HK1129584A - Immediate release formulations of memantine oral dosage forms - Google Patents

Description

Memantine oral dosage form immediate release formulation

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35u.s.c. § 119 clause to us provisional application serial No. 60/581,244 filed on 6/17 2004 and us provisional application serial No. 60/636,899 filed on 12/16 2004, both of which are incorporated herein by reference in their entirety.

Technical Field

The present invention relates to a pharmaceutical solid oral dosage form of a 1-aminocyclohexane compound composition, which exhibits immediate release properties, has superior stability properties and rapidly disintegrates in aqueous solution. The invention is particularly suited for solid pharmaceutical dosage forms of the 1-aminocyclohexane compound, wherein a therapeutically effective amount of the active ingredient is available in the environment of use shortly after administration. These compositions may be provided as dispersible tablets for administration as aqueous oral solutions. In one embodiment, the active ingredient is preferably 1-aminocyclohexane, memantine. In another preferred embodiment, the 1-aminocyclohexane is neramexane.

Background

1-aminocyclohexanes, such as memantine (1-amino-3, 5-dimethyladamantane) and neramexane (1-amino-1, 3, 3,5, 5-pentamethylcyclohexane) are moderate-avidity, uncompetitive NMDA receptor antagonists with strong voltage-dependent and rapid blocking/unblocking kinetics. Accordingly, there is a continuing need in the art for solid oral formulations of 1-aminocyclohexane compounds, and more preferably memantine hydrochloride (1-amino-3, 5-dimethyladamantane hydrochloride) and neramexane mesylate (1-amino-1, 3, 3,5, 5-pentamethylcyclohexane mesylate).

Solid Oral pharmaceutical compositions or formulations have a variety of Release properties, for example Immediate Release properties given In FDA guidelines ("Disolution Testing of Immediate Release Solid Oral delivery Forms", published 1997 8 months, part IV-A) or sustained Release properties given In FDA guidelines ("Extended Release Oral delivery Forms: Development, Evaluation, and Application of In Vitro/In Vivo diagnostics", Food and Drug Administration, CDER, 1997 9 months, page 17). Dissolution test guidelines for immediate release performance, a material that dissolves at least 80% into solution in the first 30 to 60 minutes is considered to have immediate release performance. Thus, immediate release solid dosage forms allow for the release of most or all of the active ingredient within a short period of time, e.g., 60 minutes or less, such that the drug may be rapidly absorbed. In contrast, sustained release solid oral dosage forms allow the release of the active ingredient over an extended period of time to maintain therapeutically effective plasma levels, to modify drug compliance and/or to modify other pharmacokinetics of the active ingredient over the same extended time interval.

U.S. patent No. 5,382,601 provides a solid pharmaceutical dosage form comprising memantine that exhibits extended biphasic release properties, wherein a portion of the drug is released immediately followed by sustained release of the remaining drug. The matrix of the preparation comprises both water-soluble and water-insoluble salts of casein, preferably sodium and calcium caseinate. However, casein has an unpleasant taste; as disclosed in U.S. patent No. 6,413,556, it is accompanied by the undesirable effects of certain exacerbated side effects; and is unstable in changing pH. Another concern with casein is the potential for Bovine Spongiform Encephalopathy (BSE) contamination or the spread of another source of infection, since casein is an animal-derived product.

A general method for preparing sustained release (modifiedrease) N-methyl-D-aspartate (NMDA) receptor antagonists is described in U.S. patent No. 6,194,000. The method comprises preparing an immediate release component and a sustained release component to obtain the final formulation. This patent discloses a formulation consisting of encapsulated beads which are previously coated with an organic solvent based system. However, this patent does not specifically disclose compositions comprising memantine or neramexane. Nor does the patent teach how the release rate affects T_max(time to maximum plasma concentration) or the method will result in a dose-proportional formulation.

Currently, a twice daily dosing regimen of memantine is achieved using an immediate release tablet that is not proportional to the dose. After oral administration in men, memantine is completely absorbed (absolute bioavailability is about 100%). The maximum plasma concentration (T) is reached after oral administration of 10-40mg of memantine_max) Is 3-7 hours, peak plasma concentration (C) after a single 20mg oral administration_max) Is 22-46 ng/mL. AUC and C of memantine_maxThe values are raised in proportion to the dose in the 5-40mg dose range. The elimination half-life (T) of memantine is about 60-80 hours.

There is a need for a dose-proportional memantine formulation that is easily obtainable with an immediate release formulation. The advantages of immediate release, dose-proportional formulations include improved ease of administration by increasing the dose without increasing the number of tablets that need to be administered, and improved compliance by allowing multiple doses of the target drug to be administered at lower concentrations or a single dose at higher concentrations. Another advantage of dose-proportional formulations of highly soluble and permeable drugs (particularly memantine and neramexane) is that the bioavailability is considered to be completely consistent for multiple dose concentrations (e.g., 10mg versus 80mg) and is consistent with the guidelines of the U.S. department of Health and Human service, Food and Drug Administration for Health and Human Services (Food and Drug Administration) "driver of In vivo bioavailability and bioavailability standards for imaging-Release Solid Food industry standards Administration and Biopharmacy Classification System". It is often desirable to increase the administration of a drug dose as part of an up-titration dosing regimen to achieve the desired therapeutic dose, as such dosing regimens may result in improved tolerability. Indeed, current guidelines for the treatment of alzheimer's disease using memantine suggest that the initial dose of memantine administration is 5 mg/day and is increased to a 20 mg/day dose by increasing the 5mg dose weekly. Dose-proportional formulations are important for the treatment of diseases requiring up-regulation to higher doses, such as neuropathic pain. Thus, the presence of different concentrations of immediate release formulations of memantine in the range of 2.5mg to 80mg in proportion to the dose will allow for easy and convenient administration during the up-regulation phase and during maintenance at higher therapeutic dosage levels.

Summary of The Invention

In accordance with the present invention, it has been found that 1-aminocyclohexanes, such as memantine (1-amino-3, 5-dimethyladamantane) and neramexane (1-amino-1, 3, 3,5, 5-pentamethylcyclohexane) and salts thereof, including hydrochloride, hydrobromide, mesylate and other pharmaceutically acceptable salts, can be formulated into immediate release dosage forms having dose-proportional bioavailability and superior stability properties, which preferably disintegrate rapidly.

The formulations of the invention comprise 1-aminocyclohexanes such as memantine (1-amino-3, 5-dimethyladamantane) and neramexane (1-amino-1, 3, 3,5, 5-pentamethylcyclohexane), optionally a pharmaceutically acceptable coating material, and one or more excipients which can be administered in a single oral dosage form, preferably once daily. Alternatively, the dosage form may be administered twice daily with a time interval between each administration of about 4 to about 8 hours. Preferably, the dosage form is a tablet, or an aqueous solution of a dispersible tablet.

The present invention specifically provides a dosage form that immediately releases an active agent, such as memantine or neramexane, at a rate of about 80% or greater within the first 60 minutes, after which the dosage form is passed into a use environment. Preferably, the dosage form is released to this extent within the first 30 minutes, more preferably within the first 15 minutes.

In the present invention, T for a dosage form comprising memantine is achieved within a time interval ranging from about 3 hours to about 7 hours after the dosage form enters a use environment_max. Preferably, the time intervals average from about 4 hours to about 6 hours. T for neramexane-containing dosage forms is achieved within a time interval ranging from about 2 hours to about 8 hours after the dosage forms enter a use environment_max. Preferably, the time intervals average from about 3 to about 8 hours.

In embodiments wherein the active ingredient is memantine hydrochloride, the active ingredient of the invention is generally present in an amount of about 2% w/w to about 20% w/w. Preferably, the amount is from about 3.2% w/w to about 10% w/w, more preferably from about 3.9% w/w to about 8.4% w/w, based on the weight of the entire dosage form.

In the embodiment wherein the active ingredient is neramexane mesylate, the active ingredient of the invention is typically present in an amount of about 2% w/w to about 50% w/w. Preferably, the amount is from about 2% w/w to about 40% w/w, more preferably from about 3% w/w to about 25% w/w.

In the present invention, preferred optional pharmaceutically acceptable coating materials include hydroxypropylmethylcellulose, e.g., hydroxypropyl methylcellulose(Colorcon, West Point, PA) or(Seppic, NJ) present in an amount of about 2% w/w to about 7% w/w, preferably about 2% w/w to about 5% w/w.

In suitable embodiments, the formulation comprises fillers such as starches and starch derivatives, hydrated sugar alcohols, calcium phosphates and cellulose-based excipients and derivatives thereof.

The oral dosage form of the present invention may further comprise one or more pharmaceutically acceptable carriers, excipients, anti-adherents, stabilizers, binders, colorants, disintegrants, glidants, and lubricants.

In another embodiment of the invention the dosage form comprises excipients with improved stability, which dosage form forms less than 3.0% w/w, preferably less than 2.5% w/w lactose adduct upon storage at room temperature for 36 months. The present invention has discovered the formation of lactose adducts, which is not a predictable adduct-forming reaction. One skilled in the art will recognize that adducts such as lactose adducts are formed by Maillard reactions between the 1-aminocyclohexane analogue active ingredient and the lactose excipient.

In one embodiment, the dosage form comprises filler microcrystalline cellulose which is present in an amount of about 10% w/w to about 35% w/w, wherein the composition further comprises lactose monohydrate, preferably about 18% w/w to about 22% w/w. Such dosage forms have less than 3% adduct formation within 36 months. In an alternative embodiment, the microcrystalline cellulose filler is present in an amount of about 20% w/w to about 95% w/w, preferably about 60% w/w to about 90% w/w, when lactose (or any other reducing agent) is not present. Such dosage forms have less than 0.5% adduct formation within 36 months.

