HK1124762B - Neramexane modified release matrix tablet - Google Patents

Description

Modified release matrix tablet of neramexane

[ technical field ] A method for producing a semiconductor device

The present invention relates to pharmaceutical dosage forms, and in particular to modified release dosage forms suitable for oral administration. In another aspect, the invention relates to a new use of the active compound neramexane and to methods of treatment involving this use.

[ background of the invention ]

Neramexane, also known as 1-amino-1, 3, 3, 5, 5-pentamethylcyclohexane, is a member of the orally active 1-aminocyclohexanes that has been found to be useful in the treatment of various diseases, particularly diseases of the specific nervous system, including alzheimer's disease and neuropathic pain. Such compounds and their derivatives are disclosed in detail in U.S. patent nos. 6,034,134 and 6,071,966, the subject matter of which is incorporated herein by reference. It is believed that the therapeutic effect of neramexane is inhibition of the excessive glutamate effect of the N-methyl-D-aspartate (NMDA) receptor with respect to nerve cells, and the compound is therefore also classified as an NMDA antagonist, or NMDA receptor antagonist. In detail, neramexane is apparently a low to medium affinity uncompetitive NMDA-receptor antagonist, believed to selectively block the neuroexcitatory effects associated with aberrant transport of glutamate, a neurotransmitter that plays an indispensable role in neural pathways associated with learning and memory, believed to play a role in alzheimer's disease.

Neramexane shows a therapeutic effect after oral administration. In clinical trials, oral administration may be in the form of immediate release dosage forms. Generally, neramexane is administered at least twice daily in continuous therapy to determine plasma concentrations that remain therapeutically effective.

Modified release solid oral dosage forms may allow for modified release of the active ingredient over a prolonged period of time to maintain therapeutically effective plasma concentrations and/or to modulate other pharmacokinetic properties of the active ingredient over a similar extended period of time. Immediate release solid dosage forms allow release of most or all of the active ingredient in a short time (such as 60 minutes or less) and allow rapid absorption of the drug. A multiphasic release profile (i.e., a composition containing at least an immediate release formulation and at least one modified release formulation) may be used to achieve one or more combinations of release rates to achieve a more specific therapeutic goal, such as immediate release of a portion of the drug followed by extended release. However, the regulation of the release rate of the active ingredient does not necessarily ensure that a long-term effective blood concentration is fixedly achieved or that the pharmacological effect is based solely on the release of the drug.

Low frequency administration, such as once daily administration, has been found to be desirable for most continuous drug treatments. In many studies investigating patient compliance and dosing frequency, a negative correlation between these two parameters was found. It is also believed that compliance with a treatment regimen requiring administration several times daily may be found to be difficult, particularly in patients with dementia.

A general approach to modified release of N-methyl-D-aspartate (NMDA) receptor antagonists is described in U.S. patent No. 6,194,000. The method also includes preparing an immediate release component and a modified release component to obtain the final formulation. This patent discloses a particle (non-bead) consisting of a coated core, the coating being any suitable coating using an organic solvent based system. However, not all NMDA antagonists act in the same manner, and the patent does not specifically disclose compositions containing neramexane.

Currently, a regimen of neramexane administration using immediate release tablets twice daily is employed. This may be undesirable because patient compliance decreases with increasing dosing frequency. Moreover, administration of immediate release tablets may result in a higher frequency of side effects due to a faster absorption rate. For pain treatment, it is of paramount importance to keep the pain relieved without additional discomfort. There is therefore a current and continuing need for once daily modified release formulations containing neramexane or a pharmaceutically acceptable salt of neramexane that have reliable, slower absorption over a target time period.

While there is a need for a modified release dosage form suitable for administration of neramexane, which is clearly useful for treating patients with certain alzheimer's dementia, such a dosage form has not been described or successfully developed. The development of modified release dosage forms for neramexane is challenging because of the high solubility of this molecule in aqueous media at a wide range of pH. In particular, there is a need for a modified release dosage form of neramexane that is suitable for once-a-day administration and is well tolerated. In addition, there is a need for a neramexane modified release dosage form that is robust and does not rely on digestion or the passage of the dosage form through the gastrointestinal tract.

This and other needs are addressed by the present invention as disclosed in the following specification, examples and claims.

[ summary of the invention ]

In a first aspect, the present invention provides a dosage form for oral administration of neramexane, a novel NMDA antagonist, which has been found to be useful in the treatment of alzheimer's disease (including mild, moderate or severe alzheimer's dementia) and other conditions. The dosage forms have modified release characteristics and are suitable for use in a continuous therapeutic dosing regimen. Avoiding high plasma concentration peaks.

The slow release of the active ingredient over an extended period of time allows the peak concentration at the start of administration to be low and to remain stable, and allows for slower absorption. Slower absorption is achieved when the dissolution rate is slower than absorption, so dissolution becomes a pacing step. A slowing of absorption is expected to improve the tolerability of the active ingredient.

In another embodiment, the dosage form of the present invention is a tablet designed to contain the active ingredient dispersed within a matrix formed from at least one release-controlling excipient and optionally one or more other pharmaceutically acceptable excipients. The dosage form has a dissolution time of at least about 1 hour for 10 to 70 weight percent of the active compound incorporated therein in a dose fraction.

Furthermore, the present invention provides an oral modified release dosage form comprising a therapeutically effective amount of an active compound selected from neramexane and pharmaceutically acceptable salts, solvates, isomers, conjugates, prodrugs and derivatives thereof, highly soluble in an aqueous medium and at least one release controlling excipient, wherein the amount of the excipient is selected to achieve an in vitro active compound release profile characterized by a dissolution time of at least about 1 hour for a fraction of 50 wt.% of the active compound.

According to another aspect, the present invention provides a neramexane modified release oral dosage form comprising at least one release controlling excipient and wherein the release controlling excipient is selected to achieve an in vitro drug dissolution profile which is substantially independent of the pH of the dissolution medium.

In another aspect, a modified release oral dosage form of neramexane in a compressed tablet form is provided. The tablet is comprised of at least one release-controlling excipient selected to achieve a drug dissolution profile that is substantially independent of the hardness of the tablet.

In another aspect, a modified release oral dosage form of neramexane in a compressed tablet form is provided. The tablet is a composition comprising at least one release-controlling excipient selected to achieve a drug dissolution profile substantially independent of agitation of a wide range of dissolution media.

