US 20060252788A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0252788 A1 Went et al. (43) Pub. Date: Nov. 9, 2006
(54) METHODS AND COMPOSITIONS FOR THE (60) Provisional application No. 60/669,290, filed on Apr. TREATMENT OF CNS-RELATED 6, 2005. CONDITIONS Publication Classification (76) Inventors: Gregory T. Went, Mill Valley, CA (US); Timothy J. Fultz, Pleasant Hill, (51) Int. Cl. CA (US) A6II 3/473 (2006.01) A6II 3/445 (2006.01) Correspondence Address: A6II 3L/37 (2006.01) MINTZ, LEVIN, COHN, FERRIS, GLOVSKY A6II 3 L/13 (2006.01) AND POPEO, PC. (52) U.S. Cl...... 514/294; 514/317; 514/663; ONE FINANCIAL CENTER 514/649; 514/319; 514/297 BOSTON, MA 02111 (US) (21) Appl. No.: 11/399,879 (57) ABSTRACT (22) Filed: Apr. 6, 2006 The present invention provides novel methods and compo Related U.S. Application Data sitions for the treatment and prevention of CNS-related conditions. One of the CNS-related conditions treated by the (63) Continuation-in-part of application No. 11/285,905, methods and compositions of the invention is Alzheimer's filed on Nov. 22, 2005. disease. Patent Application Publication Nov. 9, 2006 Sheet 1 of 9 US 2006/0252788A1 Figure 1A
- - NP-66O1
-O-NP-6701
-O- Namenda
resters NP-6801
Figure 1B
0.025
0.015
0.01 ------m- . . ." NP-6so
- NP-6701 0.005 - - 'Namenda 10mg BID aesthetis NP-6801
O 5 10 15 2O Time (hr) Patent Application Publication Nov. 9, 2006 Sheet 2 of 9 US 2006/0252788A1
Dissolution Profiles for Donepezil Mermantine Combination
| - A NP-6170 Donepezil -O-NP-617O Memartine
O 2 4. 6 8 10 12 14 16 Time (hr) FIGURE 2A Dissolution Profiles for Donepezil Mermantine Combination
120
100
o 3. 80 cs a 60
a 40 SS • As NP-6270 Donepezil 20 iONP-6270 Menantine
O O 2 4. 6 8. 1. 12 14 16 Time (hr) FIGURE 2B
120
100
SO
40 - A NP-6370 Donepezil 2O
O O 2 4. 6 8 10 12 14 16 Time (hr) FIGURE 2C Patent Application Publication Nov. 9, 2006 Sheet 3 of 9 US 2006/0252788A1
Dissolution Profiles for Donepezil/Memantine Combination
120
100
8O
60
40 | - A NP-6171 Donepezil 20 (NP-6171 Menantine
O O 2 4. 6 8 10 12 14 16 Time (hr) FIGURE 3A Dissolution Profiles for Donepezil/Memantine Combination
120
100 9 80 s d a 60 s S 40 s - A NP-6271 Donepezil 20 --NP-6271 Memantine
O O 2 4. s 8 10 12 14 16 Time (hr) FIGURE 3B Dissolution Profiles for Donepezil Memantine Combination
- a NP-6371 Donepezil ONP-6371 Mermantine
10 12 14 16 FIGURE 3C Patent Application Publication Nov. 9, 2006 Sheet 4 of 9 US 2006/0252788A1
Dissolution Profiles for Donepezil/Memantine Combination
120
OO
60
40 - A NP-6172 Donepezil 2O -O-NP-6172 Memantine
O 2 4 6 8 10 12 14 16 Time (hr) FIGURE 4A
Dissolution Profiles for Donepezil/Memantine Combination
120
100
80
60
40 - A NP-6272 Donepezil 20
O 2 4. 6 8 O 12 14 16 Time (hr) FIGURE 4B
Dissolution Profiles for Donepezil/Memantine Combination
- A NP-6372 Donepezil
O 2 4 6 8 10 12 14 16 Time (hr) FIGURE 4C Patent Application Publication Nov. 9, 2006 Sheet 5 of 9 US 2006/0252788A1
Dissolution Profiles for Donepezil. Memantine Combination
120
100
g 8 80
a 60 s s 40 SS - A NP-6173 Donepezil
20 d --NP-6173 Memantine
O O 2 4. 6 8 10 12 14 16 Time (hr) FIGURE 5A
Dissolution Profiles for Donepezil/Memantine Combination Capsules
100
80 e d 60 s 1. S 40
SS 2O - a NP-6273 Donepezil-- -O-NP-6273 Mermantine
O 2 4 6 8 10 12 14 16 Time (hr) FIGURE 5B
Dissolution Profiles for Donepezil/Memantine Combination
2
100
80 s a 60 s 40 SS - A NP-6373 Donepezil 20 -O-NP-6373 Menantine
O O 2 4. 6 8 1o 12 14 16 Time (hr) FIGURE 5C Patent Application Publication Nov. 9, 2006 Sheet 6 of 9 US 2006/0252788A1
Blood levels for Memantine Donepezil Combination
0.03 ,02
6 0.025 s 3. 5 0.02 8 s 0.015 .
OO1 ,04 w 0.005 .
O o O 5 10 15 20 Time (hr) FIGURE 6A
Blood Levels for MemantinelDonepezil Combination
0.03 Os - - - - - d.o.o. g 0.025 * ,07 5 0.02 does
.5 0.015 0,004
0.01 0.03
wa 2 0.005 O.O1
O d
Time (hr) FIGURE 6B
Blood Levels for Memantinel Donepezil Combination
0.025 O. ------O
8.
05
21 rNP-6272 Memantine A - - NP-6272 Donepezil
Time (hr) FIGURE 6C Patent Application Publication Nov. 9, 2006 Sheet 7 of 9 US 2006/0252788A1
Blood levels for MemantinelDonepezil Combination
0.02 2 O.018 o, O.O16 0.014 . O.O12 OO1 ..i 0.008 ,4 0.006 7 -NP-6370 Mermantine O.OO4 / 0.02 N P -6 3 7 O D O e p 2 O.OO2
O 5 10 15 20 Time (hr) FIGURE 6D
Blood levels for MemantinelDonepezil Combination
-a-. --- re-sers---ss------a res - O
.
38
0.
0.003
0.005
Time (hr) FIGURE 6E Patent Application Publication Nov. 9, 2006 Sheet 8 of 9 US 2006/0252788A1
FIGURE 7 Blood Levels for Memantine/Donepezil Combination Capsules
0.12 O.06
ESS ; WS;f 0.0
SYYYYY: W. AA 0.04
0.03
A A f A A y \\\\\\\
0.02 Memantine (IR) Ramp
arris Memantine NP-6272
- - - Donepezil (IR) Ramp O.O1
- - Donepezil NP1-6272 O O 200 400 600 800 Time (hr) Patent Application Publication Nov. 9, 2006 Sheet 9 of 9 US 2006/0252788A1
FIGURE 8 SINGLE DOSE H. dCld Tmax Cmax AUC *1 e5) BA Namenda Memantine (5mg) 6.2 0.006 629 963 99.2 Namenda Memantine (20mg 6.2 0.024 2515 38.53 99.2 Namenda Memantine (10mg) 6.2 0.012 1257 1926 99.2 Namenda Memantine (10mg BID) 16.8 0.023 2467 1363 99.2 Aricept Donepezil (10mg) 53 00101133 1887 99.6
NP-6170 Memantine Fast (IR donepezil) 130 0.024, 2685 1862 94.2 NP-6373 Memantine Slow (Slow donepezil) 204 0.019 2126 9.79 750
- - - NP-6170 Donepezil IR (Memantine Fast) 6.1 0010 1131 1639 99.3 NP-6173 Donepezil Slow (Memantine Fast) 170 0008 986 5.66 868
NP-6370 Donepezil IR (Memantine slow) 60 00101129 16.67 990
All non Namenda data was modeled with 22.5mg Namenda (80%-120%) 2011-3017 BOLD= The dCldT was adjusted for dissolution lag. (lag value is based on time at Cp=0) memaintine T12= 69 Donepezil T1/2=75hr US 2006/0252788 A1 Nov. 9, 2006
METHODS AND COMPOSITIONS FOR THE sympathetic nervous system, cranial nerve disorders, myelo TREATMENT OF CNS-RELATED CONDITIONS pathies, traumatic brain and spinal cord injuries, radiation brain injuries, multiple Sclerosis, post-meningitis syndrome, RELATED APPLICATION prion diseases, myelitic disorders, radiculitis, neuropathies, 0001. This application claims priority to U.S. Ser. No. pain syndromes, axonic brain damage, encephalopathies, 60/669,290, filed Apr. 6, 2005 and U.S. Ser. No. 11/285,905, chronic fatigue syndrome, psychiatric disorders, glucose filed Nov. 22, 2005, the contents of which are incorporated dysregulation, and drug dependence. herein by reference in their entirety. 0007. The NMDArantagonist, the AChel, or both agents may be administered in an amount similar to that typically FIELD OF THE INVENTION administered to subjects. Optionally, the amount of the 0002 This invention relates to methods and compositions NMDAr antagonist, the AChel, or both agents may be for treating CNS-related conditions, such as Alzheimer's administered in an amount greater than or less than the disease. amount that is typically administered to subjects. If desired, the amount of the NMDArantagonist in the pharmaceutical BACKGROUND OF THE INVENTION composition is less than the amount of NMDAr antagonist required in a unit dose to obtain the same therapeutic effect 0003 Acute and chronic neurological and neuropsychi for treating or preventing a CNS-related condition when the atric diseases are among the leading causes of death, dis NMDAr antagonist is administered in the absence of the ability, and economic expense in the world. Presently, AChel. Alternatively, the amount of the AChe in the phar Alzheimer's disease is the fourth leading cause of death in maceutical composition is less than the amount of the AChel the USA. Today there is no known cure for this chronic required in a unit dose to obtain the same therapeutic effect degenerative ailment, which directly affects millions of for treating or preventing a CNS-related condition when the people throughout the world. Other diseases and disorders of AChe is administered in the absence of the NMDArantago the central nervous system also result in Substantial Suffering nist. Optionally, the NMDArantagonist, the AChel, or both and cost for those afflicted by the ailments as well as their are present at a higher dose than that typically administered families and providers. to a Subject for a specific condition. For example, the amount 0004 Numerous drugs exist in the market today to treat of memantine (an NMDArantagonist) required to positively the symptoms or manage the progression of these diseases, affect the patient response (inclusive of adverse effects) may but most have modest or limited efficacy. Frequently, polyp be 2.5-80 mg per day rather than the typical 10-20 mg per harmacy is employed to optimize therapy to the specific day administered for presently approved indications i.e. needs of patients at different stages of the disease. One of the without the improved formulations described herein. A key challenges in treating these disorders is the high degree higher dose amount of the NMDArantagonist in the present of interplay amongst the pathways that control both normal invention may be employed whereas a lower dose of the and abnormal neuronal functions. The therapeutic manage NMDAr antagonist may be sufficient when combined with ment of these functions is typically determined such that the the AChe to achieve a therapeutic effect in the patient. therapeutic effects are maximized while minimizing the Optionally, lower or reduced amounts of both the NMDAr debilitating side effects of the therapies. This effort is usually antagonist and the AChe are used in a unit dose relative to more complex when multiple therapeutics are employed. the amount of each agent when administered as a mono therapy. In a preferred embodiment, the amount of the 0005 Improved therapeutics for treatment of these dis NMDAr antagonist in the pharmaceutical composition is eases and disorders are needed. equal to or greater than the amount typically administered to a subject for a specific condition as a monotherapy and the SUMMARY OF THE INVENTION amount of the AChe in the pharmaceutical composition is 0006. In general, the present invention provides methods less than the amount typically administered to a subject for and compositions for treating and preventing CNS-related a similar condition. conditions, such as neurodegenerative conditions (e.g., Alzheimer's disease and Parkinson's disease) and pain, by 0008. The invention also provides a pharmaceutical com administering to a Subject in need thereof a combination that position that includes an NMDArantagonist and an AChel. includes an N-Methyl-D-Aspartate receptor (NMDAr) Optionally, a pharmaceutically acceptable carrier is antagonist and a second agent such as acetylcholinesterase included. inhibitor (AChel). The administration of the combinations 0009. Although compositions comprising a NMDAr described herein results in the alleviation and prevention of antagonist and a second agent such as acetylcholinesterase symptoms associated with or arising from CNS-related inhibitor (AChel) have been disclosed (e.g. US 2004/ conditions such as Parkinson's disease or Alzheimer's dis 0087658), the problem of providing release of the NMDAr ease including, for example, loss of memory, loss of balance, antagonist in a desired manner (e.g. in an amount high hallucinations, delusions, agitation, withdrawal, depression, enough to treat symptoms or damaging effects of an under communication problems, cognitive loss, personality lying disease while avoiding undesirable side effects e.g. change, confusion and insomnia. The combinations of the CNS side effects) when present as a combined therapy has present invention may be used in the prevention or treatment not been addressed. In particular, the presently available of CNS-related conditions associated with Alzheimer's dis dosage forms of NMDAr antagonists need to be adminis ease and may also be helpful for the treatment and preven tered frequently and require dose escalation at the initiation tion of headaches, cerebrovascular diseases, motor neuron of therapy to avoid side effects associated with initial diseases, dementias, neurodegenerative diseases, strokes, exposure to the therapeutic agent. This leads to difficulty in movement disorders, ataxic syndromes, disorders of the achieving adequate patient compliance, which is further US 2006/0252788 A1 Nov. 9, 2006
