WO2007065036A2 - Therapeutic conjugates and methods of using same - Google Patents

Abstract

The present invention provides novel gabapentin-aminoadamantane derivative combinations (e.g. gabapentin-memantine) combinatorial compositions, methods of making the compositions, and methods for the treatment and prevention of neurological diseases, e.g., epilepsy, and neuropathic and chronic pain, using the compositions of the invention.

Description

THERAPEUTIC CONJUGATES AND METHODS OF USING SAME

FIELD OF THE INVENTION

This invention relates to methods and compositions for treating CNS-related conditions, such as epilepsy, pain and depression.

BACKGROUND

Neuropathic and chronic pain affects over 20 million Americans each year, and remains one of the most important unmet healthcare needs (Frost and Sullivan, US Pain Management Markets, 2003). The withdrawal of Cox-2 inhibitors from the market has focused even more attention on challenges within the analgesic market. Although the causes of pain are varied, there are commonalities both in the molecular alterations and the treatment remedies applied. On the molecular front, modulation of the N-methyl-D-aspartate receptor (NMDAr) complex, likely as a consequence of glutamate release in the spine, have a confirmed role in development of pain states or "wind-up" (Parsons et al., 2001). Therapeutically, the most effective analgesics for chronic pain are opiates, but the addictive/tolerance potential (itself an NMD Ar-mediated process) limits their use chronically (Newmani et ah, 2004). For these reasons, new pain therapeutics with fewer side effects are urgently needed.

Gabapentin was approved for use in the United States in 1994 as an add-on drug in adults who have partial seizures either alone or with secondarily generalized seizures. The drug's mechanism of action is unknown, although it binds to a specific receptor in the brain, inhibits voltage-dependent sodium currents, and may enhance the release or actions of gamma- aminobutyric acid (Kocsis and Honmou, 1994; Dichter and Martin, 1996). In addition to being used as a treatment for epilepsy, gabapentin is also one of the most widely prescribed analgesics for the treatment of chronic and neuropathic pain (Backonja et al., 1998). Although its mechanism is unknown, gabapentin has been shown to work in the most common models of chronic and neuropathic pain (Xiao and Bennet, 1995) and in phase 2 of the formalin pain model (Shimoyarna et al, 2002).

There are a number of reports of dramatic pain relief in persons with reflex sympathetic dystrophy and postherpetic neuralgia after only a few doses of gabapentin. Rosenberg et al (1997) in a retrospective study of gabapentin use in a pain management clinic involving 122 charts found that there was a 75% decrease in self-reported pain scores in patients with neuropathic pain, but there was no concomitant reduction of opiate use. Patients with low back pain did not have a significant improvement in pain scores. Backonja et al (1998) reported on a randomized controlled trial of the use of gabapentin in painful diabetic neuropathy. Daily pain scores were reduced significantly in those using gabapentin and not with placebo. A second randomized controlled study in the treatment of postherpetic neuralgia showed similar results (Rowbothan et al, 1998). Quality of life measures improved in both of these latter studies in the group using gabapentin. Although gabapentin is not FDA approved for use in treatment of chronic pain, its use for this indication has become widespread because it is generally well- tolerated, easily titrated, has few drug interactions, and does not require laboratory monitoring.

SUMMARY OF THE INVENTION Disclosed are dual function compounds that include gabapentin and an NMDA receptor antagonist compound (e.g. an aminoadamantine derivative such as memantine and amantadine). The compounds are useful for treating a variety of CNS-related conditions, including neuropathic and chronic pain, and epilepsy. Also provided are methods of making and using these combinatorial drugs. The combinatorial drugs are expected to have a much higher bioavailability, being delivered specifically to the brain tissues, and have the benefits of the gabapentin and the NMDA receptor antagonist compound e.g. memantine. The invention provides gabapentin-NMDA receptor antagonist compounds, e.g., gabapentin-memantine compounds and gabapentin-amantadine compounds.

Gabapentin is a widely used drug for treatment of epilepsy and neuropathic and chronic pain. Memantine is an uncompetitive, open-channel NMDA type of glutamate receptor blocker with low to moderate affinity for the (+)-MK-801 binding site, which has recently been approved as a treatment for moderate to severe dementia of the Alzheimer's type. Memantine is described, for example, in U.S.Patent Nos. 3,391,142; 5,891,885; 5,919,826; and 6,187,338. Amantadine (1-amino-adamantane) is described, for example, in U.S. Patent Nos. 3,152,180; 5,891,885; 5,919,826; and 6,187,338. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control, hi addition, the materials, methods, and examples are illustrative only and not intended to be limiting. All parts and percentages are by weight unless otherwise specified. Other features and advantages of the invention will be apparent from the following description.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the chemical structures of dual functional NMDA receptor-binding meniantine nitrates.

Figure 2 shows that administration of YQW-012 (memantine-ONO2) decreases cerebral damage after stroke in a murine cerebral ischemia model as compared to both a control and memantine alone. Use of the intraluminal suture method demonstrated (n=3 for each group) that YQW-012 was effective in decreasing cerebral damage after stroke (PO.03 from control: PO.05 from memantine).

Figure 3 is a graph depicting gabapentin reduces the number of flinches in response to formalin injection. Shown is the mean number of flinches counted in one minute epochs over the course of the 90 minute test period.

Figure 4 shows the chemical structures of novel gabapentin-memantine conjugates.

Figure 5 shows the conversion of novel gabapentin-memantine conjugates to free gabapentin and free memantine. Figure 6 shows the synthesis of gabapentin-memantine conjugates PM 1-3.

Figure 7 shows the synthesis of gabapentin-memantine conjugates PM 4-6.