In another embodiment of the invention, the dosage form comprises the lubricant magnesium stearate, which is present in an amount of about 0% to about 2% w/w, preferably about 0.2% to about 0.5% w/w.

In another embodiment, the dosage form comprises excipients that support the disintegration of the formulation. The excipient may be a starch-based excipient or derivative thereof, a cellulose-based excipient or derivative thereof, or a pyrrolidone-based excipient or derivative thereof, present in an amount of about 0.2-10% w/w.

In a preferred embodiment, the composition is in the form of a tablet. The tablet form has a hardness of about 3 to about 40 Kp. Preferably, the hardness is from about 4 to about 30 Kp. One skilled in the art will recognize that the hardness of a tablet is related to the shape and size of the tablet.

Brief description of the drawings

Fig. 1 is a plot of mean plasma concentration (ng/mL) of memantine versus dosing time (hours) after 4 hour intervals of administration of 2 tablets of instant 10mg memantine hydrochloride (closed circle) of the present invention in healthy young male and female subjects. The results for two sustained release (modified release) tablets (open circle and inverted triangle) are also shown in the plot.

Fig. 2 is a plot of mean plasma concentration (ng/mL) of memantine relative to time of administration (hours) after 4 hour intervals of administration of 2 tablets of instant 10mg memantine hydrochloride (treatment a, 30min release) (filled circles), or sustained release tablets (treatments B and C, 6 hour and 12 hour release) (open circles and inverted triangles) of the present invention in healthy young male and female subjects.

Fig. 3 is a plot of mean plasma concentration (ng/mL) of memantine relative to the first 24 hours post-dose, following 4 hour interval administration of 2 tablets of instant memantine hydrochloride 10mg tablets of the invention (treatment a) (filled circles), or sustained release tablets prepared from a HPMC-containing matrix formulation (treatments B and C) (open circles and inverted triangles) in healthy young male and female subjects.

Figure 4 depicts the dissolution of 5mg memantine hydrochloride tablets. Dissolution is expressed as a percentage of dissolution over time (hours).

Figure 5 depicts the dissolution of a 10mg memantine hydrochloride tablet. Dissolution is expressed as a percentage of dissolution over time (hours).

Figure 6 depicts the dissolution of 15mg memantine hydrochloride tablets. Dissolution is expressed as a percentage of dissolution over time (hours).

Figure 7a depicts the dissolution rate of batch a of 20mg memantine hydrochloride tablets. Dissolution is expressed as a percentage of dissolution over time (hours).

Figure 7B depicts the dissolution of 20mg memantine hydrochloride tablets from batch B. Dissolution is expressed as a percentage of dissolution over time (hours).

Figure 8 depicts the dissolution of 80mg memantine hydrochloride tablets. Dissolution is expressed as a percentage of dissolution over time (hours).

FIG. 9 plots in use(mixture of microcrystalline cellulose and colloidal silicon dioxide) at a concentration of 5mg, and in use(microcrystalline cellulose) dissolution of memantine containing microcrystalline cellulose (i.e. without lactose) at a concentration of 20mg versus the time of administration (hours).

Detailed description of the invention

According to the present invention there is provided an immediate release pharmaceutical composition for the administration of 1-aminocyclohexane, preferably memantine or neramexane, and pharmaceutically acceptable salts thereof, to human or animal patients, wherein the composition comprises an oral solid dosage form, preferably in the form of a tablet.

In the present invention, the pharmaceutical composition comprises a therapeutically effective amount of 1-aminocyclohexane, preferably memantine (free base) or neramexane (free base), or a pharmaceutically acceptable salt thereof, preferably the hydrochloride salt, and optionally a pharmaceutically acceptable coating, and optionally one or more carriers, fillers, anti-adherents, excipients, stabilizers, binders, colorants, disintegrants, glidants and lubricants, all pharmaceutically acceptable.

Memantine (1-amino-3, 5-dimethyladamantane) and neramexane (1-amino-1, 3, 3,5, 5-pentamethylcyclohexane) can be considered analogs of 1-amino-cyclohexane (as disclosed, for example, in U.S. patent nos. 4,122,193, 4,273,774, 5,061,703), and are uncompetitive NMDA receptor antagonists with systemic activity, with low to moderate affinity for the receptor, and with strong voltage-dependent and rapid blocking/unblocking kinetics. These pharmacological properties enable memantine and neramexane to block sustained activation of receptors under pathological conditions and to rapidly leave NMDA channels during normal physiological activation of the channels. Memantine and salts thereof (e.g., hydrochloride salt, MW215.77) are useful for the treatment of CNS disorders such as Alzheimer's disease. Memantine has been approved in the united states for the treatment of alzheimer's disease, and is currently approved outside the united states as an oral dosage form for the treatment of alzheimer's disease and parkinson's disease, and has been commercially available since 1982. Are currently under investigation for the treatment of neuropathic pain.

The 1-aminocyclohexane compounds of the invention having NMDA-antagonistic activity can be represented by the general formula (I):

wherein:

R^*is (A)_n-(CR¹R²)_m-NR³R⁴，

n and m are integers, and n + m is 0, 1 or 2,

a is selected from linear or branched lower alkyl (C)₁-C₆) Straight-chain or branched lower alkenyl (C)₂-C₆) And straight-chain or branched lower alkynyl (C)₂-C₆)；

R¹And R²Independently selected from hydrogen, straight or branched chainLower alkyl (C)₁-C₆) Straight-chain or branched lower alkenyl (C)₂-C₆) Straight-chain or branched lower alkynyl (C)₂-C₆) Aryl, substituted aryl and aralkyl groups;

R³and R⁴Independently selected from hydrogen, linear or branched lower alkyl (C)₁-C₆) Straight-chain or branched lower alkenyl (C)₂-C₆) And straight-chain or branched lower alkynyl (C)₂-C₆) Or together form alkylene (C)₂-C₁₀) Or alkenylene (C)₂-C₁₀) Or together with N to form a 3-7-membered azacycloalkane or azacycloalkene, including substituted (alkyl (C)₁-C₆) Alkenyl (C)₂-C₆) 3-7-membered azacycloalkane or azacycloalkene; or R³Or R⁴Independently of R^p、R^q、R^rOr R^sAre linked to form an alkylene chain-CH (R)⁶)-(CH₂)_t-, where t ═ 0 or 1, and the left side of the alkylene chain is attached to U or Y, and the right side of the alkylene chain is attached to N, and R is⁶Selected from hydrogen, linear or branched lower alkyl (C)₁-C₆) Straight-chain or branched lower alkenyl (C)₂-C₆) Straight-chain or branched lower alkynyl (C)₂-C₆) Aryl, substituted aryl and aralkyl groups; or R³Or R⁴Independently of R⁵Are linked to form-CH₂-CH₂-CH₂-(CH₂)_tAn alkylene chain of the formula-CH ═ CH-CH₂-(CH₂)_t-、-CH＝C＝CH-(CH₂)_t-or-CH₂-CH＝CH-(CH₂)_t-an alkenylene chain represented by wherein t ═ 0 or 1, and the left side of the alkylene or alkenylene chain is attached to W and the right side of the alkylene ring is attached to N;

R⁵independently selected from hydrogen, linear or branched lower alkyl (C)₁-C₆) Straight-chain or branched lower alkenyl (C)₂-C₆) And straight-chain or branched lower alkynyl (C)₂-C₆) Or R is⁵The carbon to which it is attached and the next adjacent ring carbon combine to form a double bond;

R^p、R^q、R^rand R^sIndependently selected from hydrogen, linear or branched lower alkyl (C)₁-C₆) Straight-chain or branched lower alkenyl (C)₂-C₆) Straight-chain or branched lower alkynyl (C)₂-C₆) Cycloalkyl (C)₃-C₆) And aryl, substituted aryl and aralkyl, or R^p、R^q、R^rAnd R^sMay independently form a double bond with U or with Y or with the atom to which they are attached, or R^p、R^q、R^rAnd R^sMay be combined to represent lower alkylene- (CH)₂)_x-or a lower alkylene bridge, wherein x is 2 to 5, inclusive, which alkylene bridge may in turn be connected to R⁵Combine to form another lower alkylene- (CH)₂)_y-or a lower alkenylene bridge, wherein y is 1-3, inclusive; and

the ring defined by U-V-W-X-Y-Z represents an optionally unsaturated cyclohexane ring, wherein U, W and Y represent a carbon atom, and V, X and Z each independently represent a carbon atom, CH or CH₂(or the definition of U, W, Y is interchangeable with the definitions of V, X and Z and includes the corresponding R groups R, R⁵、R^p、R^q、R^rAnd R^sArray position) of the ring atoms, and includes optical isomers, diastereomers, polymorphs, enantiomers, hydrates, pharmaceutically acceptable salts and mixtures of the compounds of formula (I).

The ring defined by U-V-W-X-Y-Z is preferably selected from the group consisting of cyclohexane, cyclohex-2-ene, cyclohex-3-ene, cyclohex-1, 4-diene, cyclohex-1, 5-diene, cyclohex-2, 4-diene and cyclohex-2, 5-diene.

The compound of formula I may be an adamantyl species.

