Methods and compositions for treatment of cns disorders

[0001] The present invention relates to methods and compositions for the treatment of conditions associated with the CNS such as Alzheimer's disease.

BACKGROUND OF THE INVENTION [0002] Acute and chronic neurological and neuropsychiatric diseases are among the leading causes of death, disability, and economic spending worldwide. Alzheimer's disease is currently the fourth leading cause of death in the US. There is no known treatment for this chronic degenerative disease that directly affects millions of people around the world. Other diseases and disorders of the central nervous system also cause significant suffering and costs for those affected by these diseases as well as for their families and insurers.

[0003] There are numerous medications on the market today for treating symptoms or arresting the progression of these diseases, but most have moderate or limited efficacy. Often, many pharmaceuticals are used to optimize therapy for the specific needs of patients at different stages of the disease. One of the key difficulties in treating these diseases is the high degree of association between pathways that regulate both normal and abnormal neuronal function. Typically, the therapeutic regulation of these functions is determined to maximize therapeutic effects while minimizing the debilitating side effects of these therapies. Usually these efforts are more complex when many therapeutic measures are used. [0004] Improved therapeutic agents are needed to treat these diseases and disorders.

SUMMARY OF THE INVENTION [0005] In general, the present invention relates to methods and compositions for the treatment and prevention of CNS related conditions such as neurodegenerative conditions (e.g., Alzheimer's disease and Parkinson's disease) and pain, by administering to a subject in need thereof, a combination that includes an N-methyl-D-aspartate (NMDAr) receptor antagonist selected from memantine or a pharmaceutically acceptable salt thereof, and a second agent, such as an acetylcholinesterase (ACheI) inhibitor selected from donepezil, rivastigmine, galantamine, tacrine, methrifonate or hupercin A. Administration of the combinations described herein results in alleviating and preventing symptoms associated with or arising from CNS related conditions such as Parkinson's disease or Alzheimer's disease, which include, for example, memory loss, loss of balance, hallucinations, delusions, agitation, withdrawal, depression , communication problems, cognitive loss, personality change, confusion and insomnia. The combinations of the present invention may be used to prevent or treat CNS related conditions associated with Alzheimer's disease, and may also be useful for the treatment and prevention of headaches, cerebrovascular disease, motor neuron diseases, dementia, neurodegenerative diseases, strokes, disorders movement, atactic syndromes, sympathetic nervous system disorders, cranial nerve disorders,

Myelopathy, traumatic brain and spinal cord injury, radiation brain damage, multiple sclerosis, meningitis syndrome, prion diseases, spinal cord inflammation, neuritis, neuropathies, pain syndromes, brain axon damage, encephalopathies, syndrome chronic fatigue, psychiatric disorders, glucose dysregulation, and substance addiction.

[0006] The NMDAr antagonist, ACheI, or both can be administered in an amount similar to that typically administered to patients. Optionally, the amount of NMDAr antagonist, ACheI, or both agents can be administered in an amount greater than or less than the amount typically administered to the subject. If desired, the amount of NMDAr antagonist in the pharmaceutical composition is less than the amount of NMDAr antagonist required in a unit dose to obtain the same therapeutic effect for the treatment or prevention of a CNS-associated condition when the NMDAr antagonist is administered in the absence of ACheI. Alternatively, the amount of ACheI in the pharmaceutical composition is less than the amount of ACheI required per unit dose to obtain the same therapeutic effect for the treatment or prevention of a CNS-associated condition when ACheI is administered in the absence of an NMDAr antagonist. Optionally, the NMDAr antagonist, ACheI, or both agents are present at a dose higher than the dose typically administered to a particular subject. For example, the amount of memantine required to positively impact patient response (including adverse effects) may be 2.5-80 mg per day instead of the typical 10-20 mg per day administered for the currently approved indications, i.e., without the improved formulations described herein. A higher amount of NMDAr antagonist dose can be utilized in the present invention, while a lower dose of NMDAr antagonist may be sufficient when combined with ACheI to achieve a therapeutic effect in a patient. Optionally, unit or dose amounts of both NMDAr antagonist and ACheI lower or reduced relative to the amount of each agent when administered as monotherapy are used. In a preferred embodiment, the amount of NMDAr antagonist in the pharmaceutical composition is equal to or higher than the amount typically administered to a particular condition as a monotherapy, and the amount of ACheI in the pharmaceutical composition is less than the amount typically administered to a subject to a similar condition.

[0007] The invention also relates to a pharmaceutical composition which comprises an NMDAr antagonist and ACheI. Optionally, a pharmaceutically acceptable carrier is included.

[0008] Although compositions comprising an NMDAr antagonist and a second agent such as an acetylcholinesterase (ACheI) inhibitor have been disclosed (e.g. US 2004/0087658), the problem of ensuring the release of the NMDAr antagonist in the desired manner (e.g. in a sufficiently high amount for treatment) has not been solved. symptoms or damaging effects of the underlying disease, while avoiding undesirable side effects (e.g. CNS side effects) when used in combination therapy. In particular, currently available dosage forms of NMDAr antagonists must be administered frequently and require dose escalation at the start of therapy to avoid side effects associated with initial exposure to the therapeutic agent. This leads to the difficulty of obtaining adequate patient compliance, which is further exacerbated by the complicated dosing regimens of therapies used for

EP 1 874 282 B1 neurological or neuropsychiatric disorders. This problem has not been resolved in the context of providing an NMDAr antagonist as a component of combination therapy.

[0009] Delivery of the NMDAr antagonist in combination with ACheI requires careful formulation formation, and the pharmacokinetic properties of two agents must be taken into account, for example, to ensure that the amount and rate of release of each agent is sufficient for therapeutic benefit while minimizing or avoiding undesirable side effects. Further, it is not only the pharmacokinetic properties of each drug that need to be considered (e.g. Tmax, half-life, etc.), but any interaction between the two agents is a further complicating factor.

[0010] In one embodiment of the invention, the NMDAr antagonist, ACheI, or both can be provided in a controlled or extended release form, with or without a direct release component, to maximize the therapeutic benefit for each and at the same time reduce undesirable side effects associated with each of them.

[0011] The term "immediate release formulation" as used herein refers to an active pharmaceutical ingredient formulation that releases more than 80 percent of the active pharmaceutical ingredient in less than one hour in a USP dissolution test method as described herein, or by the manufacturer for commercial product. Typically, the release of the active ingredient in an immediate release formulation is more than 80 percent in less than 30 minutes, as in Figures 1A and 2A.

[0012] When these drugs in oral form are delivered without the benefit of the release of regulated or prolonged components, they are released and transported to body fluids over a period of minutes to several hours. Thus, the composition of the invention may contain an NMDAr antagonist and a sustained release component, such as a coated sustained release matrix, sustained release matrix, or sustained release bead matrix. In one example, memantine (e.g., 5-80 mg) is formulated without a direct release component using a polymer matrix (e.g., Eudragit), hydroxypropyl methylcellulose (HPMC) and a polymer coating (e.g., Eudragit). Such formulations are compressed into solid tablets or granules. Optionally, a coating such as Opadry® or Surelease® is used.

[0013] As used herein, the terms "sustained release dosage form", "controlled release dosage form", and "sustained release dosage form" and similar terms are used interchangeably, and include dosage forms where the active drug substance or substances are released for an extended period of time. The term "sustained" release should be understood as distinct from direct release, and in particular this term indicates that the formulation does not release the full dose of active ingredient immediately after dosing. Such sustained release dosage forms typically allow a reduction in the frequency of dosing compared to the frequency of a conventional dosage form or direct release dosage form. The sustained release forms may or may not contain the immediate release component.

[0014] Optionally, the composition described herein is formulated such that at least one of said NMDAr antagonist or said ACheI has an in vitro dissolution profile of less than 70% in one hour, less than 90% in two hours, more than 40% in six hours, and more than 85% in 12 hours, as measured using a USP type 2 dissolution test instrument (with spatula) at 50 rpm, at 37 ± 0.5 ° using water as the dissolution medium.

[0015] As used herein, the symbol "C" refers to the concentration of active pharmaceutical ingredient in a biological sample, such as a sample of a patient's body fluid (e.g., blood, serum, and cerebrospinal fluid). The concentration of the drug in the biological sample can be determined by any standard assay method known in the art. The term "Cmax" refers to the maximum concentration achieved by a given dose of drug in a biological sample. The term "Cmean" refers to the average drug concentration in a sample over a period of time. Cmax and Cmean can be further defined as referring to specific periods of time with respect to drug administration. The time needed to reach the maximum concentration ("Cmax") in a particular type of patient's body fluid sample is referred to as "Tmax". The agents included in the combination are administered in formulations that reduce the variability of the concentration ratio of active agents over a period of time, thereby maximizing therapeutic benefit while minimizing side effects.

[0016] In a preferred embodiment, the dosage form is administered twice a day or once a day in a non-escalating form. In such cases, the monotonic increase in concentration (or Tmax effect) can be limited so that the change in concentration as a function of time (dC / dT) is changed to reduce or eliminate the need for an increased dose drug. Reduction in dC / dT can be achieved, for example, by increasing Tmax in a relatively proportional manner. Accordingly, a two-fold increase in Tmax can reduce dC / dT by an factor of approximately 2. Thus, the NMDAr antagonist can be delivered so that it is released at a rate that is significantly reduced compared to the rate for a direct release dosage form (so-called IR from immediate release), with the associated delay Tmax. The pharmaceutical composition may be formulated to give a Tmax shift of 24 hours, 16 hours, 8 hours, 4 hours, 2 hours, or at least 1 hour. A reduction of dC / dT by a factor of approximately 0.05, 0.10, 0.25, 0.5, or at least 0.8 may be associated with this. In certain embodiments, this is accomplished by releasing less than 30%, 50%, 75%, 90%, or 95% of the NMDAr antagonist into the circulatory or nervous system within one hour of such administration.

[0017] Providing such dosage forms without increasing the dose is particularly useful because they provide the drug in a therapeutically effective amount from the beginning of therapy, further improving patient compliance and adherence, and allow achieving therapeutically effective equilibrium dynamic drug concentration over a shorter period of time. This results in earlier demonstration of effectiveness and an increase in the usefulness of these therapeutic agents for such diseases and conditions where time counts. In addition, the compositions of the present invention, by their design, allow for safe administration of higher doses of the drug, which again increases the usefulness of these agents for various indications.

[0018] If desired, the NMDAr or ACheI antagonist from the combination is released into the body fluid sample being treated at a slower rate than that observed for direct release (IR) formulations with the same amount of antagonist. The release rate is measured as dC / dT over a defined period of between 0 and Tmax for the IR formulation and the dC / dT rate is less than about 80% of the speed for the IR formulation. In some embodiments, the dC / dT rate is less than about 60%, 50%, 40%, 30%, 20% or 10% rate for IR formulations. Similarly, ACheI may also be released into a patient's body fluid sample at a slower rate than observed for the same amount of IR formulation, where the release rate is measured as dC / dT over a defined period between 0 and Tmax for IR formulation and dC / dT rate is less than about 80%, 60%, 50%, 40%, 30%, 20%, or 10%, IR rates of the same NMDAr antagonist in the first 1, 2, 4, 6, 8, 10, or 12 hours.

