pharmaceutical composition (drug) is adapted or suitably prepared for administration according to a special scheme, as disclosed herein. To this end, the kit and / or package insert of the kit, and / or patient information sheet, and / or dosage form, as such, may contain relevant information.

An active ingredient (e.g., neramexane / neramexane mesylate) or a composition of the present invention can be used to make a medicament for treating tinnitus, said medicament adapted or suitably formulated for a specific administration as disclosed herein. To this end, the packaging insert and / or patient information sheet contain relevant information.

The term "titration kit" means any substrate, container or package that provides at least two doses (doses) of at least 1-aminoalkylcyclohexane. Dosages (doses) may be the same or different. When used, for example, to treat an inner ear disorder in accordance with the titration scheme of the present invention, the kit contains dosage information for 1-aminoalkylcyclohexane. The specified information can be presented on the package or inside the package, on the packaging insert / in the information leaflet for the user inside the package and / or directly on the doses, for example, by their different appearance, in particular, different shapes and / or colors for different doses of the derivative 1-aminoalkylcyclohexane.

Providing two (chemically) different pharmaceutical compositions (especially in relation to their only active ingredients) formally in the same amount within the same titration kit also falls within the scope of “providing two different doses”.

In one embodiment, the titration kit may be any kit that is capable of containing and / or attaching a 1-aminoalkylcyclohexane derivative, for example, in the form of a pharmaceutical composition delivered in any possible form in individually accessible address areas that are part of the kit. "Address zones" must be identifiable by the kit user.

In the context of the present invention, “set” means any ordered organization of three or more address zones of any type in a two-dimensional or three-dimensional substrate.

In the context of the present invention, “address zone” is understood to mean any zone in a two-dimensional or three-dimensional substrate, which is part of a set, and which the user of the titration kit can reproducibly distinguish from any other address zone. Two adjacent address zones within the set and / or between the two sets can be physically separated from each other, that is, they should not overlap and / or adjoin each other.

In accordance with the present invention, there are no restrictions as to how two different address zones can be designated / identified. Address zones can be distinguished from each other by at least one method selected from the following group, or by any combination of these methods: highlighting and / or filling and / or embossing, ensuring blister packaging in the position of the address zone, that is, matching the blister packaging the address zone, providing a notch / elevation, fabrication from different materials or with a material gradient, providing a pocket or other possible holding shell for 1-aminoalkylcyclohexane.

In accordance with the present invention, the target zones may also be determined by a 1-aminoalkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof), which may be presented in a pharmaceutical composition, said composition may be in solid dosage forms, including pills, capsules, tablets, candies or lozenges that are directly or indirectly attached or attached to the kit or parts thereof. Also within the scope of the present invention is a situation in which individual address zones of a kit may contain a “void” (that is, at least one address zone does not contain a pharmaceutical composition).

In accordance with the present invention, the term “row” means any organized organization of three or more (for example, five or more, 7 or more, 10 or more) address zones on a substrate, according to which the zones are essentially ordered in a horizontal line (assuming that the review is conducted from above and the standard coordinate system is used). It is within the scope of the present invention that the address zones of a row are shifted, offset, separated or slightly moved relative to each other to the extent that the general arrangement of the address zones allows for such horizontal ordering.

In accordance with the present invention, the term “column” means any ordered organization of three or more (for example, five or more, 7 or more, 10 or more) address zones on a substrate, according to which the zones are essentially arranged in a vertical line (assuming that the review is conducted from above and the standard coordinate system is used). It is within the scope of the present invention that the address zones of a column are shifted, offset, spaced, or slightly moved relative to each other to the extent that the general arrangement of the address zones allows such vertical ordering to be maintained.

In accordance with the present invention, the dosage form of a 1-aminoalkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof) may be a solid dosage form, including capsules, tablets and the like (see Remington's Pharmaceutical Sciences, 20th Edition, AR by Gennaro) .

The 1-aminoalkylcyclohexane derivatives of the present invention can be administered orally in a semi-solid or liquid dosage form (see Remington's Pharmaceutical Sciences, 20th Edition, by A.R. Gennaro).

For solid dosage forms — tablets or capsules — the 1-aminoalkylcyclohexane derivatives contemplated by the present invention (eg, neramexane or a pharmaceutically acceptable salt thereof) can be combined with non-toxic pharmaceutically acceptable excipients such as binding agents (eg, gelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose), fillers (e.g. lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, micr crystalline cellulose, calcium sulfate or calcium hydrogen phosphate), glidants (e.g., magnesium stearate, talc or silicon dioxide, stearic acid, sodium stearyl fumarate, glycerol behenate, calcium stearate and the like), disintegrating sodium krah (e.g. potato starch glycolate salt) or wetting agents (e.g. sodium lauryl sulfate), with coloring and flavoring / flavoring agents, gelatin, sweeteners, natural and syn tetical resins (such as gum arabic, tragacanth or alginates), buffer salts, carboxymethyl cellulose, polyethylene glycol, waxes, etc.

The tablets may be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talc, titanium dioxide and the like. Alternatively, the tablets may be coated with a polymer that dissolves in a highly volatile organic solvent or in a mixture of organic solvents. In certain embodiments, neramexane is formulated as an immediate release (IR) or modified release (MR) tablet. Immediate release solid dosage forms release all or most of the active ingredient (e.g., 90% or more) within a short period of time, e.g., 60 minutes or less, and allow rapid absorption of the drug (immediate release dosage formulations of these 1 -aminoalkylcyclohexanes, such as neramexane, are disclosed in US Published Patent Applications Nos. 2006/002999 and 2006/0198884, the subject matter of which with respect to immediate release dosage forms is included in this document by reference). Solid oral modified release dosage forms provide a sustained release of the active ingredient over a long period of time, which aims to maintain a therapeutically effective plasma level for an equally long period of time and / or to modify other pharmacokinetic properties of the active ingredient (modified release pharmaceutical formulations neramexane disclosed in published US patent application No. 2007/0141148, subject matter which is incorporated herein by reference). For example, neramexane mesylate may be presented in a modified release dosage form (including modified release tablets) to deliver a 50 mg dose of neramexane mesylate.

For gelatin capsule formulations, the 1-aminoalkylcyclohexane derivatives contemplated by the present invention (eg, neramexane) can be mixed, for example, with vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of active substances using either the aforementioned tablet excipients, for example, lactose, sucrose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives, or gelatin. Hard gelatin capsules may also be filled with liquid or semi-solid drug formulations.

The 1-aminoalkylcyclohexane derivatives contemplated by the present invention (e.g., neramexane) can also be administered in microspheres or microcapsules, e.g. made from polyglycolic acid / lactic acid (PGLA) (see, for example, US Pat. Nos. 5,814,344, 5,100,669 and 4,849,222. PCT Publication Nos. WO 95/11010 and WO 93/07861). To achieve controlled drug release, biocompatible polymers can be used, including, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acids, polyepsilone-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates and block copolymers.