Non-limiting examples of the 1-aminocyclohexane compound used in the present invention include 1-aminoalkylcyclohexane derivatives selected from the group consisting of:

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

1-amino-1 (trans), 3 (trans), 5-trimethylcyclohexane,

1-amino-1 (cis), 3 (cis), 5-trimethylcyclohexane,

1-amino-1, 3, 3, 5-tetramethylcyclohexane,

1-amino-1, 3, 3,5, 5-pentamethylcyclohexane (neramexane),

1-amino-1, 3,5, 5-tetramethyl-3-ethylcyclohexane,

1-amino-1, 5, 5-trimethyl-3, 3-diethylcyclohexane,

1-amino-1, 5, 5-trimethyl-cis-3-ethylcyclohexane,

1-amino- (1S, 5S) cis-3-ethyl-1, 5, 5-trimethylcyclohexane,

1-amino-1, 5, 5-trimethyl-trans-3-ethylcyclohexane,

1-amino- (1R, 5S) trans-3-ethyl-1, 5, 5-trimethylcyclohexane,

1-amino-1-ethyl-3, 3,5, 5-tetramethylcyclohexane,

1-amino-1-propyl-3, 3,5, 5-tetramethylcyclohexane,

n-methyl-1-amino-1, 3, 3,5, 5-pentamethylcyclohexane,

n-ethyl-1-amino-1, 3, 3,5, 5-pentamethyl-cyclohexane,

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

3, 3,5, 5-tetramethylcyclohexylmethylamine,

1-amino-1-propyl-3, 3,5, 5-tetramethylcyclohexane,

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

3-propyl-1, 3,5, 5-tetramethylcyclohexylamine hemihydrate,

1-amino-1, 3,5, 5-tetramethyl-3-ethylcyclohexane,

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

1-amino-1, 3-dimethyl-3-propylcyclohexane,

1-amino-1, 3 (trans), 5 (trans) -trimethyl-3 (cis) -propylcyclohexane,

1-amino-1, 3-dimethyl-3-ethylcyclohexane,

1-amino-1, 3, 3-trimethylcyclohexane,

cis-3-ethyl-1 (trans) -3 (trans) -5-trimethylcycloheximide,

1-amino-1, 3 (trans) -dimethylcyclohexane,

1, 3, 3-trimethyl-5, 5-dipropylcyclohexylamine,

1-amino-1-methyl-3 (trans) -propylcyclohexane,

1-methyl-3 (cis) -propylcyclohexylamine,

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

1-amino-1, 3, 3-trimethyl-5 (cis) -ethylcyclohexane,

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

cis-3-propyl-1, 5, 5-trimethylcyclohexylamine,

trans-3-propyl-1, 5, 5-trimethylcyclohexylamine,

n-ethyl-1, 3, 3,5, 5-pentamethylcyclohexylamine,

n-methyl-1-amino-1, 3, 3,5, 5-pentamethylcyclohexane,

1-amino-1-methylcyclohexane,

n, N-dimethyl-1-amino-1, 3, 3,5, 5-pentamethylcyclohexane,

2- (3, 3,5, 5-tetramethylcyclohexyl) ethylamine,

2-methyl-1- (3, 3,5, 5-tetramethylcyclohexyl) propyl-2-amine,

2- (1, 3, 3,5, 5-pentamethylcyclohexyl-1) -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, SS) trans-5-ethyl-1, 3, 3-trimethylcyclohexane,

1-amino- (1S, SS) cis-5-ethyl-1, 3, 3-trimethylcyclohexane,

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

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

1-amino-1-methyl-3 (cis) -ethyl-cyclohexane,

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

1-amino-5, 5-diethyl-1, 3, 3-trimethyl-cyclohexane,

1-amino-1, 3, 3,5, 5-pentamethylcyclohexane,

1-amino-1, 5, 5-trimethyl-3, 3-diethylcyclohexane,

1-amino-1-ethyl-3, 3,5, 5-tetramethylcyclohexane,

n-ethyl-1-amino-1, 3, 3,5, 5-pentamethylcyclohexane,

n- (1, 3, 5-trimethylcyclohexyl) pyrrolidine or piperidine,

n- [1, 3 (trans), 5 (trans) -trimethylcyclohexyl ] pyrrolidine or piperidine,

n- [1, 3 (cis), 5 (cis) -trimethylcyclohexyl ] pyrrolidine or piperidine,

n- (1, 3, 3, 5-tetramethylcyclohexyl) pyrrolidine or piperidine,

n- (1, 3, 3,5, 5-pentamethylcyclohexyl) pyrrolidine or piperidine,

n- (1, 3,5, 5-tetramethyl-3-ethylcyclohexyl) pyrrolidine or piperidine,

n- (1, 5, 5-trimethyl-3, 3-diethylcyclohexyl) pyrrolidine or piperidine,

n- (1, 3, 3-trimethyl-cis-5-ethylcyclohexyl) pyrrolidine or piperidine,

n- [ (1S, SS) cis-5-ethyl-1, 3, 3-trimethylcyclohexyl ] pyrrolidine or piperidine,

n- (1, 3, 3-trimethyl-trans-5-ethylcyclohexyl) pyrrolidine or piperidine,

n- [ (1R, SS) 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,

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

Neramexane (1-amino-1, 3, 3,5, 5-pentamethylcyclohexane) is disclosed, for example, in U.S. patent No. 6,034,134, which is incorporated herein by reference in its entirety.

Certain 1-aminocyclohexane derivatives of formula (I) include three axial alkyl substitution events, e.g. R^p，R^rAnd R⁵Together form a bridgehead to produce compounds represented by the following formulae IIb and IId (so-called 1-aminoadamantanes):

certain 1-aminocyclohexane derivatives of formula (I), wherein n + m ═ 0, U, V, W, X, Y and Z form a cyclohexane ring, and R is³And R⁴Through one or both of R^p、R^q、R^r、R^sOr R⁵The alkylene bridges formed are independently attached to the cyclohexane ring and are represented by the following formulae IIIa to IIIc:

wherein R is^p、R^q、R^r、R^sAnd R⁵As defined above for formula (I), R⁶Is hydrogen, straight or branched lower alkyl (C)₁-C₆) Straight-chain or branched lower alkenyl (C)₂-C₆) Straight-chain or branched lower alkynyl (C)₂-C₆) Aryl, substituted aryl or aralkyl, Y being saturated or being able to react with R⁶The bond together with the ring carbon to which it is attached forms a carbon-hydrogen bond, 1 ═ 0 or 1, and k ═ 0, 1, or 2, and represents a single or double bond.

Non-limiting examples of the 1-aminocyclohexane compound used in the present invention include 1-aminoadamantane and derivatives thereof selected from the group consisting of:

1-amino-3-phenyladamantane,

1-amino-methyl adamantane, a salt thereof,

1-amino-3, 5-dimethyladamantane (memantine),

1-amino-3-ethyl adamantane,

1-amino-3-isopropyladamantane,

1-amino-3-n-butyladamantane,

1-amino-3, 5-diethyladamantane,

1-amino-3, 5-diisopropyladamantane,

1-amino-3, 5-di-n-butyladamantane,

1-amino-3-methyl-5-ethyl adamantane,

1-N-methylamino-3, 5-dimethyladamantane,

1-N-ethylamino-3, 5-dimethyladamantane,

1-N-isopropyl-amino-3, 5-dimethyladamantane,

1-N, N-dimethyl-amino-3, 5-dimethyladamantane,

1-N-methyl-N-isopropyl-amino-3-methyl-5-ethyl adamantane,

1-amino-3-butyl-5-phenyladamantane,

1-amino-3-pentyladamantane,

1-amino-3, 5-diamyl adamantane,

1-amino-3-pentyl-5-hexyladamantane,

1-amino-3-pentyl-5-cyclohexyladamantane,

1-amino-3-pentyl-5-phenyladamantane,

1-amino-3-hexyladamantane,

1-amino-3, 5-dihexyladamantane,

1-amino-3-hexyl-5-cyclohexyladamantane,

1-amino-3-hexyl-5-phenyladamantane,

1-amino-3-cyclohexyladamantane,

1-amino-3, 5-dicyclohexyladamantane,

1-amino-3-cyclohexyl-5-phenyladamantane,

1-amino-3, 5-diphenyladamantane,

1-amino-3, 5, 7-trimethyladamantane,

1-amino-3, 5-dimethyl-7-ethyladamantane,

1-amino-3, 5-diethyl-7-methyladamantane,

1-N-pyrrolidine and 1-N-piperidine derivatives,

1-amino-3-methyl-5-propyladamantane,

1-amino-3-methyl-5-butyladamantane,

1-amino-3-methyl-5-pentyladamantane,

1-amino-3-methyl-5-hexyladamantane,

1-amino-3-methyl-5-cyclohexyladamantane,

1-amino-3-methyl-5-phenyladamantane,

1-amino-3-ethyl-5-propyladamantane,

1-amino-3-ethyl-5-butyladamantane,

1-amino-3-ethyl-5-pentyladamantane,

1-amino-3-ethyl-5-hexyladamantane,

1-amino-3-ethyl-5-cyclohexyladamantane,

1-amino-3-ethyl-5-phenyladamantane,

1-amino-3-propyl-5-butyladamantane,

1-amino-3-propyl-5-pentyladamantane,

1-amino-3-propyl-5-hexyladamantane,

1-amino-3-propyl-5-cyclohexyladamantane,

1-amino-3-propyl-5-phenyladamantane,

1-amino-3-butyl-5-pentyladamantane,

1-amino-3-butyl-5-hexyladamantane,

1-amino-3-butyl-5-cyclohexyladamantane,

their optical isomers, diastereomers, enantiomers, hydrates, N-methyl, N-dimethyl, N-ethyl, N-propyl derivatives, pharmaceutically acceptable salts thereof, and mixtures thereof.

Memantine (1-amino-3, 5-dimethyladamantane) is the subject of, for example, U.S. patent nos. 4,122,193 and 4,273,774, both of which are incorporated herein by reference in their entirety. For example, Neramexane is the subject of U.S. patent No. 6,034,134, which is incorporated herein by reference in its entirety.