In yet another aspect, a neramexane modified release oral dosage form is provided which exhibits a steady state low fluctuation index of neramexane plasma concentration upon once daily administration. In particular, the fluctuation index is about 0.4 or less.

Further, uses and methods of treatment relating to the dosage form of the present invention for twice-daily or once-daily administration of neramexane are provided. The method can be used for treating mild, moderate or severe Alzheimer's dementia or neuropathic pain. In addition, the method can be used to treat diabetic neuropathic pain, amyotrophic lateral sclerosis, multiple sclerosis, irritable bowel syndrome, appetite disorders, obesity, binge eating disorder, autism, attention deficit syndrome, attention deficit hyperactivity disorder, bipolar disorder, tinnitus, mycoses, or psoriasis.

Moreover, the methods can be used to treat conditions associated with cognitive impairment such as dementia, neurodegenerative dementia, mild, moderate and severe alzheimer's dementia, Parkinson's dementia, AIDS dementia, schizophrenia, attention deficit syndrome, attention deficit hyperactivity disorder, Korsakoff syndrome, cerebrovascular dementia, frontotemporal dementia, autism, corticobasal degeneration disorders including corticobasal degeneration dementia, Lewis body disease, mild cognitive impairment, dementia due to inflammation or infection, multiple sclerosis or amyotrophic lateral sclerosis.

Other embodiments of the invention will be apparent based on the following detailed description and claims.

Detailed Description

The present invention provides an oral modified release dosage form comprising a therapeutically effective amount of an active compound highly soluble in aqueous media and at least one release controlling excipient. The active compound is selected from neramexane and pharmaceutically acceptable salts, solvates, isomers, conjugates, prodrugs and derivatives thereof. The content of the rate-controlling excipient is selected to achieve an in vitro drug release profile characterized by a dissolution time of at least about 1 hour at a fraction of 10 to 70 wt.%, such as 50 wt.% of the active compound present in the dosage form.

Neramexane can be used according to the invention in any of its pharmaceutically acceptable salts, solvates, isomers, conjugates, prodrugs and derivatives, any reference herein to neramexane being understood to also refer to such salts, solvates, isomers, conjugates, prodrugs and derivatives.

In one embodiment of the invention neramexane is incorporated into the dosage form of the invention in the form of a salt thereof which has substantial aqueous solubility.

Suitable salts of neramexane may include, but are not limited to, acid addition salts such as those prepared from the following acids: hydrochloric acid, methanesulfonic acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pivalic 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-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid, p-aminosalicylic acid, 2-phenoxybenzoic acid, and 2-acetoxybenzoic acid.

The therapeutically effective dose of neramexane is defined in consideration of several factors, such as the particular condition to be treated, the weight of the patient, the condition of the patient, the administration regimen, and the like. It is presently believed that a cumulative oral daily dose of about 5 to about 150 mg, such as from about 5 mg to about 120 mg or from about 5 mg to 100 mg of neramexane or a salt of neramexane, such as neramexane mesylate, is therapeutically effective for treating at least some conditions for which neramexane is indicated to be useful. A cumulative oral daily dose of about 10 mg to about 90 mg of neramexane or a salt of neramexane, such as neramexane mesylate, may be more preferred.

Also, a cumulative daily dose of about 5 mg to about 50 mg, such as 5 mg, 6.25 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg and 50 mg of neramexane mesylate or an equimolar amount of neramexane, another pharmaceutically acceptable salt, solvate, isomer, conjugate, prodrug or derivative thereof such as neramexane hydrochloride, is therapeutically effective while avoiding excessive side effects. In addition, a cumulative daily dose of about 5 mg to about 40 mg or about 10 mg to about 30 mg of neramexane mesylate or an equimolar amount of neramexane, another pharmaceutically acceptable salt, solvate, isomer, conjugate, prodrug or derivative thereof can be used. The amounts and ranges of active compounds listed may be useful in treating or alleviating the following conditions: including cognitive impairment and other conditions associated with cognitive impairment (e.g., dementia, neurodegenerative dementia, mild, moderate, or severe Alzheimer's dementia, Parkinson's dementia, AIDS dementia, schizophrenia, attention deficit syndrome, attention deficit hyperactivity disorder, Korsakoff syndrome, cerebrovascular dementia, frontotemporal dementia, autism, corticobasal degeneration disorders including corticobasal degeneration dementia, Lewis body disease, mild cognitive impairment, dementia due to inflammation or infection, multiple sclerosis, or amyotrophic lateral sclerosis). If the modified release solid oral dosage form is intended for twice daily administration, the given amount of active ingredient can be halved. Lower or higher doses may also be suitable and therapeutically effective for treating other conditions.

Modified release dosage forms for use in the present invention are dosage forms in which the incorporated active compound is slowly released over a period of time determined in accordance with well known accepted methods (e.g., in vitro dissolution testing in accordance with USP28 or european pharmacopoeia EP5 using a typical buffer having a pH in the range of 1.0 to 7.2 as the dissolution medium), substantially longer than about 15 minutes and shorter than 24 hours, typically for a period of at least about 4 to 12 hours. This definition is independent of the shape of the release profile, i.e. whether linear, primary, secondary or square root curves of temporal dynamics, sigmoidal, etc. Thus, modified release is understood to include extended release, sustained release, slow release and similar expressions for the relevant drug release profile.

In one embodiment, the dosage form of the present invention is a formulation that releases neramexane in a non-linear manner over a period of at least about 6 hours, with the release rate decreasing over time. In another embodiment, neramexane is released in a substantially linear manner over at least 6 hours. For an incorporated dose of 50% by weight of active compound to be released, the dissolution time is generally at least 1 hour, and may be at least 1.5 hours.

In another embodiment, the dissolution time is generally at least 1 hour, and may be at least 1.5 hours, for an incorporated dose of 40% by weight of the active compound to be released.

In another embodiment, the dissolution time is generally at least 1 hour, and may be at least 1.5 hours, for an incorporated dose of 60% by weight of the active compound to be released.

In another embodiment, the dissolution time is between about 1 and 8 hours for an incorporated dose of 10 to 70% by weight of the active compound to be released.

In another embodiment, the release is non-linear, with a dissolution time of between about 1 and 5 hours or between about 1 and 4 hours or between about 1.5 and 3 hours for 50 wt.% of the incorporated dose of active compound to be released. In contrast, if the release profile is substantially linear, the dissolution time for a 50 wt.% dose is at least about 2 hours or at least about 3 hours, such as from about 4 hours to about 8 hours.