You can also use the inclusion of derivatives of 1-aminoalkylcyclohexane in the composition of semi-solid or liquid dosage forms. A 1-aminoalkylcyclohexane derivative (e.g., neramexane) can occupy from 0.1 to 99% by weight in the composition of the drug, more specifically from 0.2 to 50% by weight in the composition of the drug intended for oral administration.

In one embodiment, a 1-aminoalkylcyclohexane derivative (e.g., neramexane) is administered to a patient in a modified release dosage form. Modified-release dosage forms are a means to improve patient coherence with treatment and to provide effective and safe therapy by reducing the frequency of adverse drug reactions. Compared to immediate release dosage forms, modified release dosage forms can be used to prolong the pharmacological action after administration, as well as to reduce the variability of the concentration of the drug in the plasma between doses, that is, to eliminate or reduce acute peaks.

The modified release dosage form may include a core either coated with the drug or containing the drug. The existing core is coated with a release modifying polymer within which the drug is dispersed. The release modifying polymer gradually breaks up, that is, releases the drug over a long time. Thus, the outermost layer of the composition is effectively reduced, whereby it regulates the diffusion of the drug in the coating layer when the composition comes into contact with the aqueous environment, that is, with the contents of the gastrointestinal tract. The net diffusion rate of a drug depends mainly on the ability of the gastric juice to penetrate through the integument or matrix and on the solubility of the drug itself.

In yet another embodiment, a 1-aminoalkylcyclohexane derivative (e.g., neramexane) is included in a liquid dosage form for oral administration. Liquid preparations for oral administration may, for example, take the form of solutions, syrups, emulsions or suspensions, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. You can conveniently prepare preparations for oral administration, providing a controlled or delayed release of the active compound. Liquid oral dosage formulations of 1-aminoalkylhexanes, such as neramexane, are described in PCT International Application No. PCT / US 2004/037026, the subject matter of which is incorporated herein by reference.

The 1-aminoalkylcyclohexane derivatives of the present invention (e.g., neramexane) provided in liquid form for oral administration can be combined with non-toxic pharmaceutically acceptable inert carriers (e.g. ethanol, glycerin, water), with suspending agents (e.g. sorbitol syrup, derivatives cellulose or hydrogenated edible fats), with emulsifying agents (e.g. lecithin or gum arabic), non-aqueous vehicles (e.g. almond oil, fatty esters, Tilova alcohol or fractionated vegetable oils) with preservatives (e.g. methyl or propyl-p-gidrobenzoatami, sorbic acid), and the like. To stabilize dosage forms, stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) can also be added. For example, solutions may contain by weight from about 0.2% to 20% neramexane using sugar and a mixture of ethanol, water, glycerol and propylene glycol for balance. Optionally, such liquid dosage formulations may contain colorants, flavors / flavors, saccharin and carboxymethyl cellulose as a thickening agent or other excipients.

In yet another embodiment, a therapeutically effective amount of a 1-aminoalkylcyclohexane derivative (e.g., neramexane) is administered as an oral solution containing a preservative, a sweetener, a solubilizer and a solvent. The oral solution may include one or more buffers, flavoring agents, or additional excipients. In a further embodiment of the invention, peppermint or other flavoring excipient is added to the liquid oral composition of the neramexane derivative.

The invention also provides a pharmaceutical package or kit comprising one or more containers containing a 1-aminoalkylcyclohexane derivative (e.g., neramexane) and optionally additional ingredients of a pharmaceutical composition. In a specific embodiment, neramexane is presented as an oral solution (2 mg / ml) for administration by syringe with a capacity of 2 teaspoons (dosage of KORC ^® ). Each oral syringe is equipped with blue measurement reference marks with lines on the right side of the syringe (pointing downward) that represent units in tsp (teaspoons) and the same marks on the left side, which represent units in milliliters (ml).

The optimal therapeutically effective amount can be determined experimentally, taking into account the exact method of administration of the drug, the indications by which the drug is administered, the individual characteristics of the subject (for example, all bodies, general health, age, gender and so on), as well as the preferences and experience of the patient doctor or veterinarian.

The toxicity and therapeutic efficacy of the 1-aminoalkylcyclohexane derivatives contemplated by the invention can be determined by standard pharmaceutical procedures in experimental animals, for example by determining LD ₅₀ (dose lethal for 50% of the sample) and ED ₅₀ (dose therapeutically effective for 50% of the sample) . The ratio of doses producing a therapeutic and toxic effect is called the therapeutic index and can be expressed as the ratio of LD ₅₀ / ED ₅₀ . Derivatives of 1-aminoalkylcyclohexane / composition that exhibit large therapeutic indices are preferred.

Suitable daily doses of the active compounds of the invention for the therapeutic treatment of humans are approximately 0.01-10 mg / kg body weight when administered orally and 0.001-10 mg / kg body weight when administered parenterally. For adults, for example, suitable daily doses of neramexane mesylate include doses of 50 mg and 75 mg per day. An equimolar amount of other pharmaceutically acceptable salts, solvates, isomers, conjugates, prodrugs or derivatives of these compounds, for example neramexane hydrochloride, is also considered suitable.

The daily doses indicated in the present description can be administered, for example, in the form of one or two dose units one, two or three times a day. Suitable dosages per unit dosage may be a daily dose divided (e.g. equally) between the number of dosage units administered per day, i.e., in the usual case, will be approximately equal to the daily dose or its half, third, quarter or sixth. Thus, doses per unit dosage can be calculated based on each daily dose indicated in this document. For example, a daily (daily) dose of 5 mg can be considered in dosage units, for example, approximately 5 mg, 2.5 mg, 1.67 mg, 1.25 mg and 0.83 mg, depending on the dosage regimen chosen. Accordingly, a daily dose of 150 mg can be presented, for example, as approximate dosage units of 150 mg, 75 mg, 50 mg, 37.5 mg and 25 mg for the respective dosage regimens.

The duration of treatment can be short-term, for example, several weeks (for example, 8-14 weeks) or long-term: until the attending physician considers that further administration of the drug is not necessary.

EXAMPLES OF CHARACTERISTIC MEDICINES

Using widely used solvents, adjuvants and carriers, the active ingredients can be processed into solutions, tablets, coated tablets, capsules, and so on. Tablets suitable for oral administration can be made using conventional tabletting techniques. The following examples are illustrative only and should not be construed as limiting the scope of the invention.

MEDICINAL EXAMPLE 1: Immediate release neramexane mesylate tablets

Tables 1-4 represent the composition of immediate release neramexane tablets in doses of 12.5, 25.0, 37.5 and 50.0 mg, including active ingredients, coating agents and other excipients.