1-aminoadamantane compounds of formulae IIb and IId, including memantine, are typically prepared by alkylation of a haloadamantyl group, with bromoadamantane or chloroadamantane being preferred. Di-or tri-substituted adamantanes are obtained by additional halogenation and alkylation processes. The amino group is introduced by oxidation with chromium trioxide and bromination with HBr or with bromine and reaction with formamide, followed by hydrolysis. The amino functionality may be alkylated according to accepted methods. Methylation may be effected, for example, by reaction with chloromethyl formate and subsequent reduction. The ethyl group can be introduced by reduction of the respective acetamide. For more details on the synthesis, see, for example, U.S. patent nos. 5,061,703 and 6,034,134. Other synthetic techniques for the above compounds can be found in published U.S. application Nos. 2003/0166634 and 2004/0034055, which are incorporated herein by reference in their entirety.

According to the present invention, the 1-aminocyclohexane derivatives of formula (I) can be used as such or in the form of their pharmaceutically acceptable salts. Suitable salts of this compound include, but are not limited to, acid addition salts such as those formed with hydrochloric acid, methanesulfonic acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, maleic acid, tartaric acid, citric acid, benzoic acid, carbonic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, 2-phenoxybenzoic acid, and 2-acetoxybenzoic acid; salts with saccharin. In a preferred embodiment, the salt is memantine hydrochloride (C)₁₂H₂₁N.HCl, MW 215.77). In another preferred embodiment, the salt is neramexane (C) mesylate₁₁H₂₃N·CH₄O₃S, MW 265.42). The term "salt" may also include addition salts of the free acid. All of these salts (or other similar salts) can be prepared in conventional manner. All such salts are acceptable as long as they are non-toxic and do not substantially interfere with the desired pharmacological activity.

The invention further includes all individual enantiomers, diastereomers, racemates and other isomers of those compounds in which structural variations may exist. The invention also includes all polymorphs and solvates of these compounds, such as hydrates, as well as those solvates formed with organic solvents. These isomers, polymorphs, and solvates can be prepared by methods known in the art, e.g., crystallization from different solvents, or by regiospecific and/or enantioselective synthesis and resolution in accordance with the disclosure provided herein.

The present invention includes derivatives of the compounds of the present invention. Examples of derivatives that can be applied to the present invention include, but are not limited to, structurally related compounds consisting of tricyclic 10-carbocyclic rings with an amino group, such as nitroxyl (nitroxy) -memantine derivatives (e.g., nitroprusside, nitroglycerin, or NO-producing nitroprusside or nitroglycerin derivatives of U.S. Pat. Nos. 5,234,956 and 5,455,279).

In a preferred embodiment, the active ingredient is memantine hydrochloride. The active ingredient may be present in an amount ranging from about 2.5mg to about 80mg, preferably from about 5mg to about 60 mg. In a preferred embodiment, the composition comprises from about 2% to about 20% w/w memantine; preferably from about 3.2% to about 10% w/w memantine; most preferably from about 3.9% to about 8.4% w/w memantine.

In another preferred embodiment, the active ingredient is neramexane mesylate. The active ingredient may be present in an amount ranging from about 6.25mg to about 150mg, preferably from about 12.5mg to about 125 mg. The active ingredient, e.g., neramexane mesylate in the oral dosage form of the invention, is typically present in an amount of from about 2% w/w to about 50% w/w. Preferably, it is present in an amount of about 2% w/w to about 40% w/w, more preferably about 3% w/w to about 25% w/w.

The immediate release dosage form is optionally coated or deposited with a coating over the entire surface of the entire release core. Immediate release of the drug is achieved by various methods known in the art including the use of very thin layers or coatings that, by virtue of their thinness (i.e., less than about 100 microns), are rapidly penetrated by gastric fluid, resulting in rapid drug leaching.

Examples of rapidly disintegrating and dispersing coating materials in the present invention include lactose and microcrystalline cellulose, colloidal silicon dioxide, hydrophilic polymers such as hydroxypropylmethyl cellulose, PVA, methacrylates (e.g., hydroxypropyl methylcellulose), and the like Rohm Pharma Polymer，Pisocataway, NJ), natural polymers, such as xanthan gum, and combinations thereof (e.g., xanthan gum)It comprises microcrystalline cellulose and colloidal silicon dioxide). In formulations without lactose environment, except for the use of microcrystalline cellulose, e.g.In addition, colloidal silica may be necessary. In addition to the usual adjuvants and additives or fillers, including tableting aids, colorants, binders, fillers, glidants and lubricants (all pharmaceutically acceptable), these substances may also be present as excipients.

In a preferred embodiment of the present invention, hydroxypropylmethylcellulose is used as the coating material. The optional coating material is present in an amount of about 1mg to about 70mg, preferably about 3mg to about 60mg, more preferably about 3mg to about 40 mg. In a preferred embodiment, the composition comprises from about 2% w/w to about 5% w/w of a hydroxypropyl methylcellulose-containing coating material; more preferably from about 2% to about 4% w/w of a hydroxypropyl methylcellulose-containing coating material.

Fillers or disintegrants are used to adjust the dissolution profile. Examples of such fillers include lactose monohydrate, microcrystalline cellulose,Hydroxypropyl methylcellulose, and combinations thereof. Lactose monohydrate, when used, balances the less soluble ingredients of the composition and thus acts as a disintegrant, while microcrystalline cellulose and similar types of fillers may require additional disintegrants such as croscarmellose sodium when used in a lactose-free environment. The disintegrant in the dosage form may further comprise excipients to support disintegration of the formulation. Those skilled in the art will recognize that these excipients may be starch-based, cellulose-based or pyrrolidone-based, or derivatives thereof, in amounts of about 0.2 to about 10%.

When hydroxypropylmethylcellulose or ethylcellulose is used in the matrix tablet, the dissolution rate is much lower than the targeted immediate release rate. This is because a hydrophobic matrix sheet is formed and these polymers release the drug through a polymer erosion mechanism. Since the erosion from the hydrophobic matrix is very slow, the dissolution rate of the active ingredient which is easily dissolved out is also slow.

In one embodiment of the invention comprising a memantine formulation, lactose monohydrate is used as the filler. Lactose monohydrate is present in an amount of about 40mg to about 1,400mg, preferably about 80mg to about 1,050 mg. In another embodiment, the composition comprises from about 50% to about 80% w/w, preferably from about 60% w/w to about 75% w/w lactose monohydrate. The formation of lactose adducts is less than 3% w/w, more preferably less than 2.5% w/w.

In a preferred embodiment of the invention comprising memantine, microcrystalline cellulose (MCC) is used as the filler. In formulations comprising lactose monohydrate, MCC is used as an additional filler, present in an amount of about 13mg to about 420mg, preferably about 25 to about 315mg per unit dose. In one embodiment, MCC is present in an amount of about 10% w/w to about 35% w/w, preferably about 18% w/w to about 22% w/w.

If MCC is used as a filler in the absence of lactose monohydrate, the MCC is present in an amount of about 50mg to about 1,600mg, preferably about 100mg to about 1,200mg per unit dose. In a preferred embodiment, the composition comprises from about 20% w/w to about 95% w/w microcrystalline cellulose; more preferably from about 60% w/w to about 90% w/w. Microcrystalline cellulose provides desirable dissolution profiles in terms of acceptable or improved formulation and processing properties. Those skilled in the art will recognize that these microcrystalline cellulose based formulations contain a disintegrant. Disintegrants are starch-based, cellulose-based or pyrrolidone-based excipients, or derivatives based on any of the foregoing excipients, which are present in an amount of about 0.2-10% w/w.

Additional excipients, such as talc (anti-adherent), starch, dicalcium phosphate, mannitol, croscarmellose sodium, colloidal silicon dioxide, sodium starch glycolate, may also be used in combination. The use of a disintegrant or soluble filler can achieve rapid disintegration of the tablet, thereby exposing a large surface area and resulting in faster dissolution of the drug.

In addition, in the lactose-free formulation, the dosage form comprises excipients which form less than 3.0% of the adduct, preferably less than 2.5%, even 0%. Those skilled in the art will recognize that materials such as memantine and neramexane adducts are generated from the maillard reaction. Adducts such as lactose or other reducing sugar adducts can be formed with amines in adamantane derivatives.

The tablets of the present invention may be prepared by conventional mixing, comminuting and tableting techniques which are well known in the pharmaceutical formulation industry. Immediate release tablets may be prepared, for example, by direct compression through punches and dies adapted for rotary tablet presses, spray or compression molding, granulation followed by compression, or by forming a paste and extruding the paste into a die or cutting the extrudate into shorter sizes followed by compression. As mentioned above, the immediate release component may be applied by spraying, dipping or pan coating onto the core tablet, or as a further layer by tableting or compression. Preferably, the process for preparing tablets is a mixed direct compression process. In general, direct mixing is a difficult operation, and problems such as separation of mixing, poor compressibility, and poor content uniformity may occur. However, neither the formulation described in the present invention nor the procedure for preparing the formulation presents these problems, or these problems are substantially insignificant. Near IR spectroscopy showed good distribution of the drug in the tablets.

When tablets are prepared by direct compression, the addition of a lubricant is beneficial, sometimes important to improve powder flow and to prevent "capping" (breakage of a portion of the tablet) of the tablet when pressure is reduced. Useful lubricants are magnesium stearate and hydrogenated vegetable oils (preferably hydrogenated and refined stearic and palmitic triglycerides). In a preferred embodiment, magnesium stearate is used as a lubricant in an amount of from about 0mg to about 6mg, preferably from about 0.3mg to about 4.0 mg. In a preferred embodiment, the composition comprises from about 0% w/w to about 2% w/w magnesium stearate; more preferably from about 0.2% w/w to about 0.5% w/w magnesium stearate. Additional excipients may be added to enhance tablet hardness, improve powder flow and reduce tablet friability and adhesion to the die wall.