Figure 8 shows the synthesis of gabapentin-memantine conjugate PM 7. Figure 9 shows the synthesis of gabapentin-memantine conjugate PM 8. Figure 10 shows the synthesis of gabapentin-memantine conjugate PM 9. Figure 11 shows the synthesis of gabapentin-memantine conjugate PM 10.

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the invention provides a conjugate comprising an NMDA receptor antagonist linked to gabapentin wherein the NMDA receptor antagonist is memantine (1-amino- 3,5-dimethyladamantane) or amantadine (1-amino-adamantane). References herein to gabapentin, memantine and amantadine include their pharmaceutically acceptable salts, unless the context indicates otherwise. "Pharmaceutically Acceptable Salts" include acid addition salts and which may be formed with inorganic acids such as, for example, hydrochloric, sulphuric, or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.

The gabapentin can be linked to the aminoadamantane derivative at any suitable position on the aminoadamantane derivative. The aminoadamantane derivative is optionally attached via a linker.

The linkage can be metabolically stable (i.e., the gabapentin remains attached to the aminoadamantane compound following administration) or metabolically or physiologically labile, i.e., unstable, wherein the gabapentin is released from the aminoadamantane compound.

Suitably, the linkage is cleavable when the conjugate is present in an in vivo environment. Thus, following administration the conjugate is cleaved and the aminoadamantine derivative and gabapentin moieties are released. The linkage may, for example, be cleavable within the brain tissues/cells and/or when the conjugate is present in the blood stream. In a preferred embodiment, the linkage is cleavable after the conjugate has crossed the blood brain barrier.

In one embodiment, a linker that is labile under certain conditions is selected (e.g., at a certain pH)). Metabolically cleavable linkages are not equally labile or 'cleavable', particularly in terms of their rates of cleavage. The ease of metabolic cleavage has the following rank order: - COOR > CONH > CH=N > SO2NH > CH2N, i.e., the ester is the most readily cleaved and the alkylamine is the most stable. Even in the case of the esters, the rate of cleavage can be controlled by further substitution on the alpha (adjacent) carbon atom. In general, a more extensive amount of substitution makes cleavage more difficult, i.e., makes for a more stable linkage.

For example, the type of linker used in the conjugate can facilitate hydrolytic release of the conjugate moieties at an intracellular site. In other embodiments, the type of linker used in the conjugate facilitates the enzymatic release of the conjugate moieties at a target site.

In some embodiments, the linker functional group is hydrolyzed by an enzymatic activity found in brain tissue, including neuronal, glial and other brain cell types, such as an esterase, including an esterase having a differential expression and activity profile in the appropriate target cell type. In additional embodiments, specific release of the conjugate moieties is achieved by enzymatic or chemical release by extracellular cleavage of a cleavable linker moiety via an enzymatic activity specific for brain tissue. In some embodiments, each of the first and second functional linker groups are those which react with a hydroxyl group, a primary or secondary amino group, a phosphate group or substituted derivatives thereof, or a carboxylic acid group on the gabapentin or aminoadarnantane derivative.

When amantadine or memantine is used, the aminoadamantane derivative can be converted to the hydroxyl- or diamino-derivative, which may then conjugated to the therapeutic agent via a linker:

In some embodiments, the gabapentin is attached to the aminoadamantane derivative in the conjugate at the 1- (bridgehead) position or the 2- position.

Cleavable linkers include those that form an ester (COOR), amide (CONHR), sulfonamide (NHSO2), sulfonate (SO2R), or ether (ROR) with the corresponding functionality on the aminoadamantane and on the gabapentin. In some examples, the linker is an alkyl linker, in others, the linker is a heteroalkyl linker, in others two adjacent atoms in the linker are joined together to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl group. Some linkers include the following, where n is 0-7:

ther commercially available suitable linkers include the following:

The terminal carboxyl functionalities of the linkers can be part of an acid chloride, ROC(O)Cl, (or reactive equivalent), which form a carbamate, ROC(O)NR, when reacted with an amine, the SO2 reactants are sulfonyl chlorides, S02C1, compounds (or reactive equivalent), which form a sulfonamide when reacted with an amine. Amines and ethers are formed from the reaction of a compound having an active leaving group:

where Y is I, Br, mesyl, tosyl, etc and X is CH2, O, S, NH, NR, SO, SO2. Linkers may have more than two sites for conjugation as well. For example a linker may be of the form HO₂C(CH2)_mCH(CH₂)_nCH₂OH wherein m and n are independently integers from 0 to 5. In this embodiment, the carboxyl functionality may be coupled to one of the active agents (i.e., the gabapentin or aminoadamantane) and the two hydroxyl groups maybe coupled to the other active agent. Numerous other branched linkers may be employed providing sites enabling different stoichiometric ratios of the two active agents. The number of sites for each type of active agent will be typically from 1 to 10, preferably from 1 to 5, more preferably one, two, three or four.

Ih one embodiment, the stoichiometric ratio of the gabapentin to the aminoadamantane compound in the conjugate is greater than or equal to 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1 .

Further techniques and discussion of the linkage of aminoadamantine derivatives to therapeutic agents and formulations and uses of the same maybe found in WO 2005/019166, which is incorporated herein in its entirety.

The aminoadamantane derivative in the conjugates of the invention allows for the gabapentin to be delivered in a lower systemic dose than that which would be required if the gabapentin were administered alone. The lower dose also minimizes the side effects and/or toxic effects that may be observed when the gabapentin is administered alone and thus is more likely to interact undesirably with healthy neurons and other healthy tissues.

