HK1155362A - Pharmaceutical compositions comprising a complex of aminocyclohexane derivatives and cyclodextrin - Google Patents

Description

Pharmaceutical composition comprising an inclusion complex of an aminocyclohexane derivative and a cyclodextrin

Technical Field

The present invention relates to pharmaceutical compositions comprising 1-aminocyclohexane derivatives and cyclodextrins, which compositions exhibit advantageous safety, convenience, and dosage profiles. The compositions of the present invention have particular application in the treatment of various diseases and disorders of the Central Nervous System (CNS), including those involving impairment of cognitive function or dementia, such as alzheimer's disease.

Background

Dementia is generally defined as chronic deterioration of mental function and other cognitive skills severe enough to interfere with the ability to perform activities of daily living. Alzheimer's disease is a form of dementia characterized by ". multidot.a progressive, unalterable loss of cognitive function, associated with excessive senile plaques in the cerebral cortex and subcortical gray matter, which plaques also contain β -amyloid and neurofibrillary tangles composed of tau protein" (Merck Manual, 2004). Alzheimer's disease occurs in women about twice as many as men and it causes > 65% of dementia cases in the elderly. Vascular dementia is present in about 15% of cases together with alzheimer's disease.

It is believed that alzheimer's disease represents the fourth most common cause of medical death. The Prevalence of the Disease doubles every 5 years for those over 65 years old (National Institute on Aging: Prevalence and costs of Alzheimer's Disease, Progress Report on Alzheimer's Disease, NIH publication No.993616, 11 months 1998, Polvikoski et al, Neurology, 2001, 56: 1690-. Alzheimer's disease currently affects approximately 1 thousand 5 million people worldwide (including all ethnic and ethnic groups) and, because of the relative increase in elderly in the population, its prevalence may increase in the next two to thirty years.

Currently, alzheimer's disease is not curable, i.e., no viable treatment is available to effectively reverse its symptoms and progression. However, some drugs may alleviate specific symptoms associated with the disease and reduce the dependence on care. First-line drugs approved for the treatment of alzheimer's disease are members of the cholinesterase inhibitors class, such as donepezil (donepezil), galantamine (galantamine), and tacrine (tacrine).

1-aminocyclohexanes such as neramexane and pharmaceutically acceptable salts thereof have been found to be useful in the treatment of a variety of diseases, particularly in specific neurological diseases, including Alzheimer's disease. 1-aminocyclohexanes such as neramexane (1-amino-1, 3, 3, 5, 5-pentamethylcyclohexane) and pharmaceutically acceptable salts thereof are disclosed in, for example, U.S. patent nos. 6,034,134 and 6,071,966, and are characterized as low to moderate affinity, uncompetitive NMDA-receptor antagonists, and are believed to selectively block the effects of excitotoxins associated with glutamate abnormal conduction, neurotransmitters that play indispensable roles in neural channels associated with learning and memory, and are believed to play a role in alzheimer's disease.

Oral tablets or capsules represent the most common type of dosage form for oral administration. Typically it is swallowed with a liquid, such as water. Depending on the particular formulation design, it may also be chewed or dispersed in a liquid prior to administration. Tablets and capsules are considered particularly convenient and cost-effective.

Semisolid and liquid formulations for oral use offer particular advantages of flexible dosage and simple swallowing. Both aspects are of importance for the treatment of alzheimer's disease. Swallowing tablets has difficulty for many elderly alzheimer's patients. It may be advisable to use an elastomeric dose for the early stages of alzheimer's disease treatment and in order to achieve a dose reduction administered as a tablet, the tablet must be divided in half, in quarter or even more, which is difficult for some patients.

Liquid formulations also have certain disadvantages. Because liquid formulations contain the drug substance in already dissolved form, the taste and odor of the compound can be more readily perceived than in the case of solid dosage forms (e.g. film-coated tablets). If the taste of the drug substance is particularly poor, for example if it is bitter or has an astringent or anaesthetic effect on the oral mucosa, this unpleasant characteristic is more pronounced for the patient's perception if the drug is formulated in a liquid formulation than if the drug is formulated in a film-coated tablet or capsule. Moreover, encapsulation is a common taste masking technique for solid dosage forms, and it is technically difficult to encapsulate drug substances in liquid formulations, especially for compounds with significant water solubility. Likewise, compounds with unpleasant odors can be difficult to formulate into palatable liquid preparations. Depending on the intensity of the taste and/or odor of the compound, the reliance on the addition of sweeteners and flavoring agents may be insufficient to produce an acceptable aqueous or semi-solid formulation.

Likewise, solid formulations, which are not intended to be swallowed directly, but dispersed in a liquid such as water or saliva, cannot be readily formulated with active compounds that contain a bad taste or odor.

Conventional aqueous liquid formulations also suffer from other disadvantages, including their potential to enhance chemical breakdown of the drug substance, e.g., via hydrolysis, thus resulting in a reduction in the shelf life of the drug product. Moreover, the microbiological stability of aqueous liquid formulations is often inferior to that of solid dosage forms, such as tablets or capsules, so it is often necessary to incorporate preservatives into the aqueous liquid formulations.

1-aminocyclohexanes such as neramexane and pharmaceutically acceptable salts thereof exhibit questionable taste and odor characteristics and limit the degree of acceptance of conventional liquid or semi-solid formulations, and certain patients who would benefit from liquid formulations may instead prefer to take these drugs in tablet form.

Thus, there is a need for liquid and/or semisolid formulations containing 1-aminocyclohexane derivatives, such as neramexane and pharmaceutically acceptable salts thereof, with improved organoleptic properties, such as odor and taste.

The inventors of the present invention have found that compositions comprising 1-aminocyclohexane derivatives (including neramexane and pharmaceutically acceptable salts thereof) and one or more pharmaceutically acceptable cyclodextrins do not exhibit the disadvantages normally associated with aqueous liquid dosage forms, and that the compositions are palatable and acceptable to a greater number of patients due to their improved organoleptic properties.

Disclosure of Invention

The purpose of the invention is as follows:

it is an object of the present invention to provide compositions containing 1-aminocyclohexane derivatives (e.g. neramexane) and pharmaceutically acceptable salts thereof in combination with pharmaceutically acceptable cyclodextrins or pharmaceutically acceptable cyclodextrins of a very palatable taste, which compositions exhibit neutral or sweet taste and little or no unpleasant taste. It is another object of the present invention to provide water-soluble clathrates of 1-aminocyclohexane derivatives (e.g., neramexane) and pharmaceutically acceptable salts thereof with pharmaceutically acceptable cyclodextrins or cyclodextrin derivatives, which clathrates can be incorporated into solid, semi-solid or, especially, liquid formulations for oral administration which are chemically and microbiologically stable and have an excellent degree of palatability. It is a further object of the invention to use the composition in the treatment of CNS disorders, including alzheimer's disease. Yet further objects will be apparent hereinafter and still further objects will be apparent to those skilled in the art.