Tablet hardness is linearly affected by different pressures, tablet shapes and sizes. As the compression force increases (kN), the tablet hardness increases linearly (Kp). Preferably, the hardness value is from about 3 to about 40Kp, more preferably from about 4 to about 30 Kp. In addition, at lower compression forces and thus lower hardness values, e.g., below 3Kp, logos (logos) and product debossing (de-bumping) are "stuck" making it illegible and aesthetically displeasing. At higher pressures and hardness values, the blocking phenomenon was eliminated without affecting the dissolution at 30 minutes (see example 1).

Dose-proportional time to maximum plasma concentration (Tmax) of plasma concentration of immediate release formulation of memantine in human patients_max) In the range of about 3 to about 7 hours, more often an average of about 4 to about 6 hours, and an in vitro release rate of greater than about 80% in about 60 minutes, more preferably in about 30 minutes.

Dose-proportional time to maximum plasma concentration (T) of plasma concentration of neramexane immediate release preparation_max) In the range of about 2 to about 8 hours, more often an average of about 2 to about 7 hours, and an in vitro release rate of greater than about 80% in about 60 minutes, more preferably in about 30 minutes.

The pharmaceutical formulations of the present invention contemplate dose-proportional compositions, modifying C by varying the concentration of the formulation_maxWithout substantially affecting the T of the drug_max. The 30-minute immediate release formulation of the present invention provides the desired T_maxNot at the initial peak concentration (C)_max) Compromise in the aspect, this is a characteristic of memantine or neramexane salts.

In addition, long T_1/2Allowing the immediate release dosage form to be administered 2 times per day, or preferably 1 time per day, and achieving a relatively high C_maxThis is considered essential for the pharmacological efficacy of the product. For example, a C of 20mg memantine (2 10mg tablets administered every 4 hour interval)_maxWill fall in the range of about 15 to about 4In the range of 0ng/ml, the average is about 25 ng/ml. If the memantine or neramexane dosage form is administered 2 times per day with an interval of about 4 hours, then the mean T is_maxThat is about 8 hours ± 2 hours. In addition, the dose ratio is allowed to be adjusted upward, starting with a lower dose using substantially the same formulation composition for the patient, and varying substantially only the weight content of memantine or neramexane to achieve different dosing concentrations.

According to the present invention, an immediate release pharmaceutical composition is provided for administering memantine, or a pharmaceutically acceptable salt thereof, preferably the HCl salt thereof, to a human or animal patient 1 time per day or, if preferred, 2 times per day. According to the present invention, an immediate release pharmaceutical composition is provided for administering neramexane or a pharmaceutically acceptable salt thereof, preferably the mesylate salt thereof, to a human or animal patient 1 time per day or, if preferred, 2 times per day.

In an alternative embodiment of the invention, the fast-dissolving properties of the tablet provide a drinkable solution for patients who cannot swallow the tablet.

Memantine and neramexane formulations of the invention are useful for treating CNS disorders, including but not limited to Alzheimer's disease, Parkinson's disease, AIDS dementia (U.S. Pat. No. 5,506,231, also see Parsons et al, Neuropharmacology 1999 Jun; 38(6):735-67), neuropathic pain (U.S. Pat. No. 5,334,618), cerebral ischemia, epilepsy, glaucoma, hepatic encephalopathy, multiple sclerosis, stroke, depression (U.S. Pat. No. 6,479,553), tardive dyskinesia, malaria, Borna virus, hepatitis C (U.S. Pat. Nos. 6,034,134 and 6,071,966). Other pathologies where memantine is suitable for treatment are disclosed in U.S. patent nos. 5,614,560 and 6,444,702. Accordingly, the present invention further provides a method of treating or prophylactically treating a CNS disorder in a human or animal patient, the method comprising administering to the patient a composition of the present invention.

As used herein, "adduct formation" refers to the formation of a compound with a specifically formulated composition by a solid phase reaction. The general term "adduct" of a compound also refers to an addition compound formed by the direct association of two or more different compounds. For example, in the present invention, the lactose adduct formation may be present in a lactose-containing formulation. Such adduct formations can impair the efficacy of the product and increase the risk of other side effects.

As used herein, "therapeutically effective amount" refers to an amount of a compound that is sufficient to cause a treatment of a condition, disorder or condition when administered to a mammal. The "therapeutically effective amount" may vary depending on the compound, the disease and its severity and the age, weight, physical health and responsiveness of the mammal to be treated. In one embodiment, according to the invention, a therapeutically effective amount of memantine is an amount sufficient to treat a CNS disorder, including Alzheimer's disease or Parkinson's disease. Other uses include, but are not limited to, the treatment of dementia and depression. The effective amount of drug to achieve pharmacological effects and tablet concentration depends on the disease itself, for example in Alzheimer's disease, the patient is initially given a 5mg dose, and the dose is progressively increased to 10mg 2 times daily to 20mg 1 time daily. Similar upregulation but starting from a higher basal dose (e.g., basal values starting from about 12 to about 15mg, upregulation to about 80mg) is useful for pain relief, e.g., relief of neuropathic pain. Such adjustments can be readily achieved by providing a selection of tablets representing a standard or normal dose, for example, doses of 5mg, 10mg, 15mg, 20mg, 40mg and 80mg of active substance. Therefore, it is important to obtain a dose-proportional formulation.

As used herein, the term "pharmaceutically acceptable" means biologically or pharmacologically compatible for use in vivo, preferably means approved by a regulatory agency of the federal or a national government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

As used herein, the term "treat," "treating," and derivatives thereof, are used herein to refer to the reduction or alleviation of pain in a highly susceptible mammal or a mammal suffering from a CNS disorder, such as dementia or Parkinson's disease. The term "treatment" may refer to the reduction or alleviation of the intensity and/or duration of disease manifestations experienced by a patient in response to a given stimulus (e.g., pressure, tissue damage, hypothermia, etc.). For example, the term "treating" in connection with dementia may refer to alleviating or alleviating cognitive impairment (e.g., impaired memory and/or orientation) or general functional impairment (activities of daily living, ADL) and/or slowing or reversing the progressive deterioration of ADL or cognitive impairment. Within the meaning of the present invention, the term "treatment" also means preventing, delaying the onset of the disease (i.e. at that stage prior to the clinical manifestation of the disease) and/or reducing the risk of the disease developing or worsening. The term "protection" is used herein to mean preventing the delay or treatment, or the overall, if appropriate, progression or persistence or worsening of the disease in the patient. Within the meaning of the present invention dementia is associated with CNS disorders, including but not limited to neurodegenerative disorders, such as Alzheimer's Disease (AD).

The term "blocking" refers to the separation of a substance (e.g., a film fragment) from a tablet surface by contact with another object and the adhesion of it to the surface of another object (e.g., another tablet or tool) (see Pharmaceutical Dosage Forms: Tablets Volume3, edited by H.A. Lieberman and L.Lachman, pp.101 and 272(Marcel Dekker, Inc. 1982)). Blocking can occur when tablets are compressed or tumbled. The removed material may obscure or disappear the logo, the embossed characters, the printed characters and the numbers to appear on the surface of the tablet.

The term "dose-proportional" as used herein refers to the relationship between a drug dose and its bioavailability. For example, in the present invention, a 2-fold identical composition to prepare a dosage form delivering 2-fold of the drug will provide the same bioavailability (i.e., AUC and C) as a single dose dosage form_max). The proportionality of the dosage of the invention applies to a wide range of dosages, as discussed in detail below.

The term "about" or "approximately" means that the particular value measured by one of ordinary skill in the art is within an acceptable error range, which depends in part on how the value is measured or determined, i.e., the limits of the measurement system. For example, "about" can mean within 1 or greater than 1 standard deviation per operation in the art. Alternatively, "about" in relation to a composition may mean a range of plus or minus up to 20%, preferably up to 10%, more preferably up to 5%. Alternatively, particularly with respect to biological systems or operations, the term may mean within an order of magnitude, preferably within 5-fold, more preferably within 2-fold, of a value. When particular values are described in the present application and claims, the term "about" means within an acceptable error range for the particular value, unless otherwise specified. For example, the values provided (+ -20%) are more applicable when referring to a time period, e.g. hours. Thus, 6 hours can be, for example, 4.8 hours, 5.5 hours, 6.5 hours, 7.2 hours, and typically 6 hours.

The term "environment of use" when used in reference to a formulation refers to the gastric fluid, or simulated dissolution media, of a patient to whom the formulation is administered.

Examples

The invention will be better understood by reference to the following examples, which are intended to illustrate the invention, but not to limit it.

Example 1: preparation of memantine hydrochloride immediate-release tablet

This example describes the preparation of immediate release tablets with memantine hydrochloride dosages of 2.5, 5, 10, 15, 20, 40, 60 and 80 mg.

Materials and methods

The following table provides the composition of the immediate release tablets, including the active ingredient, coating agents and other excipients for a particular dosage form having a particular target release time period. Tables 1 and 2 provide the composition of the lactose-containing tablets and contain the same data in absolute (mg) or relative (% w/w) terms, respectively.

TABLE 1.2.5 mg to 80mg dose-proportional formulation (lactose/MCC containing)

For the dose-proportional formulations of table 1, the w/w percentages of each active ingredient and excipient are shown in table 2.

TABLE 2 weight in w/w% of tablets (lactose/MCC)

Tables 3a-3c and 4 also provide the composition of the lactose-free tablets and contain the same data expressed in absolute (mg) or relative (% w/w) terms, respectively.

TABLE 3a, 2.5mg to 80mg of dose-proportional formulation (lactose free)

Tablet core weight can be adjusted to +/-10% with filler according to filler density.

Is a mixture of microcrystalline cellulose and colloidal silicon dioxide.

TABLE 3b, 6.25mg to 125mg exact prescription composition (mg composition per tablet) of dose-proportional formulations (lactose free)

Tablet core weight can be adjusted to +/-10% with filler according to filler density.