The conjugates described herein thus provide a way to achieve effective drug concentrations at physiologically protected sites (e.g., in the brain) and a way to reach therapeutically-effective levels after systemic administration of much lower levels than are currently administered to achieve a therapeutic dose of the conjugated therapeutic agent. Administration of the gabapentin as part of the conjugate additionally results in decreased systemic metabolism, degradation and toxicity, reduced systemic adverse drug interactions, and generally reduced side effects. These biological effects can also be obtained with simplified dosage schedules, particularly for drugs with short systemic half-lives.

The choice of aminoadamantane derivative will depend in part upon the activity of the aminoadamantane when conjugated, the choice of the conjugation chemistry, and the relative concentrations needed for the aminoadamantane and gabapentin moieties to maximize effectiveness.

In one embodiment, the aminoadamantine derivative is amantadine. The current dosing for amantadine in humans is about 100-400 mg/day whereas memantine is 20 mg/day. The dosing for gabapentin is much higher ranging from 900-3600 mg/day (adjusted downward based on renal function). Given these dosages, and the fact that molecular weights of amantadine, memantine, and gabapentin only modestly differ, and the stoichiometric relationship between these active agents in the conjugate, subject to the activities of the agents in the conjugated form and those of the cleavage products, dosing of gabapentin maybe limited by the aminoadamantane; the therapeutically effective dose of memantine is about 10 to 20 fold less than the therapeutically effective dose of amantadine, meaning that when dosing based on therapeutically effective levels of aminoadamantane, amantadine should enable achievement of a higher concentration of gabapentin (or related breakdown species) in the CNS while providing a therapeutically effective amount of amantadine (or related breakdown species) in the CNS than achievable when memantine is employed as the conjugated aminoadamantane.

Accordingly, amantadine as a starting material would enable higher gabapentin- amantadine conjugate dosing as amantadine is normally dosed at a concentration much higher (approximately ten-fold) than memantine. If one were to employ memantine, the conjugate would be administered at a lower dose (than an amantadine conjugate), because of the higher specific activity of memantine (over amantadine). Aminoadamantane cleavage products other than memantine or amantadine, however, may have different relative activities enabling different dosing levels for the conjugate. Depending upon the relative activities of the components of the conjugated species, this may also be true for a non-cleavable conjugate.

A second aspect of the invention provides a pharmaceutical composition comprising a conjugate of the invention and optionally a pharmaceutically acceptable carrier.

The phrase "pharmaceutically acceptable" includes molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to the subject. Useful carriers are well known in the art, and include, e.g., water, buffered w water, 0.4% saline, 0.3% glycine, hyaluronic acid and the like.

As used herein, the term "comprising" means "including". Thus, for example, a composition "comprising" X may consist exclusively of X or may include one or more additional components.

In some embodiments, the pharmaceutical is provided in an extended release dosage form.

As used herein the terms "extended release dosage form" includes dosage forms where the active drug substance or substances are released over an extended period of time. The term "extended" release should be understood in contrast to immediate release and, in particular, the term indicates that the formulation does not release the full dose of the active ingredient immediately after dosing. The extended release forms may or may not comprise an immediate release component.

As used herein, "immediate release formulation" refers to a formulation of a pharmaceutical ingredient that releases greater than 80 percent of the pharmaceutical ingredient in less than one hour as measured using a USP type 2 (paddle) dissolution system at 50 rpm, at a temperature of 37±0.5° with a dissolution medium of water, approximately 0.1 N HCl, or a simulated gastric fluid.. Typically, the release of the active ingredient in an immediate release formulation is greater than 80 percent in less than 30 minutes.

Extended release dosage forms typically allow a reduction in dosing frequency as compared to that presented by a conventional dosage form such as a solution or an immediate release dosage form. The half-life for the conjugate will be a function of the chemistry but the half-life for gabapentin is just 6 hours and amantadine has a half-life of about 15 hours. With an extended release formulation, the dosing frequency may be reduced (currently TID for gabapentin). Extended release formulations may be prepared to provide a less variable intradose concentration of the drug which maybe of benefit to reduce undesirable adverse effects associated with higher concentrations of the drug and to increase the efficacy of the drug at a given administered dose by keeping the systemic concentration at a level that is higher than the Cmin observed for immediate release formulations.

Further, the use of extended release formulations may reduce adverse effects associated with rapid uptake of the drug in immediate release forms - a reduction in dC/dt (the slope of the drug concentration in vivo upon administration to Tmax in this example) will reduce effects observed with CNS drugs (e.g. memantine) that necessitate titration schemes (initially with sub-therapeutic doses) to avoid such effects.

As used herein, "C" refers to the concentration of an active pharmaceutical ingredient in a biological sample, such as a patient sample (e.g. blood, serum, and cerebrospinal fluid). The concentration of the drug in the biological sample may be determined by any standard assay method known in the art. The term "Cmax" refers to the maximum concentration reached by a given dose of drug in a biological sample. The term "Cmean" refers to the average concentration of the drug in the sample over time. Cmax and Cmean may be further defined to refer to specific time periods relative to administration of the drug. The time required to reach the maximal concentration ("Cmax") in a particular patient sample type is referred to as the "Tmax." The term "Cmin" refers to the minimum concentration achieved by a dosing regimen between doses subsequent to achieving a steady state condition, i.e. usually more than about five times the half- life of the active agent.

Extended release formulations may, for example, be formulated using a polymer matrix (e.g., Eudragit), Hydroxypropyl methyl cellulose (HPMC) and / or a polymer coating (e.g., Eudragit). Such formulations may, for example, be compressed into solid tablets or granules. Optionally, a coating such as Opadry® or Surelease® is used. Further guidance on extended release formulations may be found in WO 06/058059 which is incorporated herein by reference in its entirety. A third aspect of the invention provides a conjugate of the first aspect of the invention for use in medicine.