Table 1
12.5 mg film-coated neramexane mesylate tablets Component amount
[mg] Function Neramexane Mesylate 12.50 Active pharmaceutical ingredient Microcrystalline cellulose 103.25 Binder Croscarmellose sodium 6.25 Disintegrant Silicon dioxide, colloidal 1.25 Flow activator Talc 1.25 Glidant (glidant) Magnesium stearate 0.50 Lubricant Core weight 125.00 Coating (HPMC), Opadry or Sepifilm 5.00 Coating Shell weight 5.00 Total weight of coated tablet 130.00

table 2
Neramexan Mesylate 25.0 mg film-coated tablets Component amount
[mg] Function Neramexane Mesylate 25.00 Active pharmaceutical ingredient Microcrystalline cellulose 206.50 Binder Croscarmellose sodium 12.5 Disintegrant Silicon dioxide, colloidal 2,50 Flow activator Talc 2,50 Glidant (glidant) Magnesium stearate 1.00 Lubricant Core weight 250.00 Coating (HPMC), Opadry or Sepifilm 10.00 Coating Shell weight 10.00 Total weight of coated tablet 260.00

Table 3
37.5 mg film-coated neramexane mesylate tablets Component amount
[mg] Function Neramexane Mesylate 37.50 Active pharmaceutical ingredient Microcrystalline cellulose 309.75 Binder Croscarmellose sodium 18.75 Disintegrant Silicon dioxide, colloidal 3.75 Flow activator Talc 3.75 Glidant (glidant) Magnesium stearate 1,50 Lubricant Core weight 375.00 Coating (HPMC), Opadry or Sepifilm 15.00 Coating Shell weight 15.00 Total weight of coated tablet 390.00

Table 4
50.0 mg neramexane mesylate tablets, film-coated Component amount
[mg] Function Neramexane Mesylate 50.00 Active pharmaceutical ingredient Microcrystalline cellulose 413.00 Binder Croscarmellose sodium 25.00 Disintegrant Silicon dioxide, colloidal 5.00 Flow activator Talc 5.00 Glidant (glidant) Magnesium stearate 2.00 Lubricant Core weight 500.00 Coating (HPMC), Opadry or Sepifilm 20.00 Coating Shell weight 20.00 Total weight of coated tablet 520.00

EXAMPLE OF MEDICINAL COMPOSITION 2:

Neramexane Mesylate Oral Solution

Table 5 presents the composition of the oral solution of neramexane at a concentration of 2, 5, 10 and 20 mg / ml.

Table 5
Neramexane oral solution Concentration 2 mg / ml 5 mg / ml 10 mg / ml 20 mg / ml Ingredients % weight / vol. % weight / vol. % weight / vol. % weight / vol. Neramexane Mesylate 0.2 0.5 1,0 2.0 Sorbitol Solution, USP, 70% 30,0 30,0 30,0 30,0 Methylparaben, NF 0.10 0.10 0.10 0.10 Propylparaben, NF 0.01 0.01 0.01 0.01 Propylene glycol, USP 2.5 2.5 2.5 2.5 Glycerin, USP 10.0 10.0 10.0 10.0 Flavor, Natural Peppermint # 104 0.5 0.5 0.5 0.5 Citric Acid, USP, Anhydrous 0.19 0.19 0.19 0.19 Sodium Citrate, USP, Dihydrate 0.88 0.88 0.88 0.88 Purified Water, USP QS QS QS QS

EXAMPLES

The following examples illustrate the invention without limiting its scope.

EXAMPLE 1:

Placebo-Controlled, Double-Blind Finding Study of Tinnitus Treatment with Neramexane

The goal of this search project was to conduct a clinical trial evaluating the effectiveness of neramexane in the treatment of tinnitus. The main objective of this study was to compare the efficacy, tolerability, and safety of neramexane mesylate in three different dosages (25, 50, or 75 mg per day) with placebo in patients with at least moderate subjective tinnitus.

Research plan

In a double-blind, multicenter, randomized, parallel-controlled, placebo-controlled study, the efficacy of neramexane in subjects with at least moderate tinnitus was assessed. About 100 patients who met specific inclusion criteria and did not meet any specific exclusion criteria were randomly assigned to one of four double-blind treatment groups (neramexane mesylate 25, 50, 75 mg per day or placebo), which is a total of amounted to approximately 400 patients.

The double-blind, 16-week treatment period consisted of a 4-week period of dose increase and a 12-week period of treatment with a fixed dose while maintaining the drug twice a day. However, in the case of poor tolerance, the researcher could decide to reduce the dose of neramexane by 25 mg per day (or placebo, respectively). After the treatment phase, there was a 4-week follow-up period without active treatment and without the limitations of concomitant therapy. In total, seven planned visits were envisaged in this study: for screening, for evaluating baseline data, and also at the end of the 4th, 8th, 12th, 16th and 20th weeks. Study participants received either neramexane mesylate (for example, 50 mg in the form of two 25 mg tablets with immediate release, taken twice a day, daily), or placebo twice a day for 16 weeks. The dose of neramexane mesylate was increased weekly and stepwise by 12.5 or 25 mg over a 4-week titration period with an increase in the dose preceding the 12-week treatment period with a fixed dose. Following the treatment period, a four-week follow-up period was performed.

Scheduled visits to evaluate each patient were carried out as follows:

Visit 1 (screening): After signing the agreement form, the subject underwent medical examination and testing in a clinical laboratory. The suitability of the patient for the study was evaluated according to the inclusion / exclusion criteria. An initial tinnitus interview was conducted. The subject also completed the Tinnitus-Beeintrachtigungs-Fragebogen (TBF-12) questionnaire, (i.e., the modified and ratified German version of the 12 paragraph German modified and validated version (Greimel KV et al., Tinnitus-Beeintrachtigungs-Fragebogen (TBF-12) Manual. Frankfurt am Main: Swets & Zeitlinger BV; 2000) of the 25-item Tinnitus Handicap Inventory or THI (Newman CW, et al. Development of the Tinnitus Handicap Inventory. Arch Otolaryngol Head Neck Surg 1996; 122 (2): 143-148; Newman CW, 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 (Gerauschüberempfindlichkeit-Fragenbogen (GÜF)) Questionnaire (if applicable).

Visit 2 (initial assessment): The patient was questioned about adverse events and changes in concomitant treatment / disease, and these events / changes were documented. Subjects were evaluated for their suitability for the study, based on a review of the inclusion / exclusion criteria. Research procedures were discussed with the subject, as well as permitted and forbidden concomitant medication. An initial tinnitus interview was conducted. Subject also completed the TBF-12 questionnaire, the HADS-D questionnaire, and the GÜF questionnaire (if applicable). The subject was included in the study and allocated to the treatment group of the test drug (placebo or neramexane), as described below.

Visit 3 (Week 4): This visit was carried out at the end of the 4-week period of the dose increase. The patient was questioned about adverse events and changes in concomitant treatment / disease, and these events / changes were documented. Conducted a control interview on tinnitus. Subject also completed the TBF-12 questionnaire, the HADS-D questionnaire, and the GÜF questionnaire (if applicable). The patient’s consistency with drug treatment was evaluated and the drug was distributed over the next 4 weeks, as described below.