exacerbated by the complicated dosing schedules of thera 70% in one hour, less than 90% in two hours, greater than peutic modalities used for neurological or neuropsychiatric 40% in six hours, and greater than 85% in 12 hours as disorders. This problem has not been addressed in the measured using a USP type 2 (paddle) dissolution system at context of providing an NMDAr antagonist as a combined 50 rpm, at a temperature of 37+0.5° with water as a therapy. dissolution medium. 0010 Providing a NMDAr antagonist in combination 0016. As used herein, “C” refers to the concentration of with an AChe requires careful formulation and the phar an active pharmaceutical ingredient in a biological sample, macokinetic properties of the two agents will need to be Such as a patient sample (e.g. blood, serum, and cerebrospi taken into account, for instance to ensure that the amount nal fluid). The concentration of the drug in the biological and rate of release of each of the agents is sufficient for a sample may be determined by any standard assay method therapeutic benefit whilst minimizing or avoiding undesired known in the art. The term "Cmax refers to the maximum side effects. Further, not only do the pharmacokinetic prop concentration reached by a given dose of drug in a biological erties of each of the drugs (e.g. Tmax, drug half-life etc.) sample. The term "Cmean” refers to the average concentra need to be considered, but any interaction between the two tion of the drug in the sample over time. Cmax and Cmean agents is a further complicating factor. may be further defined to refer to specific time periods relative to administration of the drug. The time required to 0011. In one embodiment of the invention, the NMDAr reach the maximal concentration ("Cmax”) in a particular antagonist, the AChel, or both agents may be provided in a patient sample type is referred to as the “Tmax. The agents controlled or extended release form with or without an of the combination are administered in formulations that immediate release component in order to maximize the reduce the variability of the ratio of the concentrations of the therapeutic benefit of each, while reducing unwanted side active agents over a period of time, thereby maximizing the effects associated with each. therapeutic benefit while minimizing the side effects. 0012. As used herein, “immediate release formulation' 0017. In a preferred embodiment, the dosage form is refers to a formulation of an active pharmaceutical ingredi provided in a non-dose escalating, twice per day or once per ent that releases greater than 80 percent of the active day form. In such cases, the concentration ramp (or Tmax pharmaceutical ingredient in less than one hour in a USP effect) may be reduced so that the change in concentration dissolution method as described herein or by the manufac as a function of time (dC/dT) is altered to reduce or turer for a commercial product. Typically, the release of the eliminate the need to dose escalate the drug. A reduction in active ingredient in an immediate release formulation is dC/dT may be accomplished, for example, by increasing the greater than 80 percent in less than 30 minutes as in FIGS. Tmax in a relatively proportional manner. Accordingly, a 1A and 2A. two-fold increase in the Tmax value may reduce dC/dT by 0013 When these drugs are provided in an oral form approximately a factor of 2. Thus, the NMDAr antagonist without the benefit of controlled or extended release com may be provided so that it is released at a rate that is ponents, they are released and transported into the body significantly reduced over an immediate release (so called fluids over a period of minutes to several hours. Thus, the IR) dosage form, with an associated delay in the Tmax. The composition of the invention may contain an NMDAr pharmaceutical composition may be formulated to provide a antagonist and a Sustained release component, such as a shift in Tmax by 24 hours, 16 hours, 8 hours, 4 hours, 2 coated Sustained release matrix, a Sustained release matrix, hours, or at least 1 hour. The associated reduction in dC/dT or a Sustained release bead matrix. In one example, meman may be by a factor of approximately 0.05, 0.10, 0.25,0.5, or tine (e.g., 5-80 mg) is formulated without an immediate at least 0.8. In certain embodiments, this is accomplished by release component using a polymer matrix (e.g., Eudragit), releasing less than 30%, 50%, 75%, 90%, or 95% of the Hydroxypropyl methyl cellulose (HPMC) and a polymer NMDAr antagonist into the circulatory or neural system coating (e.g., Eudragit). Such formulations are comprsessed within one hour of Such administration. into Solid tablets or granules. Optionally, a coating Such as 0018. The provision of such non-dose escalating dosage Opadry(R) or Surelease R is used. forms are particularly useful as they provide the drug at a 0014. As used herein the terms “extended release dosage therapeutically effective amount from the onset of therapy form”, “controlled release dosage form” and “sustained further improving patient compliance and adherence and release dosage form' and like expressions are used inter enable the achievement of a therapeutically effective steady changeably and include dosage forms where the active drug state concentration of the drug in a shorter period of time. Substance or Substances are released over an extended period This results in an earlier indication of effectiveness and of time. The term "extended release should be understood increasing the utility of these therapeutic agents for diseases in contrast to immediate release and, in particular, the term and conditions where time is of the essence. Furthermore, indicates that the formulation does not release the full dose the compositions of the present invention, by virtue of their of the active ingredient immediately after dosing. Such design, allow for higher doses of the drug to be safely extended release dosage forms typically allow a reduction in administered, again increasing the utility of these agents for dosing frequency as compared to that presented by a con a variety of indications. ventional dosage form such as a solution or an immediate release dosage form. The extended release forms may or 0019. If desired, the NMDArantagonist or the AChel of may not comprise an immediate release component. the combination is released into a Subject sample at a slower rate than observed for an immediate release (IR) formulation 00.15 Optionally, the composition described herein is of the same quantity of the antagonist. The release rate is formulated such that at least one of said NMDArantagonist measured as the dC/dT over a defined period within the or said AChe has an in vitro dissolution profile less than period of 0 to Tmax for the IR formulation and the dC/dT US 2006/0252788 A1 Nov. 9, 2006
rate is less than about 80% of the rate for the IR formulation. the pharmaceutical composition into a subject. The NMDAr In some embodiments, the dC/dT rate is less than about antagonist may have a Ca/Ca of approximately 2, 1.6, 60%, 50%, 40%, 30%, 20%..or 10% of the rate for the IR 1.5, 1.4, 1.3, 1.2 or less, approximately 2 hours to at least 8, formulation. Similarly, the AChe may also be released into 12, 16, 24 hours after the NMDAr antagonist is introduced a patient sample at a slower rate than observed for an IR into a subject. The AChe may also be provided in a formulation of the same quantity wherein the release rate is controlled release dosage form. Thus, at least 50%, 60%, measured as the dC/dT over a defined period within the 70%, 80%, 90%, 95%, or essentially all of the AChel may period of 0 to Tmax for the IR formulation and the dC/dT be provided as a controlled release formulation. If provided rate is less than about 80%, 60%, 50%, 40%, 30%, 20%, or as such, the AChe may have a C/C of approximately 10%, of the rate for the IR formulation of the same NMDAr 2, 1.6, 1.5, 1.4, 1.3, 1.2 or less, approximately 2 hours to at antagonist over the first 1, 2, 4, 6, 8, 10, or 12 hours. least 6, 8, 12, 16, or 24 hours after the AChe is introduced 0020 Optionally, the sustained release formulations into a Subject. exhibit plasma concentration curves having initial (e.g., 0025 The active pharmaceutical agents may be admin from 2 hours after administration to 4 hours after adminis istered to the patient in a manner that reduces the variability tration) slopes less than 75%, 50%, 40%, 30%, 20% or 10% of the ratio of the concentrations of the active agents over a of those for an IR formulation of the same dosage of the period of time, thereby maximizing the therapeutic benefit same NMDAr antagonist. The precise slope for a given while minimizing the side effects. The present invention individual will vary according to the NMDAr antagonist differs from prior studies by providing novel combinations being used, the quantity delivered, or other factors, includ as well as formulations of combinations directed to dose ing, for Some active pharmaceutical agents, whether the optimization or release modification to reduce adverse patient has eaten or not. For other doses, e.g., those men effects associated with each agent. tioned above, the slopes vary directly in relationship to dose. 0026 Optionally, the Cratio.var of the NMDAr antago 0021. Using the sustained release formulations described nist and the AChe is less than 100%, e.g., less than 70%, herein, the NMDAr antagonist or the AChe reaches a 50%, 30%, 20%, or 10% after the agents have reached therapeutically effective steady state plasma concentration steady-state conditions. Optionally, the Cratio.var of the in a subject within the course of the first five, seven, nine, NMDAr antagonist and the AChe is less than 100%, e.g. ten, twelve, fifteen, or twenty days of administration. For less than 70%, 50%, 30%, 20%, or 10% during the first 24 example, the formulations described herein, when adminis hours post-administration of the agents. In some embodi tered at a Substantially constant daily dose (e.g., memantine ments, the Cratio.var is less than about 90% (e.g., less than at a dose ranging between 15 mg and 80 mg and preferably about 75% or 50%) of that for IR administration of the same between 20 and 45 mg) may reach a steady State plasma active pharmaceutical ingredients over the first 4, 6, 8, or 12 concentration in approximately 70%, 60%, 50%, 40%, 30%, hours after administration. or less of the time required to reach Such plasma concen 0027. In all foregoing aspects of the invention, the tration when using a dose escalating regimen. NMDAr antagonist may be an aminoadamantine derivative 0022. The ratio of the concentrations of two agents in a including memantine (1-amino-3,5-dimethyladamantane), combination is referred to as the “Cratio, which may rimantadine (1-(1-aminoethyl)adamantane), or amantadine fluctuate as the combination of drugs is released, transported (1-amino-adamantane). The AChel, an acetylcholinesterase into the circulatory system or CNS, metabolized, and elimi inhibitor, may be, e.g., donepezil/ARICEPTR), rivastigmine/ nated. An objective of the present invention is to stabilize the EXELONR), galantamine/REMINYL(R), tacrine/COG Cratio for the combinations described herein. In some NEXR, metrifonate, or huperzine-A. Thus, in some embodi embodiments, it is preferred to reduce or even minimize the ments, the NMDAr antagonist is memantine while the variation in the Cratio (termed “Cratio.var). Employing the AChe is donepezil, rivastigmine, galantamine, tacrine, met methods described herein, the release profiles of each active rifonate, or huperzine-A. pharmaceutical ingredient may be modified to produce nearly constant Cratios, thereby minimizing Cratio, var. In 0028. In some embodiments, the NMDArantagonist, the AChel, or both agents are formulated for oral, intravenous, cases where the Tmax and T1/2 of the NMDAr antagonist topical, intranasal, Subtopical transepithelial, Subdermal, or and the AChe are markedly different, e.g. by a factor of two inhalation delivery. Thus, the agents described herein may or more, the desired release profiles will likely be dissimilar be formulated as a Suspension, capsule, tablet, Suppository, in order to minimize the relative variability of the active lotion, patch, or device (e.g., a Subdermally implantable agents between doses. delivery device or an inhalation pump). If desired, the 0023 The present invention therefore features formula NMDA antagonist and the AChe may be admixed in a tions of combinations directed to dose optimization or single composition. Alternatively, the two agents are deliv release modification to reduce adverse effects associated ered in separate formulations sequentially, or within one with separate administration of each agent. The combination hour, two hours, three hours, six hours, 12 hours, or 24 hours of the NMDAr antagonist and the AChe may result in an of each other. If administered separately, the two agents may additive or synergistic response, as described below. be administered by the same or different routes of admin istration three times a day, twice a day, once a day, or even 0024. In all foregoing aspects of the invention, at least once every two days. Optionally, the two agents are provided 50%. 80, 90%. 95%, or essentially all of the NMDAr together in the form of a kit. Preferably, the NMDAr antagonist in the pharmaceutical composition may be pro antagonist and the AChe are provided in a unit dosage form. vided in a controlled release dosage form. In some embodi ments, at least 99% of the NMDArantagonist remains in the 0029. Unless otherwise defined, all technical and scien extended dosage form one hour following introduction of tific terms used herein have the same meaning as commonly US 2006/0252788 A1 Nov. 9, 2006
understood by one of ordinary skill in the art to which this (Slow) IR Donepezil (NPI-6370), E) SR Memantine invention belongs. Although methods and materials similar (Slow) SR Donepezil (slow) (NPI-6373). or equivalent to those described herein can be used in the practice or testing of the invention, Suitable methods and 0038 FIG. 7 shows plasma concentrations obtained materials are described below. All publications, patent appli using the GastroPlus software package V.4.0.2 for an SR cations, patents, and other references mentioned herein are Memantine—SR Donepezil forumulation (NPI-6272) and incorporated by reference in their entirety. In the case of an IR Memantine IR Donepezil formulation. conflict, the present Specification, including definitions, will 0039 FIG. 8 shows pharmacokinetic properties of vari control. In addition, the materials, methods, and examples ous IR formulations and SR formulations of the present are illustrative only and not intended to be limiting. All parts invention. and percentages are by weight unless otherwise specified. DETAILED DESCRIPTION OF THE BRIEF DESCRIPTION OF THE FIGURES INVENTION 0030 FIG. 1A is a graph showing that the controlled 0040. The present invention provides methods and com release formulation of memantine (Namenda) and Sustained positions for treating or preventing CNS-related conditions, release formulations of memantine (NPI-6601, NPI-6701, including psychiatric disorders (e.g., panic syndrome, gen and NPI-6801). The sustained release formulations contain eral anxiety disorder, phobic syndromes of all types, mania, 22.5 mg of memantine. These dissolution profiles were manic depressive illness, hypomania, unipolar depression, obtained from a USP II Paddle system using water as the depression, stress disorders, PTSD, somatoform disorders, medium. personality disorders, psychosis, and Schizophrenia), and drug dependence (e.g., alcohol, psychoStimulants (e.g., 0031 FIG. 1B is a graph showing predicted plasma crack, cocaine, speed, and meth), opioids, and nicotine), blood levels for 24 hours of dosing with an immediate epilepsy, headache, acute pain, chronic pain, neuropathies, release formulation of memantine (Namenda) and Sustained cereborischemia, dementias (including Alzheimer's type), release formulations of memantine (NPI-6601, NPI-6701, movement disorders, and multiple Sclerosis. The combina and NPI-6801), obtained using the Gastro-Plus software tion includes a first agent that is an NMDArantagonist and package V.4.0.2. The Sustained release formulations contain an AChel (e.g., donepezil/ARICEPTR), rivastignine/EX 22.5 mg of memantine. ELONR), galantamine/REMINYL(R), tacrine/COGNEX(R), 0032 FIG. 1C is a graph predicting plasma blood levels metrifonate, or huperzine-A). The combination is adminis at steady state for an immediate release formulation of tered such that the symptoms associated with CNS-related memantine (Namenda) and Sustained release formulations condition are alleviated or prevented, or alternatively, Such of memantine (NPI-6601, NPI-6701, and NPI-6801), that progression of the CNS-related condition is reduced. obtained using the Gastro-Plus Software package V.4.0.2. Desirably, either of these two agents, or even both agents, is The Sustained release formulations contain 22.5 mg of formulated for extended release, thereby providing a con memantine. centration over a desired time period that is high enough to be therapeutically effective but low enough to reduce or 0033 FIG. 2 shows dissolution profile of A) Sustained avoid adverse events associated with excessive levels of Release (SR) Memantine (fast)—Immediate Release (IR) either agent in the subject. Preferably, the compositions of Donepezil (NPI-6170), B) SR Memantine (medium) IR the present invention are formulated to provide a concen Donepezil (NPI-6270) and C) SR Memantine (slow) IR tration ratio variability over the dosing interval that is less Donepezil (NPI-6370). than that observed or predicted for formulations where neither component or only one component is in an extended 0034 FIG.3 shows dissolution profile of A) SR Meman release form. tine (fast). SR Donepezil (fast) (NPI-6171), B) SR Meman tine (medium). SR Donepezil (fast) (NPI-6271), C). SR NMDAr Antagonists Memantine (slow). SR Donepezil (fast) (NPI-6371). 