Summary of the invention:

the present invention relates to a composition comprising a 1-aminocyclohexane derivative selected from formula (I) and optical isomers, enantiomers, hydrates, solvates, polymorphs, pharmaceutically acceptable salts thereof

Wherein R is^*Is- (CH)₂)_n-(CR⁶R⁷)_m-NR⁸R⁹，

Wherein n + m is 0, 1 or 2,

wherein R is¹To R⁷Independently selected from hydrogen and C_1-6Alkyl radical, wherein R⁸And R⁹Independently selected from hydrogen and C_1-6Alkyl, or together represent lower-alkylene- (CH)₂)_x-wherein x is 2 to 5 inclusive;

and pharmaceutically acceptable cyclodextrins or pharmaceutically acceptable cyclodextrins.

A further aspect of the invention relates to such compositions, wherein the pharmaceutically acceptable cyclodextrin is selected from the group consisting of pharmaceutically acceptable, water soluble, natural or derivatized cyclodextrins, such as alpha-cyclodextrin, beta-cyclodextrin, optionally methylated beta-cyclodextrin, 2-O-methyl-beta-cyclodextrin, hepta- (2, 6-di-O-methyl) -beta-cyclodextrin (dimethyl-beta-cyclodextrin), acetylated dimethyl-beta-cyclodextrin, hepta- (2, 3, 6-tri-O-methyl) -beta-cyclodextrin (trimethyl-beta-cyclodextrin), sulfoalkyl ether-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, O-carboxymethyl-O-ethyl-beta-cyclodextrin, mixtures thereof, and combinations thereof, Glucuronyl-glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, beta-cyclodextrin sulfate, beta-cyclodextrin phosphate, gamma-cyclodextrin, sulfoalkyl ether-beta-cyclodextrin, and sulfobutyl ether-beta-cyclodextrin, as well as hydroxyalkyl modified cyclodextrins (including hydroxypropyl-beta-cyclodextrin such as 2-hydroxypropyl-beta-cyclodextrin, or hydroxypropyl-gamma-cyclodextrin such as 2-hydroxypropyl-gamma-cyclodextrin).

A further aspect of the invention relates to such compositions wherein the molar ratio of cyclodextrin to 1-aminocyclohexane derivative is at least about 0.1: 1.

A further aspect of the invention relates to compositions wherein the molar ratio of cyclodextrin to 1-aminocyclohexane derivative is up to 50: 1 (including compositions wherein the molar ratio is 10: 1, 5: 1, 4: 1, 3: 1, 2: 1 or 1: 1), and at least about 0.1: 1.

A further aspect of the invention relates to such compositions wherein the molar ratio of cyclodextrin to 1-aminocyclohexane derivative is 3: 1.

A further aspect of the invention relates to such compositions in the form of aqueous liquid compositions, which may optionally be applied topically and/or intravitreally to the eye.

A further aspect of the invention relates to such compositions in the form of solid compositions.

A further aspect of the invention relates to such compositions (including such compositions wherein reconstitution, e.g. of a powder, granulate or lyophilizate is with an aqueous solvent, resulting in an aqueous liquid composition) as orally disintegrating dosage forms or formulations for reconstitution, optionally in the form of a powder, granulate or lyophilizate.

A further aspect of the invention relates to such a composition, wherein the composition is a fast or very fast dissolving solid composition, such as a powder, granules or a lyophilisate.

A further aspect of the invention relates to such a composition, wherein the composition is a fast or very fast dissolving water soluble powder, granule or lyophilizate.

A further aspect of the invention relates to such compositions (including gels, creams or ointments of acceptable viscosity) in the form of a semi-solid composition, which may optionally be for topical application to the eye.

A further aspect of the invention relates to such compositions wherein the compound of formula (I) is neramexane or a pharmaceutically acceptable salt thereof.

A further aspect of the invention relates to such compositions wherein the concentration of the compound of formula (I) ranges from about 2mg/ml to about 100 mg/ml.

A further aspect of the invention relates to such a composition, wherein the composition further comprises at least one flavoring or taste masking agent other than cyclodextrin.

A further aspect of the invention relates to such compositions, wherein the composition is substantially free of preservatives.

A further aspect of the invention relates to such a composition, wherein the composition further comprises a preservative at a concentration that is less than the concentration required to effectively preserve an equivalent amount of the placebo composition.

A further aspect of the present invention relates to such a composition, wherein the composition further comprises at least one additional active ingredient.

A further aspect of the present invention relates to such a composition, wherein the composition further comprises at least one additional active ingredient selected from the group consisting of an acetylcholinesterase inhibitor.

A further aspect of the invention relates to such a composition, wherein the pharmaceutically acceptable cyclodextrin is selected from the group consisting of pharmaceutically acceptable, water soluble, natural or derivatized cyclodextrins, such as alpha-cyclodextrin, beta-cyclodextrin, optionally methylated beta-cyclodextrin, 2-O-methyl-beta-cyclodextrin, hepta- (2, 6-di-O-methyl) -beta-cyclodextrin (dimethyl-beta-cyclodextrin), acetylated dimethyl-beta-cyclodextrin, hepta- (2, 3, 6-tri-O-methyl) -beta-cyclodextrin (trimethyl-beta-cyclodextrin), sulfoalkyl ether-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, O-carboxymethyl-O-ethyl-beta-cyclodextrin, beta-cyclodextrin, Glucuronyl-glucosyl- β -cyclodextrin, maltosyl- β -cyclodextrin, β -cyclodextrin sulfate, β -cyclodextrin phosphate, γ -cyclodextrin, sulfoalkyl ether- β -cyclodextrin, and sulfobutyl ether- β -cyclodextrin, as well as hydroxyalkyl modified cyclodextrins (including hydroxypropyl- β -cyclodextrin, such as 2-hydroxypropyl- β -cyclodextrin, or hydroxypropyl- γ -cyclodextrin, such as 2-hydroxypropyl- γ -cyclodextrin).

A further aspect of the invention relates to a pharmaceutical composition comprising any of the above compositions in combination with one or more additional pharmaceutically acceptable excipients.

Another aspect of the invention relates to such pharmaceutical compositions in the form of solid compositions.

Another aspect of the invention relates to such a pharmaceutical composition in the form of an aqueous liquid composition.

Another aspect of the present invention relates to such a pharmaceutical composition in the form of a semi-solid composition.

A further aspect of the invention relates to a medicament comprising any of the above compositions.