In one embodiment of the invention, the in vitro active compound release profile is characterized by a dissolution time in the range of about 1 hour to about 3 hours for a fraction of active compound in an amount of 50% by weight.

Another characteristic of the non-linear release profile suitable for twice daily and especially once daily administration is a dissolution time of 4 hours for a dose fraction of active compound in an amount of between about 50% and about 95% by weight.

In another embodiment, the number of dose portions released after 4 hours is in the range of about 65% to about 95% by weight. In another embodiment, the number of dose portions released after 4 hours is in the range of about 55 to about 85 weight percent. Alternatively, the number of dose portions released after 4 hours is in the range of about 70% to about 85% by weight. It has been found that this release behaviour can be used to achieve and maintain a steady state therapeutic plasma concentration of neramexane even with a single daily administration.

In another embodiment, the dose fraction in the range of about 75% to about 95% by weight is released after 6 hours of dissolution time, such as about 80% to about 90% by weight.

Modified release dosage forms having the aforementioned drug release profiles have been found to be particularly useful for the continuous treatment of neramexane, such as the continuous treatment of patients suffering from conditions and disorders selected from mild, moderate or severe alzheimer's dementia and neuropathic pain. In addition, conditions such as diabetic neuropathic pain, amyotrophic lateral sclerosis, multiple sclerosis, irritable bowel syndrome, appetite disorders, obesity, binge eating disorder, autism, bipolar disorder, attention deficit syndrome, attention deficit hyperactivity disorder, tinnitus, mycoses, and psoriasis may be treated by modified release dosage forms having the aforementioned drug release profiles.

The dosage form is particularly useful in a therapeutic administration regimen which includes continuous twice daily or once daily administration.

Continuous treatment as used herein is understood to be a regular treatment period lasting at least about 2 weeks, often at least about one month. The dosage form of the invention is also suitable for continuous treatment for months or even years, since it provides the active principle ingredient neramexane to the patient in a well tolerated manner, resulting in a therapeutically effective steady state plasma concentration with only mild fluctuations.

Twice-daily and once-daily dosing regimens are understood to include in the present invention repeated administration of the active compound at approximately regular intervals. Typically, the time of administration will not differ by more than a few hours on different days. In particular, once-daily dosing regimens, a relatively uniform plasma profile can only be achieved when the time of daily administration is close, e.g., always in the morning or always in the evening, and does not differ by more than 3 or 4 hours from every other day.

Steady state, as used herein, means that a regular dosing regimen is carried out for a period of time sufficient to result in a mean plasma concentration of the active compound after administration that is similar to the mean plasma concentration after the previous administration. Similarly, peak and trough plasma concentrations are similar to the respective concentrations following the previous administration.

The time to reach steady state depends mainly on the elimination half-life of the active principle. Repeated administrations at the same time interval after 4 elimination half-lives typically result in a mean plasma concentration of about 93-94% of the mean steady state plasma concentration. Even though there is a considerable degree of biological variability in the same individual, it can be assumed that after 4-5 half-lives, the plasma concentration is practically the same as the steady state plasma concentration.

Use of the dosage forms of the present invention may comprise continuous treatment with once daily administration. The once daily administration of an immediate release formulation of neramexane results in fluctuations of the plasma concentration which increase the risk of side effects via high peak concentrations and/or increase the risk of reaching only underdose trough concentrations. The index of fluctuation of the plasma concentration-using conventional formulations according to such once-daily regimens-is in the range of 0.4 to 0.5, about twice as high as the twice-daily dosing regimen of the immediate release formulation.

The fluctuation index used in the present invention is an index representing the fluctuation between the peak and trough concentrations with respect to the mean plasma concentration:

wherein I_FAs a fluctuation index, c_ss(max)Peak plasma concentration at steady state, c_ss(min)Trough plasma concentration at steady state, and c_ss(av)Is the steady state mean plasma concentration. It is presently believed that a fluctuation index greater than about 0.45 is particularly unsuitable for continuous treatment of neramexane. According to the present invention, the neramexane release profile from the dosage form during steady state continuous once daily treatment is modified to produce a fluctuation index of no more than about 0.45 by appropriately selecting the properties, grade and relative amounts of the one or more excipients for release control according to the instructions provided by the present invention. Typically, the fluctuation index is no greater than about 0.4 during a continuous once daily treatment. In another embodiment, the dosage form of the present invention achieves a fluctuation index of no greater than about 0.38 or even no greater than about 0.35, while still using the same treatment regimen.

The release behavior of the dosage forms of the present invention can be achieved in a variety of ways, such as by several types of dosage form designs and formulation strategies. The mechanism by which drug release is controlled is not believed to be important. For example, drug release may be controlled by diffusion of neramexane through a diffusion barrier layer (such as through a polymer film), by diffusion through a matrix, by erosion of a matrix embedding or dispersing the active compound, or by a combination of more than one such mechanism.

For example, the dosage form may be designed and formulated as a coated solid single unit dosage form, such as a coated tablet, wherein the coating acts as a diffusion barrier and provides prolonged drug release. In this case, the coating contains at least one release-controlling excipient, the quality and amount of which are chosen to achieve the aforementioned release properties.

The excipient used in the present invention is a pharmaceutically acceptable, physiologically inert ingredient in a dosage form. Release controlling excipients are excipients that substantially reduce the rate at which an active compound is released from a dosage form or formulation. If the tablet coating is designed to achieve this modified release profile, the release controlling excipients in the coating are typically water insoluble polymers. Polymers that may be suitable are generally well known to those skilled in the art of pharmaceutical formulation. Examples of such polymers include alginates, ethylcellulose, cellulose acetate butyrate, methacrylate copolymers, polyoxyethylene oxide polymers, zein, polyvinyl acetate-polyvinylpyrrolidone copolymers, and the like. The polymer may be provided as an organic solution or an aqueous dispersion which is sprayed onto the tablets using conventional coating equipment. Typically, the coating solution or dispersion also contains plasticizers such as glycerin, propylene glycol, polyethylene glycol, diethyl phthalate, dibutyl sebacate, triacetin, triethyl citrate, acetyl tributyl citrate, castor oil, mono-and diglycerides, and the like. Examples of other optional excipients are pigments, flavors, sweeteners, clouding agents and anti-sticking agents.