TABLE 3c dosage-proportional memantine tablet formulation of 10mg to 80mg, high drug loading of 10mg to 80mg (lactose free) with smaller tablet size

Composition in mg per tablet

Excipient	10mg	20mg	40mg	60mg	80mg
						Memantine hydrochloride	10.0	20.0	40.0	60.0	80.0
Microcrystalline cellulose (ProSolv or Avicel)	31.7	63.4	126.9	190.3	253.7
						Colloidal silica	0.2	0.5	0.9	1.4	1.8
Croscarmellose sodium	0.9	1.8	3.6	5.4	7.2
						Talcum powder	2.0	4.1	8.1	12.2	16.2
Magnesium stearate	0.1	0.3	0.5	0.8	1.1
						Total core of tablet	45	90	180	270	360
Coating (HPMC) Opadry	1.5	3.0	6	9	12
						Total coating	46.5	93.0	186	280	372

Tablet core weight can be adjusted to +/-10% with filler according to filler density.

Colloidal silica may not be used.

For the dose-proportional formulations of table 3c, the w/w percentages of each active ingredient and excipient are shown in table 4.

TABLE 4 weight expressed as w/w% of the total concentration of tablets (without lactose), including high drug load

Each test batch of tablets was prepared according to the following method.

A blend (lactose/MCC) was prepared for tableting. About half the amount of microcrystalline cellulose and active drug was placed in 20ft³In a conical blender. The colloidal silicon dioxide and the remaining microcrystalline cellulose were sieved through a sieve of about 0.71mm and then added to the 20ft³In a conical blender. The reinforcing bar (intensive bar) was closed and the components were mixed for 6 minutes. Lactose monohydrate (as referred to in the formulation) and talc were sieved through about 0.71mm sieve and added to a conical blender. Turning off the reinforcing rod, mixing the stirrerThe contents were kept for 20 minutes. The magnesium stearate was screened through an approximately 0.8mm filter and added to a conical blender. The booster bar was turned off and the mixture was mixed for an additional 5 minutes. Those skilled in the art will recognize that the above process may be varied for MCC and other fillers. One skilled in the art will recognize that alternative methods of addition and mixing are also acceptable.

During the preparation of the tablets, the initial batch of mixed product was mixed for 2 hours before being compressed into a tablet form, and samples were obtained throughout this time period. The samples were tested for separation.

And (6) tabletting. The mixture was compressed using a rotary tablet press. Tablets were compressed at various pressures ranging from 5 to 25Kp and tested for physical properties hardness, dissolution, thickness, friability and content uniformity. For dissolution testing, tablets of different hardness were tested using USP apparatus II using 900ml of buffer pH 1.2. After compression, the tablets were passed through a tablet dust collector and a metal testing apparatus. The tablets were then coated in a perforated coating pan.

Experiments were also conducted to investigate the effect of the coating on dissolution and stability. The tablets were coated with opadry (comprising hydroxypropyl methylcellulose) material. A dissolution test apparatus at 100rpm was used to generate the results. Alternative dissolution methods, for example, 50rpm using a suitable USP apparatus are also acceptable. Samples were collected after different degrees of weight gain (based on the amount of coating) and dissolution was measured at 15, 30 and 45 minutes. To determine stability, the coated tablets were placed in an open dish for 3 months in a chamber under accelerated conditions of 40 ℃/75% RH. Dissolution tests were performed at 15, 30 and 45 minutes.

Near IR spectrum. Near infrared (near IR) analysis of memantine immediate release formulations was performed using an infrared chemical imaging system (Spectral Dimension, Olney, MD). The cross-over of the tablets was determined and the 1692nm single channel image was used as a marker for memantine. The enriched region of memantine was determined to show the distribution of the active ingredient. Different batches of memantine immediate release tablets were analyzed three times. Analysis of the data showed that the memantine distribution was similar between the different batches.

Results and discussion

No significant separation occurred in the samples obtained during the two hour mixing test. The results show that the formulation ingredients have a good distribution of the active ingredient and, once mixed, the remaining active ingredient is evenly distributed throughout the tablet matrix. A mixing time of 20 minutes (400 revolutions) was chosen as the preferred mixing time. No significant change in particle size distribution was observed regardless of mixing time, indicating that no measurable particle attrition occurred during mixing. The results fall well within the limits of the tablet USP content uniformity test.

The results of the effect of pressure on tablet hardness show that as the pressure (kN) increases, the tablet hardness (Kp) also increases linearly. Similarly, as the pressure increases, the tablet thickness (in) decreases linearly. One undesirable condition during tableting is tablet sticking. The lower punch is embossed with tablet concentrations (5, 10 or 20) and the upper punch is embossed with "FP". Sticking to the punch, especially "P", was observed at lower pressures. Producing harder tablets eliminates sticking.

The effect of tablet hardness on dissolution was further evaluated. The data show that hardness has an effect on dissolution. This effect was only observed at the 15 minute time point, which was due to disintegration of the tablet. Complete release was obtained at the 30 minute time point. The expected dissolution technical index of the product is that the product is dissolved in 30 minutes by not less than 80 percent. According to the data, the greater tablet hardness necessary to avoid sticking had no effect on the dissolution profile. Hardness and dissolution value data are shown in tables 5a and 5b and tables 6a and 6b below.

TABLE 5 dissolution of uncoated tablet cores of Memantine hydrochloride of different hardness

TABLE 5b dissolution of neramexane mesylate tablets of different hardness

(lactose-free Filler)

TABLE 6 dissolution of Memantine hydrochloride coated tablets of different hardness

TABLE 6b dissolution of neramexane mesylate coated tablets

Tablets were tested for friability because the product was film coated to mask the off-flavor of the drug. Generally, the friability value is very low, indicating that the tablets have good mechanical integrity. The uniformity of the tablet contents was evaluated and in all cases the variability of the tablet contents was low.

Initial dissolution tests were also performed. Memantine hydrochloride is a highly soluble and highly permeable drug. The target dissolution rate is desirably not less than 80% in 30 minutes to support class 1 classification for the pharmaceutical Biopharmaceutical Classification System (BCS). The tablets also showed rapid dissolution (greater than 80% in 30 minutes), even at very high hardness (20 Kp for 20mg tablets).

The results of the study also show that the coating process and the degree of coating have no influence on the dissolution and stability of the final product. After 3 months under extreme conditions, no significant change was observed, demonstrating the stability of the formulation. The dry mixing method is designed to prevent mixing separation well and it is not sensitive to the particle size distribution of the active ingredient or mixture. The tablets showed good mechanical integrity (pressure of 5mg tablet is 10kN) and good content uniformity. Two approaches are used to reduce the aggregation of memantine particles: 1) increasing the ratio of diluent to drug, thereby reducing the available routes of interaction; 2) by mixing the active ingredient with the diluent for a suitable time.

Example 2: pharmacokinetic study of memantine

This example investigated the bioavailability of immediate release tablets versus sustained release tablets of memantine.

Materials and methods

The experimental design of this example was a 57-day single-center, open-label study in 24 young, healthy subjects 18 to 35 years of age. Subjects were subjected to screening evaluations including complete medical history, comprehensive physical examination of vital signs, 12-lead ECG, clinical laboratory assessments including CBC (including differential), clinical chemistry, urinalysis, RPR/VDRL, anti-HIV 1 and 2 tests, drug abuse screening (including alcohol and nicotine), anti-HCV and HbsAg. Female subjects were subjected to a β -hCG serum pregnancy test at screening and a urine pregnancy test on day 1.

Inclusion criteria included informed consent, normal physical examination, healthy adults between the ages of 18 and 35, non-smokers, in the range of 15% of ideal body weight relative to height, and sedentary pulse rate no less than 50 beats per minute, and ECG recorded heart rate no less than 50 beats per minute. Exclusion criteria included allergy to memantine or other NMDA antagonists, presence of any clinically significant disease, resting systolic pressure at screening greater than 180mmHg or less than 100mmHg or resting diastolic pressure greater than 100mmHg or less than 60mmHg, significant ECG abnormalities, history of alcohol or drug abuse, positive test results for drug abuse, consumption of caffeine within 48 hours prior to testing or alcohol within 72 hours, participation in other clinical studies within 30 days of the study, clinical symptoms associated with memantine, concomitant medication, or women in lactation.

There were 3 treatment regimens including a 10mg Immediate Release (IR) memantine hydrochloride tablet (30 min dissolution, treatment a), a 20mg sustained release (MR) memantine hydrochloride tablet (formulation I, 6 hr dissolution, treatment B), and a second 20mg sustained release memantine hydrochloride tablet (formulation II, 12 hr dissolution, treatment C). Sustained release formulations comprise different compositions to achieve a release rate of > 70% of drug release in about 6 hours and about 12 hours. Subjects received 3 treatments in an alternating fashion on study days 1, 22 and 43, separated by a 21-day washout period, according to a randomized dosing sequence. Immediate release dosing treatment was performed at 08:00 and 12:00 on day 1. Sustained release was administered at 08:00 on day 1. After the washout period, subjects were switched to other treatment groups (MR or IR). Formulations B and C are discussed in detail in a co-pending application (attorney docket No. 03269/1200817-US1) filed concurrently with the present application.

Subjects were admitted to a non-smoking environment at approximately 19:00 on days-1, 21, and 42. A total of 6 overnight stays were made for each subject (days-1, 21, 22, 42 and 43). Subjects were diet and fluid control and received no concomitant medication.