A further aspect of the invention relates to the use of the above-described compositions for the treatment of CNS and other disorders, including hypoxia, hypoglycemia, hepatic encephalopathy, chronic neurodegenerative disease, dementia, Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-neurodegeneration, AIDS-related dementia, Olive-cerebellar atrophy, Tourette's syndrome, motor neuron disease, mitochondrial dysfunction, Korsakoff's syndrome, Creutzfeldt-Jakob disease, chronic pain, acute pain, drug resistance, dependence and addiction (e.g., opioids, cocaine, benzodiazepines)Class and alcohol), neuropathic pain, epilepsy, melancholia, anxiety, schizophrenia, spasticity, nystagmus, eye disorders, tinnitus, hepatic encephalopathy, multiple sclerosis, stroke, movement disorders, malaria, and viral infections such as hepatitis C and borna virus, conditions requiring immunomodulators, emesis, disorders of drug and alcohol abuse, cognitive disorders, cerebellar tremor, and appetite disorders.

A further aspect of the invention relates to a composition as defined above for use in the treatment of CNS disorders and other disorders, including hypoxia, hypoglycemia, hepatic encephalopathy, chronic neurodegenerative diseases, dementia, Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, multiple sclerosis, muscular dementiaAmyotrophic lateral sclerosis, AIDS-neurodegeneration, AIDS-related dementia, olivopontocerebellar atrophy, Tourette's syndrome, motor neuron disease, mitochondrial dysfunction, Korsakoff's syndrome, Creutzfeldt-Jakob disease, chronic pain, acute pain, drug resistance, dependence on addiction (e.g., opioids, cocaine, benzodiazepines)Class and alcohol), neuropathic pain, epilepsy, melancholia, anxiety, schizophrenia, spasticity, nystagmus, eye disorders, tinnitus, hepatic encephalopathy, multiple sclerosis, stroke, movement disorders, malaria, and viral infections such as hepatitis C and borna virus, conditions requiring immunomodulators, emesis, disorders of drug and alcohol abuse, cognitive disorders, cerebellar tremor, and appetite disorders.

A further aspect of the invention relates to methods of treating CNS disorders and other disorders in a subject in need thereof, including hypoxia, hypoglycemia, hepatic encephalopathy, chronic neurodegenerative disease, dementia, Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-neurodegeneration, AIDS-related dementia, Olive-cerebellar atrophy, Tourette's syndrome, motor neuron disease, mitochondrial dysfunction, Korsakoff's syndrome, Creutzfeldt-Jakob disease, chronic pain, acute pain, drug resistance, dependence and addiction (e.g., opioids, cocaine, benzodiazepines)And alcohol), neuropathic pain, epilepsy, melancholia, anxiety, schizophrenia, spasticity, nystagmus, eye disorders, tinnitus, hepatic encephalopathy, multiple sclerosis, stroke, movement disorders, malaria, and viral infections such as hepatitis C and borna virus, conditions requiring immunomodulators, emesis, disorders of drug and alcohol abuse, cognitive disorders, cerebellar tremor, and appetite disorders comprising administering an effective amount of a composition as described above。

Non-limiting examples of 1-aminocyclohexane derivatives of formula (I) for use in 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-propyl-3, 3, 5, 5-tetramethylcyclohexane,

1-amino-1, 3, 3, 5 (trans) -tetramethylcyclohexane (axial amino),

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-trimethylcyclohexylamine,

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-trimethyl cyclohexylamine,

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) -isopropyl-cyclohexane,

1-amino-1, 5, 5-trimethyl-3 (trans) -isopropyl-cyclohexane,

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,

And optical isomers, diastereomers, enantiomers, hydrates, pharmaceutically acceptable salts thereof, and mixtures thereof.

Detailed description of the invention:

as used herein, the term aqueous liquid composition means a liquid formulation in which the major liquid component is water. Optionally, the aqueous liquid composition may further comprise other liquid ingredients, such as pharmaceutically acceptable organic solvents and co-solvents. Examples of such other liquid ingredients are e.g. ethanol, glycerol, propylene glycol and polyethylene glycol. Water-miscible organic solvents and co-solvents may be incorporated, for example to dissolve poorly water-soluble ingredients, such as lipophilic materials.

The expression liquid formulation includes liquid solutions and dispersions, such as emulsions and suspensions.

As used herein, the term semi-solid composition means a formulation having a low viscosity, the main liquid component of which is water. Optionally, the semi-solid composition may further comprise other liquid ingredients, such as pharmaceutically acceptable organic solvents, co-solvents, viscosity adjusting polymers, and emulsifiers. Examples of such other liquid ingredients are ethanol, glycerol, propylene glycol and polyethylene glycol. Organic solvents which are miscible with water may be incorporated, for example to dissolve ingredients which are not readily water soluble, such as lipophilic materials.

The term semisolid composition includes gels, creams and ointments. These formulations do not flow freely as compared to liquid compositions. The viscosity of the semi-solid composition may be controlled by a polymer or combination of polymers, such as acacia and derivatives, alginic acid and derivatives, carbomer and derivatives, carboxymethylcellulose and derivatives, carageenan and derivatives, croscarmellose (croscarmellose) and derivatives, crospovidone and derivatives, dextrin and derivatives, ethylcellulose and derivatives, gelatin and derivatives, guar gum and derivatives, hydroxyethyl cellulose and derivatives, hydroxypropyl methylcellulose (hypromellose) and derivatives, hydroxypropyl methylcellulose and derivatives, lecithin and derivatives, maltodextrin and derivatives, methylcellulose and derivatives, poloxamers (poloxamer) and derivatives, polyethylene glycols and derivatives, polymethacrylates and derivatives, polyoxyethylated alkyl ethers and derivatives, polyvinyl alcohol, polyvinylpyrrolidone and derivatives, polyvinyl alcohol, polyvinyl pyrrolidone and derivatives, and mixtures thereof, Silica and derivatives, sodium starch glycolate and derivatives, sorbitol and derivatives, starch and derivatives, pregelatinized starch and derivatives, tragacanth and derivatives, and xanthan gum and derivatives.

As used herein, the term solid composition includes hard capsules, soft capsules, tablets, coated tablets, lozenges, wafers, granules, powders, lyophilizates, and the like.

1-aminocyclohexane derivatives of formula (I) (e.g. neramexane, 1-amino-1, 3, 3, 5, 5-pentamethylcyclohexane) are disclosed in U.S. Pat. Nos. 6,034,134 and 6,071,966. Compounds of formula (I), such as neramexane, can be used according to the invention in the form of any pharmaceutically acceptable salt, solvate, isomer, conjugate, and prodrug, and any reference in this specification to compounds of formula (I), such as neramexane, should be understood to also refer to such salt, solvate, isomer, conjugate, and prodrug.