However, according to typical embodiments, the dosage form of the present invention is designed as a solid modified release matrix in which the active ingredient is embedded or dispersed and which releases slowly over a prolonged period of time from the dosage form. In this case, no modified release coating is required and the matrix includes at least one release-controlling excipient.

Generally, the matrix does not disintegrate rapidly in aqueous media at physiological temperatures. The release of active compound from the matrix can be controlled by diffusion of active compound through the matrix, erosion of the matrix, or both.

In one embodiment, the matrix is designed as a tablet. In order that the matrix tablet does not disintegrate rapidly, thereby affecting the release of the modified active compound, it comprises at least one release-controlling excipient, more preferably selected from the group consisting of water-insoluble lipids and waxes, water-insoluble polymers and water-swellable polymers. If more than one release-controlling excipient is present in the matrix, excipients from different chemical subgroups may also be combined.

The compound of the release controlling excipient or excipients is selected in an amount sufficient to achieve the foregoing release profile. Depending on its type, the excipient is typically present in the solid matrix in an amount of about 10% to about 80% by weight.

Suitable release-controlling water-insoluble polymers are those including, for example, ethyl cellulose, cellulose acetate butyrate, methacrylate copolymers, zein, polyvinyl acetate, and polyvinyl acetate-polyvinyl pyrrolidone copolymers. Suitable release-controlling lipids and waxes are, for example, beeswax, natural or synthetic mono-, di-and triglycerides of medium and long chain fatty acids such as hydrogenated vegetable oils, carnauba wax, petroleum waxes, microcrystalline waxes, long chain fatty acids, long chain fatty alcohols, esters of fatty acids and fatty alcohols, and the like. Other examples of pharmaceutically acceptable water-insoluble polymers, lipids and waxes that may also be used in matrix formulations are well known to those skilled in the art of medicine.

Depending on the hydrophilicity (erodible or non-erodible) or hydrophobicity of the matrix, the matrix may be a material that swells upon contact with gastric fluid to a size large enough to facilitate retention in the stomach of an individual in a digestive state. In addition to these diffusion-based frameworks, the framework can also be in an erodible form. The digestive state is triggered by ingestion and begins with rapid and intense motor pattern changes in the upper digestive (GI) tract. This change is made up of the reduction in the amplitude of the contraction performed by the stomach and the reduction of the pyloric opening into a partially closed condition. The result is a screening procedure that allows liquid and small particles to pass through a partially open pylorus, while indigestible particles larger than the pylorus are rejected and retained in the stomach. In other words, biological fluids move through the matrix and dissolve the active ingredient, which is released by diffusion through the matrix, while modulating the release rate. The controlled release matrix of these embodiments of the invention is therefore selected to be swellable to a size sufficient to be rejected and thus retained in the stomach, resulting in a matrix that releases the drug in the stomach rather than in the intestine over an extended period of time. Reference is made to U.S. Pat. Nos. 5,007,790, 5,582,837 and 5,972,389 and to International (PCT) patent applications WO98/55107 and WO 96/26718 for disclosures of oral dosage forms that swell to a size that will prolong residence time in the stomach. Each of the documents listed in this paragraph is hereby incorporated by reference in its entirety.

In this embodiment, the solid matrix is designed as a water-swellable, hydrophilic matrix comprising a release-controlling agent selected from water-swellable polymers. Suitable backbone-forming polymers may be water soluble or water insoluble. Suitable polymers absorb substantial amounts of water upon contact with an aqueous medium, typically resulting in the formation of an aqueous gel. The strength of the aqueous gel depends on the type and amount of polymer present and on the presence of other compounds in the backbone. Drug release can occur via diffusion of the active compound through aqueous micropores or microchannels within the three-dimensional polymer gel network and also via continuous erosion or disintegration of the gel layer at most of the surface of the matrix.

Generally, the gel in the hydrophilic modified release matrix forms a process that starts in the outer regions of the tablet and progresses slowly toward the center. Thus, it is believed that during drug release several regions or layers of the matrix exist simultaneously, namely a non-hydrated core region, an intermediate gel layer surrounding the core region and an aggressive outer region. However, these views should be considered only as theoretical modes; it should not be construed as limiting the scope of any subject matter of the present application.

Among the suitable water-swellable polymers of the present invention are especially cellulosic polymers and derivatives thereof, including but not limited to methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, and microcrystalline cellulose, polysaccharides and derivatives thereof, polyalkylene oxides, polyethylene glycols, chitosan, alginates, carrageenans, galactomannans, tragacanth, agar-agar, acacia, guar gum, xanthan gum, pectins, carboxymethylcylodrostarches, chitosan, maleic anhydride copolymers, polyacrylates, polymethacrylates, methacrylate copolymers, polyvinyl alcohol, polyvinyl pyrrolidone vinyl acetate copolymers, polyvinyl pyrrolidone acetate copolymers, polyvinyl alcohol, cellulose acetate copolymers, cellulose acetate, polyvinyl alcohol, Poly (2-ethyl-2-Oxazoline), poly (ethylenediimine), polyurethane hydrogels, crosslinked polyacrylic acids and derivatives thereof, and mixtures of any of these.

Other examples are copolymers of the aforementioned polymers, including block copolymers and graft polymers. Specific examples of copolymers areAndit is a polyethylene oxide-polypropylene oxide block copolymer available from basf corporation, Chemicals div. Other examples are hydrolyzed starch polyacrylonitrile graft copolymers, known as "Super slurry" and available from Illinois Corn GrowersAssociation，Bloomington，Ill.，USA。

Of the foregoing water-swellable polymers, some can consider nonionic polymers, such as nonionic cellulose ethers. An example of such a polymer is hydroxypropyl methylcellulose (HPMC), also known as hypromellose (hypromellose), which may be used alone or in combination with other polymers.

It has surprisingly been found that hydroxypropyl methylcellulose forms a swellable matrix from which highly water soluble forms of neramexane, such as neramexane mesylate, are released over a prolonged period of time even without the addition of another release controlling excipient. This is in contrast to the general assumption that it is difficult to formulate a modified release matrix with a substantially water-soluble active agent based on only a single water-swellable polymer such as hydroxypropylmethylcellulose.