Visit 4 (8th week): This visit was carried out at the end of the first 4-week period of double-blind treatment with a fixed dose. The patient was questioned about adverse events and changes in concomitant treatment / disease, and these events / changes were documented. Blood samples were taken from subjects to determine neramexane concentration prior to dosing. Conducted a control interview on tinnitus. Subject also completed the TBF-12 questionnaire, the HADS-D questionnaire, and the GÜF questionnaire (if applicable). The patient’s consistency with drug treatment was evaluated and the drug was distributed over the next 4 weeks, as described below.

Visit 5 (Week 12): This visit was performed at the end of the second 4-week period of the double-blind fixed-dose treatment. The patient was questioned about adverse events and changes in concomitant treatment / disease, and these changes were documented. Conducted a control interview on tinnitus. Subject also completed the TBF-12 questionnaire, the HADS-D questionnaire, and the GÜF questionnaire (if applicable). The patient’s consistency with drug treatment was evaluated and the drug was distributed over the next 4 weeks, as described below.

Visit 6 (week 16, end of treatment). This visit was performed at the end of a 12-week fixed-dose double-blind treatment. The patient was questioned about adverse events and changes in concomitant treatment / disease, and these changes were documented. Assessed the results of analyzes in a clinical laboratory. A tinnitus test was conducted and the subject completed the TBF-12 questionnaire, the HADS-D questionnaire, and the GÜF questionnaire (if applicable). Tone audiometry (air conduction study) was also performed.

Visit 7 (Week 20): This visit was performed at the end of the 4-week follow-up period after taking the last dose of the test drug. A review analysis of concomitant treatment, as well as the presence of adverse events since the last visit, was performed with the subject. A tinnitus test was conducted and the subject completed the TBF-12 questionnaire, the HADS-D questionnaire, and the GÜF questionnaire (if applicable).

The introduction of neramexane

Immediate release neramexane mesylate tablets (12.5 mg and 25 mg), as well as the corresponding placebo tablets, were used as film-coated tablets.

The medicine was delivered in blister boxes, which were distributed to patients from the 2nd visit to the 5th visit. Each blister box contained 4 blister cards for 4 weeks of treatment and 1 spare blister card. Blister cards were identified by treatment week. The daily medicine in blister cards was identified by day. The test drug for each day of the study was presented in 4 separate tablets. One blister card consisted of 32 tablets (7 days, 4 tablets per day and one spare day, 4 tablets per day). One set of medication for the patient consisted of 5 boxes. Box 2 was added as a backup drug to box 1 (dose increase period) and issued only if the subject lost the blister card from box 1 or the entire box.

The test drug was given at the 2nd visit (baseline score, day 0). Each patient received one blister box containing 5 blister cards (including one spare blister) for double-blind medication (i.e., 32 tablets). Subjects were instructed to take 2 tablets twice a day (4 tablets per day), starting from the day after the test drug was issued and until the day of the next scheduled visit (visit 3). For those subjects who were divided into groups receiving the active drug, several placebo tablets were included in the dosage regimen to ensure the blind nature of treatment during the period of dose increase. The target fixed maintenance dose of 25, 50, or 75 mg per day was administered starting from the fifth week of double-blind treatment and continued until the end of the treatment period in the study. At each of the subsequent visits (visits 3, 4 and 5, corresponding to the end of the 4th, 8th and 12th week), patients with a 4-week interval received another blister box containing 5 blister cards with medicine for a double blind treatment for an interim period until the next scheduled visit. The dosage schedule is given in table 6.

Throughout the entire period of double-blind treatment, patients continued to take the medicine daily according to a 2 × 2 tablet regimen with a constant interval of 12 hours. If the patient already took the morning dose of the test drug on the day of visit 4 and 6 (8th and 16th week), the planned blood sampling was not carried out. The researcher had to re-give the patient a sufficient amount of the test drug. The patient had to continue taking the medicine 2 tablets 2 times a day with a constant interval of 12 hours and had to return to the study center to take a blood sample for analysis of the level of neramexane before taking the next dose in the interval between visits 4 and 6.

In the case of poor drug tolerance, the researcher could decide to reduce the dose by 25 mg per day, avoiding a larger pill in the morning, which corresponded to an effective dose reduction only in the groups receiving 75 mg per day and 50 mg per day of neramexane mesylate. After skipping a larger morning pill (25 mg or placebo, respectively), such patients should continue to participate in the study as planned, although they received a smaller pill in the morning (12.5 mg or placebo, respectively) and 2 tablets of different sizes (12.5 mg 25 mg or placebo, respectively) as an evening dose. Further, the dose should have remained stable until the end of the study.

Subjects were instructed to always take the test drug taking into account individual convenience, but at the same time throughout the study, if possible observing a constant 12-hour interval between doses (for example, at 6:00 and 18:00 or at 8: 00 hours and 20:00 hours). At each planned visit, the researcher asked the patient about the time points for taking the test drug on the previous day. At the end of the 4th, 8th, 12th and 16th week (or at the early termination of their participation in the study), patients returned to the research center, bringing with them the blister boxes issued to them earlier, containing 5 blister cards for assessment consistency in drug therapy.

Efficiency

Main result

The main criterion for effectiveness in this study was the change in the total score of TBF-12 compared with the initial level (visit 2) at the final visit (visit 6, that is, the 16th week).

Secondary Results

Total TBF-12 score (magnitude and absolute change from baseline) for all subsequent scheduled visits, with the exception of the final visit.

Change in the total TBF-12 score from week 16 to week 20 (magnitude and absolute change).

Factorial TBF-12 scores (values and absolute change from baseline, including change from week 16 to week 20) for all subsequent visits after the initial assessment.

The magnitude and absolute change in the scores of the GÜF hyperacusis questionnaire ("Gerauschüberempfindlichkeits-Fragebogen") compared to the initial level, including the change from the 16th week to the 20th week, total and factorial scores for all subsequent visits after the initial assessment, if the patient was presented with hyperacusia.

General clinical impression of the changes: clause 27 of the tinnitus follow-up interview was summarized after dichotomizing the answers about any improvement (values 1, 2, 3), as opposed to the lack of improvements (values 4, 5, 6, 7) and a clear improvement (values 1 , 2) in contrast to the absence of obvious improvements (values 3, 4, 5, 6, 7).

The total HADS-D score, as well as the scores for the subscales of depression and fear (magnitude and absolute change from baseline, including change from week 16 to week 20) for all visits after the initial assessment.

Values from the results of the tinnitus interview (initial and subsequent) for all visits after the initial assessment: absolute change from the initial level and change from the 16th week to the 20th week according to items 8, 9, 10, 19, 20, 21 , 24, 25, and 26 follow-up follow-up interviews.