The word "analog" or "derivative" is used herein in its conventional medical sense to refer to a molecule that is structurally similar to a reference molecule (e.g., neramexane), but has been modified in a purposeful and controlled manner to replace one or more particular substituents of the reference molecule with alternative substituents, thereby producing a molecule that is structurally similar to the reference molecule. The synthesis and screening of analogs (e.g., using structural and/or biochemical analysis) to identify slightly modified ones of known compounds, which may have improved or biased characteristics (e.g., higher potency and/or selectivity for a particular targeted receptor type, better ability to penetrate the mammalian blood-brain barrier, fewer side effects, etc.), are well known drug design approaches in medicinal chemistry.

Pharmaceutically acceptable salts include, but are not limited to: acid addition salts are prepared, for example, from hydrogen chloride, methanesulfonic acid, hydrogen bromide, hydrogen iodide, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, carbonic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p-methylbenzenesulfonic acid, cyclohexylsulfamic acid, salicylic acid, p-aminosalicylic acid, 2-phenoxybenzoic acid and 2-acetoxybenzoic acid. All of these salts (or other similar salts) can also be prepared by conventional methods. The nature of the salt is not critical, so long as it is non-toxic and does not substantially interfere with the desired pharmacological activity.

Cyclodextrins are oligosaccharides composed of glucopyranose units. The main unsubstituted or natural cyclodextrins are usually prepared by enzymatic hydrolysis of starch. It is cone-like, ring-shaped molecule with rigid structure and central cavity, and its size varies with the type of cyclodextrin. Cyclodextrins have a relatively hydrophobic internal cavity and are capable of holding lipophilic and hydrophilic molecules in the form of inclusion complexes, thus, for example, allowing less soluble drugs to be dissolved in aqueous media. Other types of inclusion complexes involving cyclodextrins have also recently been identified.

As used herein, clathrate means association of molecules through non-covalent interactions. The inclusion reaction that occurs in solution is generally an equilibrium process. However, inclusion compounds may also appear in the solid state. An inclusion compound is a structure in which a guest molecule is partially or completely contained within a cavity of a larger host molecule.

The three major types of pharmaceutically acceptable cyclodextrins are alpha-, beta-, and gamma-cyclodextrins, which contain 6, 7, and 8 glucopyranose units, respectively. In addition, a number of chemically modified cyclodextrins have been developed, mostly motivated by the idea of increasing the solubility in water and expanding their use as solubilizing excipients. Examples of such derivatives include alpha-cyclodextrin, beta-cyclodextrin, optionally methylated beta-cyclodextrin, 2-O-methyl-beta-cyclodextrin, hepta- (2, 6-di-O-methyl) -beta-cyclodextrin (dimethyl-beta-cyclodextrin), acetylated dimethyl-beta-cyclodextrin, hepta- (2, 3, 6-tri-O-methyl) -beta-cyclodextrin (trimethyl-beta-cyclodextrin), sulfoalkyl ether-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, O-carboxymethyl-O-ethyl-beta-cyclodextrin, glucuronyl-glucose-beta-cyclodextrin, beta-cyclodextrin, Glucosyl- β -cyclodextrin, maltosyl- β -cyclodextrin, β -cyclodextrin sulfate, β -cyclodextrin phosphate, γ -cyclodextrin, sulfoalkyl ether- β -cyclodextrin, and sulfobutyl ether- β -cyclodextrin (SBEBCD), and hydroxyalkyl-modified cyclodextrins (including hydroxypropyl- β -cyclodextrin, such as 2-hydroxypropyl- β -cyclodextrin (HPBCD), or hydroxypropyl- γ -cyclodextrin, such as 2-hydroxypropyl- γ -cyclodextrin (HPGCD)). As used herein, the term "cyclodextrin" includes modified forms of natural cyclodextrins.

An example of a suitable grade of hydroxypropyl- β -cyclodextrin is amorphous, optionally substituted hydroxypropyl- β -cyclodextrin having a degree of substitution, DS, in the range of about 4.5 (i.e., between about 4 and 5), such as that marketed by Klepose HPB (Roquette). It is noted that the DS value, as used herein, is defined as the average number of substituted hydroxyl groups per anhydroglucose unit, not per cyclodextrin molecule. Other examples of useful grades are optionally substituted hydroxypropyl- β -cyclodextrins with a degree of substitution DS in the range of about 5.6, or in the range of 2 to 4, or in the range of about 5, or in the range of about 6.5, respectively. An example of a suitable grade of hydroxypropyl-gamma-cyclodextrin is Cavasol^TMW8 HP (Wacker Chemie) commercially available.

The amount of cyclodextrin in the composition can be selected taking into account the type of cyclodextrin and the concentration of active ingredient that is desired to be achieved. The concentration of the active ingredient may be at least about 1 mg/ml. If the active ingredient is a neramexane compound, such as neramexane base, neramexane hydrochloride, or neramexane mesylate, the concentration can range from about 2 to about 100 mg/ml. Alternatively, the pharmaceutical composition may comprise neramexane, or a pharmaceutically acceptable salt thereof, in a range of 2 to 50 mg/ml. For example, neramexane, or a pharmaceutically acceptable salt thereof, can be formulated into such compositions at a concentration of 5-10 mg/ml.

Palatable compositions (e.g., liquid, semi-solid, or solid compositions) are obtained according to the present invention when the amount of cyclodextrin is selected such that the molar ratio of cyclodextrin to active is at least about 0.5: 1 and at most 100: 1. Another embodiment may comprise a cyclodextrin to active ratio of at least about 1: 1. Other embodiments may comprise a ratio of about 0.75: 1 to 50: 1, including 5: 1, 10: 1, and 25: 1. The molar ratio of cyclodextrin to drug substance can also be formulated to be about 1: 1 to about 10: 1, for example about 2: 1 to about 10: 1, such as about 2: 1, 3: 1 or about 6: 1, or about 7: 1, or about 8: 1, or about 9: 1, respectively.

This ratio has been found to give excellent high taste masking, which may be associated with the spontaneous formation of soluble inclusion complexes between cyclodextrin molecules and drug substances. Moreover, particularly in the case of neramexane compounds, the unpleasant odor of the active compound has been substantially reduced. The degree of taste masking is surprising in view of the high water solubility of the active compound, especially in the case of the readily soluble salt forms, such as neramexane mesylate. It is also surprising that the inclusion reaction achieves effective taste masking without eliminating other properties of the drug substance, which are believed to be a result of the state of dissolution of the drug substance in the aqueous solvent. After oral administration, for example, the active compound from the composition is rapidly absorbed and made bioavailable without delay.

If the molar ratio of cyclodextrin to active compound is selected to provide significant but not complete taste masking, as may occur if the selected ratio is in the lower portion of the range given above (e.g., a ratio of 1: 1), it is also contemplated to add one or more additional adjuvants that improve the palatability of the formulation. This is particularly true for neramexane mesylate solutions within the preferred drug concentration range. For example, one or more sweeteners may be incorporated. Furthermore, one or more auxiliary materials selected from the group consisting of flavors, odorants, and taste masking agents may be added, provided that the taste masking agent is not selected from the group consisting of cyclodextrins.