A fourth aspect of the invention provides a method of treating a CNS-related condition or a symptom thereof in a subject in need thereof comprising administering a therapeutically effective amount of a pharmaceutical composition of the second aspect of the invention. The term "therapeutically effective amount" refers to an amount of the conjugate that is necessary to achieve a desired endpoint.

A fifth aspect of the invention provides for the use of a conjugate according to the first aspect of the invention in the manufacture of a medicament for the treatment of a CNS-related condition or a symptom thereof. As will be appreciated from the foregoing the conjugates used in the various aspects of the invention may be provided in an extended release dosage form.

The term "treatment" (and grammatical variants thereof) as used herein may refer to therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease or obtain other beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of extent of condition, disorder or disease; stabilized (i. e. not worsening) state of condition, disorder or disease; delay or slowing of condition, disorder or disease progression; amelioration of the condition, disorder or disease state, remission (whether partial or total), whether detectable or undetectable; or enhancement or improvement of condition, disorder or disease.

The conjugates of the invention may be useful for treating CNS-related conditions and the symptoms thereof, such as epilepsy, pain (e.g. chronic or neuropathic pain), psychiatric disorders (e.g., panic syndrome, general anxiety disorder, phobic syndromes of all types, mania, manic depressive illness, hypomania, unipolar depression, depression, stress disorders, PTSD, somatoform disorders, personality disorders, psychosis, mood disorders, and schizophrenia), dementias or neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis), headaches or migraines, cerebrovascular diseases, motor neuron diseases, dementias, strokes, neuralgia, reflex sympathetic dystrophy, movement disorders, ataxic syndromes, disorders of the sympathetic nervous system, cranial nerve disorders, myelopathies, traumatic brain and spinal cord injuries, radiation brain injuries, multiple sclerosis, post-meningitis syndrome, prion diseases, myelitic disorders, radiculitis, neuropathies, axonic brain damage, seizures, various neuromuscular syndromes, encephalopathies, cerebroischemia, chronic fatigue syndrome, psychiatric disorders, glucose dysregulation, and drug dependence (e.g., alcohol, psychostimulants (e.g., crack, cocaine, speed, and meth), opioids, and nicotine).

In one embodiment the conjugates are used for the treatment of epilepsy. In another embodiment the conjugates are used for the treatment of pain (e.g. chronic or neuropathic).

In another embodiment the conjugates are used for the treatment of depression In some embodiments, the compositions of the invention are suitable for internal use and include a therapeutically effective amount of a pharmacologically active conjugate of the invention, alone or in combination, optionally with one or more pharmaceutically acceptable carriers.

A suitable subject can be, e.g., a human, a non-human primate (including a gorilla or chimpanzee, or orangutan), a rodent (including a mouse, rat, guinea pig, or gerbil) a dog, a cat, horse, cow, pig, sheep, rabbit, or goat.

The conjugates are administered in amounts which will be sufficient to exert their desired biological activity. A variety of preparations can be used to formulate pharmaceutical compositions containing the conjugates, including solid, semi solid, liquid and gaseous forms. Remington's Pharmaceutical Sciences, Mack Publishing Company (1995) Philadelphia, Pa.,

19th ed. Tablets, capsules, pills, powders, granules, dragees, gels, slurries, ointments, solutions suppositories, injections, inhalants and aerosols are examples of such formulations. The formulations can be administered in either a local or systemic manner or in a depot or sustained release fashion. Administration of the composition can be performed in a variety of ways. Among others, oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal and intratracheal means can be used.

Where the conjugate is given by injection, it can be formulated by dissolving, suspending or emulsifying it in an aqueous or nonaqueous solvent. Vegetable or similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids and propylene glycol are examples of nonaqueous solvents. The conjugate is preferably formulated in aqueous solutions such as Hank's solution, Ringer's solution or physiological saline buffer.

Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient. Liquid, particularly injectable compositions can, for example, be prepared by dissolving, dispersing, etc. The conjugate is dissolved in or mixed with a pharmaceutically pure solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form the injectable solution or suspension. Additionally, solid forms suitable for dissolving in liquid prior to injection can be formulated. Injectable compositions are preferably aqueous isotonic solutions or suspensions. The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers, hi addition, they may also contain other therapeutically valuable substances.

The conjugates can be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions.

Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Additionally, one approach for parenteral administration employs the implantation of a slow-release or sustained-released systems, which assures that a constant level of dosage is maintained, according to U.S. Pat. No. 3,710,795, incorporated herein by reference. Where the conjugate is given orally, it can be formulated through combination with pharmaceutically acceptable carriers that are well known in the art. The carriers enable the compound to be formulated, for example, as a tablet, pill, suspension, liquid or gel for oral ingestion by the patient. Oral use formulations can be obtained in a variety of ways, including mixing the compound with a solid excipient, optionally grinding the resulting mixture, adding suitable auxiliaries and processing the granule mixture.

The conjugates of the invention can also be administered in such oral dosage forms as timed release and sustained release tablets or capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.

For instance, for oral administration in the form of a tablet or capsule (e.g., a gelatin capsule), the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum starches, agar, alginic acid or its sodium salt, or effervescent mixtures, and the like. Diluents, include, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine. Suitable excipients include sugars such as lactose, sucrose, mannitol or sorbitol; cellulose preparations such as maize starch, wheat starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone (PVP).