Vital signs and side effects were recorded during the study. On days 1, 22 and 43 during the study, blood samples were taken from each subject at the following time points after the 08:00 dosing: 0.0 hours (pre-dose), each hour of the first 12 hours post-dose, 14 th, 24 th, 36 th, 48 th, 72 th, 96 th, 144 th, 192 th, 240 th, 288 th and 336 th hours. During the course of the study, approximately 390mL blood samples were drawn from each subject (including pre-study, post-study and follow-up clinical analyses). A total of 72 blood samples were collected for pharmacokinetic analysis during the study. Blood samples for determination of memantine concentration were collected by qualified phlebotomists using a pre-frozen 5mL green capTubes (containing heparin sodium as anticoagulant).

Collect approximately 5mL of blood directly into a pre-frozen 5-mL green capTubes (containing heparin sodium) were then dosed on days 1, 22 and 43. Blood samples were centrifuged at 2,500g for 10 minutes at 4 ℃ during the 30 minute post draw to obtain plasma, which was transferred to pre-frozen Forest coded polypropylene tubes. The samples were then snap frozen in an isopropanol/dry ice bath and stored in a freezer at-70 ℃.

A method of biological analysis. The bioanalytical method used to determine plasma memantine concentrations was validated, demonstrating the accuracy, linearity, reproducibility, and precision of the assay. The LC/MS (liquid chromatography/mass spectrometry/tandem mass spectrometry) method was developed for the determination of memantine in human plasma. Adding 10ng of the "blood plasma" standard substance to the blood plasma sample²H₆]After memantine internal standard and 0.5M sodium carbonate buffer, the mixture was extracted with ethyl acetate. The organic layer was separated and dried in vacuo at room temperature in a sample concentrator (Savant). After reconstitution in the mobile phase, the dried residue was analyzed. The composition of the reconstituted samples was separated on a Zorbax SB-C8 column (150X 4.6mm, 3.5 μm) and detected by Atmospheric Pressure Chemical Ionization (APCI) with the Selected Reaction Monitoring (SRM) cation mode. SRM uses precursor → positive product ion of m/z 180 → 163 and m/z186 → 169 to monitor memantine and its internal standard, respectively. Memantine and [ 2 ]²H₆]The protonated molecular ion of memantine is the precursor ion of the SRM mode. The peak height ratio of the memantine product ion relative to the product ion of its internal standard is the response for quantification. Method confirmed plasma standards showed accuracy within ± 8.2% deviation and precision not exceeding 7.6% CV. The accuracy of memantine in plasma quality controls was determined to be within ± 8.8% deviation, with no more than 9.8% CV. The lower limit of the quantification method is 0.5 ng/mL.

And (4) carrying out pharmacokinetic analysis. Pharmacokinetic parameters were evaluated using WinNonlin (version 3.3, pharsight corporation, Mountain View, CA). From memantine plasma after single dose administrationThe following parameters were determined: area under plasma concentration time Curve (AUC)_0-t、AUC_0-24And AUC_0-∞) Maximum plasma concentration (C)_max) Time to maximum plasma concentration (T)_max) Elimination half-life (T)_1/2) And Mean Retention Time (MRT). Maximum plasma concentration (C) of memantine was determined by observation_max) And the time to maximum plasma concentration (T)_max)。

First order rate constant, λ_zDescribed is the end-stage decline in plasma, assessed by WinNonlin (version 3.3) using the log of linear decline of the end-stage linear phase of the memantine mean plasma concentration-time curve.

The terminal elimination half-life (T) in hours was calculated by equation 1_1/2) Evaluation of (2):

equation 1

Evaluation at time t (AUC) using the Linear trapezoidal rule (equation 2) by numerical integration_0-t) Time of day or at 24 hours (AUC)_0-24) Time, area under the plasma concentration versus time curve up to the last measurable concentration.

Equation 2

Wherein C is_iIs the corresponding sampling time t_iPlasma concentration of (a).

The area under the plasma concentration-time curve (AUC) of memantine that went to infinity in time was calculated using the following formula (equation 3)_0-∞)：

Equation 3

Wherein C is_lastIs the last measurable concentration in the concentration-time curve.

MRT was calculated using the following formula (equation 4):

equation 4

Where AUMC is the area under the first moment curve.

Memantine pharmacokinetic parameters C of subjects who completed the study_max、T_max、AUC_0-t、AUC_0-24、AUC_0-∞、t_1/2And descriptive statistics of MRT.

Results

Side effects. No serious adverse events were reported. After administration of A, B and C, 19 of 23 patients (82.6%) reported a total of 42 adverse events with treatment. There was no difference between the multiple adverse events observed with the treatment. A total of 14, 12 and 16 adverse events were observed after treatments A, B and C, respectively. The most commonly occurring adverse events (i.e. occurring in 3 or more patients) are headache, dizziness, flatulence and infections.

Pharmacokinetic results. Mean plasma concentrations of memantine are depicted in figure 1 (linear scale) and in figure 2 (semi-logarithmic scale). The plots in fig. 1 and 2 show the results of three treatments. The differences are further described in fig. 3. Figure 3 depicts the mean plasma concentration of memantine during the first 24 hours post-administration. The memantine peak concentration was highest after administration of the IR formulation (treatment a) and lowest after administration of the MR formulation II (treatment C).

The mean (± SD) pharmacokinetic parameters for memantine after treatment A, B and C are listed in table 7 below.

TABLE 7

Parameter(s)	Treatment of AIR preparation I (n ═ 20)	Treatment of BMR preparation I (n)＝20)	Treatment of CMR formulation II (n ═ 20)
				Cmax(ng/mL)	24.92±4.82	20.37±3.83	17.48±4.60
Tmax(h)	8.2±2.0	12.1±2.1	19.3±7.3
				AUC0-24(ng·h/mL)	435.7±87.0	367.2±66.8	303.3±78.2
AUC0-t(ng·h/mL)	1898.2±453.0	1755.7±468.9	1653.8±589.8
				AUC0-∞(ng·h/mL)	1969.0±455.8	1828.0±489.9	1730.1±609.4
T1/2(h)	57.4±14.2	59.6±15.4	59.1±15.5
				MRT(h)	83.9±17.8	87.4±19.4	89.0±20.2

A statistical comparison of memantine parameters is listed in table 8 below.

Table 8.

The absorption of memantine in sustained release tablets is delayed compared to immediate release tablets. Sustained release formulations reduce the rate and extent of absorption of memantine following administration compared to immediate release formulations. Importantly, the absorption Rate (T) of the IR tablet_max) Is delayed for 8.2 hours (i.e., respectivelyFor extended release tablets I and II, about 4 hours to 12.1 hours and to 19.3 hours after BID administration of the first tablet).

Comparing log-transformed C_max、AUC_0-24、AUC_0-tAnd AUC_0-∞With a 90% confidence interval, treatment a (IR tablets) showed a significantly higher mean C than treatment B (MR formulation I)_maxValues, but not within AUC parameter values. Comparing log-transformed C_max、AUC_0-24、AUC_0-tAnd AUC_0-∞90% confidence interval of treatment a (IR tablets) versus treatment C (MR formulation II) at mean C_maxAnd significantly higher in AUC values. These results demonstrate that IR tablets have improved bioavailability compared to sustained release formulations.

Gender Pair Elimination half-Life and weight-adjusted C following administration of IR formulations_max、AUC_0-tAnd AUC_0-∞The values had no statistically significant effect.

Discussion of the related Art

In this study, a single daily dose of 20mg of memantine (administered as 2 immediate release tablets of 10mg dose, at 4 hour intervals) was found to be safe and well tolerated. No serious adverse events were observed in this study.

The rate and extent of absorption of memantine is highest after administration of the immediate release tablet. For immediate release tablets (treatment A, 30min release), extended release tablet formulation I (treatment B, 6 hr release) and extended release tablet formulation II (treatment C, 12 hr release), C_maxValues averaged 24.92, 20.37, and 17.48ng/mL, respectively. AUC for immediate Release tablet (treatment A), extended Release tablet preparation I (treatment B) and extended Release tablet preparation II (treatment C)_0-∞The averages were 1969, 1827, and 1730 ng-h/mL, respectively. For treatments A, B and C, average T_max8.2 hours, 12.1 hours and 19.3 hours, respectively. Delayed T of two sustained release formulations_maxIndicating a slower rate of absorption relative to the immediate release tablet. These results demonstrate that both sustained release and immediate release formulations achieve the desired release profile.

Example 3: preparation of Memantine hydrochloride tablet capable of being released immediately within 30-min

This example illustrates the composition of 30-minute immediate release tablets of memantine with and without lactose monohydrate.

The process for preparing the tablets was the same as disclosed in example 1. In particular, tablets are prepared from the following active ingredients, coating agents and other excipients listed in tables 9 and 10 below. Tables 9 and 10 summarize tablets containing lactose monohydrate, which contain the same data expressed in absolute (mg) or relative (% w/w) terms, respectively.

TABLE 9 lactose monohydrate/MCC containing 30min Release tablets (weights are in mg/tablet)

For the dose-proportional formulations of table 10, the percentage ranges for each ingredient are determined in table 9.

TABLE 10 weight expressed as w/w% of tablets containing lactose monohydrate

Tables 11 and 12, which contain the same data in absolute (mg) or relative (% w/w) terms, respectively, summarize tablets without lactose.

TABLE 11 lactose-free 30min Release tablets (weights are in mg/tablet)

For the dose-proportional formulations of table 11, the percentage ranges for each ingredient are shown in table 12.

TABLE 12 weight in w/w% of tablets

Figures 4,5, 6, 7 and 8 show the dissolution of 30min IR tablets of 5mg, 10mg, 15mg, two batches of 20mg and 80mg formulations containing lactose monohydrate and MCC, respectively. Figure 9 shows the dissolution of 5mg and 20mg lactose-free formulations. In fig. 7, another batch of 20mg of the formulation showed approximately 65% at the initial time point of 15 minutes, but the stability was higher than 80%. The variation varies from batch to batch. The results show that more than 80% of the drug is released within 30 minutes, and in many cases, more than 80% of the drug is released within 15 minutes.