As used herein, sweeteners are natural or synthetic compounds that have a sweet taste and are physiologically acceptable. Examples of natural sweeteners include general sugars and sugar alcohols such as sucrose, glucose, fructose, maltose, maltitol, xylitol, lactitol, mannitol, and sorbitol. Sugar alcohols may be used to improve the taste of the present compositions, for example with sorbitol. Useful concentrations for sorbitol or other sugars and sugar alcohols range from about 5% (w/v) to about 25% (w/v), with 10% (w/v) also being useful.

In another embodiment, artificial sweeteners may also be incorporated into the composition in addition to or in place of natural sweeteners. Artificial sweeteners that may be used include sodium saccharin, sodium cyclamate, acesulfame potassium, neohesperidin dihydrochalcone, and aspartame, as well as any other sweetener that has been found to be safe for human use. The appropriate concentration depends on the individual sweetener selected, but is also relevant to the selection of the particular cyclodextrin. For example, hydroxypropyl- β -cyclodextrin has provided a rather sweet taste, such that the addition of sweeteners may not further increase the palatability of the formulation.

Suitable flavoring agents which further improve the taste of aqueous compositions containing aminocyclohexane derivatives of cyclodextrin, including neramexane and pharmaceutically acceptable salts thereof, include grapes, oranges, mints, spearmint, cherries, licorice and fennel seeds. In particular, the minty taste is physicochemically and organoleptically compatible with the main ingredients of the compositions of the present invention and results in a palatable formulation.

If any oily flavouring ingredient is used (e.g. peppermint oil), it may also be necessary or useful to add adjuvants which can facilitate solubilisation of the oil in the aqueous phase. For example, surfactants or water-miscible organic cosolvents may also be used for this purpose. Propylene glycol may be incorporated to achieve solubilization when it is a mint oil or other mint flavored product.

The inclusion compound of the present invention produces a strong taste masking effect without inhibiting the preservation effect of the active ingredient, which may be useful for liquid compositions. As a result of the antimicrobial effect retained by the drug substance, the compositions of the present invention may be formulated without the addition of any additional preservatives. Thus, in one embodiment, the compositions of the present invention are substantially free of preservatives. In this context, the word "substantially" means that no preservative is detectable in the composition or is present only at concentrations that are generally considered to be irrelevant for any preservation effect.

The liquid composition optionally comprises at least one preservative, but at a concentration insufficient to effectively preserve an equivalent amount of the placebo composition. As used herein, an equivalent amount of the placebo composition is intended to be a composition that is substantially free of active ingredients, with properties and other ingredients approximately the same as the reference composition containing the drug.

Whether a composition is effectively preserved can be determined by tests known to those skilled in the art, such as a preservation efficiency test (USP <51>), in which five challenge organisms are added to a test composition at intervals depending on the product classification. In an appropriate series, this test may also be performed to determine the minimum effective concentration of a particular preservative for a given composition, e.g., corresponding to a non-drug containing composition such as a composition of the present invention. For example, it may be found that in order to effectively preserve a particular placebo composition containing sorbic acid, the preservative must be present at a concentration of at least about 0.1% (w/v). In this case, the reference composition comprising the 1-aminocyclohexane derivative may contain sorbic acid at a substantially lower concentration, for example about 0.05% (w/v) or less. In another embodiment, the preservative concentration is selected to be no more than about one-fifth, including no more than about one-tenth, of the concentration required to effectively preserve an equivalent amount of the placebo composition.

For reproducible product quality and reliable stability, the composition can be adjusted to a specific pH by incorporating one or more suitable excipients selected from the group consisting of physiologically acceptable acids, bases, and acidic and basic salts. For example, the pH of the composition may be buffered to a value selected from the range of about pH 4 to about pH 10 using a combination of citric acid and sodium citrate. In particular, the pH may be adjusted to a value of about pH 4.5 to about pH 8 using a pharmaceutically acceptable buffer or mixture, such as citrate buffer.

Other further adjuvants conventionally used in pharmaceutical formulations may be incorporated which appear to be suitable for adapting the composition to the specific needs of a particular drug candidate, or to a specific use or target population. Examples of potentially suitable adjuvants are thickeners such as lyogels including carageenan, alginates, xanthan gum, and soluble cellulose esters; a colorant; stabilizers, for example antioxidants, or crystallization inhibitors, for example glycerol, propylene glycol, or polyvinylpyrrolidone.

Optionally, the composition may further comprise another active ingredient other than an aminocyclohexane derivative. As used herein, an active ingredient is a pharmaceutically acceptable compound or mixture of compounds for the diagnosis, prevention or treatment of a disorder, disease or condition. The words "active compound", "active ingredient", "drug", and "drug substance" are used interchangeably. Additional active ingredients include acetylcholinesterase inhibitors such as donepezil, rivastigmine (rivastigmine), tacrine, galantamine, physostigmine, huperzine A, zanapazil (zanapezil), gentamimine (gantigmine), fensenine (phensenine), Phenylethanitromeserine (PENC), cyclsmerine, thiacyclsmerine, SPH 1371 (galantamine-plus), ER 127528, RS 1259, and F3796.

It has surprisingly been found that inclusion complexes between neramexane and pharmaceutically acceptable salts thereof and a cyclodextrin or a combination of cyclodextrins form spontaneously in aqueous media. Inclusion formation occurs with all types of natural cyclodextrins and cyclodextrin derivatives, including beta-and gamma-cyclodextrins and hydroxypropyl-beta-or hydroxypropyl-gamma-cyclodextrins.

The formation of inclusion complexes occurs spontaneously in aqueous solution at standard room temperature, unlike many other known cyclodextrin inclusion complexes whose preparation requires the use of heat and/or long stirring times. Thus, the preparation of the composition is technically simple, fast and cost-effective. In most cases, the ingredients are simply weighed and mixed with a defined amount of water or co-solvent, followed by stirring until dissolution occurs. The mixture may be stirred and/or heated. The solution may be further processed by filtration or centrifugation to remove residual particles. If a solid clathrate is desired, the solution may be dried, for example by spray drying or freeze drying.

The formation of the inclusion complex can also be achieved using conventional single pot wet granulation processes or fluidized bed granulation processes, using only a limited amount of aqueous medium or organic solvent or co-solvent or mixtures thereof. The inclusion complex may also be formed by spray drying a neramexane cyclodextrin solution. For conventional granulation methods, neramexane and cyclodextrin can be homogeneously blended and then granulated with an aqueous solution or a co-solvent containing an aqueous solution. The granulation process may also be carried out by granulating neramexane with a cyclodextrin solution, or by granulating a cyclodextrin powder with a neramexane solution. Only in the case of the addition of water-insoluble ingredients would it be helpful to dissolve the adjuvant in a certain amount of surfactant or cosolvent before mixing it with the remaining ingredients.