Data analysis

All performance analyzes were carried out in the ITT sample using the Lost-Forward Survey (LOCF) approach. To determine the sensitivity, an additional analysis of the sample “according to the protocol” and all observed cases was carried out. All statistical criteria used to evaluate the main performance indicator (confirming testing), and the criteria of secondary performance indicators (trial), as well as all other statistical criteria used for exploratory analysis, were criteria of a two-sided hypothesis, implemented at a 5% significance level. Descriptive statistics were calculated for all variables.

The change in the overall TBF-12 score by week 16 from baseline (visit 2) was analyzed in a two-way ANCOVA model using the treatment group and research center as factors, and the total TBF-12 score as covariates.

To evaluate secondary efficacy parameters, a comparison was made between neramexane and placebo, if appropriate, for visits in a two-way ANCOVA model using the treatment group and research center as factors, and the corresponding initial value of the efficacy parameter as covariates.

Discussion

This clinical study has shown promising results in evaluating efficacy and safety indicators. In addition, this study also demonstrated that the dosing schedule shown in Table 6 provided an acceptable dropout rate due to adverse events even when using a dose of 75 mg per day. These results are shown in table 7.

Table 7
Frequency distribution of patients with the most frequent adverse events during treatment leading to withdrawal according to the preferred term (EFS) Placebo
(N = 112) Neramexane
25 mg / day
(N = 108) Neramexane
50 mg / day
(N = 107) Neramexane
75 mg / day
(N = 102) Preferred Term ¹
(MedDRA 9.1) n % n % n % n % Any adverse event leading to retirement fifteen (13.4) 9 (8.3) 23 (21.5) 29th (28.4) Dizziness four (3.6) 2 (1.9) 6 (5.6) fifteen (14.7) Vertigo one (0.9) 0 (0,0) four (3.7) 3 (2.9) Fatigue 0 (0,0) 0 (0,0) 2 (1.9) 2 (2.0) Headache 3 (2.7) 0 (0,0) one (0.9) 2 (2.0) Hyperhidrosis one (0.9) 0 (0,0) 0 (0,0) 2 (2.0) Influenza 0 (0,0) 0 (0,0) 0 (0,0) 2 (2.0) Nausea one (0.9) 0 (0,0) 2 (1.9) 2 (2.0) Decreased visual acuity 0 (0,0) 0 (0,0) 0 (0,0) 2 (2.0) Tinnitus 0 (0,0) 2 (1.9) 0 (0,0) one (1,0) Paresthesia 0 (0,0) 0 (0,0) 2 (1.9) 0 (0,0) Depression one (0.9) one (0.9) 2 (1.9) 0 (0,0) Cardiovascular disorder 0 (0,0) 0 (0,0) 2 (1.9) 0 (0,0) ¹ Observed in at least 2 patients in any treatment group.
EFS = safety-assessed, N = number of patients in the appropriate treatment group, n = number of patients with an adverse event during treatment that led to the withdrawal.
The calculation of percentages is based on N.

The results demonstrate that the dosing schedule shown in table 6, or the proposed dosing schedule shown in table 8 below, allows individual titration to the target dose, selected by body weight: 50 mg per day with body weight up to 90 kg or 75 mg per day for patients with body weight ≥90 kg.

Table 8
Proposed Dosing Schedule for Neramexane Mesylate Double blind period A week Treatment group one 2 3 four 5-17 (13 weeks) Neramexane 50 mg 0 (placebo) / 12.5 12.5 / 12.5 12.5 / 25 25/25 25/25 Neramexane 75 mg * 0 (placebo) / 12.5 12.5 / 12.5 12.5 / 25 25/25 37.5 / 37.5 Placebo 0/0 0/0 0/0 0/0 0/0

After taking the medicine from the four-week dose-increase kit, patients could continue treatment with a maintenance dose of 50 mg or 75 mg neramexane mesylate per day. For example, patients starting treatment with neramexane first took the medicine from a 4-week starter kit (i.e., a titration kit), and then switched to taking 25 or 37.5 mg tablets twice a day, depending on their body weight, so that receive a daily maintenance dose of 50 or 75 mg. Thus, the proposed dosing schedule, shown in table 8, allows patients to receive two different maintenance doses, adapted by body weight, starting from the 5th week.

EXAMPLE 2:

Placebo-controlled double blind clinical trial of neramexan for tinnitus treatment

The goal of this project was to conduct a clinical trial to further evaluate the effectiveness of neramexane in the treatment of tinnitus. The main objective of this study was to compare neramexane mesylate with placebo in terms of efficacy, tolerability, and safety in subjects with the first manifestation of persistent unilateral or bilateral subjective tinnitus.

Research plan

In a double-blind, multicenter, randomized, parallel-controlled, placebo-controlled study, the efficacy of neramexane in subjects with tinnitus was evaluated. Patients who met specific inclusion criteria and did not meet any exclusion criteria were randomized to double-blind treatment groups.

The double-blind, 16-week period of treatment consisted of a 4-week period of dose increase and a 12-week treatment of a fixed dose with a constant dose maintenance. However, in the case of poor tolerance, the researcher could decide to reduce the dose by 25 mg per day. After the treatment phase, a 4-week follow-up period was conducted without active treatment and without the limitations of concomitant therapy. In total, seven planned visits were envisaged in this study: screening, initial assessment, and visits at the end of the 4th, 8th, 12th, 16th and 20th weeks.

Scheduled visits to evaluate each patient were carried out as follows:

Visit 1 (screening): After signing the agreement form, the subject underwent medical examination and testing in a clinical laboratory. The suitability of the patient for the study was evaluated according to the inclusion / exclusion criteria. An initial tinnitus interview was conducted. The subject also filled out the Tinnitus-Beeintrachtigungs-Fragebogen (TBF-12) questionnaire, i.e., the modified and ratified German version of the 12 paragraph German modified and validated version (Greimel KV et al., Tinnitus-Beeintrachtigungs-Fragebogen (TBF-12). Manual. Frankfurt am Main: Swets & Zeitlinger BV; 2000) of the 25-item Tinnitus Handicap Inventory or THI (Newman CW, et al. Development of the Tinnitus Handicap Inventory. Arch Otolaryngol Head Neck Surg 1996; 122 (2): 143 -148; Newman CW, 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 (Gerauschüberempfindlichkeit-Fragenbogen (GÜF)) Questionnaire (if applicable).

Visit 2 (initial assessment): The patient was questioned about adverse events and changes in concomitant treatment / disease, and these events / changes were documented. Subjects were evaluated for their suitability for the study, based on a review of the inclusion / exclusion criteria. Research procedures were discussed with the subject, as well as permitted and forbidden concomitant medication. An initial tinnitus interview was conducted. Subject also completed the TBF-12 questionnaire, the HADS-D questionnaire, and the GÜF questionnaire (if applicable). The subject was included in the study and allocated to the treatment group of the test drug (placebo or neramexane), as described below.