The different grades of hydroxypropyl methylcellulose of the present invention include HPMC 2208, HPMC2906, and HPMC 2910. These grades differ in the degree of substitution of both their methyl (or methoxy) and hydroxypropyl (or hydroxypropoxy) groups. In HPMC 2208, cellulose has an average of about 22% (range: 19 to 24%) of the original hydroxyl groups reacted to methoxy groups and an average of about 8% (range: 7 to 12%) reacted to hydroxypropoxy groups. HPMC2906 is about 29% methoxy and about 6% hydroxypropoxy, and HPMC 2910 is about 29% methoxy and about 10% hydroxypropoxy. A typical grade of hydroxypropyl methylcellulose is HPMC 2208, which is commercially available as Methocel K100M CR. This grade of Methocel is also characterized by a relatively high molecular weight, showing an apparent viscosity of about 100,000cP for a 2 wt.% aqueous solution at 20 ℃.

The relative amount of water-swellable polymer required to achieve the desired release profile depends inter alia on the type and grade of polymer selected, the presence or absence of other excipients having an effect on drug release and on the drug content of the matrix. In the case of hydroxypropylmethylcellulose, the ratio of polymer to active compound is generally selected in the range of from about 10: 1 to about 1: 10, and may be from about 5: 1 to about 1: 5. If a high viscosity HPMC such as Methocel K100M CR is selected as the primary release-controlling excipient, the typical ratio between HPMC and active compound is from about 4: 1 to about 1: 4 or from about 2: 1 to about 1: 2. For example, if the matrix is designed to hold a dose of neramexane mesylate of about 50 mg, the Methocel K100M CR content according to this embodiment is from about 5 mg to about 100 mg or from about 12.5 mg to about 200 mg.

It has also been found possible to combine the drug and the water-swellable polymer with another excipient selected from dry binders or tabletting aids (sometimes also referred to as tableting aids), fillers, diluents or extenders. These excipients increase the internal matrix binding force after compression. Which generally have a high degree of plastic deformation force. Its effect on drug dissolution or drug release may be rather moderate. Examples of suitable ingredients for such excipients are lactose anhydrous, lactose monohydrate, calcium phosphate, dicalcium phosphate, dibasic calcium phosphate, calcium sulfate, sucrose, glucose, mannitol, sorbitol, cellulose, microcrystalline cellulose and co-processed mixtures of lactose and microcrystalline cellulose (commercially available as e.g. Cellactose). A typical dry binder is microcrystalline cellulose, such as commercially available Avicel PH.

Various types of microcrystalline cellulose are suitable for use in carrying out the present invention. The grade difference of the commercial products is mainly the particle size and the water content, and should be selected according to the preparation method of the framework. For example, Avicel PH 102 and certain other Avicel grades have been found to be particularly useful for making matrix tablets by direct compression.

The amount of dry binder or tableting aid present in the dosage form of the invention is selected according to various formulation criteria, such as the type and grade of dry binder or tableting aid, the type, grade and amount of water-swellable polymer, the active compound drug loading, the presence or absence of other excipients having an effect on compressibility, and the like. Generally, this content is at least about 10% by weight and often at least about 15% by weight relative to the weight of the backbone. In another embodiment, the amount is between about 15% and about 60% by weight, such as between about 15% and about 50% by weight.

The ratio of the water-swellable polymer and dry binder or tableting aid in the matrix is generally in the range from about 6: 1 to 1: 6, such as from about 5: 1 to 1: 5, and in particular embodiments from about 3: 1 to about 1: 3, and from about 2: 1 to 1: 2, respectively. In another embodiment, the water-swellable polymer is hydroxypropyl methylcellulose, especially Methocel K100M CR and the dry binder or tableting aid is microcrystalline cellulose present in a ratio of about 2: 1 to about 1: 2 in the matrix, the total content of the two excipients in the matrix being about 50 wt% to about 85 wt%, such as between about 60 wt% to about 75 wt%.

As previously mentioned, one embodiment of the dosage form is designed as a compressed matrix, i.e., a compressed matrix tablet. There are various methods available and suitable for preparing such tablets, the general methods being compression of granules prepared by wet or dry granulation and direct compression of powder mixtures into compacts. Both methods are well known to those skilled in the art.

Wet granulation involves weighing the ingredients, including the active compound and most of the excipients, adding a liquid binder solution, mixing the ingredients, allowing them to aggregate, sieving in a moist state, drying, dry-sieving, lubricating and tableting the resulting blend. The advantages of the wet granulation method include improved cohesiveness and compressibility of the powder, good particle size distribution suitable for compression, reduced dust and air pollution, and prevention of component separation.

In dry granulation, the ingredients are weighed, mixed and compacted, such as by rolling and then broken up or sieved. The sieved granules are lubricated and compressed into tablets. Since no liquid binder solution is used for agglomeration, the powder mixture granulated in dry form must contain at least one dry binder, such as microcrystalline cellulose, polyvinylpyrrolidone, or a co-processed mixture of lactose and microcrystalline cellulose. One advantage of dry granulation is that it is applicable to the processing of sensitive materials, such as moisture-or heat-sensitive ingredients, because no water is added during processing and no heating is required to dry the granules.

Direct compression methods are those involving compacting a powder mixture into tablets without prior granulation. This method is potentially cost effective because it avoids the procedural steps involved in preparing the particles, and is also suitable for processing sensitive active compounds. Dry binders or tabletting aids are usually present in the formulation or it is desired to achieve effective tablet strength. However, direct compression methods are not always effective. For example, certain powder mixtures do not have sufficient product flow on a tablet press or do not produce adequate tablet physical characteristics, and in such cases, granulation is preferably used.

Powder mixtures of water-swellable polymers, dry binders or tabletting aids and water-soluble salts of neramexane and optionally other excipients have been found to be suitable for use in the direct compression process. Typically, the three components (i.e., water-swellable polymer, dry binder, and neramexane salt) comprise at least about 75% by weight of the powder mixture, and optionally no more than about 25% by weight of other excipients. In another embodiment, the water-swellable polymer (or mixture of water-swellable polymers), dry binder or tableting aid (or mixture of more than one such member), and active compound together comprise at least about 85 wt%, such as from about 85 wt% to about 99.9 wt%, or from about 90 wt% to about 99.5 wt% of the matrix formulation. In another embodiment, it constitutes from about 95% to about 99% by weight of the backbone.

According to another embodiment, the invention is a direct compression comprising a powder mixture comprising hydroxypropyl methylcellulose, such as Methocel K100M CR, microcrystalline cellulose, such as Avicel PH 102 and neramexane mesylate. Typically, each of these three components comprises from about 10% to about 50% by weight of the powder compacted to form the skeleton. In another embodiment, the ratio of neramexane mesylate to the other two components is from about 1: 1 to about 1: 5, more preferably from about 1: 1 to about 1: 3, such as about 1: 2.