[0019] Optionally, sustained release formulations exhibit plasma concentration curves having an initial slope (e.g., from 2 hours after administration to 4 hours after administration) less than 75%, 50%, 40%, 30%, 20% or 10 % slope for an IR formulation of the same dose of the same NMDAr antagonist. The exact slope value for a given individual will vary depending on the amount given, or other factors, for some pharmaceutical active agents including whether the patient is full or not. For other doses, e.g., those mentioned above, the slopes change directly depending on the dose.

[0020] Using the sustained release formulations described herein, the NMDAr or ACheI antagonist achieves a therapeutically effective plasma concentration at steady state in the subject within the first five, seven, nine, ten, twelve, fifteen, or twenty days of administration. For example, the formulations described herein, when administered at a substantially constant daily dose (e.g., memantine at a dose ranging between 15 mg and 80 mg, and preferably between 20 and 45 mg) can reach steady-state plasma concentration within approximately 70%, 60%, 50%, 40%, 30%, or less time required to reach this plasma concentration when using the dose escalation mode.

[0021] The concentration ratio of the two agents in combination is referred to as "Cratio"; it may fluctuate as the drug combination is released, transported to the cardiovascular or CNS system, metabolized, and eliminated. The purpose of the present invention is to stabilize Cratio for the combinations described herein. In some embodiments, it is preferred to reduce or even minimize the variability of Cratio (referred to as "Cratio, var"). Using the methods described herein, the release profiles of each pharmaceutical active ingredient can be modified to achieve almost constant Cratio values, thereby minimizing Cratio, var. In cases where Tmax and T1 / 2 NMDAr antagonists and ACheI are significantly different, e.g., by a factor of two or more, release profiles desirable to minimize relative variability of active agents between doses will likely be dissimilar.

[0022] Thus, a feature of the present invention are formulations or combinations directed to dose optimization or release modification to reduce the adverse effects associated with the separate administration of each agent. The combination of NMDAr antagonist and ACheI may give an additive or synergistic response as described below.

[0023] In all preceding aspects of the invention, at least 50%, 80, 90%, 95%, or substantially all of the NMDAr antagonist in the pharmaceutical composition may be provided in a controlled release dosage form. In some embodiments, at least 99% of the NMDAr antagonist remains in the sustained release dosage form one hour after the pharmaceutical composition has been introduced into the subject. The NMDAr antagonist may have a Cmax / Cmean ratio of approximately 2, 1.6, 1.5, 1.4, 1.3, 1.2 or less, from approximately 2 hours to at least 8, 12, 16, 24 hours after the NMDAr antagonist has been introduced into the subject. Also, ACheI may be provided in a controlled release dosage form. Thus, at least 50%, 60%, 70%, 80%, 90%, 95%, or substantially all of ACheI can be provided as a controlled release formulation. If ACheI is provided as such, it may have a Cmax / Cmean value of approximately 2, 1.6, 1.5, 1.4, 1.3, 1.2 or less, from approximately 2 hours to at least 6 , 8, 12, 16, or 24 hours after the introduction of ACheI into the treated body.

[0024] Pharmaceutical active agents can be administered to a patient in a manner that reduces the variability of the concentration ratio of active agents over a period of time, thereby maximizing therapeutic benefit while minimizing side effects. The present invention differs from previous research by providing new combinations as well as formulation combinations targeted at dose optimization or release modification to reduce the adverse effects associated with each agent.

[0025] Optionally, the ratio of Cratio, var NMDAr antagonist and ACheI is less than 100%, e.g., less than 70%, 50%, 30%, 20%, or 10% after the agents reach dynamic equilibrium conditions. Optionally, the ratio of Cratio, var NMDAr antagonist and ACheI is less than 100%, e.g. less than 70%, 50%, 30%, 20%, or 10% during the first 24 hours after administration of the agents. In some embodiments, the Cratio, var ratio is less than about 90% (e.g., less than about 75% or 50%) of the value for IR administration of the same active pharmaceutical ingredients within the first 4, 6, 8, or 12 hours after administration.

[0026] In all preceding aspects of the invention, the NMDAr antagonist is memantine or a pharmaceutically acceptable salt thereof. ACheI, an acetylcholinesterase inhibitor, can be donepezil / ARICEPT®, rivastigmine / EXELON®, galantamine / REMINYL®, tacrine / COGNES®, methrifhonate, or hupercin A. tacrine, methrifonate, or hupercin A. In some embodiments, the NMDAr antagonist, ACheI, or both agents are formulated for oral, intravenous, intranasal, topical epithelial, subcutaneous, or inhalation delivery. Thus, agents described herein may be formulated as a suspension, capsule, tablet, suppository, liquid, patch, or device (e.g., a skin implanted dosing device or inhalation pump). If desired, the NMDAr antagonist and ACheI may be mixed into single composition. Alternatively, two agents are delivered in separate formulations sequentially, or within one hour, two hours, three hours, six hours, 12 hours, or 24 hours in succession. If administered separately, the two agents may be administered by the same or different routes of administration three times a day, twice a day, once a day, or even once every two days. Optionally, two agents are provided together in the form of a kit. preferably,

The NMDAr antagonist and ACheI are provided in unit dose form. Unless otherwise specified, 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, useful 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 event of a conflict, this patent specification, including the definitions, decides. In addition, the materials, methods and examples are for illustrative purposes only and are not intended to limit the invention. All parts and percentages are by weight unless otherwise stated.

BRIEF DESCRIPTION OF THE FIGURES [0027]

FIGURE 1A is a graph showing a controlled release formulation of memantine (Namenda) and sustained release formulation of memantine (NPI-6601, NPI-6701, and NPI-6801). Sustained release formulations contain 22.5 mg memantine. These dissolution profiles were obtained from a USP type II device with a paddle using water as the environment.

FIGURE 1B is a graph showing predicted plasma levels for 24 hours dosing using a memantine direct release formulation (Namenda) and a memantine sustained release formulation (NPI-6601, NPI-6701, and NPI-6801), obtained using the software package Gastro-Plus version 4.0.2. Sustained release formulations contain 22.5 mg memantine.

FIGURE 1C is a graph showing predicted dynamic steady state plasma levels for direct memantine release formulation (Namenda) and sustained release formulation of memantine (NPI-6601, NPI-6701, and NPI-6801), obtained using the Gastro software package -Plus version 4.0.2. Sustained release formulations contain 22.5 mg memantine.

FIGURE 2 shows the dissolution profile for the composition: A) sustained release (SR) (rapid) - immediate release (IR) donepezil (NPI-6170), B) sustained release (SR) (indirect) - donepezil release direct (IR) (NPI6270) and C) sustained release (SR) (slow) memantine - immediate release (IR) donepezil (NPI-6370).

FIGURE 3 shows the dissolution profile for the composition: A) sustained release (SR) (fast) - donepezil sustained release (SR) (rapid) (NPI-6171), B) sustained release (SR) (intermediate) - donepezil sustained release (SR) (rapid) (NPI-6271), C) sustained release (SR) (slow) - memantine sustained release (SR) (rapid) (NPI-6371).

FIGURE 4 shows the dissolution profile for the composition: A) sustained release (SR) (rapid) - donepezil sustained release (SR) (intermediate) (NPI-6172), B) sustained release (SR) (intermediate) - donepezil on pod7 release

Held (SR) (intermediate) (NPI-6272), C) sustained release (SR) (slow) - donepezil sustained release (SR) (intermediate) (NPI-6372).

FIGURE 5 shows the dissolution profile for the composition: A) sustained release (SR) (fast) - donepezil sustained release (SR) (slow) (NPI-6173), B) sustained release (SR) (intermediate) - donepezil sustained release (SR) (slow) (NPI-6273), C) sustained release (SR) (slow) - memantine sustained release (SR) (slow) (NPI-6373).

FIGURE 6 shows plasma concentrations obtained using the GastroPlus version 4.0.2 software package for the following compositions: A) sustained release (SR) (rapid) release - donepezil immediate release (IR) (NPI-6170), B) sustained release (SR) (rapid) memantine - sustained release (SR) (slow) ( NPI-6173), C) sustained release (SR) (intermediate) - donepezil sustained release (SR) (intermediate) (NPI-6272), D) sustained release (SR) (slow) - donepezil release direct (IR) (NPI-6370), E) sustained release (SR) (slow) release - donepezil sustained release (SR) (slow) (NPI-6373).

FIGURE 7 shows plasma concentrations obtained using the GastroPlus version 4.0.2 software package for the sustained release (SR) formulation - sustained release (SR) donepezil (NPI-6272) and the direct release (IR) formulation - donepezil direct release (IR).

FIGURE 8 shows the pharmacokinetic properties of various IR formulations and SR formulations of the present invention.

DETAILED DESCRIPTION OF THE INVENTION [0028] The present invention relates to methods and compositions for treating or preventing conditions associated with the CNS, including psychiatric disorders (e.g., panic syndrome, generalized anxiety disorder, anxiety syndromes of all types, mania, manic depression, mild manic condition, unipolar depression, depression, stress disorder, post-traumatic stress disorder, somatoform disorder, personality disorder, psychosis, and schizophrenia), and substance dependence (e.g., alcohol, stimulants (e.g., smoking cocaine, cocaine, amphetamine, and methamphetamine), synthetic opiates, and nicotine), epilepsy, headache, acute pain, chronic pain, neuropathy, cerebral ischemia, dementia (including Alzheimer's), movement disorders, and multiple sclerosis. The combination includes the first agent, which is an NMDAr antagonist selected from memantine or a pharmaceutically acceptable salt thereof, and an ACheI selected from donepezil / ARICEPT®, rivastigmine / EXELON®, galantamine / REMINYL®, tacrine / COGNEX®, methrifhonate, or hupercin A. The combination is administered so that the symptoms associated with the CNS related condition are alleviated or prevented, or alternatively, that the progression of the CNS related condition is reduced. Preferably, either or both of these two agents are formulated for sustained release, thereby providing a concentration that is high enough to be therapeutically effective but low enough to reduce or avoid effects over a desired period of time.

Adverse effects associated with excessive levels of any agent in the subject. Preferably, the compositions of the present invention are formulated to provide variation in concentration ratios over a time interval between doses that is less than the variation observed or anticipated for the formulation where none of the ingredients or only one component is present in sustained release form.

NMDAr antagonists [0029] An NMDAr antagonist selected from memantine or a pharmaceutically acceptable salt thereof can be used in the methods and compositions of the invention, especially those that are non-toxic when used in the combination of the invention. The term "non-toxic" is used in relative terms and is intended to mean any substance that has been approved by the United States Food and Drug Administration ("FDA") for administration to humans or, according to recognized regulatory criteria and practice, is FDA Approved or similar enforcement agency from any country for administration to humans or animals.