0041 Any NMDAr antagonist can be used in the meth 0035 FIG. 4 shows dissolution profile of A) SR Meman ods and compositions of the invention, particularly those tine (fast) SR Donepezil (medium) (NPI-6172), B) SR that are non-toxic when used in the combination of the Memantine (medium)—SR Donepezil (medium) (NPI invention. The term "nontoxic' is used in a relative sense 6272), C). SR Memantine (slow)—SR Donepezil (medium) and is intended to designate any Substance that has been (NPI-6372). approved by the United States Food and Drug Administra tion (FDA) for administration to humans or, in keeping 0036 FIG. 5 shows dissolution profile of A) SR Meman with established regulatory criteria and practice, is suscep tine (fast) SR Donepezil (slow) (NPI-6173), B) SR tible to approval by the FDA or similar regulatory agency for Memantine (medium) SR Donepezil (Slow) (NPI-6273), any country for administration to humans or animals. C) SR Memantine (slow). SR Donepezil (slow) (NPI 0042. The NMDArantagonist may be an amino-adaman 6373). tane compound including, for example, memantine 0037 FIG. 6 shows plasma concentrations obtained (1-amino-3,5-dimethyladamantane), rimantadine (1-(1-ami using the GastroPlus software package V.4.0.2 for the fol noethyl)adamantane), amantadine (1-amino-adamantane), lowing compositions: A) SR Memantine (fast)—IR Done as well as pharmaceutically acceptable salts thereof. pezil (NPI-6170), B) SR Memantine (fast). SR Donepezil Memantine is described, for example, in U.S. Pat. Nos. (Slow) (NPI-6173), C). SR Memantine (medium) SR 3,391,142; 5,891.885; 5,919,826; and 6,187,338. Amanta Donepezil (medium) (NPI-6272), D) SR Memantine dine is described, for example, in U.S. Pat. Nos. 3,152, 180; US 2006/0252788 A1 Nov. 9, 2006
5,891,885; 5,919,826; and 6,187,338. Additional aminoada rivastigmine, described in U.S. Pat. No. 4,948,807, are all mantane compounds are described, for example, in U.S. Pat. presently approved by the United States FDA for the treat Nos. 4,346,112: 5,061,703; 5,334,618; 5,382,601; 6,444, ment of mild to moderate Alzheimer's disease. The use of 702; 6,620,845; and 6,662,845. All of these patents are these AChels commonly results in severe nausea, diarrhea, incorporated herein by reference. Vomiting, and other side effects, including cardiovascular 0043. Further NMDArantagonists that may be employed side effects, most of which are dose dependent. Furthermore, include, for example, ketamine, eliprodil, ifenprodil, dizo the interruption of therapy typically requires re-titration of cilpine, remacemide, iamotrigine, riluzole, aptiganel, phen the dosing starting at the lowest levels (Am. Fam. Phys. cyclidine, flupirtine, celfotel, felbamate, neramexane, sper 68(7): 136572 (2003)). Ultimately, patients cannot tolerate mine, spermidine, levemopamil, dextromethorphan ((+)-3- hydroxy-N-methylmorphinan) and its metabolite, chronic AChe therapy. dextrorphan ((+)-3-hydroxy-N-methylmorphinan), a phar 0048. The pharmaceutical composition may be formu maceutically acceptable salt or ester thereof, or a metabolic lated to provide donepezil in an amount ranging between 1 precursor of any of the foregoing. and 10 mg/day, 2 and 5 mg/day, or 2 and 4 mg/day; 0044) The pharmaceutical composition may be formu rivastigmine in an amount ranging between 1 and 12 lated to provide memantine in an amount ranging between 1 mg/day, 2 and 6 mg/day, or 2 and 5 mg/day; or galantamine and 80 mg/day, 5 and 40 mg/day, or 10 and 20 mg/day; in an amount ranging between 1 and 24 mg/day, 2 and 16 amantadine in an amount ranging between 25 and 500 mg/day, or 2 and 12 mg/day. Pediatric doses will typically be mg/day, 25 and 300 mg/day, or 100 and 300 mg/day; or lower than those determined for adults. Representative dos dextromethorphan in an amount ranging between 1 and 5000 ing can be found in the PDR by anyone skilled in the art. mg/day, 1 and 1000 mg/day, 100 and 800 mg/day, or 200 and 500 mg/day. Pediatric doses will typically be lower than 0049 Table 2 shows exemplary the pharmacokinetic those determined for adults. Representative dosing can be properties (e.g., Tmax and T1/2) of donepezil, rivastigmine, found in the PDR by anyone skilled in the art. galantamine, and Huperzine-A.
TABLE 2
Pharmacokinetics and Tox in humans for selected Aches Human PK Main Dose-Dependent Compound T/3 (hrs) Tmax (hrs) Normal Dose Adverse Event ARICEPT (R)/Donepezil 70 3–4 5-10 mg day Nausea, diarrhea, insomnia EXELON (R)/Rivastigmine 1.5 1-2.5 6-12 mg day Nausea, vomiting REMINYL (R) Galantamine 7 1-2.5 16–24 mg day Nausea, vomiting, anorexia HUPERZINE-A 4.8 1.3 100–400 Ig day Nausea, hyperactivity, dizziness
0045 Table 1 shows exemplary the pharmacokinetic Making Controlled Release Formulations properties (e.g., Tmax and T1/2) of memantine, amantadine, and rimantadine. 0050 A pharmaceutical composition according to the invention is prepared by combining a desired NMDAr TABLE 1. antagonist or antagonists with one or more additional ingre dients that, when administered to a subject, causes the Pharmacokinetics and Tox in humans for selected NMDAr antagonists NMDArantagonist to be released at a targeted concentration range for a specified period of time. The NMDArantagonist Human Tmax PK (t/2) in Normal Dose Dependent may be provided so that it is released at a dC/dT that is Compound in hrs hrs Dose Tox significantly reduced over an instant release (so called IR) dosage form, with an associated delay in the Tmax. The Memantine 60 3 10–20 mg day, Dose escalation starting at 5 mg required, hallucination pharmaceutical composition may be formulated to provide a Amantadine 15 3 100–300 mg/day Hallucination shift in Tmax by 24 hours, 16 hours, 8 hours, 4 hours, 2 Rimantadine 25 6 100–200 mg day Insomnia hours, or at least 1 hour. The associated reduction in dC/dT may be by a factor of approximately 0.05, 0.10, 0.25, 0.5 or at least 0.8. In addition, the NMDAr antagonist may be Acetylcholinesterase Inhibitor provided such that it is released at rate resulting in a C/C of approximately 2 or less for approximately 2 0046) The AChe of the combination described herein is hours to at least 8 hours after the NMDAr antagonist is an acetylcholinesterase inhibitor (e.g., donepezil/ARI introduced into a subject. CEPTR), rivastigmine/EXELONR, galantamine/REMI NYL(R), tacrine/COGNEX(R), metrifonate, or huperzine-A). 0051. In addition, the NMDAr antagonist may be pro vided such that it is released at a rate resulting in a 0047 Donepezil, described in U.S. Pat. No. 4,895,841, C/C (3. of approximately 2 or less for approximately 2 galantamine, described in U.S. Pat. No. 4,663,318, and hours to at least 8 hours after the NMDAr antagonist is US 2006/0252788 A1 Nov. 9, 2006 introduced into a subject. Optionally, the Sustained release 0057. In addition to the specific combinations disclosed formulations exhibit plasma concentration curves having herein, combinations made of a first NMDArantagonist and initial (e.g., from 2 hours after administration to 4 hours after the AChe may be identified by testing the ability of a test administration) slopes less than 75%, 50%, 40%, 30%, 20% combination of a selected NMDAr antagonist and one or or 10% of those for an IR formulation of the same dosage of more AChels to lessen the symptoms of a CNS-related the same NMDAr antagonist. The precise slope for a given disorder. Preferred combinations are those in which a lower individual will vary according to the NMDAr antagonist therapeutically effective amount of the NMDAr antagonist being used or other factors, including whether the patient has and/or the AChe is present relative to the same amount of eaten or not. For other doses, e.g., those mentioned above, the NMDArantagonist and/or the AChe required to obtain the slopes vary directly in relationship to dose. The deter the same effect when each agent is tested separately. mination of initial slopes of plasma concentration is described, for example, by U.S. Pat. No. 6,913,768, hereby 0058. The amounts and ratios of the NMDAr antagonist incorporated by reference. and the AChe are conveniently varied to maximize the therapeutic benefit and minimize the toxic or safety con 0.052 Optionally, the composition described herein is cerns. The NMDArantagonist may range between 20% and formulated such the NMDAr antagonist has an in vitro 200% of its normal effective dose and the AChe may range dissolution profile less than 70% in one hour, less than 90% between 20% to 200% of its normal effective dose. The in two hours, greater than 40% in six hours, and greater than precise ratio may vary according to the condition being 85% in 12 hours as measured using a USP type 2 (paddle) treated. In one example, the amount of memantine ranges dissolution system at 50 rpm, at a temperature of 37+0.5° between 2.5 and 80 mg per day and the amount of donepezil with water as a dissolution medium. ranges between 1 and 20 mg/day. 0053 Desirably, the compositions described herein have 0059 When the memantine is in a controlled-release an in vitro dissolution profile that is substantially identical to form, the preferred dosage range is 10 mg to 80 mg per day; the dissolution profile shown for the formulations shown in daily doses of about 22.5, 27.5, 32.5, 37.5, 42.5, 47.5, 52.5, FIGS. 1A and 2-5 and, upon administration to a subject at a 57.5, 62.5, 67.5, 72.5, 77.5 mg are particularly preferred. Substantially constant daily dose, achieves a plasma concen When the donepezil is in a controlled-release form, the tration profile that is substantially identical to those shown preferred dosage range 1 mg to 10 mg per day; daily doses in FIGS. 1B,6, and 7. of about 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 0054) A release profile, i.e., the extent of release of the 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0 mg per day are NMDArantagonist over a desired time, can be conveniently particularly preferred. In a particularly preferred embodi determined for a given time by calculating the Ca/Ca ment the memantine dose is 30-45 mg per day, taken in for a desired time range. For example, the NMDArantago combination with a donepezil dose of 2-4 mg/day, admin nist can be provided so that it is released at C/C of istered as a single dosage form, with no dose escalation over approximately 2 or less for approximately 2 hours to at least time. The combination dosage form preferably has Sustained 6 hours after the NMDAr antagonist is introduced into a release formulations for memantine, donepezil or both, Such subject. One of ordinary skill in the art can prepare combi that the dissolution profile of the two drugs in the combi nations with a desired release profile using the NMDAr nation tablet are “matched, especially with regards to the antagonists and formulation methods described below. Tmax, dC/dT (normalized for the dose of NMDAr antago nist and AChel) in a human. For memantine and donepezil, 0.055 Optionally, the AChe may also be prepared as a which have similar pharmacokinetic properties, in vitro controlled release formulation as described above for the dissolution profiles will also be similar. NMDAr antagonist. 0060. In a preferred embodiment of this invention, 0056. Using the formulations described herein, therapeu memantine and donepezil are formulated into beads or tic levels may be achieved while minimizing debilitating pellets (as described herein) with substantially similar dis side-effects that are usually associated with immediate solution profiles. More preferably, beads or pellets of release formulations. Furthermore, as a result of the reduc memantine are prepared with a dissolution profiles similar to tion in the time to obtain peak plasma level and the poten that shown for memantine in FIG. 4B and, separately, beads tially extended period of time at the therapeutically effective or pellets of donepezil are prepared with a dissolution profile plasma level, the dosage frequency may be reduced to, for similar to that shown for donepezil in the same figure. The example, once or twice daily dosage, thereby improving preferred pellets are approximately 0.4 mg each and contain patient compliance and adherence. For example, side effects approximately 60 g memantine or donepezil and easily including psychosis and cognitive deficits associated with characterized by known methods. The beads may be filled the administration of NMDArantagonists may be lessened into gelatin capsules by mass or number to achieve the in severity and frequency through the use of controlled preferred mass of memantine of 30-45 mg per capsules and release methods that shift the Tmax to longer times, thereby donepezil of 2-4 mg per capsule. For example, a 42 mg reducing the dC/dT of the drug. Reducing the dC/dT of the memantine 3.6 mg donepezil combination may be prepared drug not only increases Tmax, but also reduces the drug by combining 700 memantine beads with 60 donepezil concentration at Tmax and reduces the Cmax/Cmean ratio beads in each capsule, equivalent to 280 mg memantine providing a more constant amount of drug to the Subject beads plus 24 mg donepezil beads per capsule. being treated over a given period of time and reducing adverse events associated with dosing. With regards to the 0061 Additionally, different release profiles for each AChel, the lower dC/dT and Cmean will result in a lower active pharmaceutical ingredient may be prepared and com incidence of cardiovascular or gastric side effects and other bined in prescribed ratios to adjust the release profile for adverse events. each of the ingredients, enabling the more rapid develop US 2006/0252788 A1 Nov. 9, 2006