The powder mixture may comprise one or more other excipients. Among other excipients, there are members of the lubricant class, such as magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, mineral oil, hydrogenated vegetable oil, and polyethylene glycol; and glidants such as colloidal silicon dioxide, starch, calcium or magnesium stearate and talc.

Lubricants are generally used in concentrations of about 0.1% to about 2% by weight relative to the weight of the skeleton. A representative lubricant is magnesium stearate, which also has certain slip properties. If magnesium stearate is selected, a range of about 0.2% to about 1.5%, particularly about 0.25% to about 1% by weight can be used.

Similarly, the amount of glidant is selected to be relatively low, such as less than about 5 wt%. Among the representative glidants are colloidal silicon dioxide and talc. If one or both of these glidants are incorporated, the amount of glidant in the matrix is generally in the range of about 0.25 wt% to about 2.5 wt%, or about 0.5 wt% to about 1.5 wt%.

Surprisingly, it was found that the matrix dosage form has excellent tablet properties. For example, the release profile of the active compound was found to be relatively independent of the compressive force, at least over a wide range of practically useful compressive forces. A mixture of Methocel K100M CR, Avicel PH 102, neramexane mesylate, magnesium stearate, and colloidal silicon can be compressed on a standard rotary tablet press using a primary compression force in the range of about 5kN to about 21 kN. The tensile strength of the formed tablets ranges substantially from about 30N to about 100N, with higher compression forces resulting in harder tablets. However, the dissolution profiles of these tablets were substantially the same, and even when the hardest tablet having the same composition was compared with the softest tablet, a significantly tough formulation was shown. In particular, it was found that in the hardness range of about 40N to about 80N, the dissolution profile is substantially independent of the hardness or tensile strength of the tablet. The tensile strength may vary from about 30N to about 500N, such as from about 40N to about 300N or from about 50N to about 200N. Furthermore, the tensile strength of the film coated tablet may be higher than 120N.

Another excellent feature of the tablet according to the invention is that although neramexane mesylate is an acid addition salt of neramexane, whose pH dependent dissolution behavior can be expected, the above defined matrix release active compound is relatively independent of the pH of the dissolution medium.

The terms "relatively unrelated" and "substantially unrelated", as used herein, are intended to mean that the in vitro release profiles of the two tablets or matrices at any point in time after the initial period of drug release (0 to 1 hour) differ by no more than about 10% of the incorporated dose.

According to another embodiment, the dosage form of the present invention is designed as a compressed matrix which is coated with a coating, such as a sugar or polymer coating, to mask the taste of the active compound, which generally has a poor taste.

The taste-masking coating used in the present invention is a coating that does not substantially affect the drug release profile of the modified release matrix. In other words, there is no substantial difference between the parts of the dose released at any time point from the uncoated matrix and the matrix formulated and processed identically but with a taste-masking coating, except perhaps at the initial stage of drug release. Substantial differences are still to be understood as differences of 10% or more of the dose of active compound incorporated into the matrix. It is believed that the greatest effect of taste masking coatings on the shape of the drug release profile occurs at the initial stages of drug release, such as at the first 15 or 30 minutes, regardless of the overall release profile of the modified release dosage form.

Typically, the coating of the matrix is a polymeric film coating. Film compositions suitable for taste masking are well known in the medical community and may be based on various types of polymers. In general, taste-masking coatings prevent the active compound from coming into direct contact with saliva during administration and dissolving or disintegrating rapidly after swallowing the dosage form.

Suitable polymers for the coating include, for example, cationic methacrylate copolymers, such as dimethylaminoethyl methacrylate methyl methacrylate copolymer (DMA-MMA), which are insoluble in aqueous media above pH 5, such as saliva, but soluble in acidic media, such as gastric juice. Other polymers that may be suitable include hydroxypropyl fibers

Cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, methacrylic acid copolymers other than DMA-MMA, polyvinyl alcohol-polyethylene glycol copolymers, ethyl acrylate-methyl methacrylate copolymers, polyvinyl alcohol, carrageenan and mixtures thereof.

The coating composition may comprise other excipients to improve the properties of the coating or its processability, such as one or more excipients selected from the following types: plasticizers, stabilizers, pigments, colorants, dispersants, surfactants, sugars, fillers, anti-sticking agents, water vapor permeation modifiers, and the like. Commercially available coating compositions are often premixes of one or more film-forming polymers and at least one other excipient. Commercially available coating compositions that may be used are sepifilms comprising water soluble grades, such as Sepifilm 002, Sepifilm 003, Sepifilm 752, Sepifilm LP grades, including Sepifilm LP 770; water soluble grades of Kollicoat, such as Kollicoat IR and Kollicoat Protect; there are also Opadry, Instacoat, LustreClear and similar products at almost all levels.

The taste-masking coating may have other functions. For example, the coating may improve the mechanical and even chemical stability of the matrix tablet, and may also improve the appearance of the tablet, its appeal to the patient, swallowability, and other features.

The coating may be applied to the matrix by any conventional technique and equipment, such as pan coating or fluid bed coating. Typically, an aqueous, liquid alcohol (hydroalcoholic) or organic liquid comprising a dispersed or dissolved film-forming polymer(s) and any optional other excipients is atomized and deposited onto an optionally de-dusted, pre-formed tablet core under a continuous stream of warm air to dry the coating composition on the tablet core.

According to the present invention, the modified release dosage form is for providing once daily administration of neramexane or a pharmaceutically acceptable salt thereof to a human or animal subject. Neramexane formulations of the present invention are useful for the treatment of CNS disorders including, but not limited to, alzheimer's disease, parkinson's disease, AIDS dementia, neuropathic pain, diabetic neuropathic pain, cerebral ischemia, epilepsy, glaucoma, hepatic encephalopathy, multiple sclerosis, stroke, depression, tardive dyskinesia, amyotrophic lateral sclerosis, irritable bowel syndrome, appetite disorders, binge eating disorders, autism, attention deficit syndrome, attention deficit hyperactivity disorder, bipolar disorder, tinnitus, mycoses, psoriasis, malaria, born virus and hepatitis C. Other lesions suitable for treatment with neramexane are disclosed in the art. Of particular importance is the ability to provide uninterrupted pain relief. Thus, the invention further provides a method of therapeutic or prophylactic treatment of a CNS disorder in a human or animal subject, which method comprises administering to the subject a dosage form of the invention.