Alternatively, the conjugates are delivered in an aerosol spray preparation from a pressurized pack, a nebulizer or from a dry powder inhaler. Suitable propellants that are used in a nebulizer include, for example, dichlorodifluoro-methane, trichlorofluoromethane, dichlorotetrafluoroethane and carbon dioxide. The dosage is determined by providing a valve to deliver a regulated amount of the compound in the case of a pressurized aerosol.

Furthermore, preferred conjugates for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. Other preferred topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of active ingredient would range from 0.01% to 15%, w/w or w/v.

For solid compositions, excipients include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like may be used. The conjugate defined above, may be also formulated as suppositories using for example, polyalkylene glycols, for example, propylene glycol, as the carrier. In some embodiments, suppositories are advantageously prepared from fatty emulsions or suspensions.

The conjugates of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines, hi some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No. 5,262,564. For example, the conjugates described herein can be provided as a complex with a lipophilic compound or non-immunogenic, high molecular weight compound constructed using methods known in the art. An example of nucleic-acid associated complexes is provided in US Patent No. 6,011,020.

The conjugates of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl-methacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the conjugates of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and other substances such as for example, sodium acetate, triethanolamine oleate, etc. The dosage regimen utilizing the conjugates is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular conjugate employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest etc. the progress of the condition.

Although a therapeutically effective amount of a conjugate will vary according to the patient being treated, suitable doses will typically include at least 0.1, 1, 10, 100 mg of the compound. Suitable doses will typically be less than 20, 50, 100, 250, 500, 1000, 2000, 4000 mg of the compound. Preferably, a dose contains between about 1 mg and 1000 mg of the compound. More preferably, a dose contains between about 5 mg and 500 mg of the compound.

In some cases, it may be necessary to use dosages outside of the stated ranges to treat a patient. Those cases will be apparent to the prescribing physician. Where it is necessary, a physician will also know how and when to interrupt, adjust or terminate treatment in conjunction with a response of a particular patient.

Conjugates may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Preferably, the conjugates are administered once or twice day only or once every other day. Tmax and Cmax for a conjugate in a subject (and the gabapentin not conjugated to an aminoadamantane) can be calculated using methods known in the art (see, e.g., the USP (United States Pharmacopoeia) and US Patent no.6,555,581). Tmax and Cmax can be calculated using samples extracted from brain or cerebrospinal fluid. Values can also be calculated based on samples taken from tissues such as serum. It is expected that altered serum values of a conjugate as compared to the therapeutic agent delivered when not conjugated to the therapeutic agent will reflect delivery of the conjugate from tissues outside the blood-brain barrier to the brain. Synthesis of novel dual functional mernantine conjugates

Dual functional NMDA receptor-binding memantine nitrates (Fig. 1) have been described, which specifically deliver NO to the NMDA receptor site (detailed synthesis of these drugs is described in US patent 6,444,702, the contents of which are incorporated by reference in their entirety). These compounds are designed to have dual functions, i.e., binding to the NMDA receptors and release the NOx⁺ functionality. Our work shows that these memantine nitrates, YQW-007, -012 and -035 have dual actions on the NMDA receptors and are neuroprotective, hi addition, they did not lower the blood pressure of rats when administered intravenously (i.v.) or intraperitoneally (i.p.) at neuroprotective doses.

Blocking of memantine and memantine nitrates at the NMDA receptor channel

Blocking of the dual functional memantine nitrates at the NMDA receptor was studied with whole-cell patch clamp recordings of native NMDA receptors in cultured mouse cerebrocortical neurons. Application of NMDA (200 μM) evokes an inward current. NMDA receptor antagonists can inhibit this NMDA-evoked current. For example, memantine inhibits this NMDA-evoked current in a concentration-dependent fashion with ICs₀ values in the range of 0.5-3 μM (Blanpied et al., 1997; Chen and Lipton, 1997; Kashiwagi et al., 2002; Parsons et al, 1993; Sobolevsky et al., 1998). In our experiments we found that the IC₅₀ values of memantine, YQW-012 and -035 are 0.5, 10 and 100 μM, respectively. These data demonstrated that YQW- 012 and -035 bound to the NMDA receptors although their affinities were lower than that of memantine.

In vivo protection by YQW-012 in a murine cerebral ischemia model

The suture technique was used to produce a 2 hr occlusion of the middle cerebral artery

(MCA), following the same protocol for focal cerebral ischemia/reperfusion as mentioned elsewhere in this proposal (Chen et al., 1998). However, here we used C57B1/6 mice instead of rats. For memantine the loading dose was 20 mg/kg i.p. with a maintenance dose of 1 mg/kg/12 hr, as this had been previously shown to produce parenchymal levels of 1-10 μM memantine in the brain, which we have shown to be neuroprotective (Chen et al., 1998). To produce a neuroprotective concentration of YQW-012, based on our in vitro studies, the loading dose was 100 mg/kg i.p. and the maintenance dose was 40 mg/kg i.p. every 12 hr. In each case, drug or vehicle control was initially administered 2 hr after MCA occlusion. YQW-012 was more neuroprotective than memantine under this paradigm (Fig. 2). Additional preliminary studies (not shown) revealed that YQW-012 was more neuroprotective than amantadine at similar doses (amantadine was also tested because of its similar affinity for the NMDA receptor as YQW-012, as demonstrated in our electrophysiological studies of on- and off-rate of drug action) as in Chen and Lipton (1997). The animals were sacrificed and analyzed with TTC staining 48 hr after MCA occlusion (Chen et al., 1998). These data demonstrate that memantine nitrate had neuroprotective effect in this murine cerebral ischemia model.