Generally, the cyclodextrin/drug inclusion complex can be prepared using various methods, such as solution method, coprecipitation method, slurry method, kneading method, milling method (T Loftsson, pharmaceutical technology 12, 41-50, 1999). Slurry and kneading methods are more commonly used for the inclusion of compounds that are poorly soluble in water, while solution and precipitation methods can be readily used for both water-soluble and poorly soluble compounds.

The liquid and semi-solid compositions of the present invention may be filled into containers containing multiple doses. Suitable containers hold volumes ranging from about 5ml or 5g to about 1,000ml or 1,000g, and other containers can hold from about 10ml (or g) to about 500ml (or g). The volume is selected taking into account the concentration of the particular formulation and the time period for which the product is to be used. For example, the container may be selected to contain a desired medication for a number of days, weeks or months. In a preferred embodiment, the container is selected to hold enough medication for at least about 4 weeks. In another embodiment, the container is selected to hold about 50ml (or g), about 100ml (or g), about 200ml (or g), about 250ml (or g), or about 500ml (or g).

Suitable containers may be of glass or suitable plastics, such as polypropylene or polyethylene, and typically have a reclosable closure. Optionally the closure system is child-resistant.

The container may further comprise means for measuring and/or dispensing a dose of the composition. Conventional measuring devices, such as pipettes, i.e. glass tubes fitted with rubber bulbs, are integrated into the closure and removed when the container is opened. Alternatively, a non-removable dropper is integrated into the bottle neck.

The container or container system may also contain a measuring cup that provides a scale indicating the amount of liquid taken in most cases. For example, the scale may range from about 0.5ml to about 10ml, and from about 1ml to about 5ml, or may indicate a dosage of the formulation in grams, or drug substance in mg, instead of volume. The measuring cup may be part of the container closure system or it may be provided as a separate device provided in a secondary package in which the container is located.

The composition of the present invention may be a solid composition. Furthermore, the 1-aminocyclohexane derivative and the cyclodextrin may be present in a solid composition in the form of an inclusion, or the composition may comprise both components in a non-inclusion form, the inclusion form forming spontaneously when the composition is used in an aqueous environment.

The compositions of the present invention may be in the form of a formulation for reconstitution, such as a powder, granule, tablet, wafer (wafer) or lyophilizate, for the preparation of a ready-to-use liquid or semi-solid formulation for oral administration. At this time, unless the composition does not contain a liquid, the composition may be combined in the same manner as described above in the case of the liquid composition in view of the same effects and advantages. Or alternatively, the product is designed to be mixed with a liquid, such as water or a mixture of water and a co-solvent, prior to administration. The solid composition for reconstitution is more stable and may exhibit a longer shelf life, is also lighter and less expensive to transport and store than a liquid composition that is immediately available. However, immediately available liquid formulations are convenient for patients who are reluctant to handle the formulation prior to administration.

Solid formulations for reconstitution can be prepared using conventional pharmaceutical processing procedures. For example, it may be prepared in a similar manner to the liquid compositions described above, and then dried, for example by lyophilization or spray drying.

Alternatively, solid compositions can be designed and formulated for oral administration without reconstitution. In this context, oral administration is understood to encompass all forms of oral use, including both oral and buccal administration. Examples of dosage forms for intraoral administration are formulations which disintegrate in the mouth rather than in gastric juice, which formulations are also known as orally disintegrating dosage forms, fast dissolving tablets and oral wafers. Examples of formulations for oral administration include conventional hard or soft capsules and tablets.

As used herein, in connection with the compositions of the present invention, the phrase "rapidly dissolve" means that at least 85% of the 1-aminocyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof) is released within 30 minutes as measured using a paddle (50rpm) or basket type (100rpm) apparatus at a temperature of about 37 ℃ and a volume of about 900ml, and the phrase "very rapidly dissolve" means that at least 85% of the 1-aminocyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof) is released within 15 minutes as measured using a paddle (50rpm) or basket type (100rpm) apparatus at a temperature of about 37 ℃ and a volume of about 900 ml.

As used herein, the term drug includes a drug product that may represent a composition, or in combination with a container, or other packaging mechanism, a drug delivery device, a liquid for reconstitution, or another composition containing a drug substance in a kit or combination package.

According to some embodiments, the present invention relates to the administration of a composition comprising 1-aminocyclohexane derivatives (including neramexane and pharmaceutically acceptable salts thereof) to an individual in need thereof. For example, the compositions of the invention are useful for the treatment of CNS disorders and other disorders, including hypoxia, hypoglycemia, hepatic encephalopathy, chronic neurodegenerative diseases, dementia, Alzheimer's disease, bloodVascular dementia, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-neurodegenerative disease, AIDS-related dementia, olivopontocerebellar atrophy, Tourette's syndrome, motor neuron disease, mitochondrial dysfunction, Korsakoff's syndrome, Creutzfeldt-Jakob disease, chronic pain, acute pain, drug resistance, dependence and addiction (e.g., opioids, cocaine, benzodiazepines)Class and alcohol), neuropathic pain, epilepsy, melancholia, anxiety, schizophrenia, spasticity, nystagmus, eye disorders, tinnitus, hepatic encephalopathy, multiple sclerosis, stroke, movement disorders, malaria, and viral infections such as hepatitis C and borna virus, conditions requiring immunomodulators, emesis, disorders of drug and alcohol abuse, cognitive disorders, cerebellar tremor, and appetite disorders.

The word "treating" as used herein means alleviating or reducing at least one symptom of a disease in a subject. Within the meaning of the present invention, the word "treatment" also means suppressing, delaying onset (i.e. the period before clinical manifestation of the disease) and/or reducing the risk of development or worsening of the disease.

The word "therapeutically effective" for a dose or amount refers to an amount of a compound or pharmaceutical composition that is sufficient to produce the desired activity upon administration to a mammal in need thereof.