A "therapeutically effective amount" is an amount of a compound that, when administered to a mammal to treat a state, disorder or condition, is sufficient to effect such treatment. A "therapeutically effective amount" is one which depends on the compound, the disease and its severity, and the age, weight, physical condition and response of the mammal to be treated. In one embodiment, according to the present invention, a therapeutically effective amount of neramexane is an amount sufficient to treat a CNS disorder, including alzheimer's disease or parkinson's disease. In another embodiment, a therapeutically effective amount is an amount that can treat neuropathic pain or other pain conditions (such as visceral hypersensitivity). Other uses include, but are not limited to, the treatment of dementia and depression. The effective amount of the drug for pharmacological action and thus the tablet strength depends on the disease itself.

The term "treating" as used herein is used herein to mean relieving or alleviating at least one symptom of a disease in a subject, including, for example, pain, Alzheimer's disease, vascular dementia, or Parkinson's disease. The term "treating" may refer to relieving or easing the intensity and/or duration of disease manifestations in a subject in response to a particular stimulus (e.g., stress, tissue damage, cold, etc.). For example, in relation to dementia, the term "treating" may mean relieving or resolving cognitive impairment (such as impaired memory and/or orientation) or impaired full function (activities of daily living, ADL) and/or slowing or reversing the progressive impairment of ADL or cognitive impairment. In the sense of the present invention, the term "treatment" also means to halt, delay the onset of a disease (i.e. the period before clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease. The term "protect" is used herein to mean preventing the delay or treatment or (where appropriate) the development or persistence or exacerbation of a disease in an individual. Dementia in the sense of the present invention is associated with CNS disorders including, without limitation, neurodegenerative diseases such as Alzheimer's Disease (AD), Down's syndrome and cerebrovascular dementia (VaD).

[ embodiment ] A method for producing a semiconductor device

The invention is further illustrated by the following examples, which, however, should not be construed as limiting the scope of the invention.

Examples

Example 1: preparation of neramexane modified release type skeleton tablet

Matrix tablets containing about 25 mg or 50 mg or 75 mg or 100 mg neramexane mesylate were prepared as follows. Appropriate amounts of neramexane mesylate, hydroxypropyl methylcellulose (HPMC, in this case Methocel K100M CR), microcrystalline cellulose (MCC, in this case Avicel PH 102), magnesium stearate and colloidal silicon dioxide (SiO)₂Aerosil200 in this example) was weighed and blended using a free fall blender (Bohle PTM 200). Or appropriate amounts of neramexane mesylate, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate, and colloidal silicon dioxide are sieved prior to blending using a free-fall blender. The appropriate amount for each batch was calculated based on the target content for each dosage element as shown in table 1. The optical characteristics of the powder blend do not show a lack of homogeneity, such as flake, agglomerate or segregation tendencies. All blendAll showed good powder flow properties and were free flowing. The bulk and tap densities of all blends did not differ significantly.

TABLE 1

The powders were separately compressed into biconvex matrix tablets using a conventional rotary tablet press applying a primary compression force of about 10 to 20 kN. For example, after manufacture, all batches of 50 mg of the formulation were found to have an average neramexane mesylate content of between 47.5 and 52.5 mg/tablet, such as between 50 and 52 mg/tablet, the content uniformity complying with the requirements of the european pharmacopoeia and the us pharmacopoeia.

Example 2: coating of neramexane modified release type skeleton tablet

Example 1 matrix tablets prepared were coated with white water soluble coating composition Sepifilm LP 770 white using a porous or non-porous standard pan coater under controlled atmosphere. The tablets were weighed and dusted prior to coating. The coating dispersion was then sprayed onto the tablets using a 1.0 mm nozzle. The temperature of the tablet core during coating is between 34 and 39 ℃. The inlet temperature was between 59 and 64 ℃ and the spray rate was about 40 to 53 g/min. Spraying was continued until the tablet weight gain was about 4%. The optical appearance of the coated tablets was excellent. Apparently no blocking, smooth surface, bright and extremely uniform without any cracks or damages.

Example 3: drug delivery from modified release matrix tablets

Tablets were prepared according to example 1 with a drug release profile determined using a blue dissolution apparatus according to USP XXVII, with an agitation rate of 100rpm and phosphate buffer pH 6.8 as dissolution medium. At specific time intervals, samples of the dissolution medium were removed and analyzed for neramexane content and the results for formulations a-D are shown in table 2.

TABLE 2

The results demonstrate how the drug release profile of the dosage forms of the present invention can be easily fine-tuned by varying the relative amounts of water-swellable polymers in matrix tablets.

Example 4: preparation of neramexane matrix tablets with different tensile strengths

Neramexane modified release matrix tablets were prepared according to example 1, having the same quality and quantitative composition as formulation B (table 1), except that the main compression force was varied: one batch of tablets (B-soft type) was compressed using a low compression force of about 5kN and the second batch (B-hard type) was compressed using a high compression force of about 21 kN. The hardness or tensile strength of the tablets formed is greatly changed: the B-soft type batch of tablets had a hardness in the range of 33 to 38N, whereas the batch B-hard type had a hardness of 85 to 96N.

Example 5: drug delivery from neramexane tablets with different tensile strengths

The tablets prepared in example 4 were tested for drug release properties as described in example 3. The results demonstrate a significantly tough formulation and are listed in table 3.

TABLE 3

Example 6: pH-independent drug release from neramexane matrix tablets

Neramexane modified release matrix tablet according to formulation B was prepared as described in example 1. The film was then coated as described in example 2. The drug release profile of the film coated tablets was studied in a blue set-up and an agitation rate of 100rpm at pH 1.2, pH 4.5 and pH 7.4.

The shape of the release profiles was very similar and there was only a very small difference between the observed profiles, showing a very robust formulation and a very low pH dependence at a wide range of pH values. In fact, at any point in time, the maximum difference observed between the proportion of doses released at the two pH conditions was only 6%. The results are shown in Table 4.

TABLE 4

Example 7: calculation of plasma Curve achievable with Neramexane matrix tablets

The time plasma concentration of neramexane was determined after a single dose of 25 mg of neramexane mesylate in immediate release formulation was administered to several volunteers. From the plasma concentration profile, the mean absorption and excretion rates were calculated. Using these data, the expected steady state neramexane plasma concentration profile for the following treatment regimen was calculated: (a) administering twice daily 25 mg of neramexane mesylate in the form of an immediate release formulation, (B) administering once daily 50 mg of neramexane mesylate in the form of an immediate release formulation and (c) administering once daily 50 mg of neramexane mesylate in the form of formulation B of example 1. From the simulated plasma curves, the respective fluctuation indexes were calculated.