ment of formulations for development purposes or special the combination, or both agents may be formulated to ized formulations for individual products. provide controlled, extended release (as described herein). For example, a pharmaceutical composition that provides 0062 For a specified range a physician or other appro controlled release of the NMDAr antagonist, the AChel, or priate health professional will typically determine the best both may be prepared by combining the desired agent or dosage for a given patient, according to his sex, age, weight, agents with one or more additional ingredients that, when pathological state, and other parameters. In some cases, it administered to a subject, causes the respective agent or may be necessary to use dosage outside of the range stated agents to be released at a targeted rate for a specified period in pharmaceutical packaging insert to treat a Subject. Those of time. The two agents are preferably administered in a cases will be apparent to the prescribing physician or manner that provides the desired effect from the first and veterinarian. second agents in the combination. Optionally, the first and 0063. In some embodiments, the combinations of the second agents are admixed into a single formulation before invention achieve therapeutic levels while minimizing they are introduced into a subject. The combination may be debilitating side-effects that are usually associated with conveniently sub-divided in unit doses containing appropri immediate release formulations. Furthermore, as a result of ate quantities of the first and second agents. The unit dosage the delay in the time to obtain peak plasma level and the form may be, for example, a capsule or tablet itself or it can potentially extended period of time at the therapeutically be an appropriate number of Such compositions in package effective plasma level, the dosage frequency may be reduced form. The quantity of the active ingredients in the unit to, for example, once or twice daily dosage, thereby improv dosage forms may be varied or adjusted according to the ing patient compliance and adherence. particular need of the condition being treated. 0064. Accordingly, the combination of the invention 0067. Alternatively, the NMDAr antagonist and the allows the NMDArantagonist and the AChe to be admin AChe of the combination may not be mixed until after they istered in a combination that improves efficacy and avoids are introduced into the subject. Thus, the term “combina undesirable side effects of both drugs. For example, side tion' encompasses embodiments where the NMDArantago effects including psychosis and cognitive deficits associated nist and the AChe are provided in separate formulations and with the administration of NMDAr antagonists may be are administered sequentially. For example, the NMDAr lessened in severity and frequency through the use of antagonist and the AChe may be administered to the Subject controlled-release methods that shift the Tmax to longer separately within 2 days, 1 day, 18 hours, 12 hours, one hour, times, thereby reducing the dC/dT of the drug. Reducing the a half hour, 15 minutes, or less of each other. Each agent may dC/dT of the drug not only increases Tmax, but also reduces be provided in multiple, single capsules or tablets that are the drug concentration at Tmax and reduces the Cmax/ administered separately to the subject. Alternatively, the Cmean ratio providing a more constant amount of drug to NMDAr antagonist and the AChe are separated from each the Subject being treated over a given period of time and other in a pharmaceutical composition Such that they are not reducing adverse events associated with dosing. Similarly, mixed until after the pharmaceutical composition has been side effects associated with the use of AChels may also be introduced into the Subject. The mixing may occur just prior reduced in severity and frequency through controlled release to administration to the subject or well in advance of methods. administering the combination to the Subject. 0068). If desired, the NMDAr antagonist and the AChel 0065. In certain embodiments, the combinations provide may be administered to the Subject in association with other additive effects. Additivity is achieved by combining the therapeutic modalities, e.g., drug, Surgical, or other inter active agents without requiring controlled release technolo ventional treatment regimens. Accordingly, the combination gies. In other embodiments, particularly when the pharma described herein may be administered simultaneously or cokinetic profiles of the combined active pharmaceutical within 14 days, 7 days, 5 days, 3 days, one day, 12 hours, 6 ingredients are dissimilar, controlled release formulations hours, 3 hours, or one hour of additional therapeutic modali optimize the pharmacokinetics of the active pharmaceutical ties. Where the combination includes a non-drug treatment, agents to reduce the variability of the Cratio over time. the non-drug treatment may be conducted at any Suitable Reduction of Cratio variability over a defined time period time so long as a beneficial effect from the co-action of the enables a concerted effect for the agents over that time, combination and the other therapeutic modalities is maximizing the effectiveness of the combination. The Cratio achieved. For example, in appropriate cases, the beneficial variability (“Cratio.var) is defined as the standard deviation effect is still achieved when the non-drug treatment is of a series of Cratios taken over a given period of time temporally removed from the administration of the thera divided by the mean of those Cratios multiplied by 100%. peutic agents, perhaps by days or even weeks. The Cratio for the controlled release formulation of drugs with significantly different pharmacokinetic properties is 0069. The preparation of pharmaceutical or pharmaco more consistent than for the IR administration of the same logical compositions are known to those of skill in the art in drugs over any significant time period, including shortly light of the present disclosure. General techniques for for after administration and at steady state. mulation and administration are found in "Remington: The Science and Practice of Pharmacy, Twentieth Edition.” Lip Modes of Administration pincott Williams & Wilkins, Philadelphia, Pa. Tablets, cap 0.066 The combination of the invention may be admin Sules, pills, powders, granules, dragées, gels, slurries, oint istered in either a local or systemic manner or in a depot or ments, solutions Suppositories, injections, inhalants and Sustained release fashion. The two agents may be delivered aerosols are examples of Such formulations. in an oral, transdermal or intranasal formulation. In a 0070. In some embodiments, the first agent and second preferred embodiment, the NMDArantagonist, the AChe of agent of the combination described herein are provided US 2006/0252788 A1 Nov. 9, 2006 within a single or separate pharmaceutical compositions. 24 hours) thereby maintaining both agents in a constant ratio "Pharmaceutically or Pharmacologically Acceptable' and concentration for optimal therapeutic benefits for both includes molecular entities and compositions that do not acute and chronic administration. Preferred Cratio,var Val produce an adverse, allergic or other untoward reaction ues may be less than about 30%, 50%, 75%, 90% of those when administered to an animal, or a human, as appropriate. for IR administration of the same active pharmaceutical "Pharmaceutically Acceptable Carrier includes any and all ingredients over the first 4, 6, 8, or 12 hours after adminis Solvents, dispersion media, coatings, antibacterial and anti tration. Preferred Cratio, Var values are less than about 100%, fungal agents, isotonic and absorption delaying agents and 70%, 50%, 30%, 20%, 10%. the like. The use of Such media and agents for pharmaceu tical active substances is well known in the art. Except 0074 Formulations that deliver this constant, measurable insofar as any conventional media or agent is incompatible profile also allow one to achieve a monotonic ascent from an with the active ingredient, its use in the therapeutic compo acute ratio to a desired chronic ratio for drugs with widely sitions is contemplated. Supplementary active ingredients varying elimination half-lives. Compositions of this type can also be incorporated into the compositions. "Pharma and methods of treating patients with these compositions are ceutically Acceptable Salts' include acid addition salts and embodiments of the invention. Numerous ways exist for which are formed with inorganic acids such as, for example, achieving the desired release profiles, as exemplified below. hydrochloric or phosphoric acids, or Such organic acids as 0075. In some embodiments, the first agent and second acetic, oxalic, tartaric, mandelic, and the like. Salts formed agent of the combination described herein are provided with the free carboxyl groups can also be derived from within a single or separate pharmaceutical compositions. inorganic bases such as, for example, sodium, potassium, "Pharmaceutically or Pharmacologically Acceptable' ammonium, calcium, or ferric hydroxides, and Such organic includes molecular entities and compositions that do not bases as isopropylamine, trimethylamine, histidine, procaine produce an adverse, allergic or other untoward reaction and the like. when administered to an animal, or a human, as appropriate. Formulations for Oral Administration "Pharmaceutically Acceptable Carrier includes any and all Solvents, dispersion media, coatings, antibacterial and anti 0071 Combinations can be provided as pharmaceutical fungal agents, isotonic and absorption delaying agents and compositions that are optimized for particular types of the like. The use of Such media and agents for pharmaceu delivery. For example, pharmaceutical compositions for oral tical active substances is well known in the art. Except delivery are formulated using pharmaceutically acceptable insofar as any conventional media or agent is incompatible carriers that are well known in the art and described further with the active ingredient, its use in the therapeutic compo below. The carriers enable the agents in the combination to sitions is contemplated. Supplementary active ingredients be formulated, for example, as a tablet, pill, capsule, solu can also be incorporated into the compositions. "Pharma tion, Suspension, powder, liquid, or gel for oral ingestion by ceutically Acceptable Salts' include acid addition salts and the subject. which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or Such organic acids as 0072 The NMDAr antagonist, the AChel of the inven acetic, oxalic, tartaric, mandelic, and the like. Salts formed tion, or both agents may be provided in a controlled, with the free carboxyl groups can also be derived from extended release form. In one example, at least 50%, 90%, inorganic bases such as, for example, sodium, potassium, 95%, 96%, 97%, 98%, 99%, or even in excess of 99% of the ammonium, calcium, or ferric hydroxides, and Such organic NMDAr antagonist is provided in an extended release bases as isopropylamine, trimethylamine, histidine, procaine dosage form. A release profile, i.e., the extent of release of and the like. the NMDAr antagonist or the AChe over a desired time, may be conveniently determined for a given time by calcu 0076 Suitable methods for preparing combinations in lating the C/C for a desired time range to achieve a which the first agent, AChel, or both agents are provided in given acute or chronic steady state serum concentration extended release-formulations include those described in profile. Thus, upon the administration to a Subject (e.g., a U.S. Pat. No. 4,606,909 (hereby incorporated by reference). mammal such as a human), the NMDAr antagonist has a This reference describes a controlled release multiple unit Cmax/Cmean of approximately 2.5, 2, 1.5, or 1.0 approxi formulation in which a multiplicity of individually coated or mately 1, 1.5, 2 hours to at least 6, 8, 9, 12, 18, 21, or 24 microencapsulated units are made available upon disinte hours following such administration. If desired, the release gration of the formulation (e.g., pill or tablet) in the stomach of the NMDArantagonist may be monophasic or multipha of the animal (see, for example, column 3, line 26 through sic (e.g., biphasic). Moreover, the AChe may be formulated column 5, line 10 and column 6, line 29 through column 9. as an extended release composition, having a C/C of line 16). Each of these individually coated or microencap approximately 2.5, 2, 1.5, or 1.0, approximately 1, 1.5, 2 Sulated units contains cross-sectionally Substantially homog hours to at least 6, 8, 9, 12, 18, 21, or 24 hours following enous cores containing particles of a sparingly soluble active administration to a subject. One of ordinary skill in the art Substance, the cores being coated with a coating that is can prepare combinations with a desired release profile Substantially resistant to gastric conditions but which is using the NMDArantagonists and the AChe