[0030] The NMDAr antagonist is memantine (1-amino-3,5-dimethyl adamantane) as well as pharmaceutically acceptable salts thereof. Memantine is described, for example, in US Patent Nos. 3,391,142; 5,891,885; 5,919,826; and 6,87,338.

[0031] The pharmaceutical composition may be formulated to provide memantine in an amount ranging between 1 and 80 mg / day, 5 and 40 mg / day or 10 and 20 mg / day. Pediatric doses will typically be lower than those determined for adults. Representative dosages can be found by any specialist in the field in the Physicians' Desk Reference.

[0032] Table 1 shows exemplary pharmacokinetic properties (e.g., Tmax and T1 / 2) for memantine and comparative NMDAr antagonists of amantadine and rimantadine.

Table 1. Pharmacokinetics and toxicity of selected NMDAr antagonists in humans

<td>Relationship</td><td>Human pharmacokinetics (T1 / 2) in the hour</td><td>Tmax in hours</td><td>Normal dose</td><td>Toxicity depends on dose</td>

<td>memantine</td><td> 60</td><td> 3</td><td>10-20 mg / day, starting at 5 mg</td><td>Dose increase required, hallucination</td>

<td>amantadine</td><td> 15</td><td> 3</td><td>100 - 300 mg / day</td><td>Hallucination</td>

<td>rimantadine</td><td> 25</td><td> 6</td><td>100 - 200 mg / day</td><td>Insomnia</td>

Acetylcholinesterase inhibitor [0033] ACheI in the combination described herein is an acetylcholinesterase inhibitor selected from donepezil / ARICEPT®, rivastigmine / EXELON®, galantamine / REMINYL®, tacrine / COGNEX®, methrifhonate, or hupercin A.

[0034] Donepezil, described in US Patent No. 4,895,841, galantamine, described in US Patent No. 4,663,318, and rivastigmine, described in US Patent No. 4,948,807, they are all currently approved by the FDA (USA) for the treatment of mild to moderate Alzheimer's disease. Stoso9

These ACheI commonly cause severe nausea, diarrhea, vomiting, and other side effects, including cardiovascular side effects, most of which are dose dependent. In addition, discontinuation of therapy typically requires re-escalation of dosage from the lowest levels (Am. Fam. Phys. 68 (7): 136572 (2003)). Finally, patients cannot tolerate chronic ACheI therapy.

[0035] The pharmaceutical composition may be formulated to deliver donepezil in an amount ranging between 1 and 10 mg / day, 2 and 5 mg / day, or 2 and 4 mg / day; rivastigmine in an amount ranging between 1 and 12 mg / day, 2 and 6 mg / day, or 2 and 5 mg / day; or galantamine in an amount ranging between 1 and 24 mg / day, 2 and 16 mg / day, or 2 and 12 mg / day. Pediatric doses will typically be lower than those determined for adults. Representative dosages can be found by any specialist in the field in the Physicians' Desk Reference.

[0036] Table 2 shows exemplary pharmacokinetic properties (e.g., Tmax and T1 / 2) for donepezil, rivastigmine, galantamine, and hupercin A.

Table 2. Pharmacokinetics and toxicity of selected ACheI in humans

<td>Relationship</td><td>Human pharmacokinetics, T1 / 2 (H)</td><td>Tmax (h)</td><td>Normal dose</td><td>The main adverse effects are dose dependent</td>

<td>ARICETT® / donepezil</td><td> 70</td><td> 3 -4</td><td>5 - 10 mg / day</td><td>Nausea, diarrhea, insomnia</td>

<td>EXELON® / rivastigmine</td><td> 1,5</td><td> 1 -2,5</td><td>6 - 12 mg / day</td><td>Nausea, vomiting</td>

<td>REMINYL® / galantamine</td><td> 7</td><td> 1 -2,5</td><td>16 - 24 mg / day</td><td>Nausea, vomiting, anorexia</td>

<td>HUPERCIN A.</td><td> 4,8</td><td> 1,3</td><td>100 - 400 μg / day</td><td>Nausea, hyperactivity, dizziness</td>

Preparation of controlled release formulations [0037] By combining the desired NMDAr antagonist or antagonists with one or more additional ingredients, a pharmaceutical composition of the invention is prepared which, when administered to a subject, releases the NMDAr antagonist in a target concentration range over a specified period of time. The NMDAr antagonist can be delivered such that it is released at a dC / dT ratio, which is significantly reduced relative to an immediate release (IR) dosage form, associated with this delay Tmax. The pharmaceutical composition can be formulated to obtain a Tmax shift of 24 hours, 16 hours, 8 hours, 4 hours, 2 hours, or at least 1 hour. A reduction of the dC / dT ratio by approximately 0.05, 0.10, 0.25, 0.5 or at least 0.8 may be associated with this. In addition, the NMDAr antagonist can be delivered such that it is released at a rate that gives an average Cmax / Cmean ratio of approximately 2 or less for approximately 2 hours to at least 8 hours after the NMDAr antagonist has been introduced into the subject.

[0038] In addition, the NMDAr antagonist may be delivered such that it is released at a rate giving a Cmax / Cmean ratio of approximately 2 or less for approximately 2 hours to at least 8 hours after the NMDAr antagonist has been introduced into the subject.

EP 1 874 282 B1

Optionally, sustained release formulations exhibit plasma concentration curves having initial slopes (e.g., from 2 hours after administration to 4 hours after administration) less than 75%, 50%, 40%, 30%, 20% or 10% slopes for IR formulations of the same dosage of the same NMDAr antagonist. The specific slope for a given individual will depend on the NMDAr antagonist used or other factors, including whether the patient is full or not. For other doses, e.g., those mentioned above, the slopes change directly depending on the dose. The determination of initial plasma concentration slopes is described, for example, by US Patent No. 6,913,768, which is incorporated herein by reference.

[0039] Optionally, the composition described herein is formulated such that the NMDAr antagonist has an in vitro dissolution profile of less than 70% in one hour, less than 90% in two hours, more than 40% in six hours, and more than 85% over 12 hours as measured using a USP type 2 dissolution tester (with a paddle) at 50 rpm at 37 ± 0.5 ° using as water dissolution medium.

[0040] Preferably, the compositions described herein have an in vitro dissolution profile that is substantially identical to the dissolution profile shown for the formulation shown in FIGURES 1A and 2-5 and, when administered to a subject at a substantially constant daily dose, reaches a plasma concentration profile that is substantially identical to the profiles shown in FIGURES 1B, 6, and 7.

[0041] The release profile, i.e., the extent of NMDAr antagonist release over a desired time, can be conveniently determined for a given time by calculating the ratio C_max/ C_mean for the desired time range. For example, an NMDAr antagonist can be delivered so that it is released at a C value_max/ C_mean approximately 2 or less, for approximately 2 hours to at least 6 hours after the NMDAr antagonist has been introduced into the subject. One of ordinary skill in the art can make combinations having the desired release profile using NMDAr antagonists and the formulation methods described below.

[0042] Optionally, ACheI can also be prepared as a controlled release formulation as described above for an NMDAr antagonist.

[0043] By using the formulations described herein, therapeutic levels can be achieved while minimizing the debilitating side effects that are typically associated with direct release formulations. In addition, by reducing the time to peak plasma levels and the potentially prolonged period of time at a therapeutically effective plasma level, the dosing frequency can be reduced to, for example, once or twice daily dosing, thereby improving patient compliance and compliance. For example, the severity and frequency of side effects including psychosis and cognitive deficits associated with the administration of NMDAr antagonists can be alleviated by using controlled release methods that shift Tmax toward longer times, thereby reducing the drug's dC / dT. Decreasing dC / dT drug not only increases Tmax, but also reduces drug concentration at Tmax and reduces the Cmax / Cmean ratio, ensuring a more constant amount of drug being treated over a given period of time and reducing the adverse effects associated with dosage. Regarding ACheI, lower dC / dT and Cmean values ​​will result in a lower incidence of cardiovascular or food side effects and other adverse effects.

[0044] In addition to the specific combinations disclosed herein, combinations made from the first NMDAr antagonist and ACheI can be identified by testing the ability of the test combination of the selected NMDAr antagonist and one or more ACheI to reduce the symptoms of a CNS related disorder. Preferred combinations are those in which a therapeutically effective amount of NMDAr and / or ACheI antagonist is present lower relative to the amount of the same NMDAr and / or ACheI antagonist needed to achieve the same effect when each agent is tested separately.

[0045] The amounts and ratios of the NMDAr antagonist and ACheI are conveniently varied to maximize therapeutic benefit and minimize toxicity or safety risks. The amount of NMDAr antagonist may range between 20% and 200% of its normal effective dose, and the amount of ACheI may range between 20% to 200% of its normal effective dose. A close ratio may vary depending on the condition being treated. In one example, the amount of memantine ranges between 2.5 and 80 mg per day and the amount of donepezil ranges between 1 and 20 mg / day.

[0046] When memantine is in a controlled release form, the preferred dosage range is 10 mg to 80 mg per day; daily doses of about 22.5, 27.5, 32.5, 37.5, 42.5, 47.5, 52.5, 57.5, 62.5, 67.5, 72.5 are particularly preferred 77.5 mg. When donepezil is in a controlled release form, the preferred dosage range is 1 mg to 10 mg per day; daily doses of about 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0 are particularly preferred, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0 mg per day. In a particularly preferred embodiment, the memantine dose is 30-45 mg per day, taken in combination with a donepezil dose of 2-4 mg / day, administered as a unit dose form, without increasing the dose over a period of time. The dosage form of the combination preferably has sustained release formulations for memantine, donepezil or both, such that the dissolution profiles of the two drugs in the tablet combination are "matched", especially in terms of Tmax, dC / dT (dose normalized NMDAr antagonist and ACheI) in man. For memantine and donepezil, which have similar pharmacokinetic properties, in vitro dissolution profiles will also be similar.

[0047] In a preferred embodiment of the present invention, memantine and donepezil are formulated as spheres or granules (as described herein) with substantially similar dissolution profiles. More preferably, memantine beads or granules are produced with dissolution profiles similar to the profile shown for memantine in Figure 4B, and donepezil beads or granules having a dissolution profile similar to the profile shown for donepezil in the same figure are separately prepared. Preferred granules have approximately 0.4 mg each and contain approximately 60 μg of memantine or donepezil and can easily be characterized by known methods. The balls can be filled into gelatin capsules, by measuring their weight or number, to achieve a preferred memantine mass of 30-45 mg per capsule and donepezil 2-4 mg per capsule. For example, a combination of 42 mg memantine and 3.6 mg donepezil can be made by combining 700 memantine beads with 60 donepezil beads in each capsule, which is equivalent to 280 mg memantine beads plus 24 mg donepezil beads per capsule.