An adduct is formed. The adduct is formed as a result of the reaction between memantine and lactose monohydrate and a similar excipient known as a reducing sugar. No adduct was formed in the lactose-free/MCC-only formulation. Adduct formation was detected using HPLC method with an evaporative light scattering detector. Products stored for more than 40 months in the ambient environment contain adduct levels of up to about 2.5%. The adduct data is listed in table 13.

Watch 13

Concentration of	Dosing interval/Condition	Adduct%	Formulation of
				5mg	7 month ambient environment	0.61	lactose/MCC
5mg	25 ℃/60% RH for 36 months	2.32	lactose/MCC
				20mg	25 ℃/60% RH for 36 months	1.30	lactose/MCC
20mg	5 month ambient environment	0.37	lactose/MCC
				5mg	40 ℃/75% RH for 3 months	Not detected (<0.2％)	MCC (lactose-free)
20mg	40 ℃/75% RH for 3 months	Not detected (<0.2％)	MCC (lactose-free)

Adduct levels below about 3%, preferably below about 2.5% are acceptable as determined by ICH guidelines Q3B (R), FDA guidelines, Rockville, MD.

* * *

The present invention is not intended 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 also intended to fall within the scope of the appended claims.

It is further understood that all numerical values are approximate and are provided for descriptive purposes.

The disclosures of patents, patent applications, publications, product specifications, and protocols cited throughout this application are hereby incorporated by reference in their entirety for all purposes.

Claims (42)

1. An immediate release solid oral dosage form comprising (i) an active ingredient selected from the group consisting of 1-aminocyclohexane compounds and pharmaceutically acceptable salts thereof, and (ii) optionally a pharmaceutically acceptable coating, said dosage form exhibiting dose-proportionality and said dosage form releasing more than about 80% of said active ingredient within about the first 60 minutes upon entry into a use environment, wherein said dosage form exhibits a mean T_maxFrom about 2 to about 8 hours, an active ingredient loading of from about 2.5 to about 150mg, and wherein the dosage form is obtained by direct compression.

2. The immediate release solid oral dosage form according to claim 1, wherein said oral dosage form releases more than about 80% of said active ingredient within the first 30 minutes after entering a use environment.

3. The immediate release solid oral dosage form according to claim 2, wherein said oral dosage form releases more than about 80% of said active ingredient within the first 15 minutes after entering a use environment.

4. The immediate release solid oral dosage form according to claim 1, wherein the active ingredient is memantine hydrochloride.

5. The immediate release solid oral dosage form according to claim 1, wherein the active ingredient is neramexane mesylate.

6. The immediate release solid oral dosage form according to claim 4, wherein the active ingredient is present in an amount of about 2% w/w to about 20% w/w.

7. The immediate release solid oral dosage form according to claim 6, wherein the active ingredient is present in an amount of about 3.2% w/w to about 10% w/w.

8. The immediate release solid oral dosage form according to claim 6, wherein the active ingredient is present in an amount of about 3.9% w/w to about 8.4% w/w.

9. The immediate release solid oral dosage form according to claim 1, wherein the pharmaceutically acceptable coating comprises hydroxypropylmethylcellulose.

10. The immediate release solid oral dosage form according to claim 1, wherein the pharmaceutically acceptable coating comprises a methacrylic acid-ethyl acrylate copolymer.

11. The immediate release solid oral dosage form according to claim 1, wherein the pharmaceutically acceptable coating is present in an amount of about 2% w/w to about 7% w/w.

12. The immediate release solid oral dosage form according to claim 11, wherein the pharmaceutically acceptable coating is present in an amount of about 2% w/w to about 5% w/w.

13. The immediate release solid oral dosage form according to claim 1, further comprising one or more pharmaceutically acceptable carriers, excipients, anti-adherents, fillers, stabilizers, binders, colorants, disintegrants, glidants and lubricants.

14. The immediate release solid oral dosage form according to claim 1, further comprising a pharmaceutically acceptable filler.

15. The immediate release solid oral dosage formulation according to claim 1, exhibiting less than 3% w/w adduct formation.

16. The immediate release solid oral dosage formulation according to claim 1, exhibiting less than 2.5% w/w adduct formation.

17. The immediate release solid oral dosage formulation according to claim 1, exhibiting adduct formation of less than 0.5% w/w.

18. The immediate release solid oral dosage form according to claim 14, wherein the pharmaceutically acceptable filler is microcrystalline cellulose.

19. The immediate release solid oral dosage form according to claim 18, wherein the microcrystalline cellulose is present in an amount from about 10% w/w to about 35% w/w, and wherein the solid oral dosage form further comprises lactose monohydrate.

20. The immediate release solid oral formulation according to claim 19, wherein the microcrystalline cellulose is present in an amount of about 18% w/w to about 22% w/w.

21. The immediate release solid oral dosage form according to claim 18, wherein the microcrystalline cellulose is present in an amount of about 20% w/w to about 95% w/w, wherein the solid oral dosage form is lactose free.

22. The immediate release solid oral dosage form according to claim 21, wherein the microcrystalline cellulose is present in an amount from about 60% w/w to about 90% w/w.

23. The immediate release solid oral dosage form according to claim 1, wherein the hardness of the solid oral dosage form is in the range of about 3 to about 40 Kp.

24. The immediate release solid oral dosage form according to claim 23, wherein the hardness of the solid oral dosage form is in the range of about 4 to about 30 Kp.

25. The immediate release solid oral dosage form according to claim 1, further comprising a lubricant.

26. The immediate release solid oral dosage form according to claim 25, wherein the lubricant is magnesium stearate.

27. The immediate release solid oral dosage form according to claim 26, wherein magnesium stearate is present in an amount from about 0% to about 2% w/w.

28. The immediate release solid oral dosage form according to claim 27, wherein magnesium stearate is present in an amount from about 0.2% to about 0.5% w/w.

29. The immediate release solid oral dosage form according to claim 1, wherein the solid oral dosage form is a tablet.

30. The immediate release solid oral dosage form according to claim 1, wherein the solid oral dosage form comprises:

a) from about 2% w/w to about 10% w/w memantine hydrochloride;

b) about 2% w/w to about 5% w/w hydroxypropyl methylcellulose;

c) about 10% w/w to about 35% w/w microcrystalline cellulose;

d) about 50% w/w to about 70% w/w lactose monohydrate;

e) about 0% w/w to about 3% w/w colloidal silica;

f) about 3% w/w to about 5% w/w talc; and

g) about 0% w/w to about 2% w/w magnesium stearate.

31. The immediate release solid oral dosage form according to claim 1, wherein the solid oral dosage form comprises

a) From about 3.2% w/w to about 10% w/w memantine hydrochloride;

b) about 2% w/w to about 4% w/w hydroxypropyl methylcellulose;

c) about 18% w/w to about 22% w/w microcrystalline cellulose;

d) about 65% w/w to about 70% w/w lactose monohydrate;

e) about 0% w/w to about 0.5% w/w colloidal silica;

f) about 4% w/w to about 5% w/w talc; and

g) about 0.2% w/w to about 0.5% w/w magnesium stearate.

32. The immediate release solid oral dosage form according to claim 1, wherein the solid oral dosage form comprises:

a) from about 2% w/w to about 10% w/w memantine hydrochloride;

b) about 2% w/w to about 5% w/w hydroxypropyl methylcellulose;

c) about 20% w/w to about 95% w/w microcrystalline cellulose;

d) about 0% w/w to about 3% w/w colloidal silica;

e) about 0% w/w to about 5% w/w talc; and

f) about 0% w/w to about 2% w/w magnesium stearate;

g) from about 0% w/w to about 3% w/w croscarmellose sodium.

33. The immediate release solid oral dosage form according to claim 1, wherein the solid oral dosage form comprises:

a) from about 3.2% w/w to about 10% w/w memantine hydrochloride;

b) about 2% w/w to about 4% w/w hydroxypropyl methylcellulose;

c) about 60% w/w to about 90% w/w microcrystalline cellulose;

d) about 0% w/w and about 0.5% w/w colloidal silica;

e) about 4% w/w to about 5% w/w talc; and

f) about 0.2% w/w to about 0.5% w/w magnesium stearate;

g) from about 1.8% w/w to about 2.2% w/w croscarmellose sodium.

34. The immediate release solid oral dosage form according to claim 1, wherein the solid oral dosage form is lactose-free.

35. Use of an active ingredient selected from memantine and pharmaceutically acceptable salts of memantine, and optionally a pharmaceutically acceptable coating, for the manufacture of an immediate release solid oral dosage form according to claims 1-33 for the treatment of mild, moderate or severe alzheimer's disease.

36. Use of an active ingredient selected from neramexane and pharmaceutically acceptable salts of neramexane, and optionally a pharmaceutically acceptable coating, for the preparation of an immediate release solid oral dosage form according to claims 1 to 3 for the treatment of mild, moderate or severe alzheimer's disease.

37. Use of an active ingredient selected from memantine and pharmaceutically acceptable salts of memantine and optionally a pharmaceutically acceptable coating for the manufacture of an immediate release solid oral dosage form according to claims 1-33 for the treatment of neuropathic pain.

38. Use of an active ingredient selected from neramexane and pharmaceutically acceptable salts of neramexane, and optionally a pharmaceutically acceptable coating, for the preparation of an immediate release solid oral dosage form according to claims 1-3 for the treatment of neuropathic pain.

39. A method of treating a disorder selected from mild, moderate and severe alzheimer's dementia and neuropathic pain, wherein the method comprises administering the immediate release solid oral dosage form of claim 1.

40. The method of claim 39, wherein the administration is once daily.

41. The method of claim 40, wherein the administration is twice daily.

42. The method of claim 41 wherein the dosage forms are administered at about 4 hour intervals.