and formula erodable under the conditions prevailing in the Small intes tion methods known in the art or described below. tine. 0073. As shown in Tables 1 and 2, the pharmacokinetic 0077. The combination may alternatively be formulated half-lives of the drugs of both classes vary from about 1.5 using the methods disclosed in U.S. Pat. No. 4,769,027, for hours to 70 hours. Thus, suitable formulations may be example. Accordingly, extended release formulations conveniently selected to achieve nearly constant concentra involve prills of pharmaceutically acceptable material (e.g., tion profiles over an extended period (preferably from 8 to Sugar/starch, salts, and waxes) may be coated with a water US 2006/0252788 A1 Nov. 9, 2006 permeable polymeric matrix containing an NMDArantago to 24 hours and can be used with a range of compounds, nist and next overcoated with a water-permeable film con including poorly soluble or highly soluble drugs. OROS(R) taining dispersed within it a water Soluble particulate pore technology can be used to deliver high drug doses meeting forming material. high drug loading requirements. By targeting specific areas 0078. One or both agents of the combination may addi of the gastrointestinal tract, OROS(R) technology may pro tionally be prepared as described in U.S. Pat. No. 4,897.268, vide more efficient drug absorption and enhanced bioavail involving a biocompatible, biodegradable microcapsule ability. The osmotic driving force of OROS(R) and protection delivery system. Thus, the NMDAr antagonist may be of the drug until the time of release eliminate the variability formulated as a composition containing a blend of free of drug absorption and metabolism often caused by gastric flowing spherical particles obtained by individually pH and motility microencapsulating quantities of memantine, for example, 0081 Alternatively, the combination may be prepared as in different copolymer excipients which biodegrade at dif described in U.S. Pat. No. 5,395,626 features a multilayered ferent rates, therefore releasing memantine into the circula controlled release pharmaceutical dosage form. The dosage tion at a predetermined rates. A quantity of these particles form contains a plurality of coated particles wherein each may be of Such a copolymer excipient that the core active has multiple layers about a core containing an NMDAr ingredient is released quickly after administration, and antagonist and/or the AChe whereby the drug containing thereby delivers the active ingredient for an initial period. A core and at least one other layer of drug active is overcoated second quantity of the particles is of such type excipient that with a controlled release barrier layer therefore providing at delivery of the encapsulated ingredient begins as the first least two controlled releasing layers of a water Soluble drug quantity's delivery begins to decline. A third quantity of from the multilayered coated particle. ingredient may be encapsulated with a still different excipi ent which results in delivery beginning as the delivery of the 0082. By way of example, extended release oral formu second quantity beings to decline. The rate of delivery may lation can be prepared using additional methods known in be altered, for example, by varying the lactide/glycolide the art. For example, a suitable extended release form of the ratio in a poly(D.L-lactide-co-glycolide) encapsulation. either active pharmaceutical ingredient or both may be a Other polymers that may be used include polyacetal poly matrix tablet composition. Suitable matrix forming materials mers, polyorthoesters, polyesteramides, polycaprolactone include, for example, waxes (e.g., carnauba, bees wax, and copolymers thereof, polycarbonates, polyhydroxybuter paraffin wax, ceresine, shellac wax, fatty acids, and fatty ate and copolymers thereof, polymaleamides, copolyax alcohols), oils, hardened oils or fats (e.g., hardened rapeseed alates and polysaccharides. oil, castor oil, beef tallow, palm dil, and Soya bean oil), and polymers (e.g., hydroxypropyl cellulose, polyvinylpyrroli 0079. In one embodiment of the invention, the NMDAr done, hydroxypropyl methyl cellulose, and polyethylene antagonist, the AChel, or both agents may be provided in a glycol). Other Suitable matrix tabletting materials are micro controlled or extended release form with or without an crystalline cellulose, powdered cellulose, hydroxypropyl immediate release component in order to maximize the cellulose, ethyl cellulose, with other carriers, and fillers. therapeutic benefit of each, while reducing unwanted side Tablets may also contain granulates, coated powders, or effects associated with each. When these drugs are provided pellets. Tablets may also be multi-layered. Multi-layered in an oral form without the benefit of controlled or extended tablets are especially preferred when the active ingredients release components, they are released and transported into have markedly different pharmacokinetic profiles. Option the body fluids over a period of minutes to several hours. ally, the finished tablet may be coated or uncoated. Thus, the composition of the invention may contain an NMDArantagonist and a Sustained release component. Such 0083. The coating composition typically contains an as a coated Sustained release matrix, a Sustained release insoluble matrix polymer (approximately 15-85% by weight matrix, or a Sustained release bead matrix. In one example, of the coating composition) and a water soluble material memantine (e.g., 5-80 mg) is formulated without an imme (e.g., approximately 15-85% by weight of the coating com diate release component using a polymer matrix (e.g., position). Optionally an enteric polymer (approximately 1 to Eudragit), Hydroxypropyl methyl cellulose (HPMC) and a 99% by weight of the coating composition) may be used or polymer coating (e.g., Eudragit). Such formulations are included. Suitable water soluble materials include polymers compressed into Solid tablets or granules or formed into Such as polyethylene glycol, hydroxypropyl cellulose, pellets for capsules or tablets. Optionally, a coating Such as hydroxypropyl methyl cellulose, polyvinylpyrrolidone, Opadry(R) or Surelease R is used. polyvinyl alcohol, and monomeric materials such as Sugars (e.g., lactose. Sucrose, fructose, mannitol and the like), Salts 0080 Separately prepared pellets, preferably release con (e.g., sodium chloride, potassium chloride and the like), trolling pellets, combined in any manner provide the flex organic acids (e.g., fumaric acid. Succinic acid, lactic acid, ibility of making ratios of NMDAr antagonist to AChel and tartaric acid), and mixtures thereof. Suitable enteric containing compositions ranging from 0.1:100 to 100:0.1 polymers include hydroxypropyl methyl cellulose, acetate more preferably from 1:100 to 100:1, most preferably 1:10 Succinate, hydroxypropyl methyl cellulose, phthalate, poly to 10:1 by mass or by numbers of pellets (see Example 7), vinyl acetate phthalate, cellulose acetate phthalate, cellulose and at the desired release profiles for each of the active acetate trimellitate, shellac, Zein, and polymethacrylates ingredients. Optionally, the NMDArantagonist, the AChel, containing carboxyl groups. or both agents are prepared using the OROS(R) technology, described for example, in U.S. Pat. Nos. 6,919,373, 6,923, 0084. The coating composition may be plasticised 800, 6,929,803, 6,939,556, and 6,930,128, all of which are according to the properties of the coating blend Such as the hereby incorporated by reference. This technology employs glass transition temperature of the main agent or mixture of osmosis to provide precise, controlled drug delivery for up agents or the solvent used for applying the coating compo US 2006/0252788 A1 Nov. 9, 2006 sitions. Suitable plasticisers may be added from 0 to 50% by have a skin penetration rate of at least 10 mole/cm/hour. weight of the coating composition and include, for example, At least 5% of the active material will flux through the skin diethyl phthalate, citrate esters, polyethylene glycol, glyc within a 24 hour period. The penetration through skin of erol, acetylated glycerides, acetylated citrate esters, dibu specific formulations may be measures by standard methods tylsebacate, and castor oil. If desired, the coating composi in the art (for example, Franz et al., J. Invest. Derm. tion may include a filler. The amount of the filler may be 1% 64:194-195 (1975)). to approximately 99% by weight based on the total weight of the coating composition and may be an insoluble material 0090 Pharmaceutical compositions containing the NMDAr antagonist and/or AChe of the combination may Such as silicon dioxide, titanium dioxide, talc, kaolin, alu also be delivered in an aerosol spray preparation from a mina, starch, powdered cellulose, MCC, or polacrilin potas pressurized pack, a nebulizer or from a dry powder inhaler. S1. Suitable propellants that can be used in a nebulizer include, 0085. The coating composition may be applied as a for example, dichlorodifluoro-methane, trichlorofluo Solution or latex in organic solvents or aqueous solvents or romethane, dichlorotetrafluoroethane and carbon dioxide. mixtures thereof. If solutions are applied, the solvent may be The dosage may be determined by providing a valve to present in amounts from approximate by 25-99% by weight deliver a regulated amount of the compound in the case of based on the total weight of dissolved solids. Suitable a pressurized aerosol. solvents are water, lower alcohol, lower chlorinated hydro carbons, ketones, or mixtures thereof. If latexes are applied, 0091 Compositions for inhalation or insufflation include the solvent is present in amounts from approximately Solutions and Suspensions in pharmaceutically acceptable, 25-97% by weight based on the quantity of polymeric aqueous or organic solvents, or mixtures thereof, and pow ders. The liquid or Solid compositions may contain Suitable material in the latex. The solvent may be predominantly pharmaceutically acceptable excipients as set out above. Water. Preferably the compositions are administered by the oral, 0.086 The pharmaceutical composition described herein intranasal or respiratory route for local or systemic effect. may also include a carrier Such as a solvent, dispersion Compositions in preferably sterile pharmaceutically accept media, coatings, antibacterial and antifungal agents, isotonic able solvents may be nebulized by use of inert gases. and absorption delaying agents. The use of Such media and Nebulized solutions may be breathed directly from the agents for pharmaceutically active Substances is well known nebulizing device or the nebulizing device may be attached in the art. Pharmaceutically acceptable salts can also be used to a face mask, tent or intermittent positive pressure breath in the composition, for example, mineral salts such as ing machine. Solution, Suspension or powder compositions hydrochlorides, hydrobromides, phosphates, or Sulfates, as may be administered, preferably orally or nasally, from well as the salts of organic acids such as acetates, propri devices that deliver the formulation in an appropriate man onates, malonates, or benzoates. The composition may also . contain liquids, such as water, Saline, glycerol, and ethanol, as well as Substances Such as wetting agents, emulsifying 0092. In some embodiments, for example, the composi agents, or pH buffering agents. Liposomes, such as those tion may be delivered intranasally to the cribriform plate rather than by inhalation to enable transfer of the active described in U.S. Pat. No. 5,422,120, WO95/13796, WO agents through the olfactory passages into the CNS and 91/14445, or EP 524.968 B1, may also be used as a carrier. reducing the systemic administration. Devices used for this 0087 Additional methods for making controlled release route of administration are included in U.S. Pat. No. 6,715, formulations are described in, e.g., U.S. Pat. Nos. 5,422,123; 485. Compositions delivered via this route may enable 5,601,845; 5,912,013; and 6,194,000, all of which are increased CNS dosing or reduced total body burden reduc hereby incorporated by reference. ing systemic toxicity risks associated with certain drugs. Formulations for Other Routes of Administration 0093. Additional formulations suitable for other modes of administration include rectal capsules or Suppositories. 0088 Alternatively, the compositions of the present For Suppositories, traditional binders and carriers may invention may be administered transdermally. Preparation include, for example, polyalkylene glycols or triglycerides; for delivery in a transdermal patch can be performed using Such suppositories may be formed from mixtures containing methods also known in the art, including those described the active ingredient in the range of 0.5% to 10%, preferably generally in, e.g., U.S. Pat. Nos. 5,186,938; 6,183,770; 196-2%. 4,861,800; 4.284.444 and WO 89/09051. A patch is a particularly useful embodiment in cases where the therapeu 0094. The combination may optionally be formulated for tic agent has a short half-life or requires reduction in dC/dT. delivery in a vessel that provides for continuous long-term Patches can be made to control the release of skin-permeable delivery, e.g., for delivery up to 30 days, 60 days, 90 days, active ingredients over a 12 hour, 24 hour, 3 day, and 7 day 180 days, or one year. For example the vessel can be period. In one example, a 2-fold daily excess of an NMDAr provided in a biocompatible material Such as titanium. antagonist is placed in a non-volatile fluid along with the Long-term delivery formulations are particularly useful in opiate narcotic agent, non-steroidal anti-inflammatory agent, Subjects with chronic conditions, for assuring improved or anesthetic. Given the amount of the agents employed patient compliance, and for enhancing the stability of the herein, a preferred release will be from 12 to 72 hours. combinations. Formulations for continuous long-term deliv 0089 Transdermal preparations of this form will contain ery are provided in, e.g., U.S. Pat. Nos. 6,797.283: 6,764, from 1% to 50% active ingredients. The compositions of the 697; 6,635,268, and 6,648,083. invention are provided in the form of a viscous, non-volatile 0095. If desired, the agents may be provided in a kit?as a liquid. Preferably, both members of the combination will combined preparation. The kit/combined preparation can US 2006/0252788 A1 Nov. 9, 2006