Treatment regimen (a) was found to have a fluctuation index of about 0.22, regimen (b) a fluctuation index of about 0.47, and regimen (c) a fluctuation index of about 0.33. These results reflect that regimens (a) and (c) are considered acceptable in terms of risk of side effects and risk of underdosing trough concentrations, but regimen (b) is not. Although the fluctuation in plasma concentration is small for regimen (a), twice daily administration is required, and is therefore considered inconvenient compared to once daily regimen (c), at least for continuous treatment.

The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to be encompassed by the appended claims.

It should be further understood that all numerical values are abbreviated and are provided for purposes of illustration.

Patents, patent applications, publications, product descriptions and conventions are set forth throughout this disclosure, the disclosures of which are incorporated herein by reference in their entirety.

Claims (24)

1. An oral modified release dosage form comprising: a therapeutically effective amount of an active compound selected from neramexane and water-soluble and pharmaceutically acceptable salts thereof, wherein the active compound is dispersed within a solid matrix comprising a release-controlling excipient selected from the group consisting of polyvinylpyrrolidone vinyl acetate copolymer, polyvinyl acetate, and hydroxypropyl methylcellulose, wherein the hydroxypropyl methylcellulose is present in a mixture with microcrystalline cellulose; wherein the dosage form exhibits a dissolution time of at least 1 hour for a 50% by weight dose fraction of the active compound incorporated therein.

2. The dosage form as claimed in claim 1, wherein the dosage form exhibits a dissolution time in the range from 1 hour to 3 hours for an amount of active compound of 50% by weight of the dose fraction.

3. An oral modified release dosage form comprising: a therapeutically effective amount of an active compound selected from neramexane and water-soluble and pharmaceutically acceptable salts thereof, wherein the active compound is dispersed within a solid matrix comprising a release-controlling excipient selected from the group consisting of polyvinylpyrrolidone vinyl acetate copolymer, polyvinyl acetate, and hydroxypropyl methylcellulose, wherein the hydroxypropyl methylcellulose is present in a mixture with microcrystalline cellulose; wherein the dosage form shows a dissolution time of 4 hours for a dose fraction of active compound in an amount of between 65 and 95 wt.%.

4. An oral modified release dosage form comprising: a therapeutically effective amount of an active compound selected from neramexane and water-soluble and pharmaceutically acceptable salts thereof, wherein the active compound is dispersed within a solid matrix comprising a release-controlling excipient selected from the group consisting of polyvinylpyrrolidone vinyl acetate copolymer, polyvinyl acetate, and hydroxypropyl methylcellulose, wherein the hydroxypropyl methylcellulose is present in a mixture with microcrystalline cellulose; wherein the dosage form shows a dissolution time of 4 hours for a dose fraction of active compound in an amount of between 70 and 85 wt.%.

5. The dosage form as claimed in any of claims 1 to 4, wherein the active compound is neramexane mesylate.

6. The dosage form as claimed in any one of claims 1 to 4, further comprising one or more additional excipients.

7. The dosage form as claimed in any one of claims 1 to 4, wherein the content of the release-controlling excipient in the solid matrix is between 10% and 80% by weight.

8. The dosage form of claim 6, wherein the additional excipient is selected from the group consisting of dry binders, lubricants, and glidants.

9. The dosage form of claim 8, wherein the dry binder is selected from the group consisting of lactose, lactose monohydrate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, sucrose, glucose, mannitol, sorbitol, cellulose, and polyvinylpyrrolidone.

10. The dosage form of claim 8, wherein the dry binder is selected from microcrystalline cellulose.

11. The dosage form of claim 8, wherein the lubricant is selected from the group consisting of magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, mineral oil, hydrogenated vegetable oil, and polyethylene glycol.

12. The dosage form as claimed in claim 8, wherein the glidant is selected from the group consisting of colloidal silicon dioxide, starch, calcium or magnesium stearate, and talc.

13. The dosage form according to any one of claims 1 to 4, wherein the solid matrix is in the form of a compressed tablet.

14. The dosage form of claim 13, wherein the compressed tablet is a direct compression tablet.

15. The dosage form of claim 13, wherein the compressed tablet is coated with a taste-masking coating.

16. The dosage form of claim 15, wherein the coating is a polymeric coating.

17. The dosage form as claimed in any one of claims 1 to 4, wherein the release-controlling excipient is selected to achieve an in vitro active compound dissolution profile which is substantially independent of the pH of the dissolution medium.

18. The dosage form as claimed in any one of claims 1 to 4, wherein the release-controlling excipient is a polyvinylpyrrolidone vinyl acetate copolymer.

19. The dosage form as claimed in any one of claims 1 to 4, wherein the release-controlling excipient is polyvinyl acetate.

20. The dosage form as claimed in any one of claims 1 to 4, wherein the release-controlling excipient is hydroxypropylmethylcellulose present in admixture with microcrystalline cellulose.

21. The dosage form as claimed in any of claims 1 to 4, wherein the weight ratio of the active compound to the release-controlling excipient is in the range from 10: 1 to 1: 10.

22. The dosage form as claimed in claim 21, wherein the weight ratio of the active compound to the release-controlling excipient is in the range from 2: 1 to 1: 2.

23. The dosage form as claimed in any one of claims 1 to 4, wherein the active compound is dispersed in a matrix in the form of a compressed tablet and wherein the release controlling excipient is selected to achieve an in vitro active compound dissolution profile which is substantially independent of the hardness of the compressed tablet, wherein the hardness is in the range of 40N to 80N.

24. An oral modified release dosage form comprising: a therapeutically effective amount of an active compound selected from neramexane and pharmaceutically acceptable salts thereof; and at least one release-controlling excipient selected from the group consisting of polyvinylpyrrolidone vinyl acetate copolymer, polyvinyl acetate, and hydroxypropyl methylcellulose, wherein the hydroxypropyl methylcellulose is present in a mixture with microcrystalline cellulose, wherein the release-controlling excipient is selected to achieve a fluctuation index of neramexane plasma concentration of 0.4 or less at steady state upon once-daily administration.