Visit 3 (Week 4): This visit was carried out at the end of the 4-week period of the dose increase. The patient was questioned about adverse events and changes in concomitant treatment / disease, and these events / changes were documented. Conducted a control interview on tinnitus. Subject also completed the TBF-12 questionnaire, the HADS-D questionnaire, and the GÜF questionnaire (if applicable). The patient’s consistency with drug treatment was evaluated and the drug was distributed over the next 4 weeks, as described below.

Visit 4 (8th week): This visit was carried out at the end of the first 4-week period of double-blind treatment with a fixed dose. The patient was questioned about adverse events and changes in concomitant treatment / disease, and these changes were documented. Blood samples were taken from subjects to determine neramexane concentration prior to dosing. Conducted a control interview on tinnitus. Subject also completed the TBF-12 questionnaire, the HADS-D questionnaire, and the GÜF questionnaire (if applicable). The patient’s consistency with drug treatment was evaluated and the drug was distributed over the next 4 weeks, as described below.

Visit 5 (Week 12): This visit was performed at the end of the second 4-week period of the double-blind fixed-dose treatment. The patient was questioned about adverse events and changes in concomitant treatment / disease, and these events / changes were documented. Conducted a control interview on tinnitus. Subject also completed the TBF-12 questionnaire, the HADS-D questionnaire, and the GÜF questionnaire (if applicable). The patient’s consistency with drug treatment was evaluated and the drug was distributed over the next 4 weeks, as described below.

Visit 6 (week 16, end of treatment). This visit was performed at the end of a 12-week fixed-dose double-blind treatment. The patient was questioned about adverse events and changes in concomitant treatment / disease, and these events / changes were documented. Assessed the results of analyzes in a clinical laboratory. A tinnitus test was conducted and the subject completed the TBF-12 questionnaire, the HADS-D questionnaire, and the GÜF questionnaire (if applicable). Tone audiometry (air conduction study) was also performed.

Visit 7 (Week 20): This visit was performed at the end of the 4-week follow-up period after taking the last dose of the test drug. A review analysis of concomitant treatment, as well as the presence of adverse events since the last visit, was performed with the subject. A tinnitus test was conducted and the subject completed the TBF-12 questionnaire, the HADS-D questionnaire, and the GÜF questionnaire (if applicable).

The introduction of neramexane

The modified release neramexane mesylate tablets (12.5 mg, 25 mg, 37.5 mg, 50 mg and 75 mg), as well as the corresponding placebo tablets, were administered once daily.

The medicine was delivered in blister boxes, which were distributed to patients from the 2nd visit to the 5th visit. Each blister box contained 4 blister cards for 4 weeks of treatment and 1 spare blister card. Blister cards were identified by treatment week. The daily medicine in blister cards was identified by day.

The test drug was given at the 2nd visit (baseline score, day 0). Each patient received one blister box containing 5 blister cards (including one spare blister) of drugs for double-blind treatment. The treatment schedule is shown in table 9.

Table 9
The introduction of neramexane mesylate Double blind period A week Treatment group one 2 3 four 5-16 (12 weeks) Neramexane 50 mg 12.5 25 37.5 fifty fifty Neramexane 75 mg * 12.5 25 37.5 fifty 75 Placebo 0/0 0/0 0/0 0/0 0/0

Efficiency

Main result

The main criterion for effectiveness in this study was the change in the total score of TBF-12 compared with the initial (visit 2) at the final visit (visit 6, that is, the 16th week).

Secondary Results

Total TBF-12 score (magnitude and absolute change from baseline) for all subsequent scheduled visits, with the exception of the final visit.

Change in the total TBF-12 score from week 16 to week 20 (values and absolute changes).

Factorial TBF-12 scores (values and absolute change from baseline, including change from week 16 to week 20) for all subsequent visits after the initial assessment.

The magnitude and absolute change in the scores of the GÜF hyperacusis questionnaire ("Gerauschüberempfindlichkeits-Fragebogen") compared to the initial level, including the change from the 16th week to the 20th week, total and factorial scores for all subsequent visits after the initial assessment, if the patient was presented with hyperacusia.

General clinical impression of the changes: clause 27 of the tinnitus follow-up interview was summarized after dichotomizing the answers about any improvement (values 1, 2, 3), as opposed to the lack of improvements (values 4, 5, 6, 7) and a clear improvement (values 1 , 2) in contrast to the absence of obvious improvements (values 3, 4, 5, 6, 7)

The total HADS-D score, as well as the scores for the subscales of depression and fear (magnitude and absolute change from baseline, including change from week 16 to week 20) for all visits after the initial assessment.

Values from the results of the tinnitus interview (initial and subsequent) for all visits after the initial assessment: absolute change from the initial level and change from the 16th week to the 20th week according to items 8, 9, 10, 19, 20, 21 , 24, 25, and 26 follow-up follow-up interviews.

Data analysis

All performance analyzes were carried out in the ITT sample using the Lost-Forward Survey (LOCF) approach. To determine the sensitivity, an additional analysis of the sample “according to the protocol” and all observed cases was carried out. All statistical criteria used in assessing the main performance indicator (confirmatory testing), and the criteria of secondary performance indicators (trial), as well as other statistical criteria used for exploratory analysis, were criteria of a two-sided hypothesis, implemented at a 5% significance level. Descriptive statistics were calculated for all variables.

The change in the overall TBF-12 score by week 15 from baseline (visit 2) was analyzed in a two-way ANCOVA model using the treatment group and research center as factors, and the total TBF-12 score as covariates.

For statistical evaluation of secondary efficacy parameters, a corresponding comparison was made between neramexane and placebo, if appropriate, for visits in a two-way ANCOVA model using the treatment group and research center as factors, and the corresponding initial value of the efficacy parameter as covariates.

This clinical study has shown promising results in evaluating efficacy and safety indicators.

EXAMPLE 3:

A placebo-controlled, double-blind, search-based hearing loss treatment with neramexane

The goal of this search project was to conduct a clinical trial evaluating the effectiveness of neramexane in the treatment of hearing loss. It could be expected that patients suffering from hearing loss of various degrees and receiving treatment with neramexane, when compared with patients receiving placebo treatment, would demonstrate an improvement in the main criterion (change in hearing threshold compared to the initial level) and secondary criteria (change in hearing in different frequencies on a tonal audiogram compared to the initial level). The audibility threshold level can be defined as the average level of audibility threshold levels in pure tones when tested at frequencies of 0.25, 0.5, 1, 2, and 4 kHz.

Research plan

The main objective of this study was to study the safety and efficacy of neramexane mesylate in daily doses of up to 75 mg in the treatment of hearing loss compared with placebo.

The introduction of neramexane

25 mg modified release neramexane mesylate tablets and the corresponding placebo tablets were used as film-coated tablets.

The dose of neramexane mesylate (or placebo) was increased to a maximum daily dose of 75 mg, starting with a daily dose of 25 mg for one week and increasing the dose in increments of 25 mg at weekly intervals.