additionally include instructions for use. In some embodi tonias, benign essential tremor, tardive dystonia, tardive ments, the kit/combined preparation includes in one or more dyskinesia, and Tourette's syndrome), ataxic syndromes, containers the NMDArantagonist and, separately, in one or disorders of the sympathetic nervous system (e.g., Shy more containers, the AChe described herein. The NMDAr Drager, Olivopontoicerebellar degeneration, striatonigral antagonist and AChe may be mixed together prior to degenration, PD, HD, Gullian Barre, causalgia, complex administration or may be administered separately to the regional pain syndrome types I and II, diabetic neuropathy, subject. Where they are administered separately to the and alcoholic neuropathy), Cranial nerve disorders (e.g., patient they may be administered at the same time as Trigeminal neuropathy, trigeminal neuralgia, Menier's Syn separate formulations, at different times and over different drome, glossopharangela neuralgia, dysphagia, dysphonia, periods of time, which may be separate from one another or and cranial nerve palsies), myelopethies, traumatic brain and overlapping. The NMDAr antagonist and AChe may be spinal cord injury, radiation brian injury, multiple Sclerosis, administered in any order. Post-menengitis syndrome, prion diseases, myelities, radi culitis, neuropathies (e.g., Guillian-Barre, diabetes associ 0096. In other embodiments, the kit/combined prepara ated with dysproteinemias, transthyretin-induced neuropa tion provides a combination with the NMDArantagonist and thies, neuropathy associated with HIV, neuropathy the AChe mixed in one or more containers. The kits/ associated with Lyme disease, neuropathy associated with combined preparations include a therapeutically effective herpes Zoster, carpal tunnel syndrome, tarsal tunnel Syn dose of an agent for treating dementia or other CNS-related drome, amyloid-induced neuropathies, leprous neuropathy, condition. Bell’s palsy, compression neuropathies, sarcoidosis-induced 0097 Preparation of a pharmaceutical composition for neuropathy, polyneuritis cranialis, heavy metal induced neu delivery in a subdermally implantable device can be per ropathy, transition metal-induced neuropathy, drug-induced formed using methods known in the art. Such as those neuropathy), axonic brain damage, encephalopathies, and described in, e.g., U.S. Pat. Nos. 3,992,518; 5.660,848; and chronic fatigue syndrome. All of the above disorders may be 5,756,115. treated with the combinations and methods described herein. Indications Suitable for Treatment with the Combination Administration of the Compositions 0099 Immediate release formulations of memantine 0.098 Any subject experiencing or at risk of experiencing (e.g., Namenda) are typically administered at low doses a CNS-related disorder including dementia (e.g., Alzhe (e.g., 5 mg/day) and progressively administered at increas imer's disease, Parkinson's disease, Picks disease, fronto ing frequency and dose over time to reach a steady state temporal dementia, Vascular dementia, normal pressure serum concentration that is therapeutically effective. hydrocephalus, HD, and MCI), neuro-related conditions, According to the manufacturer's recommendation, dementia-related conditions, such as epilepsy, seizure dis Namenda, an immediate release formulation of memantine, orders, acute pain, chronic pain, chronic neuropathic pain is first administered to Subjects at a dose of 5 mg per day. may be treated using the combinations and methods After a period of time, subjects are administered with this described herein. Epileptic conditions include complex par dose twice daily. Subjects are next administered with a 5 mg tial, simple partial, partials with secondary generalization, and 10 mg dosing per day and finally administered with 10 generalized—including absence, grand mal (tonic clonic), mg Namenda twice daily. Using this approved dosing regi tonic, atonic, myoclonic, neonatal, and infantile spasms. men, a therapeutically effective steady state serum concen Additional specific epilepsy syndromes are juvenile myo tration may be achieved within about thirty days following clonic epilepsy, Lennox-Gastaut, mesial temporal lobe epi the onset of therapy. Using a sustained release formulation lepsy, nocturnal frontal lobe epilepsy, progressive epilepsy (at a constant daily dose of 22.5 mg, for example), a with mental retardation, and progressive myoclonic epi therapeutically effective steady state concentration may be lepsy. The combinations of the invention are also useful for the treatment and prevention of pain caused by disorders achieved substantially sooner, without using a dose escalat including cerebrovascular disease, motor neuron diseases ing regimen. Such concentration is predicted to be achieved (e.g., ALS, Spinal motor atrophies, Tay-Sachs, Sandoff within 13 days of the onset of therapy. Furthermore, the disease, familial spastic paraplegia), neurodegenerative dis slope during each absorption period for the Sustained release eases (e.g., familial Alzheimer's disease, prion-related dis formulation is less (i.e. not as steep) as the slope for eases, cerebellar ataxia, Friedrich's ataxia, SCA, Wilson's Namenda. Accordingly, the dC/dt of the sustained release disease, RP, ALS, Adrenoleukodystrophy, Menke's Sx, cere formulation is reduced relative to the immediate release bral autosomal dominant arteriopathy with subcortical inf formulation even though the dose administered is larger than arcts (CADASIL); spinal muscular atrophy, familial ALS, for the immediate release formulation. Based on this model, muscular dystrophies, Charcot Marie Tooth diseases, neu a Sustained release formulation of memantine may be rofibromatosis, Von-Hippel Lindau, Fragile X, spastic administered to a subject in an amount that is approximately paraplesia, psychiatric disorders (e.g., panic syndrome, gen the full strength dose (or that effectively reaches a thera eral anxiety disorder, phobic syndromes of all types, mania, peutically effective dose) from the onset of therapy and manic depressive illness, hypomania, unipolar depression, throughout the duration of treatment. Accordingly, a dose depression, stress disorders, PTSD, somatoform disorders, escalation would not be required. Similarly, the controlled personality disorders, psychosis, and Schizophrenia), and release methods described herein may be employed to drug dependence (e.g., alcohol, psychostimulants (eg. crack, reduce the dC/dT for other NMDAr antagonists or AChels cocaine, speed, meth), opioids, and nicotine), Tuberous enabling the administration of the combinations without the Sclerosis, and Wardenburg Syndrome), strokes (e.g., throm requirement for dose escalation. botic, embolic, thromboembolic, hemmorhagic, Venocon 0.100 Treatment of a subject with the combination may strictive, and venous), movement disorders (e.g., PD, dys be monitored using methods known in the art. The efficacy US 2006/0252788 A1 Nov. 9, 2006 12 of treatment using the combination is preferably evaluated EXAMPLE 3 by examining the Subject's symptoms in a quantitative way, e.g., by noting a decrease in the frequency of adverse Release Profile of Memantine and Galantamine symptoms, behaviors, or attacks, or an increase in the time for Sustained worsening of symptoms. In a Successful treat 0.104 Release proportions are shown in Table 4 below for ment, the Subjects status will have improved (i.e., frequency a combination of memantine and galantamine. The cumu of relapses will have decreased, or the time to sustained lative fraction is the amount of drug Substance released from progression will have increased). the formulation matrix to the serum or gut environment (e.g., 0101 The invention will be illustrated in the following U.S. Pat. No. 4,839,177) or as measured with a USP II non-limiting examples. Paddle system using water as the dissolution medium.
EXAMPLE 1. TABLE 4
In vivo Method for Determining Optimal Release profile of memantine and donepezil Steady-State Concentration Ratio (Cratios) 0102) A dose ranging study is performed using, for MEMANTINE GALANTAMINE example, the dementia model (APP23 mouse model T/3 = 60 hrs T/3 = 7 hrs described by Van Dam et al. (See Psychopharmacology Time cum. fraction A cum. fraction B 2005, 180(1):177-190), or the Tg2576 model described by Dong et al (Psychopharmacology 2005, 181 (1): 145-152). 1 O.2 O.2 An isobolic experiment ensues in which the drugs are 2 O.3 O.3 combined in fractions of their EDXXs to add up to ED100 4 0.4 0.4 (e.g., ED50:ED50 or ED25:ED75). The plot of the data is 8 O.S O.S constructed. The experiment points that lie below the 12 O.6 O6 straight line between the ED50 points on the graph are 16 0.7 0.7 indicative of synergy, points on the line are indicative of 2O O.8 O.8 additive effects, and points above the line are indicative of 24 O.9 1.O inhibitory effects. The point of maximum deviation from the isobolic line is the optimal ratio. This is the optimal steady state ratio (Cratio, Ss) and is adjusted based upon the agents half-life. Similar protocols may be applied in a wide variety EXAMPLE 4 of validated animal models. Tablet Containing a Combination of Memantine EXAMPLE 2 and Galantamine Combinations of an NMDAr Antagonist and an 0105. An extended release dosage form for administra AChe tion of memantine and galantamine is prepared as three 0103 Representative combination ranges and ratios are individual compartments. Three individual compressed tab provided below for compositions of the invention. The lets are prepared, each having a different release profile, are ranges given in Table 3 are based on the formulation encapsulated into a gelatin capsule which is then closed and strategies described herein. sealed. The components of the three tablets are as follows.
TABLE 3
Adult Dosage and Ratios for Combination Therapy
Achel Quantity, mg/day/AChel:NMDA Ratio Range)
NMDA drug Donepezil Rivastigmine? Galantimine? Tacrine mg day ARICEPT (R) EXELON (R) REMINYL (R) COGNEX (R) Huperzine-A Metrifonate
Memantine 1-20 1-24 3-48 8-160 O.O2-0.8 8-8O 2.5-8O (0.012–8) (0.012–9.6) (0.038–19) (0.1–64) (0.0025-0.32) (0.1-32) Amantadine? 1-20 1-24 3-48 8-160 O.O2-0.8 8-8O SO 400 (0.0025-0.4) (0.0025-0.48) (0.0075-0.96) (0.02–3.2) (0.0005–0.016) (0.02–1.6) Rimantadine? 1-20 1-24 3-48 8-160 O.O2-0.8 8-8O SO 200 (0.005-0.4) (0.005-0.48) (0.015–0.96) (0.043.2) (0.0001–0.016) (0.04–1.6) US 2006/0252788 A1 Nov. 9, 2006 13
0108. The tablets are prepared by wet granulation of the TABLE 5 individual drug particles and other core components as may be done using a fluid-bed granulator, or are prepared by Immediate Release Dosage form direct compression of the admixture of components. Tablet Component 1 (Table 5) is an immediate release dosage form, releasing TABLET 1 (immediate release): Function Amount per tablet the active agents within 1-2 hours following administration. Memantine Active agent O mg It contains no memantine to avoid the dC/dT effects of the Galantamine HBr Active agent 10.25 mg Dicalcium phosphate dihydrate Diluent 26.6 mg current dosage forms. Tablets 2 (Table 6) and 3 (Table 7) are Microcrystalline cellulose Diluent 26.6 mg coated with the delayed release coating material as may be Sodium starch glycolate Disintegrant 1.2 mg carried out using conventional coating techniques such as Magnesium Stearate Lubricant 0.6 mg spray-coating or the like. The specific components listed in the above tables may be replaced with other functionally equivalent components, e.g., diluents, binders, lubricants, 0106) fillers, coatings, and the like. TABLE 6 0.109 Oral administration of the capsule to a patient will Delayed Release (3-5 hours) Dosage form result in a release profile having three pulses, with initial release of galantamine from the first tablet being Substan Component tially immediate, release of the memantine and galantamine TABLET 2 (3–5 hour release): Function Amount per tablet from the second tablet occurring 3-5 hours following admin Memantine Active agent 10 ng istration, and release of the memantine and galantamine Galantamine HBr Active agent 10.25 ng Dicalcium phosphate dihydrate Diluent 26.6 ng from the third tablet occurring 7-10 hours following admin Microcrystalline cellulose Diluent 26.6 ng istration. Sodium starch glycolate Disintegrant 1.2 ng Magnesium Stearate Lubricant O6 ng EXAMPLE 5 Eudragit RS30D Delayed release 4.76 ng Talc Coating component 3.3 ng Triethyl citrate Coating component O.9S ng Pellets Containing Memantine or Donepezil 0110 Memantine HCl (or Donepezil HCl) containing 01.07 pellets were prepared by wet massing. Memantine HCl (or Donepezil HCl) was weighed and sieved through a No. 20 TABLE 7 screen into the bowl of low shear planetary mixer. To this, microcrystalline cellulose was weighed and added through Delayed Release (7-10 hours) Dosage form No. 20 screen and blended with Memantine HCl (or Done Component pezil HCl) using a spatula, then in a planetary mixer on low TABLET 3 (Release delayed speed. Eudragit NE 400, accurately weighed was incremen 7–10 hours): Function Amount per tablet tally added to the powder blend, allowing sufficient time Memantine Active agent 12.5 ng between additions for complete distribution. To avoid accu Galantamine HBr Active agent 5.125 ng mulation at the bottom and to loosen the material, the bottom Dicalcium phosphate dihydrate Diluent 26.6 ng Microcrystalline cellulose Diluent 26.6 ng was periodically scraped. Purified water was blended into Sodium starch glycolate Disintegrant 1.2 ng the mixture in 10 mL increments (the first of which was used Magnesium Stearate Lubricant O6 ng to rinse the beaker containing Eudragit NE 40D) until a Eudragit RS30D Delayed release 6.5 ng Talc Coating component 4.4 ng uniform blend appropriate for extrusion was obtained. Triethyl citrate Coating component 1.27 ng Experimental batches were prepared with 10 to 50 ml water. Wet massing was followed by extrusion, spheronization and drying by procedures well known in the prior art.