[0048] Additionally, various release profiles can be obtained for each active pharmaceutical ingredient and combined in prescribed proportions to match the release profile for

Of each of the ingredients, which allows faster development of formulations for development purposes or specialized formulations for individual products.

[0049] For a particular range, a physician or other healthcare professional will typically determine the best dosage for a given patient according to his sex, age, weight, pathological condition, and other parameters. In some cases, it may be necessary to use a dose outside the range on the pharmaceutical package leaflet for treatment. These cases will be obvious to the prescribing doctor or veterinarian.

[0050] In some embodiments, the combinations of the invention achieve therapeutic levels, while minimizing the debilitating side effects that are typically associated with immediate release formulations. In addition, due to the delay in achieving peak plasma levels and the potentially prolonged period of time at therapeutically effective plasma levels, the dosing frequency can be reduced to, for example, once or twice daily dosing, thereby improving patient compliance and compliance.

[0051] Accordingly, the combination of the invention allows the NMDAr antagonist and ACheI to be administered in a combination that improves the efficacy and avoids the undesirable side effects of these two drugs. For example, the severity and frequency of side effects including psychosis and cognitive deficits associated with the administration of NMDAr antagonists can be attenuated by using controlled release methods that shift Tmax toward longer times, thereby reducing the drug's dC / dT. Decreasing dC / dT drug not only increases Tmax, but also reduces drug concentration at the time of Tmax and reduces the Cmax / Cmean ratio, providing the patient with a more constant amount of drug over a given period of time and reducing adverse effects associated with dosage. Similarly, the methods of controlled release can also reduce the severity and frequency of side effects associated with the use of ACheI.

[0052] In certain embodiments, the combinations provide additive effects. Additivity is achieved by combining active agents without requiring controlled release technology. In other embodiments, particularly when the pharmacokinetic profiles of the combined active pharmaceutical ingredients are dissimilar, controlled release formulations optimize the pharmacokinetics of active pharmaceuticals to reduce Cratio variability over a period of time. Reducing the Cratio variability over a defined period of time allows the measures to act in concert over that period of time, maximizing the effectiveness of the combination. Cratio variability ("Cratio.var") is defined as the standard deviation of a series of Cratio values ​​measured over a given time period divided by the average of these Cratio values ​​multiplied by 100%. Cratio for controlled-release drug formulations with significantly different pharmacokinetic properties is more consistent than for IR administration of the same drugs over any significant period of time, including shortly after administration and at steady state.

Modes of administration [0053] The combination of the invention may be administered either in a local or systemic manner, or in a depot or sustained release form. Two agents can be delivered in oral, transdermal, or nasal formulation. In a preferred embodiment, the antagonist

EP 1 874 282 B1

NMDAr, ACheI from the combination, or both can be formulated to provide controlled, sustained release (as described herein). For example, a pharmaceutical composition that provides controlled release of an NMDAr antagonist, ACheI, or both, can be prepared by combining the desired agent or agents with one or more accessory ingredients that when administered causes the release of the respective agent or agents at a target rate over a specified period of time . The two agents are preferably administered in a manner that provides the desired effect of the first and second agents in combination. Optionally, the first and second agents are mixed in a single formulation before they are introduced into the treated organism. The combination can conveniently be divided into unit doses containing the correct amounts of first and second agents. The unit dosage form can be, for example, the capsule or tablet itself, or it can be the correct number of such compositions in the form of a packet. The amount of active ingredients in unit dosage forms can be varied or adapted to the individual needs of the condition being treated.

[0054] Alternatively, the NMDAr and ACheI antagonists of the combination may not be mixed until after introduction into the treated organism. Thus, the term "combination" includes embodiments where the NMDAr antagonist and ACheI are provided in separate formulations and administered sequentially. For example, the NMDAr antagonist and ACheI may be administered to the subject separately in a course of 2 days, 1 day, 18 hours, 12 hours, one hour, half hour, 15 minutes or less. Each of the agents may be provided in a number of individual capsules or tablets, which are administered separately to the subject. Alternatively, in the pharmaceutical composition the NMDAr antagonist and ACheI are separated from each other so that they do not mix with each other until after the pharmaceutical composition has been introduced into the treated organism. Mixing may occur just prior to administration to the subject or much earlier before administration of the combination to the subject.

[0055] If desired, the NMDAr antagonist and ACheI may be administered to a subject in conjunction with other therapies, e.g., medications, surgery, or other interventional treatment regimens. Accordingly, the combination described herein can be administered simultaneously or within 14 days, 7 days, 5 days, 3 days, one day, 12 hours, 6 hours, 3 hours, or one hour after additional therapies. When the combination includes non-drug treatment, non-drug treatment may be performed at any useful time as long as the beneficial effect of the combination of the combination and other therapies is achieved. For example, where appropriate, a beneficial effect is still achieved when non-drug treatment is removed temporarily, perhaps for days, or even weeks.

[0056] The preparation of pharmaceutical or pharmacological compositions is known to those skilled in the art in light of the present disclosure. General formulation and administration techniques are found in "Remington: Science and Practice of Pharmacy," 20th edition, Lippincott Williams &amp; Wilkins, Philadelphia, PA. Examples of such formulations are tablets, capsules, pills, powders, granules, dragees, gels, suspensions, ointments, suppository solutions, injections, inhalants and aerosols.

[0057] In some embodiments, the first agent and second agent of the combination described herein are provided in single or separate pharmaceutical compositions. The term "pharmaceutically or pharmacologically acceptable" includes individuals

Molecular and compositions that do not give rise to a harmful, allergic, or other undesirable reaction when administered to an animal or human being, as appropriate. "Pharmaceutically acceptable carrier" includes all solvents, dispersing media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is known in the art. Except that any conventional environment or agent is incompatible with the active ingredient, use in therapeutic compositions is contemplated. Additional active ingredients can also be included in the composition. "Pharmaceutically acceptable salts" include acid addition salts that are prepared from inorganic acids such as, for example, hydrochloric or phosphoric acid, or organic acids such as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with free carboxyl groups may also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or iron (III) hydroxides, and organic bases such as isopropylamine, trimethylamine, histidine, procaine, and the like.

Formulations for oral administration [0058] The combinations can be delivered as pharmaceutical compositions that are optimized for particular types of delivery. For example, pharmaceutical compositions for oral delivery are formulated using pharmaceutically acceptable carriers that are known in the art and described below. Carriers allow formulation of the agents in combination, for example, as tablets, pills, capsules, solution, suspension, powder, liquid or gel for oral ingestion by the subject.

[0059] The NMDAr antagonist, ACheI of the invention, or both can be delivered in a controlled, sustained release dosage form. In one example, at least 50%, 90%, 95%, 96%, 97%, 98%, 99%, or even more than 99% of the NMDAr antagonist is provided in a sustained release dosage form. The release profile, i.e., the degree of release of the NMDAr or ACheI antagonist over a desired time range, can be conveniently determined for a given time by calculating Cmax / Cmean for the desired time range to achieve a given acute or chronic serum concentration profile at a steady state. Thus, when administered to a subject (e.g., a mammal such as a human), the NMDAr antagonist has a Cmax / Cmean ratio of approximately 2.5, 2, 1.5, or 1.0, approximately 1, 1.5, 2 hours up to at least 6, 8, 9, 12, 18, 21, or 24 hours after such administration. If desired, NMDAr antagonist release can be monophasic or multiphasic (e.g., biphasic). In addition, ACheI can be formulated as a sustained release composition having a Cmax / Cmean ratio of approximately 2.5, 2, 1.5, or 1.0, approximately 1, 1.5, 2 hours for at least 6, 8 , 9, 12, 18, 21, or 24 hours after administration to the subject. One of ordinary skill in the art can make combinations with the desired release profile using NMDAr and ACheI antagonists and formulation methods known in the art or described below.

[0060] As shown in Tables 1 and 2, the pharmacokinetic half-lives of drugs from both classes vary from about 1.5 hours to 70 hours. Thus, useful formulations can be conveniently selected to achieve almost constant concentration profiles over a prolonged period (preferably from 8 to 24)

EP 1 874 282 B1 hours), thereby maintaining both agents in a constant ratio and concentration for optimal therapeutic benefits for both acute and chronic administration. Preferred Cratio, var values ​​may be less than about 30%, 50%, 75%, 90% values ​​for IR administration of the same active pharmaceutical ingredients within the first 4, 6, 8, or 12 hours after administration. Preferred Cratio, var values ​​are less than about 100%, 70%, 50%, 30%, 20%, 10%.

[0061] Formulations that give this consistent, measurable profile also allow for a monotonic increase from the acute ratio to the desired chronic ratio for drugs with widely varying elimination half-lives. Compositions of this type and methods of treating patients with these compositions are embodiments of the invention. There are numerous ways to achieve the desired release profiles, as shown in the examples below.

[0062] In some embodiments, the first agent and second agent of the combination described herein are provided in single or separate pharmaceutical compositions. The term "pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce a harmful, allergic, or other undesirable reaction when administered to an animal or human, as appropriate. "Pharmaceutically acceptable carrier" includes all solvents, dispersing media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is known in the art. Except that any conventional environment or agent is incompatible with the active ingredient, use in therapeutic compositions is contemplated. Additional active ingredients can also be included in the composition. "Pharmaceutically acceptable salts" include acid addition salts that are prepared from inorganic acids such as, for example, hydrochloric or phosphoric acid, or organic acids such as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with free carboxyl groups may also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or iron (III) hydroxides, and organic bases such as isopropylamine, trimethylamine, histidine, procaine, and the like.

[0063] Useful methods for making combinations wherein the first agent, ACheI, or both, are provided in sustained release formulations include the methods described in US Patent No. 4,606,909 (which is incorporated herein by reference). This reference describes the formulation of multiple controlled release units in which many separate coated or microencapsulated units become available when the preparation breaks down (e.g., pills or tablets) in the stomach of the animal (see, for example, column 3, line 26 to column 5, line 10, and column 6, line 29 to column 9, line 16). Each of these separately coated or microencapsulated units contains substantially homogeneous cross-section cores containing particles of a sparingly soluble active substance, the cores being coated with a coating that is substantially resistant to stomach conditions but which erodes under predominant conditions in the small intestine.

[0064] The combination may alternatively be formulated using methods disclosed in, for example, US Patent No. 4,769,027. Accordingly, sustained release formulations include solidified granules of a pharmaceutically acceptable material (e.g., sugar / starch, salts, and waxes), which

EP 1 874 282 B1 may be coated with a water-permeable polymer matrix containing the NMDAr antagonist, and then coated with a water-permeable film containing water-soluble pore-forming particles dispersed therein.