The term "nystagmus" as used herein encompasses both congenital and acquired diseases, including subtypes thereof. The term nystagmus also includes pathological conditions and nystagmus caused by toxic or metabolic causes, including subtypes thereof. The term nystagmus also includes ocular tremor or vibratory pseudoscopic vision. Moreover, nystagmus also includes downward-looking nystagmus, upward-looking nystagmus, seesaw-like nystagmus, periodic alternating nystagmus, and acquired vibratory nystagmus. Conditions/diseases mentioned in the category "congenital nystagmus" include, but are not limited to, idiopathic diseases, albinism, aniridia, Leber congenital amaurosis, bilateral optic nerve aplasia, bilateral congenital cataract, rod cell monochromatic color vision, optic nerve or macular disease, persistent lens vascular membrane, occult nystagmus and nystagmus block syndrome. Examples of diseases/conditions falling within the definition of "pathological nystagmus" include, but are not limited to, peripheral nystagmus, positional nystagmus, gaze-induced nystagmus, post-tremor, spontaneous nystagmus, and central nystagmus. Examples of conditions/disorders falling within the definition of "acquired nystagmus" include, but are not limited to, benign paroxysmal positional vertigo, head trauma, stroke, meniere's disease and other balance disorders, multiple sclerosis, brain tumors, Wernike's syndrome (Werneke-Korsakoff syndrome), encephalopathy, extramedullary syndrome, optic nerve dysplasia, Noonan syndrome, Pelizaeus-Merzbacher disease, superior semicircular canal syndrome (superior nuclear disease syndrome), tullio's phenomenon, and Horner's syndrome. Examples of conditions/dysfunctions falling within the definition of nystagmus due to toxic or metabolic causes include, but are not limited to, those due to alcohol, lithium, barbiturates, phenytoin, salicylates, benzodiazepinesLSD, phenylcyclidine, aminoglycosides, anticonvulsants, sedatives, methylenedioxy methamphetamine, west's encephalopathgy, thiamine deficiency and poisoning.

The word "eye disease" as used herein includes ocular hypertension, glaucoma, low-pressure glaucoma, diabetic retinopathy, age-related macular degeneration, diabetic macular edema, ischemic optic neuropathy, optic nerve trauma, optic neuritis, retinal vein occlusion, retinal artery occlusion, retinal edema, retinal ischemia, retinal damage due to, for example, photocoagulation and accidental laser injury.

The word "pharmaceutically acceptable" as used in connection with the compositions of the present invention means that the molecular entities and other ingredients of the composition are physiologically acceptable and do not generally produce an untoward response when administered to a mammal (e.g., a human). The word "pharmaceutically acceptable" may also mean approved by a regulatory agency of the federal or a state government, or listed in the U.S. pharmacopeia (u.s.pharmacopeia), or other generally recognized pharmacopeia, for use in mammals, and more particularly in humans.

The word "about" or "approximately" generally means within 20%, alternatively within 10%, including within 5%, of a given value or range. Alternatively, particularly in biological systems, the word "about" means within a logarithmic range (i.e., an order of magnitude of a factorial), including within two or one-half of a given value.

The compositions of the present invention may be used to prepare a medicament for the treatment of at least one of the mentioned dysfunctions, wherein the medicament is or is suitably prepared for specific administration as disclosed herein (e.g. once daily, twice daily, or three times daily). For this purpose, the instructions for the patient contain corresponding information.

Detailed description of the preferred embodiments

The following examples illustrate the invention but are not intended to limit its scope.

Example 1

In the presence of neramexane mesylate and hydroxypropyl-beta-cyclodextrin (HPBCD; grade: Kleptase;)^TMHPB) or hydroxypropyl-gamma-cyclodextrin (HPGCD; grade: cavasol^TMW8 HPPharma) and detected by Isothermal Titration Calorimetry (ITC). The experiments were performed on a Microcal MCS-ITC instrument. The process consists of: a small amount of the test solution, here neramexane mesylate solution, was repeatedly added to the receiving solution, here the cyclodextrin solution, in the calorimeter via an electrically-powered microliter syringe. When combined, an exothermic or endothermic signal is generated, which represents the sum of all thermal events, includingInclusion itself, but also includes heat of dilution or (de) protonation. Titration curves were evaluated using Microcal Origin software V2.9 with a raw data evaluation module for titration calorimetry evaluation.

Experiments were performed using an aqueous phosphate buffered solution at pH 6 as solvent. Solutions of neramexane mesylate, HPBCD, and HPGCD were prepared at various concentrations, and numerous titrations were performed using different maximum molar ratios of neramexane to cyclodextrin (after complete addition of drug substance), ranging from 1.25 to 5. Titrations with solvent solution alone and in combination with cyclodextrin solution were performed to obtain a curve indicative of the heat of dilution, which can be used as baseline data for correcting the inclusion curve.

In all cases, inclusion occurred spontaneously. In the case of HPBCD, an exothermic event, and in the case of HPGCD, an endothermic event. Furthermore, the stoichiometry of the bonding and the calculated equilibrium constant depend on the final (maximum) molar ratio of neramexane to cyclodextrin. In the case of HPBCD, for example at a final molar ratio of 5, the stoichiometry of the linkage (neramexane per cyclodextrin molecule) is 0.84 and the equilibrium constant is 788M^-1And at a final molar ratio of 1.25, the stoichiometry is 0.4 and the equilibrium constant is 413M^-1. An example of the results obtained with HPGCD at a final molar ratio of 1.8 gave a stoichiometry of 0.93 and an equilibrium constant of 112M^-1。

Example 2

Equimolar amounts of neramexane mesylate and hydroxypropyl-beta-cyclodextrin (HPBCD; grade: Kleptase)^TMHPB), hydroxypropyl- γ -cyclodextrin (HPGCD; grade: cavasol^TMW8 HPPharma) or unsubstituted beta-cyclodextrin (BCD; grade: kleptose^TM) Dissolved together in water and subsequently dried by evaporation under vacuum in a Rotavapor apparatus. Samples of the resulting material were analyzed by solid state NMR (nuclear magnetic resonance) spectroscopy, some of which were also analyzed by XRD (X-ray diffraction). In brief, it was shown by NMR spectroscopy that the sample did contain a true inclusion complex of the drug substance with cyclodextrin, and by XRD it was confirmed that the inclusion complex with HPBCD was amorphous, butBCD is used for crystallization.

NMR experiments were also performed by one-dimensional and two-dimensional solid state NMR, where the two-dimensional technique is two-quantum/one-quantum correlation spectroscopy, as described in SP Brown and HW Spiess (advanced solid state NMR methods for elucidating the structure and dynamics of molecular, macromolecular, and supramolecular systems, Chemical Review101, 4125-4155, 2001). In the experimental series, neramexane mesylate was compared with the corresponding cyclodextrin physical mixture in a.m. samples. Spectra were measured at two-quantum excitation times (22 and 44 μ s). In the case of the test samples (obtained by drying the neramexane/cyclodextrin solution), clear cross peaks were observed, indicating that at least some of the methyl protons of neramexane mesylate (1.1ppm) must be located very close relative to certain protons of cyclodextrin (e.g. 4.2ppm for BCD). In the case of neramexane-BCD inclusion, these cross peaks were at about 1ppm in the single quantum dimension and at about 5ppm in the double quantum dimension for both excitation times. In contrast, the corresponding profile of the corresponding physical mixture is without any evidence of cross peaks, even at longer excitation times. Thus, a cross peak of clathrates indicates true clathrates, rather than artifacts due to overlapping of broad peaks.