Treatment began in the evening on the 1st day of the study. The daily starting dose was 25 mg of neramexane mesylate at one time, and patients took it for 7 days before going to bed. From day 8, the daily dose of neramexane mesylate was increased to 50 mg for the next 7 days (two tablets in the evening for one week). From the 15th day, the dose of neramexane mesylate for patients was increased to 75 mg. Patients continued to take neramexane for 13 weeks (three tablets once a day in the evening for 13 weeks). Patients who did not tolerate a dose of 75 mg per day could reduce this dose by 25 mg (to 50 mg per day) for the remainder of the time scheduled for the treatment plan. For example, patients who did not tolerate a dose of 75 mg were allowed to return to a dose of 50 mg. After this, the patients were asked to remain at a dose of 50 mg until the end of the scheduled treatment schedule for a total duration of 7 weeks. This treatment schedule is shown in table 10.

Table 10
The introduction of neramexane mesylate 2-week double-blind period of dose increase 14-week double-blind fixed-dose period 4-week follow-up period Treatment group one 2 3-16 17-20 Neramexane Mesylate 0/25 0/50 0/75 mg per day - Placebo 0/0 0/0 0/0 -

Efficiency

Main result

Change in the level of the auditory threshold compared with the initial estimate for the left / right ear (dB), calculated as the average value of the audible threshold levels of pure tones of 0.25, 0.5, 1, 2 and 4 kHz.

Secondary Results

The change in the level of the auditory threshold of high frequency compared with the initial estimate for the left / right ear (dB), calculated as the average value for the levels of the auditory threshold of pure tones of 4, 6, 8 and 10 kHz.

Change in individual frequencies (thresholds of audibility) compared with the initial level on a tonal audiogram (air conduction).

The number of responders (patients responding to treatment).

The result reported by patients on the 11-point Likert scale (0 = hearing is not a problem, 10 = hearing is the maximum possible problem).

Change in hearing impairment based on an assessment of the threshold of hearing:

no frequency hearing loss <20 dB;

slight hearing loss of 2-40 dB;

moderate hearing loss> 40-70 dB;

severe hearing loss> 70-95 dB;

total hearing loss> 95 dB.

Data analysis

All performance analyzes were carried out in the ITT sample using the Lost-Forward Survey (LOCF) approach. To determine the sensitivity, an additional analysis of the sample “according to the protocol” and all observed cases was carried out. All statistical criteria used in assessing the main performance indicator (confirmatory testing), and the criteria of secondary performance indicators (trial), as well as all other statistical criteria used for exploratory analysis, were criteria for a two-sided hypothesis, implemented at a 5% significance level. Descriptive statistics were calculated for all variables.

Change by the 16th week compared to the initial assessment (visit 2) of the left / right ear hearing threshold level (dB), calculated as the average threshold value of the clear tone audibility level at frequencies of 0.25, 0.5, 1, 2 and 4 kHz, was analyzed in a two-way ANCOVA model using the treatment group and research center as factors, and the auditory threshold for initial assessment was used as covariates.

For statistical evaluation of secondary efficacy parameters, a comparison was made between neramexane and placebo, if appropriate, for visits in a two-way ANCOVA model using the treatment group and research center as factors, and the corresponding initial value of the efficacy parameter as covariates.

The group treated with neramexane, when compared with the placebo group, showed improvement by the main criterion, as well as by the secondary criteria of effectiveness.

Titration kits related to the scope of the present invention can be better understood in connection with the following examples, which are given as an illustration, but not to limit the scope of the invention.

Example 4

The titration kit shown in FIG. 1-4, contains two physically separated elements, hereinafter referred to as “shell” and “insert”. The shell is not shown in the figure. The outer shell may be a sleeve that slides over the insert (1) and is essentially fitted to it, that is, the outer dimensions of the insert when folded essentially correspond to the inner dimensions of the shell. The insert (1) can also be presented without a shell.

If a shell is used, then the insert (1) is entirely enclosed in this shell, being completely folded, and the titration kit is properly closed (see figure 3).

When closed, the kit containing the packaging and dosage forms in different doses may further contain instructions on a separate insert, this insert being inserted into the space between the shell and the insert. The insert may also be attached (partially) to either the insert (1) or the sheath.

As shown in figure 1, the insert (1) consists of a flat central region (2) in the form of a "square". Four rectangular platforms (hereinafter referred to as “flap valves”) (3) and (4) are attached to the outer edges of the indicated flat central region. The square may be made of plasticized cardboard material. The square, as such, does not contain additional parts, especially blister cavities. Product information can be printed in this area.

In the fully expanded state of the insert (1), as shown in FIGS. 1 and 2, four flap valves (3) and (4) are attached to the square (2) and extend along the length of each of the four outer sides (edges) of the square. Flap valves can be made of a double layer of the same material as the square. The valves contain blister cavities for holding dosage forms, which will be described in more detail below.

All flap valves (3), (4) can be folded along the first edge of the pre-folding (which is the aforementioned outer edge of the square). Opposing each other flap valves contain inside the flat platform a second edge, which is also pre-folded. This separation of the distances between the edges of the two sets of opposing flap valves allows you to fold the valves taking into account the size of the blisters, which, as a rule, have a thickness of the order of several millimeters (see figure 2). As shown in FIG. 2, the flap valves (3) are folded first in order (5), and the flap valves (4) are folded over the valves (3) by the following movement (6). After folding, the flap valves lie perpendicular to each other, with one set of a pair of valves (4) lying on top of another set of a pair of valves (3), that is, folded valves completely cover the central square (2), without going beyond it (see Fig. 3 and 4).

One flap valve contains one “row” or “column”, and the remaining valves contain two “rows” or “columns” containing more than two, for example seven, blister cavities, respectively (some lines of blisters look like “rows”, and others as "columns" depending on how the insert is oriented) (see figure 1).

In the expanded state of the insert (Fig.1 and 2), the "rows" and "columns" do not touch each other and are clearly separated from each other.

The insert can be marked as follows: the flap valve, containing one row / column of seven blisters, has one marking printed on it and indicating the week number (that is, "week 1"), and the remaining flap valves, each of which contains two a row / column of seven blisters, has one marking printed on it and indicating the week number (that is, from "week 2" to "week 4").

Consecutive weeks can be arranged on adjacent valves (that is, the week 2 and week 4 valves are located directly on the sides of the week 1 valve, while the week 3 valve is on the opposite side of the square).

Alternatively, consecutive weeks are arranged in pairs opposite each other (that is, the “Week 3” and “Week 4” valves are located directly on the sides of the “Week 1” valve, while the “Week 2” valve is on the opposite side of the square) .