[0065] One or both agents of the combination can additionally be prepared as described in US Patent No. 4,897,268, regarding a biocompatible, biodegradable delivery system from microcapsules. Thus, the NMDAr antagonist can be formulated as a composition containing a blend of bulk spherical particles obtained by separately microencapsulating specific amounts of memantine, for example, in various copolymer excipients that biodegrade at different rates and thus release memantine into the circulation at predetermined rates. A certain amount of these particles may have a copolymer excipient such that the active ingredient of the core is released quickly after administration, and thereby provides the active ingredient during the initial period. The second amount of particles has an excipient of the type such that delivery of the encapsulated component begins when delivery of the first amount begins to end. The third amount of ingredient may be encapsulated with yet another excipient that causes delivery to begin when delivery of the second portion begins to end. The delivery rate can be changed, for example, by changing the lactide / glycolide ratio in the encapsulating material which is poly (D, L-lactide-co-glycolide). Other polymers that can be used include polyacetal polymers, polyorthoesters, polyesteramides, polycaprolactone and its copolymers, polycarbonates, polyhydroxybutyrate and its copolymers, polymaleamides, copolysylates and polysaccharides.

[0066] In one embodiment of the invention, the NMDAr antagonist, ACheI, or both can be provided in a controlled or extended release form, with or without a direct release component, to maximize the therapeutic benefit for each and at the same time reduce undesirable side effects associated with each of them. When these drugs are delivered in oral form without the benefit of releasing regulated or sustained ingredients, they are released and transported to body fluids over a period of minutes to several hours. Thus, the composition of the invention may comprise an NMDAr antagonist and a sustained release component, such as a coated sustained release matrix, sustained release matrix, or sustained release bead matrix. In one example, memantine (e.g., 5-80 mg) is formulated without a direct release component using a polymer matrix (e.g., Eudragit), hydroxypropyl methylcellulose (HPMC) and a polymer coating (e.g., Eudragit). Such formulations are compressed into solid tablets or granules or formed into granules for capsules or tablets. Optionally, a coating such as Opadry® or Surelease® is used.

[0067] Separately produced granules, preferably controlled release granules, combined in any manner provide flexibility in obtaining compositions for NMDAr antagonist to ACheI ratios in the range from 0.1: 100 to 100: 0.1, more preferably from 1: 100 to 100: 1, most preferably 1: 10 to 10: 1 on a weight or pellet basis (see Example 7), and with the desired release profiles for each of the active ingredients. Optionally, the NMDAr antagonist, ACheI, or both, are prepared using OROS® technology, described for example in US Patent Nos. 6,919,373, 6,923,800, 6,929,803, 6,939,556, and 6,930,128, all of which are references herein. This technology uses

Osmosis to achieve precise, controlled release of drugs for up to 24 hours and can be used for a number of compounds, including poorly soluble or highly soluble drugs. OROS® technology can be used to deliver high doses of medicines that meet the high dose requirements of medicines. By targeting specific areas of the digestive tract, OROS® technology can provide more effective drug absorption and increased bioavailability. The osmotic driving force of the OROS® system and drug protection up to the moment of release eliminate the variation in absorption and metabolism of the drug often caused by gastric pH and intestinal motility.

[0068] Alternatively, the combination which can be made as described in US Patent No. 5,395,626 is characterized by a controlled release multilayer pharmaceutical dosage form. The dosage form contains a plurality of coated particles, each having a plurality of layers around a core containing an NMDAr antagonist and / or ACheI, so that the drug containing the core and at least one other layer of the active drug ingredient are coated with a controlled release barrier layer, thus providing at least two controlled-release layers of the water-soluble drug from the multilayer coated particle.

[0069] For example, a sustained release oral formulation may be prepared using additional methods known in the art. For example, a useful sustained release form of any one or both active pharmaceutical ingredients may be a tablet matrix composition. Useful matrix materials include, for example, waxes (e.g., carnauba wax, beeswax, paraffin wax, ceresin, shellac wax, fatty acids, and fatty alcohols), oils, hardened oils or fats (e.g., hardened rapeseed oil, castor oil, beef tallow, palm oil, and soybean oil), and polymers (e.g., hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and polyethylene glycol). Other useful materials for the tablet matrix are microcrystalline cellulose, powdered cellulose, hydroxypropyl cellulose, ethyl cellulose, with other carriers, and fillers. The tablets may also contain granules, coated powders, or granules. The tablets may also be multilayered. Multilayer tablets are particularly preferred when the active ingredients have significantly different pharmacokinetic profiles. Optionally, the finished tablet may be coated or uncoated.

[0070] The coating composition typically comprises an insoluble matrix polymer (approximately 15-85% based on the weight of the coating composition) and water-soluble material (eg, approximately 15-85% based on the weight of the coating composition). Optionally, an enteric polymer (approximately 1 to 99% based on the weight of the coating composition) may be used or incorporated. Suitable water-soluble materials include polymers such as polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and monomeric materials such as sugars (e.g., lactose, sucrose, fructose, mannitol and the like), sodium chloride , potassium chloride and the like), organic acids (e.g., fumaric acid, succinic acid, lactic acid, and tartaric acid), and mixtures thereof. Suitable enteric polymers include hydroxypropyl methylcellulose succinate acetate, hydroxypropyl methylcellulose phthalate, polyvinyl phthalate acetate, cellulose phthalate acetate, cellulose trimellitate acetate, shellac, zein, and polymethacrylates containing carboxyl groups.

[0071] The coating composition may be plasticized according to the properties of the coating compound such as the glass transition temperature of the main agent or mixture of agents or the solvent used to apply the coating compositions. Suitable plasticizers can be added in an amount of 0 to 50% based on the weight of the coating composition and include, for example, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, acetylated citrate esters, dibutyl sebacate, and castor oil. If desired, the coating composition may contain a filler. The amount of filler can be 1% to approximately 99% by weight based on the total weight of the coating composition and it can be insoluble material such as silicon dioxide, titanium dioxide, talc, kaolin, alumina, starch, powdered cellulose, microcrystalline cellulose, or polacryline potassium.

[0072] The coating composition may be applied as a solution or latex in organic solvents or aqueous solvents or mixtures thereof. If solutions are applied, the solvent may be present in amounts of approximately 25-99% by weight based on the total weight of dissolved solids. Suitable solvents are water, lower alcohol, lower chlorinated hydrocarbons, ketones, or mixtures thereof. If latexes are used, the solvent is present in amounts of approximately 25-97% by weight based on the amount of polymeric material in the latex. The solvent may be mainly water.

[0073] The pharmaceutical composition described herein may also contain a carrier such as a solvent, dispersion medium, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. The use of such media and agents for pharmaceutically active substances is known in the art. Pharmaceutically acceptable salts may also be used in the composition, for example, mineral salts such as hydrochlorides, hydrobromides, phosphates, or sulfates, as well as salts of organic acids such as acetates, propionates, malonates, or benzoates. The composition may also contain liquids such as water, saline, glycerol, and ethanol as well as substances such as wetting agents, emulsifiers, or pH buffering agents. Liposomes such as those described in US Patent No. 5,422,120, WO 95/13796, WO 91/14445, or EP 524.961 B1 may also be used as a carrier.

[0074] Additional methods for preparing controlled release formulations are described, e.g., in US Patent Nos. 5,422,123; 5,601,845; 5,912,013; and 6,194,000, all of which reference herein.

Formulations for other routes of administration [0075] Alternatively, the compositions as disclosed herein may be administered transdermally. A transdermal patch delivery formulation can be made using methods also known in the art, including methods described generally, e.g. in US Patent Nos. 5,186,938; 6,183,770; 4,861,800; 4,284,444 and WO 89/09051. The patch is a particularly useful embodiment in cases where the therapeutic agent has a short half-life or requires a dC / dT reduction. Patches can be made to release regulated skin penetrating active ingredients over a period of 12 hours, 24 hours, 3 days, and 7 days. In one example, a two-fold excess of the daily amount of NMDAr antagonist is placed in a non-volatile fluid along with an opioid narcotic, non-steroidal anti-inflammatory drug, or agent

Anesthetic. For the amount of agents used herein, the beneficial release will be from 12 to 72 hours.

[0076] Transdermal preparations of this form will contain from 1% to 50% active ingredients. The compositions of the invention are provided in the form of a viscous, non-volatile liquid. Preferably, both components of the combination will have a skin penetration rate of at least 10^-9mol / cm²/hour. At least 5% of the active material will pass through the skin within 24 hours. Penetration of appropriate formulations through the skin can be measured by standard methods known in the art (e.g., Franz et al., J. Invest. Derm. 64: 194-195 (1975)).

[0077] Pharmaceutical compositions containing the NMDAr and / or ACheI antagonist in combination may also be provided in the form of an aerosol spray formulation from a pressurized pack, atomizer, or dry powder inhaler. Useful propellants that can be used in the atomizer include, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and carbon dioxide. In the case of a pressurized aerosol, the dosage may be determined by providing a valve to deliver a controlled amount of the compound.

[0078] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as specified above. Preferably the compositions are administered by the oral, nasal or respiratory route for local or systemic effect. The compositions preferably in sterile pharmaceutically acceptable solvents can be sprayed by using inert gases. The spray solutions can be inhaled directly from the spray device, or the spray device can be attached to a face mask, tent, or respirator with periodic hypertension. Solution, suspension or powder compositions can be administered, preferably orally or nasally, from devices that deliver the formulation in the proper manner.

[0079] Instead of the inhalation method, the composition can also be delivered intranasally to a sieve plate to allow active agents to be transferred through the nasal passages to the CNS and reduce systemic administration. Devices used for this route of administration are included in US Patent No. 6,715,485. Compositions delivered through this route may allow increased CNS dosing or reduced overall body load, reducing the systemic toxicity hazards associated with certain drugs.

[0080] Additional formulations useful for other modes of administration include rectal capsules or suppositories. For suppositories, traditional binders and carriers may include, for example, polyalkylene glycols or triglycerides; such suppositories can be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably 1% -2%.

[0081] The combination may optionally be formulated for vessel delivery that allows continuous long-term delivery, e.g., for delivery up to 30 days, 60 days, 90 days, 180 days, or one year. For example, the vessel may be made of biocompatible material such as titanium. Formulations for long-term delivery are particularly useful in patients suffering from chronic conditions, to provide improved patient compliance, and

EP 1 874 282 B1 to increase the stability of the combination. Formulations for continuous long-term delivery are given, e.g., in US Patent Nos. 6,797,283; 6,764,697; 6,635,268, and 6,648,083.

[0082] If desired, then agents may be provided in a kit / as a combined preparation. The combination set / preparation may additionally contain instructions for use. In some embodiments, the combination kit / preparation comprises in one or more containers an NMDAr antagonist and, separately, in one or more containers, the ACheI described herein. The NMDAr antagonist and ACheI may be mixed together prior to administration or may be administered to the subject separately. When administered to the patient separately, they can be administered simultaneously as separate formulations, at different times and at different periods of time, which can be separated or overlapping. The NMDAr antagonist and ACheI can be administered in any order.