Example 3

Preparations containing neramexane mesylate and hydroxypropyl-beta-cyclodextrin (HPBCD; grade: Klepose) by dissolving a weighed amount of the active compound and cyclodextrin in sterile water which has been measured^TMHPB) aqueous liquid composition. Subsequently, the remaining auxiliary materials are added with stirring. Sterile water was then added until the final volume was reached. The solution was filled into a 5ml glass bottle. Additionally, for comparative purposes, solutions without cyclodextrin were prepared. Table 1 shows the composition of the test solutions, all amounts are in g unless otherwise indicated.

Test solution A showed a cyclodextrin/neramexane molar ratio of 1: 1 and test solution B a ratio of 2: 1.

TABLE 1

Example 4

The test solution samples prepared in example 3 were blind and tested for palatability by 18 individuals. The scale of scores was 1 to 6(1 being the best scale), the average scale of taste for solution a was 3.0 and solution B was 2.7. The taste described is little or no bitter. The odor is generally found to be almost neutral. In contrast, solution C had an average rating of 3.9 and was described as very bitter and irritating.

Example 5

The test solution samples prepared in example 3 were evaluated for their characteristics with respect to microorganisms. For this purpose, a test of the european pharmacopoeia IV "effectiveness of antimicrobial preservation" (5.1.3) was carried out. In this test, samples were contaminated with substantial amounts of five major microbial contaminants (e.coli (Escherichia coli), pseudomonas aeruginosa, Staphylococcus aureus (Staphylococcus aureus), Candida albicans (Candida albicans), Aspergillus niger) and cultured for 14 and 28 days, respectively, before analysis of the same microorganisms. As a result, all of the tested solutions met the criteria for effective storage of the oral formulations.

The scope of the invention is not limited to the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such variations are intended to fall within the scope of the claims.

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

Claims (14)

1. A composition comprising a compound selected from formula (I) and optical isomers, enantiomers, hydrates, solvates, polymorphs, and pharmaceutically acceptable salts thereof

Wherein R is^*Is- (CH)₂)_n-(CR⁶R⁷)_m-NR⁸R⁹，

Wherein n + m is 0, 1 or 2,

wherein R is¹To R⁷Independently selected from hydrogen and C_1-6Alkyl radical, wherein R⁸And R⁹Independently selected from hydrogen and C_1-6Alkyl, or together represent lower-alkylene- (CH)₂)_x-, where x is 2 to 5, both inclusive;

and pharmaceutically acceptable cyclodextrins or pharmaceutically acceptable cyclodextrins.

2. The composition of claim 1, wherein the composition is an aqueous liquid composition.

3. The composition of claim 1, wherein the composition is a semi-solid composition.

4. The composition of claim 1, wherein the composition is a solid composition.

5. A composition according to any one of the preceding claims wherein the pharmaceutically acceptable cyclodextrin is selected from the group consisting of α -cyclodextrin, β -cyclodextrin, optionally methylated β -cyclodextrin, 2-O-methyl- β -cyclodextrin, hepta- (2, 6-di-O-methyl) - β -cyclodextrin (dimethyl- β -cyclodextrin), acetylated dimethyl- β -cyclodextrin, hepta- (2, 3, 6-tri-O-methyl) - β -cyclodextrin (trimethyl- β -cyclodextrin), 2-hydroxypropyl- β -cyclodextrin, sulfoalkyl ether- β -cyclodextrin, sulfobutyl ether- β -cyclodextrin, O-carboxymethyl-O-ethyl- β -cyclodextrin, O-hydroxy methyl-O-ethyl- β -cyclodextrin, p-methyl-n-butyl ether-, Glucuronyl-glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, beta-cyclodextrin sulfate, beta-cyclodextrin phosphate, gamma-cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin, sulfoalkyl ether-beta-cyclodextrin, and sulfobutyl ether-beta-cyclodextrin.

6. The composition according to any one of claims 1-4, wherein the pharmaceutically acceptable cyclodextrin is selected from the group consisting of β -and γ -cyclodextrins optionally substituted with hydroxyalkyl.

7. A composition according to any one of the preceding claims wherein the compound of formula (I) is neramexane or a pharmaceutically acceptable salt thereof.

8. A composition as claimed in any one of the preceding claims wherein the molar ratio of cyclodextrin to compound of formula (I) is at least about 0.1: 1.

9. A composition according to any one of the preceding claims wherein the concentration of the compound of formula (I) ranges from about 2mg/ml to about 100 mg/ml.

10. The composition of claim 4, wherein the composition is an orally disintegrating dosage form or a formulation for reconstitution, optionally in the form of a powder, granules or lyophilizate.

11. The composition of claim 10, wherein the aqueous liquid composition is obtained upon reconstitution with an aqueous solvent.

12. A medicament containing a composition as claimed in any one of the preceding claims.

13. Use of a composition according to any one of claims 1 to 11 for the preparation of a medicament for the treatment of CNS dysfunction or a condition selected from: hypoxia, hypoglycemia, hepatic encephalopathy, chronic neurodegenerative disease, dementia, Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-neurodegeneration, AIDS-related dementia, olivopontocerebellar atrophy, Tourette's syndrome, motor neuron disease, mitochondrial dysfunction, Korsakoff's syndrome, Creutzfeldt-Jakob disease, chronic pain, acute pain, drug resistance, dependence and addiction (for example)Such as opioids, cocaine, benzodiazepinesClass and alcohol), neuropathic pain, epilepsy, melancholia, anxiety, schizophrenia, spasticity, nystagmus, eye disorders, tinnitus, hepatic encephalopathy, multiple sclerosis, stroke, movement disorders, malaria, and viral infections such as hepatitis C and borna virus, conditions requiring immunomodulators, emesis, disorders of drug and alcohol abuse, cognitive disorders, cerebellar tremor, and appetite disorders.

14. A composition according to any one of claims 1 to 11 for use in the treatment of CNS dysfunction or a condition selected from: hypoxia, hypoglycemia, hepatic encephalopathy, chronic neurodegenerative disease, dementia, Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-neurodegeneration, AIDS-related dementia, olivopontocerebellar atrophy, Tourette's syndrome, motor neuron disease, mitochondrial dysfunction, Korsakoff's syndrome, Creutzfeldt-Jakob disease, chronic pain, acute pain, drug resistance, dependence and addiction (e.g., opioids, cocaine, benzodiazepines, adenosineClass and alcohol), neuropathic pain, epilepsy, melancholia, anxiety, schizophrenia, spasticity, nystagmus, eye disorders, tinnitus, hepatic encephalopathy, multiple sclerosis, stroke, movement disorders, malaria, and viral infections such as hepatitis C and borna virus, conditions requiring immunomodulators, emesis, disorders of drug and alcohol abuse, cognitive disorders, cerebellar tremor, and appetite disorders.