Each row of blisters (for one week) can be located against the background of the painted strip, and the color can be represented by darker shades of gray / blue as the dose increases (that is, gray for the 1st week and dark blue for the 4th weeks). Each flap valve also contains one set of seven digital indicators, varying daily from "1" to "28", located next to each blister and indicating the sequence of days for four weeks. In particular, one flap valve may have blisters marked "day 1, 2, 3, 4, 5, 6, 7", the next flap valve may have blisters marked "day 8, 9, 10, 11, 12, 13, 14 "and so on (see FIG. 1). The above markings can be presented on the inside and outside of the flap valve (see FIGS. 1 and 4).

The outer part of each flap valve can also be marked in the lower left corner with a value indicating the corresponding dose of the 1-aminoalkylcyclohexane derivative (e.g. neramexane mesylate).

EXAMPLE 5

The titration set shown in FIGS. 5 and 6 contains an insert (10), which essentially represents a “chain” consisting of two or more (for example, four) folding compartments (11) - (14), i.e. , rectangular blocks containing, in this case, seven or fourteen blister cavities per block. The compartments are interconnected by articulated joints (15), for example, made of flexible material such as paper.

The compartments / blocks of the chain (11) through (14) are comparable in size to the flap valves (3) and (4) discussed in the previous example.

Four compartments (blocks) form a "chain" of compartments, that is, the first compartment through the fold is connected to the second compartment, the second compartment through the fold is connected to the third compartment, and the third compartment through the fold is connected to the fourth compartment (see FIGS. 5 and 6) .

In the fully deployed state (figure 5), four compartments lie flush with each other.

In a fully collapsed state, the four blocks / compartments lie on top of each other, forming a rectangular box-shaped block of the same length and width as each individual compartment.

In the intermediate state, due to the presence of flexible joints (hinges) between two adjacent compartments, the four blocks / compartments form a profile in the form of the letter "M" with various degrees of compression or tension (see Fig.6). Optionally, you can attach a leaflet (15) containing the necessary information.

Each compartment can be labeled weekly (varying from the label “week 1” to the label “week 4”), by dose and by day of the week.

In addition, an increase in dose between sets can be indicated by the color of the background strip located under the seven blisters, the color intensity of this strip increasing in the direction from the leftmost compartment ("week 1") to the rightmost compartment ("week 4").

EXAMPLE 6

The titration kit shown in Fig. 7 contains a rectangular base, which is divided into four sections. Each section consists of seven blister cavities (in one row) or fourteen blister cavities (in two rows of seven).

Each section can be labeled by week (varying from the label "week 1" to the label "week 4"), by dose and by day of the week.

EXAMPLE 7

The titration kit shown in Fig. 8 contains a circular base, which is divided into four sections. Each section consists of seven blister cavities (in one row) or fourteen blister cavities (in two rows of seven).

Each section can be labeled by week (varying from the label "week 1" to the label "week 4"), by dose and by day of the week.

EXAMPLE 8

The titration set shown in Fig. 9 is built on a folding base made, for example, of a flexible material such as paper and divided into four compartments. The first compartment through the fold is connected to the second compartment, the second compartment through the fold is connected to the third compartment, and the third compartment through the fold is connected to the fourth compartment.

Each compartment consists of seven blister cavities (in one row) or fourteen blister cavities (in two rows of seven).

Each compartment can be labeled weekly (varying from the label “week 1” to the label “week 4”), by dose and by day of the week.

The scope of the present invention is not limited to the specific embodiments described. Indeed, a person skilled in the art from the foregoing description will appreciate various modifications of the invention in addition to those described herein. Such modifications should fall within the scope of the attached claims.

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

Claims (14)

1. The use of a derivative of 1-aminoalkylcyclohexane selected from neramexane and its pharmaceutically acceptable salts for treating an inner ear disorder, wherein said derivative is administered by a titration regimen that includes increasing the dose of neramexane or its pharmaceutically acceptable salt with a stepwise dose increase of 25 mg or 12, 5 mg at weekly intervals over a period of four to five weeks to achieve an effective dose of 50 to 75 mg per day. 2. The use according to claim 1, where the titration scheme includes increasing the dose of neramexane or its pharmaceutically acceptable salt over a four-week period of time to achieve an effective dose of 50 mg per day. 3. The use according to claim 1, where neramexane or its pharmaceutically acceptable salt is administered according to the following scheme: once a day daily in the first week at a dose of 12.5 mg, twice a day daily in the second week at 12.5 mg for each admission, twice a day daily in the third week, with one dose of 12.5 mg and another dose of 25 mg, and also twice a day daily in the fourth week, 25 mg for each dose. 4. The use according to claim 1, where neramexane or its pharmaceutically acceptable salt is administered as follows: once a day daily in the first week at a dose of 25 mg, once a day daily in the second week at a dose of 50 mg, and also, optional , once a day daily in the third week at a dose of 75 mg. 5. The use according to claim 1, where the titration scheme includes increasing the dose of neramexane or its pharmaceutically acceptable salt over a five-week period of time to achieve an effective dose of 75 mg per day. 6. The use according to claim 1, where neramexane or its pharmaceutically acceptable salt is administered according to the following scheme: once a day daily in the first week at a dose of 12.5 mg, twice a day daily in the second week at 12.5 mg for each admission, twice a day daily in the third week, with one dose of 12.5 mg and another dose of 25 mg, twice a day daily in the fourth week of 25 mg for each dose, and also twice a day daily for the fifth week of 37.5 mg per dose. 7. The use according to claim 1, where in those weeks when different doses are administered, a dose containing a higher concentration is administered second in order every day. 8. The use according to claim 1, where the pharmaceutically acceptable salt of neramexane is neramexane mesylate. 9. The use according to claim 1, where the inner ear disorder is selected from tinnitus, vertigo, hearing loss, chronic earache, perilymphatic fistula, secondary endolymphatic edema, labyrinthitis and vestibular neuritis, auditory nerve neuroma, ototoxicity, autoimmune disease of the inner ear (AIED ) and Meniere's disease. 10. The use according to claim 6, where in those weeks when different doses are administered, a dose containing a higher concentration is administered second in order every day. 11. The use of a 1-aminoalkylcyclohexane derivative selected from neramexane and a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating an inner ear disorder, wherein said medicament is formulated for administration by a titration regimen that includes increasing the dose of neramexane or its pharmaceutically acceptable salt with a gradual increase 25 mg or 12.5 mg doses at weekly intervals over a period of four to five weeks to achieve an effective dose of 50 to 75 mg in a day. 12. The use of claim 11, wherein the pharmaceutically acceptable salt of neramexane is neramexane mesylate. 13. A method of treating an inner ear disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a 1-aminoalkylcyclohexane derivative selected from neramexane and its pharmaceutically acceptable salts, wherein the 1-aminoalkylcyclohexane derivative is administered by a titration schedule that includes increasing the dose of neramexane or its a pharmaceutically acceptable salt with a gradual dose increase of 25 mg or 12.5 mg at weekly intervals over a period of four to five weeks to achieve effective dose of 50 to 75 mg per day. 14. The method according to item 13, where the pharmaceutically acceptable salt of neramexane is neramexane mesylate.

Images