[0083] In other embodiments, the combination kit / preparation provides a combination with an NMDAr antagonist and ACheI mixed in one or more containers. The combination kits / formulations comprise a therapeutically effective dose of an agent for treating dementia or other CNS related condition.

[0084] The preparation of a pharmaceutical composition for delivery in an implantation device under the skin can be performed using methods known in the art, such as those described, for example, in US Patent Nos. 3,992,518; 5,660,848; and 5,756,115.

Indications useful for treatment with a combination [0085] Any patient experiencing or at risk of experiencing a CNS related disorder including dementia (e.g., Alzheimer's disease, Parkinson's disease, Pick's disease, frontal dementia, vascular dementia, normotensive hydrocephalus, Huntington's chorea, and mild cognitive impairment), neuron related conditions, dementia related conditions such as epilepsy, seizure disorders, acute pain, chronic pain, chronic neuropathic pain. Epileptic conditions include complex partial epilepsy, simple partial epilepsy, partial generalized epilepsy, generalized loss of consciousness, large seizures (tonic-clonic) epilepsy, tonic epilepsy with increased muscle tone, atonic epilepsy with loss of muscle tone without loss of consciousness, myoclonic epilepsy familial progressive, perinatal epilepsy, and flexion seizures. Additional specific epileptic syndromes are juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, temporal epilepsy, frontal lobe epilepsy, progressive retardation epilepsy, and progressive myoclonic epilepsy. The combinations of the invention are also useful for the treatment and prevention of pain caused by disorders including cerebrovascular disease, motoneuron diseases (e.g., amyotrophic lateral sclerosis, spinal cord, Tay-Sachs disease, Sandoff's disease, familial spasmodic paraplegia), neurodegenerative diseases ( e.g., familial Alzheimer's disease, prion diseases, cerebellar ataxia, Friedreich's disease, cerebellospinal ataxia, Wilson's disease, RP, amyotrophic lateral sclerosis, adrenoleukodystrophy, Menkes' disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL); spinal muscular atrophy, familial amyotrophic lateral sclerosis,

Muscle dystrophy, Charcot-Marie-Tooth disease, neurofibromatosis, Von Hippel Lindau syndrome, fragile chromosome X syndrome, spasmodic paraplegia, psychiatric disorders (e.g., panic syndrome, generalized anxiety disorder, anxiety disorder of all types, mania, manic disease depressive, mild manic state, unipolar depression, depression, stress disorder, post-traumatic stress disorder, somatoform disorder, personality disorder, psychosis, and schizophrenia), and substance addiction (e.g., alcohol, stimulants (e.g., smoking cocaine, cocaine, amphetamine, methamphetamine), synthetic opiates, and nicotine), tuberous sclerosis, and Waardenburg syndrome), strokes (e.g., thrombotic, embolic, thrombotic) with embolism, hemmorhagic, vasoconstriction, and venous), movement disorders (e.g., Parkinson's disease, dystonia, essential tremor, late dystonia, tardive dyskinesia, and Tourette syndrome), atactic syndromes, sympathetic nervous system disorders (e.g. . Shy-Drager's syndrome, atrophic-bridge-cerebellar syndrome, striatal degeneration, Parkinson's disease, Huntington's chorea, Guillain-Barry syndrome, burning pain, complex local pain syndromes type I and II, diabetic neuropathy and alcoholic neuropathy), cranial nerve disorders (e.g., trigeminal neuropathy, trigeminal neuralgia, Menier syndrome, glossopharyngeal neuralgia, dysphagia, dysphonia, and cranial nerve paralysis), myelopathy, traumatic brain and spinal cord injury, radiation brain damage, multiple sclerosis, meningitis syndrome, prion diseases, myelitis, radiculitis, neuropathies (e.g., Guillain-Barry syndrome, disproteinemia diabetes, transthyretin-induced neuropathies, HIV-related neuropathy, Lyme disease-related neuropathy, herpes zoster-related neuropathy, carpal tunnel syndrome, tarsal syndrome, amyloid-induced neuropathy, leprosy neuropathy, Bell's palsy, crushed neuropathy, sarcoidosis-induced neuropathy, polyneuritis, heavy metal-induced neuropathy, transition metal-induced neuropathy, drug-induced neuropathy), brain axonal damage, encephalopathy, and chronic syndrome. All of the above disorders can be treated with the combinations and methods described herein.

Administration of compositions [0086] Direct release memantine formulations (e.g., Namenda) are typically administered at low doses (e.g., 5 mg / day) and are gradually administered with increasing frequency and dose over time to achieve steady state serum concentration which is therapeutically effective. As recommended by the manufacturer, Namenda, a direct release memantine formulation, is first administered to patients at a dose of 5 mg per day. After a certain period of time, this dose is given to the patients twice a day. Doses of 5 mg and 10 mg per day are then given to the patient, followed by 10 mg Namenda twice a day. With this approved dosing regimen, therapeutically effective serum steady-state concentrations can be achieved within approximately thirty days of the beginning of therapy. By using a sustained release formulation (e.g., with a fixed daily dose of 22.5 mg), a therapeutically effective dynamic equilibrium concentration can be achieved substantially earlier without using a dose escalation regimen. It is anticipated that this level will be reached within 13 days of starting therapy. In addition, the slope during each absorption period of the sustained release formulation is smaller (i.e. not as steep) as the slope for

EP 1 874 282 B1

Namenda. Accordingly, the dC / dt value for a sustained release formulation is reduced relative to a direct release formulation, even though the dose administered is greater than for a direct release formulation. Based on this model, a sustained release memantine formulation from the start of therapy and during treatment can be administered to the subject in an amount that approximately corresponds to the full dose (or which effectively achieves a therapeutically effective dose). Therefore, no dose increase would be needed. Similarly, the controlled release methods described herein can be used to reduce dC / dT for other NMDAr or ACheIs antagonists, allowing administration of the combination without requiring dose escalation.

[0087] Treatment of the subject of the combination can be monitored using methods known in the art. The effectiveness of treatment using the combination is preferably assessed by examining the patient's symptoms in a quantitative manner, e.g., by noting a decrease in the frequency of adverse symptoms, behaviors or attacks, or by extending the time until the symptoms worsen. With successful treatment, the condition of the subject will improve (i.e., the frequency of relapses will decrease, or the time until the disease progresses permanently).

[0088] The invention will be illustrated by the following examples, which do not limit it.

Example 1: Method for determining the optimal concentration ratio at dynamic equilibrium (Cratio, ss) in vivo. [0089] Dosage range testing is performed using, for example, a dementia model (mouse APP23 model which was described by Van Dam et al. (See Psychopharmacology 2005 , 180 (1): 177 190), or the model Tg2576, which was described by Dong et al (Psychopharmacology 2005, 181 (1): 145-152). This results in an isobol experience. - from the word bolus}, in which drugs are combined in fractions corresponding to their EDxx values ​​to add to ED100 (e.g., ED50: ED50 or ED25: ED75). A data chart is being built. Experimental points that lie below the straight line between ED50 points on the graph indicate synergy, points on the straight line indicate additive effect, and points above the straight line indicate inhibitory effects. The point of greatest deviation from the isobol line is the optimal ratio. This is the optimal ratio for dynamic equilibrium (C_{ratio, ss}) and it is selected based on the half-lives of the funds. Similar procedures can be used for a wide variety of proven animal models.

Example 2: Combinations of NMDAr antagonist and ACheI [0090] Representative ranges and ratios for the combinations are given below for the compositions of the invention. The ranges given in Table 3 are based on the formulation strategies described herein. Comparative examples are indicated by an asterisk (*).

Table 3: Dosage and ratios for combination therapy in adults

<td></td><td colspan="6">Amount AChel, mg / day (Range of AChel: NMDA ratios)</td>

<td>NMDA drug mg / day</td><td>Donepezyl / ARCEPT®</td><td>Ryvastigmine / EXELON®</td><td>Galantamine / REMINYL®</td><td>Takryna / COGNEX®</td><td>Hupercin A.</td><td>metryfonate</td>

<td>Memantine /</td><td> 1 -20</td><td> 1 -24</td><td> 3 -18</td><td> 8 -160</td><td> 0,02 -0,8</td><td> 8 -80</td>

<td> 2,5 -80</td><td> (0,012 -8)</td><td> (0,012 -9,6)</td><td> (0,038 19)</td><td> (0,1 -64)</td><td> (0,0025 -0,32)</td><td> (0,1 -32)</td>

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<td></td><td colspan="6">Amount AChel, mg / day (Range of AChel: NMDA ratios)</td>

<td>Amantadine /</td><td> 1 -20</td><td> 1 -24</td><td> 3 -48</td><td> 8 -160</td><td> 0,02 -0,8</td><td> 8 -80</td>

<td> 50 - 400*</td><td> (0,0025 -0,4)</td><td> (0,0025 -0,48)</td><td> (0,0075 -0,96</td><td> (0,02 - 3,2)</td><td> (0,0005 0,016)</td><td> (0,02 - 1,6)</td>

<td>Rimantadine /</td><td> 1 -20</td><td> 1 -24</td><td> 3 -48</td><td> 8 -160</td><td> 0,02 -0,8</td><td> 8 -80</td>

<td> 50 - 200*</td><td> (0,005 -0,4)</td><td> (0,005 -0,48)</td><td> (0,015 -0,96)</td><td> (0,01- 3,2)</td><td> (0,0001 0,016)</td><td> (0,04 - 1,6)</td>

Example 3: Release profile of memantine and galantamine [0091] Release ratios are shown in Table 4 below for a combination of memantine and galantamine. Cumulative fraction means the amount of drug substance released from the formulation matrix into the serum or intestinal environment (e.g., US Patent No. 4,839,177) or as measured using a USP type 2 dissolution tester with a spatula, using water as the dissolution medium.

Table 4: Release profile of memantine and donepezil

<td></td><td>T1 / 2 MEMANTINE = 60 hours</td><td>T1 / 2 GALANTAMINE - 7 hours</td>

<td>Time</td><td>Cumulative fraction A</td><td>Cumulative fraction B</td>

<td> 1</td><td> 0,2</td><td> 0,2</td>

<td> 2</td><td> 0,3</td><td> 0,3</td>

<td> 4</td><td> 0,4</td><td> 0,4</td>

<td> 8</td><td> 0,5</td><td> 0,5</td>

<td> 12</td><td> 0,6</td><td> 0,6</td>

<td> 16</td><td> 0,7</td><td> 0,7</td>

<td> 20</td><td> 0,8</td><td> 0,8</td>

<td> 24</td><td> 0,9</td><td> 1,0</td>

Example 4: Tablet containing a combination of memantine and galantamine [0092] The extended release dosage form for administration of memantine and galantamine is prepared as three separate compartments. Three individual compressed tablets are prepared, each with a different release profile, placed in a gelatin capsule, which is then closed and sealed. The ingredients of the three tablets are as follows.