Phase II formalin results

In an animal formalin pain model, we found that gabapentin decreased the response to formalin injection in Phase II (Fig. 3). The effect was statistically significant for Phase π responses regardless of whether they were measured over 60 minutes (F = 4.74, p < 0.01 by ANOVA) or 90 minutes (F = 5.41, p < 0.01). The highest doses tested (30 and 100 mg/kg) showed the most robust analgesic effect.

Summary of preliminary data for novel gabapentin- memantine conjugates

We have successfully synthesized and tested a number of novel memantine conjugate compounds. In these compounds, memantine is used as a carrier to deliver a second moiety specifically to the NMDA receptors. Thus, the compounds have dual functions, i.e. binding to the NMDA receptor and possessing secondary drug-like activity. Based on this breakthrough groundwork, we plan to use memantine or amantadine as a carrier to deliver gabapentin to the CNS (e.g. to the brain) to increase its bioavailability and reduce side effects. In addition, this combinatory drug will have the benefits of both the aminoadamantine derivative (e.g. memantine) and gabapentin, two of the very useful drugs for the treatment of neurologic diseases.

The conjugates allow for the additive or synergistic combination of gabapentin and memantine / amantadine to increase the relative absorption and brain/plasma ratio of gabapentin. Using a cleavable linker allows for gabapentin and memantine / amantadine to both be delivered to the CNS to treat pain syndromes and other CNS-related conditions in a more effective manner. The novel gabapentin-memantine compounds (Fig. 4) have at least two advantages. First, incorporating a memantine or amantadine moiety to gabapentin increases gabapentin's bioavailability; and second, the gabapentin-aminoadamantane derivative (e.g. gabapentin- memantine) has the functions of both gabapentin and the aminoadamantane derivative (e.g. memantine), leading to an additive or synergistic beneficial effect.

Although gabapentin is a useful drug, its bioaviailability is poor, and as dose increases, its bioavailability decreases. The bioavailability of gabapentin is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/ day given in 3 divided doses, respectively. Its half-life is approximately 6 hr, and thus it has to be given three or four times a day to patients to achieve a lasting therapeutic effect. The poor absorption is due to the limited capability of its transport mechanism. Oral gabapentin is absorbed in the small intestine and then crosses the blood-brain barrier, both processes mediated by a L-type-amino acid transporter (LAT) (Stewart et al, 1993; Taylor et al, 1998; Luer et al, 1999). Because LAT has a low K(m), making it particularly susceptible to substrate saturation. Variable expression and saturation of LAT lead to unpredictable drug exposure and potentially ineffective therapy in some patients. The absorption of gabapentin from colon is further restricted by lipid membrane permeation. Based on a log octanol-water partition coefficient of -1.1 (Volhner et al, 1986), colonic absorption of this zwitterionic drug should be minimal.

The current invention may improve the bioavailability by increasing the absorption of the drug from the gastrointestinal tract and / or increasing the half life of the gabapentin moiety and / or increasing the transport of that moiety across the blood brain barrier. Each of these elements is an improvement that may reduce the total daily dose of the gabapentin moiety to achieve a therapeutic efficacy, and the combination of two or more of these elements is anticipated to have a marked effect on the same.

It has been shown that both the free amino and carboxylic acid moieties are needed for transport by LAT (Uchino et al, 2002). Thus, the combinatory gabapentin-memantine / gabapentin-amantadine compounds are not expected to be transported by LAT anymore because the carboxylic acid moiety of gabapentin has been converted into a memantine / amantadine ester. Instead, gabapentin-memantine / gabapentin-amantadine will be transported by high capacity transport mechanisms located in both the small and large intestine. Indeed, gabapentin prodrugs have been shown to have improved absorption efficiency and were absorbed in both the small and large intestine by nutrient transporters (Cundy et al., 2004a, 2004b). Furthermore, due to the increased LogP, gabapentin-memantine / gabapentin-amantadine will have greatly improved cell membrane permeation. Most importantly, gabapentin-memantine / gabapentin- amantadine carries gabapentin specifically to the brain cells. This target-specific delivery of gabapentin will further increase its bioavailability, and reduces side effects.

Gabapentin-memantine / gabapentin-amantadine not only increases the bioavailability of gabapentin, it has the functions of both gabapentin-memantine / gabapentin-amantadine.

Although both gabapentin and memantine / amantadine have been used to treat neurological diseases such as epilepsy, neuropathic pain, and depression among others, they act by different mechanisms in the human brain. Because of the different mechanisms of action, these two drugs will have synergistic effects. For example, by inhibiting the overflow of glutamate, memantine / amantadine has therapeutic potential in numerous CNS disorders ranging from acute neurodegeneration (e.g., stroke and traumatic brain injury), chronic neurodegeneration (e.g., Parkinson's disease, AD, Huntington's disease, amyotrophic lateral sclerosis) to symptomatic treatment of epilepsy, multiple sclerosis, drug dependence and chronic pain. Since there is growing evidence that NMDA receptor activation might play a crucial role in epilepsy, memantine and amantadine become compounds of interest in preventing and treating seizures (for review see Rogawski and Loscher, 2004).

On the other hand, antiepileptic drugs (AEDs) such as gabapentin are commonly prescribed for nonepileptic conditions, including migraine headache, chronic neuropathic pain, mood disorders, schizophrenia and various neuromuscular syndromes. In many of these conditions, as in epilepsy, the drugs act by modifying the excitability of nerve (or muscle) through effects on voltage-gated sodium and calcium channels or by promoting inhibition mediated by gamma-aminobutyric acid (GABA) A receptors. In neuropathic pain, chronic nerve injury is associated with the redistribution and altered subunit compositions of sodium and calcium channels that predispose neurons in sensory pathways to fire spontaneously or at inappropriately high frequencies, often from ectopic sites. AEDs may counteract this abnormal activity by selectively affecting pain-specific firing; for example, many AEDs suppress high- frequency action potentials by blocking voltage-activated sodium channels in a use-dependent fashion. Alternatively, AEDs may specifically target pathological channels; for example, gabapentin binds to alpha2delta voltage-activated calcium channel subunits in brain tissues that are overexpressed in sensory neurons after nerve injury. Gabapentin increases the concentration and probably the rate of synthesis of GABA in brain, which may enhance non- vesicular GABA release during seizures. Mechanism of Action

The compounds are designed to increase gabapentin' s bioavailability and to have dual functions. They are expected to be effectively absorbed in the small and large intestines, and readily cross the blood-brain barrier. They will be cleaved by the non-specific carboxylate esterases, releasing free gabapentin and memantine (Fig. 5). Due to differences in steric hindrance to carboxylate esterases, some of the compounds will be cleaved faster than the others. The cleavage can take place in blood stream or in brain tissues/cells, and the ideal place is the brain tissues. If the cleavage occurs outside the brain tissues, gabapentin' s bioavailability will be improved, and the drug will have dual functions; however, gabapentin will not be carried specifically to the brain cells because the deliver vehicle i.e., memantine, is lost before it gets to the brain. This some how compromises the purpose of targeted delivery of gabapentin, but will still provide us with a promising new drug.

EXAMPLES

Example 1: Synthesis of novel gabapentin-memantine conjugates

In compounds PM 1-3, the COOH moiety of gabapentin is linked to a linker through a ester bond, which is then linked to memantine through a carbamoyl bond. In PM 4-6, the NH2 moiety of gabapentin is linked to a linker through a carbamoyl bond, which is then linked to memantine through another carbamoyl bond. Free gabapentin and memantine will be released after the ester and carbamoyl bonds are cleaved. Both the ester and carbamoyl bonds are substrates of carboxylate esterase. The length of linkers of PM 1-6 is different, and this is designed to produce different steric hindrance to carboxylate esterase. We will perform experiments to find out which linker is optimal. For compounds PM 7-10, when the linker is cleaved, free gabapentin is generated; however, the other parts are not memantine. These compounds are designed to facilitate the transport of gabapentin and to compare their effects with those of PM 1-6.

Synthesis of compounds PM 1-3

Compounds PM-1-3 will be synthesized as illustrated in Fig. 6. The amino moiety of the commercially available gabapentin is protected with a BOC group first to afford intermediate 1. The latter compound is coupled to the linker di-hydroxyl compounds (the di-alcohols are commercially available) using DCC as a catalyst to generate intermediate 2. Treatment of compound 2 with 4-nitrophenyl chloroformate produces intermediate 3. Memantine is allowed to react with compound 3 affording the targeted compounds PM 1-3.

Synthesis of compounds PM 4-6

Compound PM 4-6 will be synthesized as illustrated in Fig. 7. Di-hydroxy alcohol is treated with 4-nitrophenyl chloroformate producing intermediate 4, which is then treated with memantine followed by gabapentin affording compounds PM 4-6.

Synthesis of compound PM- 7

Compound PM-7 will be synthesized as illustrated in Fig. 8. Gabapentin is coupled to compound 5 in the presence of DCC affording PM-7.

Synthesis of compound PM-8

Compound PM-8 is synthesized as illustrated in Fig. 9. Memantine is treated with the commercially available compound 5 to generate intermediate 7. The latter is coupled to compound 1 to generate intermediate 8. The BOC protective group of 7 is removed by treatment with anhydrous HCl in ethyl acetate affording PM-8. Synthesis of compound PM-9

Compound PM-9 is synthesized as illustrated in Fig. 10. Compound 4 is treated with 4- nitrophenyl chloroformate to form intermediate 9, which is then treated with memantine to afford PM-9.

Synthesis of compound PM-10

Compound PM-10 is synthesized as illustrated in Fig. 11. Compound 7 is treated with 4- nitrophenyl chloroformate to form intermediate 10, which is then treated with gabapentin to afford PM-10. The compounds are purified by either crystallization or flash column chromatography, and their structures are confirmed by NMR, MS and elemental analysis.

Example 2: Evaluating NMDA receptor activity and dual functions in vitro

Evaluation of the activity of these gabapentin-memantine conjugates can include, e.g., monitoring maintenance of NMDAr activity.

Electrophysiological recordings of recombinant channels from oocytes

The in vitro characterization of these drugs can include, e.g., two components: recombinant mutant and wild-type cerebral cortical responses. Xenopus oocytes are prepared as described (Goldin, 1992). hi brief, stage V and VI xenopus laevis oocytes are harvested and defolliculated with collagenase (Sigma). Up to 25 ng cRNA of wild-type and/or mutant NRl and NR2A subunits are injected into each oocyte. Injected oocytes are incubated at 18 ⁰C in ND96 medium (in mM): NaCl, 96; KCl, 2; CaCl2, 1.8; MgCtø, 1; HEPES, 10; adjusted to pH 7.5, and supplemented with 550 μg/ml sodium pyruvate and 100 μg/ml gentamicin. Two-electrode voltage-clamp recordings are performed 2-7 days after cRNA injection using a dual-electrode voltage-clamp amplifier (Warner Instrument Corp., Model OC-725A). Micropipettes are filled with 3 M KCl. Oocytes are voltage-clamped at -60 to -80 mV during recordings unless otherwise indicated. The general recording Ringer's solution contains barium to minimize intrinsic calcium-activated chloride currents in oocytes and contains (in mM): 1 BaCtø, 95 NaCl, 2 KCl, 5 HEPES, pH adjusted to 7.5 with NaOH. Ten μM glycine was added to all the solutions and 200 μM NMDA was used to elicit the NMDA-activated currents. NMDA-evoked responses are collected and analyzed using MacLab v3.5 (ADInstruments) and Axograph v3.5.5 software (Axon Instruments). After subtracting the mean leak current in the absence of agonist or antagonist, current- voltage curves are constructed by ramping voltage slowly (50 mV/s) from - 120 to +60 mV during application of NMDA plus glycine in the presence or absence of 100 μM

Mg²⁺.

Example 3: Evaluating NMDA receptor activity and dual functions in vivo

Evaluation of the activity of these gabapentin-memantine conjugates can include, e.g. , monitoring gabapentin elevation in the CNS.

PKproperties

Test compounds are dissolved in 0.9% saline. Compounds will be administered by intraperitoneal injection using 3 ml syringes and 25 gauge needles. The dosing volume will be 5 ml/kg. Free gabapentin and memantine will be used as positive controls.

Animals (Male Sprague-Dawley rats (Hsd:Sprague Dawley®^TMSD®^TM, Harlan, Indianapolis, Indiana, U.S.A.) weighing 299 ± 1 g) will be employed. Eight groups of 3 animals each will be injected, and serum samples will be taken at 0.25, 0.5, 1, 2, 4 and 8 hours. Groups of 3 animals will be sacrificed at 1, 2, and 4 hr, and brains will be harvested. Brain levels of the drugs will be measured. Samples will be sent for LC/MS/MS analysis to confirm the levels of the memantine-gabapentin conjugate, free memantine and free gabapentin.

Example 4: Evaluating NMDA receptor activity and dual functions in vivo

Evaluation of the activity of these gabapentin-memantine conjugates can include, e.g., monitoring gabapentin elevation in vivo models of pain.

Formalin Model of Neuropathic Pain

Test compounds are dissolved in 0.9% saline. Compounds will be administered by intraperitoneal injection using 3 ml syringes and 25 gauge needles. The dosing volume was 5 ml/kg. Both the free gabapentin and memantine and a mixture of gabapentin and memantine will be used as positive controls.

Animals (Male Sprague-Dawley rats weighing 299 ± 1 g) will be tested for paw movement response to injection of 5% formalin solution (50 μl in saline) using the Automated Nociception Analyzer Yaksh, et al. This device uses a magnetic detection system to measure paw movements. This has been shown to generate responses indistinguishable from alternatives such as weighted behavioral scoring of formalin-induced behaviors. Small metal bands will be attached to the right hind paw of rats just before they were placed individually in each of 4 circular test chambers (4 per session) 30 minutes prior to formalin injection. Some rats were injected with test drugs 15 minutes prior to formalin injection (saline 1, morphine, tramadol groups), whereas others were injected with test drugs 50 minutes prior to formalin injection (saline 2, gabapentin, memantine, naproxen). To initiate the experiment rats were injected with 50 μl of 5% formalin subcutaneously on the dorsal surface of the right hindpaw and placed in the test chambers. The instrument then recorded rapid foot movements, counting them in one minute epochs.

Various animal models (neuropathic and chronic pain, and epilepsy) known in the art ar used to identify the best therapeutic indication for the new compounds. Preclinical efficacy, pharmacokinetics and toxicity studies are performed.

Animals are kept in cages in the MH-approved facility. During the investigations outlined in this proposal, all care will be taken to minimize any pain or discomfort that the animals may experience. All procedures are performed with gentle care to avoid unnecessary discomfort, distress, pain, or injury.

Animals are killed by cervical dislocation under anesthesia. This procedure is consistent with the recommendations of the Panel on Euthanasia of the American Veterinary Medical Association (AVMA) as an appropriate euthanasia method for immature rodents.

OTHER EMBODIMENTS

While the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. Literature Cited.

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Claims

What is claimed is:

1. A conjugate comprising an NMDA receptor antagonist linked to gabapentin or a pharmaceutically acceptable salt thereof, wherein the NMDA receptor antagonist is memantine (l-amino-3,5-dimethyladamantane), amantadine (1-amino-adamantane) or a pharmaceutically acceptable salt of memantine or amantadine.

2. The conjugate according to claim 1 wherein the NMDA receptor antagonist is amantadine or a pharmaceutically acceptable salt thereof.

3. The conjugate according to claim 1 wherein the NMDA receptor antagonist is memantine or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising a conjugate according to any one of claims 1 to 3 and optionally a pharmaceutically acceptable carrier.

5. The pharmaceutical composition according to claim 4 wherein the pharmaceutical composition is provided in an extended release dosage form.

6. The conjugate according to any one of claims 1 to 3 for use in medicine.

7. A method of treating a CNS-related condition in a subject in need thereof comprising administering a therapeutically effective amount of a pharmaceutical composition according to claim 4 or 5.

8. Use of a conjugate according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment of a CNS-related condition.

9. The use according to claim 8 wherein the medicament is an extended release dosage form.

10. A method or use according to any one of claims 7 to 9 wherein the CNS-related condition is selected from the group consisting of epilepsy, pain or depression.

11. A method of treating epilepsy, pain or depression in a subj ect in need thereof comprising orally administering a therapeutically effective amount of a pharmaceutical composition according to claim 4 or 5 wherein the NMDA receptor antagonist is memantine or a pharmaceutically acceptable salt thereof.

12. A method of treating epilepsy, pain or depression in a subject in need thereof comprising orally administering a therapeutically effective amount of a pharmaceutical composition according to claim 4 or 5 wherein the NMDA receptor antagonist is amantadine or a pharmaceutically acceptable salt thereof.