TABLE 8 Pellets containing Menantine HCl Percent in Wt. solid per Target Wt. per Actual Wt. Component Supplier Formula' Batch (grams) Batch (g) per Batch (g) Memantine HCI 20.0% SO.O SO.O SO.OO Eudragit NE 40D Degussa 30.0% 75.0 187.5 187.50 Microcrystalline Cellulose FMC Corp 50.0% 12SO 125.0 125.00 (Avicel PH 101) Purified Water NA NA SO.O 1O.O
TOTAL 100.0% 2SO.O NA NA based on solid in the final product US 2006/0252788 A1 Nov. 9, 2006
0111
TABLE 9
Pellets containing Donepezil HCl
Percent in Wt. solid per Target Wt. per Actual Wt. Component Supplier Formula' Batch (grams) Batch (g) per Batch (g)
Donepezil HCl 20.0% 40.O 4O.O 39.98 Eudragit NE 40D Degussa 30.0% 6O.O 1SO.O 1SO.OS Microcrystalline Cellulose FMC Corp SO.0% 1OO.O 1OO.O 1OOOO (Avicel PH 101) Purified Water NA NA SO.O 1O.O
TOTAL 100.0% 2OO.O NA NA
based on solid in the final product
EXAMPLE 6 dispersion prepared from 25% Surelease) to 20% Meman tine HCl (or Donepezil HCl) pellets. Memantine HC1/Donepezil HCl Formulations 0113 Formulations of Sustained Release (SR) Meman tine HCl (or Donepezil HCl), slow, were obtained by apply 0112 Formulations of Sustained Release (SR) Meman ing a subcoat of Opadry (10% final bead weight), functional tine HCl (or Donepezil HCl), fast and medium, were coating of plasticized Eudragit RS (35% final pellet weight) obtained by applying a subcoat of Opadry (2% final pellet and triethylcitrate (plasticizer, 10% of the functional coat weight) followed by a functional coating of Surelease (15% ing) to 20% Memantine HCl (or Donepezil HCl) pellets.
TABLE 10
Memantine SR Products
SR Memantine SR Memantine SR Memantine Product Pellets (Fast) Pellets (Medium) Pellets (Slow)
“Label Claim' (mg O.164 Blend of 40% O.100 active mg pellets) “Fast' and 60% Sample weight (mg 134.6 136.2 Slow” 2O7.9 208.9 pellets) 16 hr “Assay” Value (mg 23:41 23.44 17.97 18.24 released) “Assay” Value (mg O.174 0.172 O.O864 O.O873 active mg pellets) Average Assay Value (mg O.173 O.O869 active mg pellets) Amount of pellets for 22.5 mg 13.O.O 52.O 1554 259.0 dose (mg) US 2006/0252788 A1 Nov. 9, 2006
0114 TABLE 13-continued TABLE 11 Menantine-Donepezil Dosage Combinations Donepezil Immediate Release (IR) Product Memantine Donepezil Product IR Donepezil HCI Wt. Solid Wt. Solid Label Claim (mg active/mg granulation) 0.0357 dosage Unit dosage Unit Sample weight (mg pellets) 1406 143.7 Product (in mg) Formulation (in mg) Formulation “Assay Value (mg released) 4.25 4.28 Assay Value (mg active mg granulation) O.O3O2 O.O298 NPI-6271 52.O SR (Fast) 28.4 SR (Fast) Average Assay Value (mg active/mg gran) O.O3O 1554 SR (Slow) Amount of granulation for 5 mg dose (mg) 166.7 NPI-6371 259.0 SR (Slow) 28.4 SR (Fast) NPI-6172 13O.O SR (Fast) 29.0 SR (medium) NPI-6272 52.O SR (Fast) 29.0 SR (medium) 0115)
TABLE 12
Donepezil SR Product
SR Donepezil SR Donepezil SR Donepezil HC Pellets HC Pellets HCI Product (Fast) (Medium) Pellets (Slow)
“Label Claim' (mg O.18O O.166 O.156 active/mg pellets) Sample weight (mg pellets) 113.8 113.9 135.6 135.5 128.8 128.3 16 hr “Assay” Value 2003 2O.OO 23.26 23:46 1927 1986 (mg released) “Assay Value O.176 O.176 O.172 0.173 O.1SO 0.155 (mg active/mg pellets) Average Assay Value O.176 O.172 O.152 (mg active/mg pellets) Amount of pellets for 5 mg dose 28.4 29.0 32.8 (mg)
EXAMPLE 7 TABLE 13-continued Dosage Formulation of Memantine-Donepezil Menantine-Donepezil Dosage Combinations Combination Memantine Donepezil 0116 Various combinations of memantine and donepezil Wt. Solid Wt. Solid were prepared by filling the respective pellets in hard gelatin dosage Unit dosage Unit capsules as shown in Table 13. The separately prepared Product (in mg) Formulation (in mg) Formulation pellets provide the flexibility of making ratios of memantine 1554 SR (Slow) to donepezil pellets ranging from 0.1:100 to 100:0.1, more NPI-6372 259.0 SR (Slow) 29.0 SR (medium) preferably from 1:100 to 100:1, most preferably 1:10 to NPI-6173 13O.O SR (Fast) 32.8 SR (Slow) 10:1. NPI-6273 52.O SR (Fast) 32.8 SR (Slow) 1554 SR (Slow) NPI-6373 259.0 SR (Slow) 32.8 SR (Slow) TABLE 13 SR = Sustained Release, Menantine-Donepezil Dosage Combinations IR = Immediate Release Memantine Donepezil EXAMPLE 8 Wt. Solid Wit. Solid dosage Unit dosage Unit Product (in mg) Formulation (in mg) Formulation Dissolution Profiles NPI-6170 13O.O SR (Fast) 166.7 IR NPI-6270 52.O SR (Fast) 166.7 IR 0.117) The dissolution profiles of the various memantine 1554 SR (Slow) donepezil combinations (as shown in Example 7) were NPI-6370 259.0 SR (Slow) 166.7 IR obtained from USP II (paddle) dissolution system at 50 rpm, NPI-6171 13O.O SR (Fsst) 28.4 SR (Fast) at a temperature of 37.0+0.5°C., using water as the medium (FIGS. 2A-2C, 3A-3C, 4A-4C and 5A-5C). US 2006/0252788 A1 Nov. 9, 2006
0118 For the dissolution analysis, 10 mL dissolution 0.122 For the preparation of a drug-in-adhesive acrylate, solutions of memantine and donepezil were diluted with 3 5g of memantine and 1 g of rivastigmine are dissolved in 10 mL of 0.1% formic acid. Standards of memantine or done g of ethanol and this mixture is added to 20 g of Durotak pezil were also prepared and diluted with 3 mL of 0.1% 387-2287 (National Starch & Chemical, U.S.A.). The drug formic acid. A 1 mL aliquot of the diluted solution or gel is coated onto a backing membrane (Scotchpak 1012; standard was transferred into an HPLC vial. A 10 uLaliquot 3M Corp., U.S.A.) using a coating equipment (e.g., RK Print of the solution or standard was injected onto the LC/MS/MS Coat Instr. Ltd., Type KCC 202 control coater). The wet layer for analysis. A C18 reversed phase column (Phenomenex, thickness is 400 um. The laminate is dried for 20 minutes at Luna 5 L, Phenyl-Hexyl 50x2 mm) was used for analysis. room temperature and then for 30 minutes at 40° C. A Memantine and donepezil were separated from endogenous polyester release liner is laminated onto the dried drug gel. interfering Substances and Subsequently eluted from the The sheet is cut into patches and stored at 2-8°C. until use HPLC column by a mobile phase of 33% acetonitrile, 33% (packed in pouches). The concentration of memantine in the methanol and 34% formic acid for mass quantification. A patches ranges between 5.6 and 8 mg/cm, while rivastig mass spectrometer set at mass-to-charge ratios (m/z) of mine ranges between 1.1 and 1.6 mg/cm. The nearly 180.51s 162.70 and 380.14s.288.18 was used to detect and continuous infusion of the components provides a much quantify memantine and donepezil, respectively. Data were more consistent Cratio over time maximizing the additive or processed and calculated by an automated data acquisition synergistic effects of the combinations of the present inven system (Analyst 1.2, Applied Biosystems, Foster City, tion to achieve the optimal therapeutic effects. Calif.). EXAMPLE 11 EXAMPLE 9 Multiple Dose Safety Study in Alzheimer's Patients Release Profiles of IR and SR with an Extended Release Memantine, Extended Memantine-Donepezil Formulations Release Donepezil Combination 0119) The in vivo release profiles were obtained using the 0123. A study to determine safety and pharmacokinetics Gastro-Plus software package V.4.0.2 (FIGS. 6A-6E. 7). of an extended release combination formulation of meman Exemplary human PK release profiles are shown in FIG. 7. tine and donepezil is described below. The study results are The release profiles and pharmacokinetic properties for a expected to assess the frequency of adverse events as well as controlled release combination product made according to evaluate the pharmacokinetic parameters at higher doses. Examples 5-7 as compared to IR administration of presently marketed products are shown in FIG. 7 and the table in FIG. 8. For the IR administration, oral dosing is per the manu Purpose To determine the safety and pharmacokinetics of facturers’ recommendation (5 mg memantine q.d., incre repeated doses of drug. mented on a weekly basis to 5 mg BID, 10 mg in the Dosage: Based on previous single ascending dose (SAD) study, either e.g. 22.5 mg memantine SR + 4 mg morning and 5 mg in the evening, and 10 mg memantine donepezil SR, 45 mg memantine SR + 4 mg b.i.d.thereafter, 5 mg donepezil q.d. for two weeks, increas donepezil SR, or 45 mg memantine SR + 8 mg ing to 10 mg donepezil q.d. thereafter). For the SR formu donepezil SR, QD for 30 days lation NPI-6272, the 22.5 mg memantine and 10 mg done Concurrent Controls memantine IR or memantine IR plus donepezil IR (both dosed as per manufacturers labels) pezil are provided in a controlled release oral delivery Route: Oral formulation releasing the active agents as shown in FIG. 4B. Subject Population: Males or females diagnosed with dementia of the The SR product dC/dT is considerably lower than the IR Alzheimer's type. (Age range 50–80?) form for a similar dose for both memantine and donepezil. Structure: 4 arm Study Sites: TBD As measured, the dC/dT for memantine at 22.5 mg is Blinding: Patients blinded comparable to that for a 5 mg IR dosage form. Thus, the SR Method of Subject Random with equal number of males and females in formulations provide a more gradual increase in the drug Assignment: each group and equal age distributions within groups during each patient dose. Total Sample Size: 24 Subjects 6 per dosing arm Primary Efficacy None 0120 In addition to achieving the desired release profile, Endpoint: Adverse Events: Monitored at least twice daily for behavioral, this combination formulation will exhibit a preferred cardiovascular, and gastrointestinal effects reported decrease Cmax/Cmean, even with a higher dose of the for high doses of memantine or donepezil (including NMDAr antagonist and AChel, thus the present invention dizziness, headache, confusion, constipation, may provide greater doses for increased therapeutic effect hypertension, coughing, nausea, diarrhea, vomiting). Blood Collection By canula through first day of study period then 2-4 without escalation that might otherwise be required. Fur times daily for rest of study thermore, the increased dosing allows less frequent admin Analysis Assays to measure memantine, donepezil, and istration of the therapeutic agents. potentially other physiological parameters, adverse events EXAMPLE 10 A Patch Providing Extended Release of Memantine and Rivastigmine EXAMPLE 12 0121. As described above, extended release formulations Treatment of Alzheimer's Patients with an of an NMDAr antagonist are formulated for topical admin Extended Release Memantine, Extended Release istration. Memantine transdermal patch formulations are Donepezil Combination prepared as described, for example, in U.S. Pat. Nos. 6,770, 0.124. A study to determine effectiveness of two extended 295 and 6,746,689. release combination formulations of memantine and done US 2006/0252788 A1 Nov. 9, 2006 17 pezil is described below. The study results are expected to 5. The pharmaceutical composition of claim 1, wherein establish a more rapid onset of efficacy without increase in the pharmaceutical composition is a non-dose escalating, adverse effects (confirming tolerability of a non-dose esca twice per day, once per day, or once everyother day dosage lating dosing regimen (i.e., administration of Substantially form. identical doses of memantine and donepezil throughout the 6. The pharmaceutical composition of claim 1, wherein term of dosing)). the NMDArantagonist is selected from the group consisting of memantine, amantadine, rimantadine, ketamine, eliprodil, ifenprodil, dizocilpine, remacemide, iamotrigine, riluzole, aptiganel, phencyclidine, flupirtine, celfotel, felbamate, ner Purpose To determine the efficacy of combination therapy, non-dose escalated amexane, spermine, spermidine, levemopamil, dex Study Dosages: 22.5 mg memantine SR + 4 mg donepezil SR, tromethorphan, dextrorphan, and pharmaceutically accept 45 mg memantine SR + 4 mg donepezil SR able salts thereof. Concurrent Controls memantine IR (Namenda) or memantine IR plus 7. The pharmaceutical composition of claim 1, wherein donepezil IR (Aricept) both per manufacturers dosing labels (as of 2004). said AChe is selected from the group consisting of done Route: Oral pezil, rivastigmine, tacrine, metrifonate, Huperzine-A, and Subject Population: Males or females diagnosed with dementia