Table 5: Direct release dosage form

<td>Ingredient</td><td>Function</td><td>Quantity per tablet</td>

<td>TABLET 1 (direct release):</td><td></td><td></td>

<td>memantine</td><td>Active agent</td><td>0 mg</td>

<td>Galantamine HBr</td><td>Active agent</td><td>10.25 mg</td>

<td>Dicalcium phosphate dihydrate</td><td>Thinner</td><td>26.6 mg</td>

<td>Microcrystalline cellulose</td><td>Thinner</td><td>26.6 mg</td>

<td>Sodium starch glycolate</td><td>Disintegrating agent</td><td>1.2 mg</td>

<td>Magnesium stearate</td><td>Lubricant</td><td>0.6 mg</td>

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Table 6: Delayed release dosage form (3-5 hours)

<td>Ingredient</td><td>Function</td><td>Quantity per tablet</td>

<td>TABLET 2 (release 3-5 hours):</td><td></td><td></td>

<td>memantine</td><td>Active agent</td><td>10 mg</td>

<td>Galantamine HBr</td><td>Active agent</td><td>10.25 mg</td>

<td>Dicalcium phosphate dihydrate</td><td>Thinner</td><td>26.6 mg</td>

<td>Microcrystalline cellulose</td><td>Thinner</td><td>26.6 mg</td>

<td>Sodium starch glycolate</td><td>Disintegrating agent</td><td>1.2 mg</td>

<td>Magnesium stearate</td><td>Lubricant</td><td>0.6 mg</td>

<td>Eudragit RS30D</td><td>Delayed release</td><td>4.76 mg</td>

<td>Talc</td><td>Shell component</td><td>3.3 mg</td>

<td>Triethyl citrate</td><td>Shell component</td><td>0.95 mg</td>

Table 7: Delayed release dosage form (7-10 hours)

<td>Ingredient</td><td>Function</td><td>Quantity per tablet</td>

<td>TABLET 3 (delayed release 7-10 hours):</td><td></td><td></td>

<td>memantine</td><td>Active agent</td><td>12.5 mg</td>

<td>Galantamine HBr</td><td>Active agent</td><td>5,125 mg</td>

<td>Dicalcium phosphate dihydrate</td><td>Thinner</td><td>26.6 mg</td>

<td>Microcrystalline cellulose</td><td>Thinner</td><td>26.6 mg</td>

<td>Sodium starch glycolate</td><td>Disintegrating agent</td><td>1.2 mg</td>

<td>Magnesium stearate</td><td>Lubricant</td><td>0.6 mg</td>

<td>Eudragit RS30D</td><td>Delayed release</td><td>6.5 mg</td>

<td>Talc</td><td>Shell component</td><td>4.4 mg</td>

<td>Triethyl citrate</td><td>Shell component</td><td>1.27 mg</td>

[0093] Tablets are made by wet granulation of individual drug particles and other core components, as can be done using a fluid bed granulator, or are prepared by direct compression of a mixture of ingredients. Tablet 1 (Table 5) is a direct release dosage form releasing active agents within 1-2 hours after administration. To avoid dC / dT effects, the current dosage forms do not contain memantine. Tablets 2 (Table 6) and 3 (Table 7) are coated with a delayed release coating material as can be done using conventional techniques such as spray coating or the like. The specific ingredients listed in the above tables can be replaced by other functionally equivalent ingredients, e.g., diluents, binders, lubricants, fillers, coatings, etc.

[0094] Oral administration of the capsule to a patient will give a release profile having three pulses, with the initial release of galantamine from the first tablet, which is essentially direct release, release of memantine and galantamine from the second tablet occurring within 3-5 hours after

The administration and release of memantine and galantamine from the third tablet occurring within 7-10 hours after administration.

Example 5: Granules containing memantine or donepezil [0095] Granules containing memantine HCl (or donepezil HCl) were prepared by wet mixing. Memantine HCl (or donepezil HCl) was weighed and sieved through a No. 20 screen into a low shear planetary bowl. Microcrystalline cellulose was weighed and added to this through a No. 20 screen and mixed with memantine HCl (or Donepezil HCl) using a spatula and then in a planetary mixer at low speed. The carefully weighed Eudragit NE 400 was gradually added to the powder mix, leaving enough time for subsequent distribution between successive additions. The bottom was periodically scraped off to avoid material collecting on the bottom and losses. Purified water was mixed into the mixture in 10 mL portions (the first of which was used to rinse the beaker containing Eudragit NE 40D) until a homogeneous extrudable mixture was obtained. Experimental batches were prepared using 10 to 50 ml water. Wet mixing was followed by extrusion, spheronization and drying, using procedures known in the art.

Table 8: Granules containing memantine HCl

<td>Ingredient</td><td>Supplier</td><td>Percentage in formulation¹</td><td>Weight solid per batch (g)</td><td>Target weight per lot (g)</td><td>Weight real per batch (g)</td>

<td>Memantine HCl</td><td></td><td> 20,0%</td><td> 50,0</td><td> 50,0</td><td> 50,00</td>

<td>Eudragit NE 40D</td><td>Degussa</td><td> 30,0%</td><td> 75,0</td><td> 187,5</td><td> 187,50</td>

<td>Cellulose microcrystalline (Avicel PH 101)</td><td>FMC Corp</td><td> 50,0%</td><td> 125,0</td><td> 125,0</td><td> 125,00</td>

<td>Purified Water</td><td></td><td>ON</td><td>ON</td><td> 50,0</td><td> 10,0</td>

<td></td><td>TOGETHER</td><td> 100,0%</td><td> 250,0</td><td>ON</td><td>ON</td>

<td colspan="6">¹ for solids in the finished product</td>

Table 9: Granules containing donepezil HCl

<td>Ingredient</td><td>Supplier</td><td>Percentage in formulation¹</td><td>Weight solids per batch (grams)</td><td>Target weight per lot (g)</td><td>Weight real per batch (g)</td>

<td>Donepezil HCl</td><td></td><td> 20,0%</td><td> 40,0</td><td> 40,0</td><td> 39,98</td>

<td>Eudragit NE 40D</td><td>Degussa</td><td> 30,0%</td><td> 60,0</td><td> 150,0</td><td> 150,05</td>

<td>Microcrystalline cellulose (Avicel PH 101)</td><td>FMC Corp</td><td> 50,0%</td><td> 100,0</td><td> 100,0</td><td> 100,00</td>

<td>Purified Water</td><td></td><td>ON</td><td>ON</td><td> 50,0</td><td> 10,0</td>

<td></td><td>TOGETHER</td><td> 100,0%</td><td> 200,0</td><td>ON</td><td>ON</td>

<td colspan="6">¹for solids in the finished product</td>

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Example 6: Memantine HCl / donepezil HCl formulations [0096] Fast and indirect sustained release (SR) formulations of memantine HCl (or donepezil HCl) were obtained by applying an Opadry subcoating (2% of the final weight of the granules) followed by a Surelease functional coating (15%) dispersion made with 25% Surelease) on 20% memantine HCl (or donepezil HCl) granules.

[0097] Slow sustained release (SR) formulations of memantine HCl (or donepezil HCl) were obtained by applying an Opadry subcoat (10% of the final weight of the ball), a functional coating of plasticized Eudragit RS (35% of the final weight of the granules) and triethyl citrate (plasticizer, % functional coating) on ​​granules of 20% memantine HCl (or donepezil HCl).

Table 10: Sustained release memantine (SR) products

<td>Product</td><td colspan="2">Memantine SR granules (fast)</td><td colspan="2">Memantine SR granules (intermediate)</td><td colspan="2">Memantine SR granules (slow)</td>

<td>Nominal content (mg active ingredient / mg granules)</td><td colspan="2"> 0,164</td><td colspan="2" rowspan="5">A mix of 40% "fast" and 60% "slow"</td><td colspan="2"> 0,100</td>

<td>Sample weight (mg granules)</td><td rowspan="2"> 134,6 23,41</td><td rowspan="2"> 136,2 23,44</td><td rowspan="2"> 207,9 17,97</td><td rowspan="2"> 208,9 18,24</td>

<td>Result of analysis after 16 h (mg released)</td>

<td>Result of the analysis (mg active ingredient / mg granules)</td><td> 0,174</td><td> 0,172</td><td> 0,0864</td><td> 0,0873</td>

<td>Average analysis results (mg active ingredient / mg granules)</td><td colspan="2"> 0,173</td><td colspan="2"> 0,0869</td>

<td>Number of granules per dose: 22.5 mg (mg)</td><td> 130,0</td><td></td><td> 52,0</td><td> 155,4</td><td> 259,0</td><td></td>

Table 11: Direct release (IR) donepezil

<td>Product</td><td colspan="2">Donepezil HCl, direct release</td>

<td>Nominal content (mg active ingredient / mg granules)</td><td colspan="2"> 0,0357</td>

<td>Sample weight (mg granules)</td><td> 140,6</td><td> 143,7</td>

<td>Result of analysis (mg released)</td><td> 4,25</td><td> 4,28</td>

<td>Result of the analysis (mg active ingredient / mg granules)</td><td> 0,0302</td><td> 0,0298</td>

<td>Average analysis results (mg active ingredient / mg granules)</td><td colspan="2"> 0,030</td>

<td>Amount of granules per 5 mg (mg) dose</td><td colspan="2"> 166,7</td>

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Table 12: Donepezil sustained release (SR) product

<td>Product</td><td colspan="2">Donepezil HCl granules, SR (fast)</td><td colspan="2">Donepezil HCl granules, SR (intermediate)</td><td colspan="2">Donepezil HCl granules, SR (slow)</td>

<td>Nominal content (mg active ingredient / mg granules)</td><td colspan="2"> 0,180</td><td colspan="2"> 0,166</td><td colspan="2"> 0,156</td>

<td colspan="2">Sample weight (mg granules) 113.8</td><td> 113,9</td><td> 135,6</td><td> 135,5</td><td> 128,8</td><td> 128,3</td>

<td>Result of analysis after 16 h (mg released)</td><td> 20,03</td><td> 20,00</td><td> 23,26</td><td> 23,46</td><td> 19,27</td><td> 19,86</td>

<td>Result of the analysis (mg active ingredient / mg granules)</td><td> 0,176</td><td> 0,176</td><td> 0,172</td><td> 0,173</td><td> 0,150</td><td> 0,155</td>

<td>Average analysis results (mg active ingredient / mg granules)</td><td colspan="2"> 0,176</td><td colspan="2"> 0,172</td><td colspan="2"> 0,152</td>

<td>Number of granules per 5 mg (mg) dose</td><td colspan="2"> 28,4</td><td colspan="2"> 29,0</td><td colspan="2"> 32,8</td>

Example 7: Dosage formulation for the memantine-donepezil combination [0098] Various combinations of memantine and donepezil were prepared by filling into appropriate granules of hard gelatin capsules as shown in Table 13. Granules produced separately provide flexibility in producing memantine to donepezil granule ratios from 0, 1: 100 to 100: 0.1, more preferably from 1: 100 to 100: 1, most preferably 1: 10 to 10: 1.

Table 13: Dosing combinations of memantine - donepezil

<td>Product</td><td colspan="2">memantine</td><td colspan="2">donepezil</td>

<td></td><td>Substance Weight solid / dosage unit (mg)</td><td>formulation</td><td>Substance Weight solid / dosage unit (mg)</td><td>formulation</td>

<td>NPI-6170</td><td> 130,0</td><td>SR (fast)</td><td> 166,7</td><td>IR</td>

<td>NPI-6270</td><td> 52,0</td><td>SR (fast)</td><td> 166,7</td><td>IR</td>

<td></td><td> 155,4</td><td>SR (slow)</td><td></td><td></td>

<td>NPI-6370</td><td> 259,0</td><td>SR (slow)</td><td> 166,7</td><td>IR</td>

<td>NPI-6171</td><td> 130,0</td><td>SR (fast)</td><td> 28,4</td><td>SR (fast)</td>

<td>NPI-6271</td><td> 52,0</td><td>SR (fast)</td><td> 28,4</td><td>SR (fast)</td>

<td></td><td> 155,4</td><td>SR (slow)</td><td></td><td></td>

<td>NPI-6371</td><td> 259,0</td><td>SR (slow)</td><td> 28,4</td><td>SR (fast)</td>

<td>NPI-6172</td><td> 130,0</td><td>SR (fast)</td><td> 29,0</td><td>SR (intermediate)</td>

<td>NPI-6272</td><td> 52,0</td><td>SR (fast)</td><td> 29,0</td><td>SR (intermediate)</td>

<td></td><td> 155,4</td><td>SR (slow)</td><td></td><td></td>

<td>NPI-6372</td><td> 259,0</td><td>SR (slow)</td><td> 29,0</td><td>SR (intermediate)</td>

<td>NPI-6173</td><td> 130,0</td><td>SR (fast)</td><td> 32,8</td><td>SR (slow)</td>

<td>NPI-6273</td><td> 52,0</td><td>SR (fast)</td><td> 32,8</td><td>SR (slow)</td>

<td></td><td> 155,4</td><td>SR (slow)</td><td colspan="2"></td>

<td>NPI-6373</td><td> 259,0</td><td>SR (slow)</td><td> 32,8</td><td>SR (slow)</td>

<td colspan="5">SR = sustained release, IR = direct release</td>

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Example 8: Dissolution profiles [0099] Dissolution profiles of various memantine-donepezil combinations (as shown in Example 7) were obtained using a USP type 2 dissolution test instrument (with paddle) at 50 rpm at 37.0 ± 0 , 5 ° C, using water as the environment (Figures 2A -2C, 3A -3C, 4A -4C and 5A -5C).

[0100] For dissolution analysis, 10 mL aliquots of memantine and donepezil dissolution solutions were diluted with 3 mL of 0.1% formic acid. Memantine or donepezil standard solutions were also prepared and diluted with 3 ml of 0.1% formic acid. A 1 mL sample of diluted solution or standard was transferred to an HPLC vial. A 10 μL sample or standard was injected onto the LC / MS / MS system for analysis. A C18 reverse phase column (Phenomenex, Luna 5 μ, Phenyl-Hexyl 50 x 2 mm) was used for the analysis. Memantine and donepezil were separated from endogenous interfering substances and subsequently eluted from the HPLC column with a mobile phase containing 33% acetonitrile, 33% methanol and 34% formic acid for quantitative mass spectrometry. A mass spectrometer set for mass to charge ratios (m / z) of 180.51&gt; 162.70 and 380.14&gt; 288.18, respectively, was used to detect and quantify memantine and donepezil. Data was processed and calculated by an automated data collection system (Analyst 1.2, Applied Biosystems, Foster City, CA).

Example 9: Release Profiles for Memantine-donepezil IR and SR Formulations [0101] In vivo release profiles were obtained using the Gastro-Plus version 4.0.2 software package (Figures 6A -6E, 7). Exemplary pharmacokinetic release profiles in humans are shown in Figure 7. Release profiles and pharmacokinetic properties for the controlled release combination product prepared according to Examples 5-7 compared to IR administration of currently marketed products are shown in Figure 7 and in the table in Figure 8. Oral dosing for IR administration is in accordance with the manufacturer's instructions (5 mg memantine once daily, increased to 5 mg twice a day at weekly intervals, 10 mg in the morning and 5 mg in the evening, followed by 10 mg memantine twice daily; 5 mg donepeziluraz daily for two weeks , then increased to 10 mg donepezil once a day). For the SR NPI-6272 formulation, 22.5 mg memantine and 10 mg donepezil are provided in a controlled release oral formulation releasing active agents as shown in Figure 4B. The dC / dT ratio for SR is significantly lower than for IR at a similar dose for both memantine and donepezil. As measured, the dC / dT for memantine at 22.5 mg is comparable to the 5 mg IR dosage form. Thus, sustained release formulations provide a more gradual increase in drug level during each patient dosage.

[0102] In addition to achieving the desired release profile, this combination formulation will exhibit a favorable decrease in Cmax / Cmean, even at a higher NMDAr and ACheI dose, therefore the present invention may provide higher doses for an increased therapeutic effect without increasing the dose that would otherwise be needed case. In addition, increased dosing allows less frequent administration of therapeutic agents.

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Example 10: Patch providing sustained release of memantine and rivastigmine [0103] As described above, extended release formulations of the NMDAr antagonist are formulated for topical administration. Formulations of transdermal memantine patches are prepared as described, for example, in US Patent Nos. 6,770,295 and 6,746,689.

[0104] To make the drug formulation in an acrylate adhesive, 5 g memantine and 1 g rivastigmine are dissolved in 10 g ethanol and the mixture is added to 20 g Durotak 387-2287 (National Starch &amp; Chemical, USA). A drug gel is coated on a base film (Scotchpak 1012; 3M Corp., USA) using a coating device (e.g., RK Print Coat Instr. Ltd, a regulated coating device type KCC 202). The wet layer thickness is 400 μm. The laminate is dried for 20 minutes at room temperature and then for 30 minutes at 40 ° C. A polyester protective film is applied to the dried drug gel. The sheet is cut and stored at 2-8 ° C until use (packed in bags). The concentration of memantine in patches is between 5.6 and 8 mg / cm², and rivastigmine concentrations range between 1.1 and 1.6 mg / cm². The almost continuous penetration of the ingredients provides much more consistent Cratio values ​​over time, maximizing the additive or synergistic effects of the combinations of the present invention to achieve optimal therapeutic effects.

Example 11: Multiple dose safety study in Alzheimer's disease patients using a combination of prolonged release memantine and prolonged release donepezil.

[0105] The following describes the study to determine the safety and pharmacokinetics of a combination of memantine and donepezil sustained release formulations. The results of the study are expected to assess the frequency of adverse events as well as determine pharmacokinetic parameters at higher doses.

<td>Goal</td><td>Determination of safety and pharmacokinetics of repeated doses of the drug.</td>

<td>Dosage:</td><td>Based on previous single dose escalation study (single ascending dose, SAD), or e.g. 22.5 mg memantine SR + 4 mg donepezil SR, or 45 mg memantine SR + 4 mg donepezil SR, or 45 mg memantine SR + 8 mg donepezil SR, once a day for 30 days</td>

<td>Parallel comparative tests:</td><td>memantine IR, Albomemantine IR plus donepezil IR (both drugs dosed according to the manufacturers' instructions)</td>

<td>Road:</td><td>oral</td>

<td>Treated population:</td><td>Men or women diagnosed with Alzheimer's dementia. (age range 50 -80?)</td>

<td>Structure:</td><td>4 test groups</td>

<td>Test locations:</td><td>TBD</td>

<td>Blank test:</td><td>For patients</td>

<td>Method of assigning patients:</td><td>Random, with an equal number of men and women in each group, and equal age distributions in the groups</td>

<td>Total Sample Size:</td><td>24 treated, 6 per dose group</td>

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<td>Primary performance endpoint:</td><td>Lack</td>

<td>Adverse effects:</td><td>Behavior, cardiovascular, and gastrointestinal at least twice daily behavior reported for high doses of megantine or donepezil (including dizziness, headache, confusion, constipation, hypertension, cough, nausea, diarrhea, vomiting).</td>

<td>Blood collection</td><td>Through the cannula on the first day of the study period, then 2-4 times a day for the rest of the study</td>

<td>analyzes</td><td>Determination of memantine, donepezil, and potentially other physiological parameters, adverse effects</td>

Example 12: Treatment of patients suffering from Alzheimer's disease with a combination of prolonged release memantine and donepezil prolonged release.

[0106] The following describes the study to determine the efficacy of two combinations of memantine and donepezil sustained release formulations. The results of the study are expected to achieve a faster onset of efficacy without increasing adverse effects (confirming the tolerability of the dosage regimen without increasing the dose (i.e., administration of substantially identical doses of memantine and donepezil over the entire dosing period)).

<td>Goal</td><td>Determining the effectiveness of combination therapy without increasing the dose</td>

<td>Dosages tested:</td><td>22.5 mg memantine SR + 4 mg donepezil SR, 45 mg memantine SR + 4 mg donepezil SR</td>

<td>Parallel comparative tests:</td><td>Memantine IR (Namenda), Albomemantine IR plus donepezil IR (Aricept), both drugs dosed according to the manufacturers' instructions (from 2004).</td>

<td>Road:</td><td>oral</td>

<td>Treated population:</td><td>Men or women with Alzheimer's dementia. (age range 50 -80)</td>

<td>Structure:</td><td>4 test groups</td>

<td>Test locations:</td><td>multicenter</td>

<td>Blank test:</td><td>For patients</td>

<td>Method of assigning patients:</td><td>Random, with an equal number of men and women in each group, and equal age distributions in the groups</td>

<td>Total Sample Size:</td><td>400 treated, 100 per dose group</td>

<td>Primary performance endpoint:</td><td>Improvement of ADAS-Cog, SIBIC, HAM-D during 7, 14, 21, 42, 63, 84 days, neuropsychiatric indicator on these days.</td>

<td>Performance check:</td><td>Checked twice a week for the first 4 weeks and then every week.</td>

<td>Adverse effects:</td><td>Controlled behavior at least twice a day, cardiovascular, and gastrointestinal effects reported for high doses of memantine or donepezil (including dizziness, headache, confusion, constipation, hypertension, cough, nausea, diarrhea, vomiting).</td>

<td>Blood collection:</td><td>Through the cannula at the following times: Day 1: 0.4, 8, 12 hours Days 2, 4, 6, 8, 10, 12, 14, 17, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 before the next dose</td>

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<td>analysis:</td><td>Efficacy, adverse effects and laboratory determinations measuring the tested drugs.</td>

[0107] Additional embodiments are found in the claims.

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