of the pharmaceutically acceptable salts thereof. Alzheimer's type. (Age range 50–80) 8. The pharmaceutical composition of claim 1, wherein Structure: 4 arm Study Sites: Multi-center said pharmaceutical composition is formulated for oral, Blinding: Patients blinded transnasal, parenteral, Subtopical transepithelial, transder Method of Subject Random with equal number of males and females in mal patch, Subdermal, or inhalation delivery. Assignment: each group and equal age distributions within groups 9. The pharmaceutical composition of claim 1, wherein Total Sample Size: 400 subjects, 100 per arm Primary Efficacy Improvement of ADAS-Cog, SIBIC, HAM-D in or said pharmaceutical composition is formulated as a Suspen Endpoint: neuropsychiatric index at 7, 14, 21, 42, 63, 84 days. Sion, capsule, tablet, Suppository, lotion, or patch. Efficacy Monitored twice per week for first 4 weeks, then 10. The pharmaceutical composition of claim 1, wherein Monitoring:weekly thereafter. the NMDAr antagonist is memantine and the AChe is Adverse Events: Monitored at least twice daily for behavioral, cardiovascular and gastrointestinal effects reported donepezil or pharmaceutically acceptable salts thereof. for high doses of memantine or donepezil (including 11. The pharmaceutical composition of claim 6, wherein dizziness, headache, confusion, constipation, the NMDArantagonist is memantine and wherein the com hypertension, coughing, nausea, diarrhea, vomiting). position is formulated to provide memantine in an amount of Blood Collection: By canula at the following time points: Day 1:0, 4, 8, 12 hours 2.5-80 mg per day, 20-67.5 mg per day, 22.5-57.5 mg per Days 2, 4, 6, 8, 10, 12, 14, 17, 21, 28, 35, 42, 49, day or 42.5-80 mg per day. 56, 63, 70, 77, 84 pre-dose trough 12. A method of preventing or treating a CNS-related Analysis: Efficacy, adverse events, and laboratory assays condition comprising administering to a Subject in need measuring study drugs. thereof a therapeutically effective amount-of: (a) an NMDAr antagonist; and (b) an acetylcholinesterase inhibitor, What is claimed is: wherein at least one of said NMDAr antagonist or said 1. A pharmaceutical composition comprising: second agent is provided in an extended release dosage form and wherein the agent in said extended release (a) an NMDAr antagonist; dosage form has an in vitro dissolution profile less than 70% in one hour, less than 90% in two hours, greater (b) an acetylcholinesterase inhibitor (AChel), than 40% in six hours, and greater than 85% in 12 hours wherein at least one of said NMDAr antagonist or said as measured using a USP type 2 (paddle) dissolution second agent is provided in an extended release dosage system at 50 rpm, at a temperature of 37+0.5° with form and wherein the agent in said extended release water as a dissolution medium. dosage form has an in vitro dissolution profile less than 13. The method of claim 12, wherein said CNS-related 70% in one hour, less than 90% in two hours, greater condition is Alzheimer's disease or Parkinson's disease. than 40% in six hours, and greater than 85% in 12 hours 14. The method of claim 12, wherein said NMDAr as measured using a USP type 2 (paddle) dissolution antagonist is provided in an extended release dosage form. system at 50 rpm, at a temperature of 37+0.5° with 15. The method of claim 14, wherein said NMDAr water as a dissolution medium. antagonist is administered at a Substantially identical daily dose. 2. The pharmaceutical composition of claim 1, wherein 16. The method of claim 15, wherein said NMDAr said NMDArantagonist has a dC/dT less than about 80% of antagonist reaches a therapeutically effective steady state the rate for the IR formulation. plasma concentration in said Subject within fifteen 3. The pharmaceutical composition of claim 1, wherein said administering. said NMDArantagonist has a C/C of approximately 17. The method of claim 14, wherein said NMDAr 1.6 or less approximately 2 hours to at least 12 hours after antagonist has a dC/dT less than about 80% of the rate for said composition is introduced into a Subject. the IR formulation. 4. The pharmaceutical composition of claim 1, wherein 18. The method of claim 14, wherein said NMDAr the relative Cratio.var of said NMDAr antagonist and said antagonist has a Ca/Ca of approximately 1.6 or less second agent is less than 100% from 2 hour to 12 hours after approximately 2 hours to at least 12 hours after said com said composition is introduced into a Subject. position is introduced into a Subject. US 2006/0252788 A1 Nov. 9, 2006
19. The method of claim 12, wherein the relative Cratio of that for an IR formulation of the same NMDArantagonist .var of said NMDAr antagonist and said AChe is less than at the same administered dose. 100% from 2 hour to 12 hours after said composition is 36. Use of an NMDArantagonist and an acetylcholinest introduced into a subject. erase inhibitor in the manufacture of a combined preparation 20. The method of claim 19, wherein the relative Cratio for preventing or treating a CNS-related condition wherein .var of said NMDAr antagonist and said AChe is less than at least one of said NMDAr antagonist or said acetylcho 70% of the corresponding IR formulation from 2 hour to 12 linesterase inhibitor has an in vitro dissolution profile less hours after said composition is introduced into a Subject. than 70% in one hour, less than 90% in two hours, greater 21. The method of claim 12, wherein said NMDAr than 40% in six hours, and greater than 85% in 12 hours as antagonist is selected from the group consisting of meman measured using a USP type 2 (paddle) dissolution system at tine, amantadine, rimantadine, ketamine, eliprodil, ifen 50 rpm, at a temperature of 37+0.5° with water as a prodil, dizocilpine, remacemide, iamotrigine, riluzole, apti dissolution medium. ganel, phencyclidine, flupirtine, celfotel, felbamate, 37. The use according to claim 36 wherein the combined neramexane, spermine, spermidine, levemopamil, dex preparation comprises the NMDAr antagonist and the ace tromethorphan, dextrorphan, and pharmaceutically accept tylcholinesterase inhibitor are as separate formulations. able salts thereof. 38. The use according to claim 36 wherein the combined 22. The method of claim 21, wherein said NMDAr preparation comprises the NMDAr antagonist and the ace antagonist is memantine or a pharmaceutically acceptable tylcholinesterase inhibitor as a single formulation. salt thereof. 39. The use according to claim 38 wherein the single 23. The method of claim 22, wherein the amount of formulation is a non-dose escalating formulation. memantine ranges between 10 and 80 mg per dose. 40. Use of an NMDArantagonist in the manufacture of a 24. The method of claim 23, wherein the amount of medicament for preventing or treating a CNS-related con memantine ranges between 20-60 mg per dose. dition in a subject in need thereof by combination therapy 25. The method of claim 23, wherein the amount of wherein said combination therapy comprises administration memantine ranges between 40 and 80 mg per dose. of said NMDAr antagonist and an acetylcholinesterase 26. The method of claim 13, wherein said acetylcholinest inhibitor to the subject, and wherein at least one of said erase inhibitor is selected from the group consisting of NMDArantagonist or said AChe has an in vitro dissolution donepezil, rivastigmine, tacrine, metrifonate, Huperzine-A, profile less than 70% in one hour, less than 90% in two and pharmaceutically acceptable salts thereof. hours, greater than 40% in six hours, and greater than 85% 27. The method of claim 12, wherein the NMDArantago in 12 hours as measured using a USP type 2 (paddle) nist is memantine and acetylcholinesterase inhibitor is done dissolution system at 50 rpm, at a temperature of 37+0.5° pezil or pharmaceutically acceptable salts thereof. with water as a dissolution medium. 28. The method of claim 12, wherein said NMDAr 41. Use of an AChe in the manufacture of a medicament antagonist and said second agent are administered simulta for preventing or treating a CNS-related condition in a neously or sequentially. subject in need thereof by combination therapy wherein said 29. The method of claim 12, wherein said NMDA antago combination therapy comprises administration of said nist and said second agent are administered as a single AChe and an NMDAr antagonist to the subject, and composition. wherein at least one of said NMDAr antagonist or said 30. A method of treating, preventing or reducing a con AChe has an in vitro dissolution profile less than 70% in dition associated with a deregulation in NMDAr activity one hour, less than 90% in two hours, greater than 40% in comprising administering to a Subject at risk of Suffering or six hours, and greater than 85% in 12 hours as measured Suffering from said condition a composition comprising an using a USP type 2 (paddle) dissolution system at 50 rpm, NMDAr antagonist provided in an extended release dosage at a temperature of 37+0.5° with water as a dissolution form and a second agent, wherein said second agent AChel medium. selected from the group consisting of donepezil, rivastig 42. A kit comprising: mine, tacrine, metrifonate, Huperzine-A, wherein said com position is administered at a substantially identical daily (a) an NMDAr antagonist; dose. (b) an acetylcholinesterase inhibitor selected from the 31. The method of claim 30, wherein said pharmaceutical group consisting of donepezil, rivastigmine, tacrine, composition is administered to said subject no more than metrifonate, Huperzine-A; and once every 24 hours. 32. The method of claim 30, wherein said daily dose of (c) instructions for treating or preventing CNS related said NMDAr antagonist ranges between 15 and 35 mg. conditions such as Alzheimer's disease, 33. The method of claim 32, wherein said daily dose of and wherein at least one of said NMDAr antagonist or said NMDAr antagonist ranges between 20 and 25 mg. said AChe has an in vitro dissolution profile less than 34. The method of claim 30, wherein said NMDAr 70% in one hour, less than 90% in two hours, greater antagonist reaches a therapeutically effective steady state than 40% in six hours, and greater than 85% in 12 hours plasma concentration in said Subject within fifteen days of as measured using a USP type 2 (paddle) dissolution said administering. system at 50 rpm, at a temperature of 37+0.5° with 35. The method of claim 30, wherein the mean plasma water as a dissolution medium. concentration profile of said NMDAr antagonist in said 43. The kit of claim 42, wherein said NMDArantagonist Subject has an initial slope in a Subject has an initial slope and said second agent are formulated as a single formula from 2 hours to 4 hours after administration less than 50% tion. US 2006/0252788 A1 Nov. 9, 2006
44. The pharmaceutical composition of claim 1, wherein wherein memantine and doneZepil are both provided in an the NMDAr antagonist and the AChe are formulated as extended release dosage form, said extended release pellets, and wherein the ratio of the active pharmaceutical dosage form having an in vitro dissolution profile less ingredients and the quantities of active pharmaceutical than 70% in one hour, less than 90% in two hours, ingredients may be varied by adjusting the quantities and greater than 40% in six hours, and greater than 85% in ratios of pellets in the final dosage form. 12 hours as measured using a USP type 2 (paddle) 45. The pharmaceutical composition of claim 44, wherein dissolution system at 50 rpm, at a temperature of the ratio of NMDAr antagonist to AChe ranges from 37+0.5° with water as a dissolution medium; O.1:100 to 100:0.1 46. The pharmaceutical composition of claim 45, wherein 48. The pharmaceutical composition of claim 47, wherein the ratio of NMDArantagonist to AChe ranges from 1:100 the ratio of dosing of said composition reduces gastro to 100:1. intestinal and cardiovascular side effects. 47. A pharmaceutical composition comprising: 49. The pharmaceutical composition of claim 47, the release profile of memantine is substantially identical to the (a) memantine in a dose ranging between 20 and 30 mg: release profile of donepezil. and (b) donepezil in a dose ranging between 2 and 5 mg: