U.S. patent application number 15/142519 was filed with the patent office on 2016-08-25 for compositions for the treatment of cns-related conditions.
The applicant listed for this patent is Adamas Pharmaceuticals, Inc.. Invention is credited to Timothy J. Fultz, Laurence R. Meyerson, Gregory T. Went.
Application Number | 20160243058 15/142519 |
Document ID | / |
Family ID | 37036831 |
Filed Date | 2016-08-25 |
United States Patent
Application |
20160243058 |
Kind Code |
A1 |
Went; Gregory T. ; et
al. |
August 25, 2016 |
COMPOSITIONS FOR THE TREATMENT OF CNS-RELATED CONDITIONS
Abstract
The invention provides methods for treating CNS-related
conditions with amantadine and donepezil, in which the amantadine
is in an extended release form, wherein the extended release
amantadine formulation provides a change in plasma concentration as
a function of time (dC/dT) that is less than 40% of the dC/dT of
the same quantity of an immediate release form of amantadine.
Inventors: |
Went; Gregory T.; (Mill
Valley, CA) ; Fultz; Timothy J.; (Jasper, GA)
; Meyerson; Laurence R.; (Las Vegas, NV) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Adamas Pharmaceuticals, Inc. |
Emeryville |
CA |
US |
|
|
Family ID: |
37036831 |
Appl. No.: |
15/142519 |
Filed: |
April 29, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15090396 |
Apr 4, 2016 |
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15142519 |
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14613220 |
Feb 3, 2015 |
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15090396 |
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13863140 |
Apr 15, 2013 |
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14613220 |
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13559478 |
Jul 26, 2012 |
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13863140 |
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13536763 |
Jun 28, 2012 |
8338486 |
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13559478 |
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12757795 |
Apr 9, 2010 |
8283379 |
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13536763 |
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11399879 |
Apr 6, 2006 |
8058291 |
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12757795 |
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11285905 |
Nov 22, 2005 |
7619007 |
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11399879 |
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12840132 |
Jul 20, 2010 |
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13536763 |
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12512701 |
Jul 30, 2009 |
8168209 |
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12840132 |
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11285905 |
Nov 22, 2005 |
7619007 |
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12512701 |
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60669290 |
Apr 6, 2005 |
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60630885 |
Nov 23, 2004 |
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60635365 |
Dec 10, 2004 |
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60701857 |
Jul 22, 2005 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 29/00 20180101;
A61K 9/48 20130101; A61K 9/4808 20130101; A61K 9/282 20130101; A61P
25/16 20180101; A61K 31/13 20130101; A61P 25/04 20180101; A61K 9/20
20130101; A61K 9/2013 20130101; A61K 9/7061 20130101; A61K 2300/00
20130101; Y02A 50/30 20180101; A61K 9/2813 20130101; A61K 31/445
20130101; A61P 25/30 20180101; A61K 9/1652 20130101; A61P 25/00
20180101; A61K 9/2054 20130101; A61K 9/2059 20130101; A61K 9/0053
20130101; Y02A 50/401 20180101; A61K 9/2009 20130101; A61K 45/06
20130101; A61K 9/1635 20130101; A61P 25/24 20180101; A61P 25/28
20180101; A61P 25/20 20180101; A61K 31/13 20130101; A61K 2300/00
20130101; A61K 31/445 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/13 20060101
A61K031/13; A61K 31/445 20060101 A61K031/445; A61K 9/20 20060101
A61K009/20; A61K 9/00 20060101 A61K009/00 |
Claims
1. A method of treating a patient with a neurological condition,
comprising orally administering to a human subject in need thereof:
(a) 22.5 mg to 30 mg memantine or a pharmaceutically acceptable
salt thereof provided in a sustained release dosage form, wherein
wherein said sustained release memantine provides a change in mean
plasma concentration of memantine as a function of time (dC/dT)
that is: (1) less than about 50% of the dC/dT provided by the same
quantity of an immediate release form of memantine, determined in a
time period between 0-Tmax of the immediate release form of
memantine; and (2) 2.1 ng/ml/hr or less, determined in a time
period of 0 to 4 hours; wherein dC/dT is measured in a single-dose
human PK study; and (b) a therapeutically effective amount of
immediate release donepezil.
2. The method of claim 1, wherein the dC/dT of 2.1 ng/mL/hr or less
is determined in a time period of 2 to 4 hours.
3. The method of claim 1, wherein the neurological condition is
selected from the group consisting of Alzheimer's disease,
dementia, Parkinson's disease, and neuropathic pain.
4. The method of claim 3, wherein the dC/dT of 2.1 ng/mL/hr or less
is determined in a time period of 2 to 4 hours.
5. The method of claim 1, wherein the sustained release oral dosage
form comprises 25 mg to 30 mg memantine or a pharmaceutically
acceptable salt thereof.
6. The method of claim 5, wherein the dC/dT of 2.1 ng/mL/hr or less
is determined in a time period of 2 to 4 hours.
7. The method of claim 6, wherein the neurological condition is
selected from the group consisting of Alzheimer's disease,
dementia, Parkinson's disease, and neuropathic pain.
8. The method of claim 5, wherein the neurological condition is
selected from the group consisting of Alzheimer's disease,
dementia, Parkinson's disease, and neuropathic pain.
9. The method of claim 1, wherein the sustained release oral dosage
form comprises 28 mg memantine or a pharmaceutically acceptable
salt thereof.
10. The method of claim 9, wherein the dC/dT of 2.1 ng/mL/hr or
less is determined in a time period of 2 to 4 hours.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/090,396, filed Apr. 4, 2016, which is a
continuation of U.S. patent application Ser. No. 14/613,220, filed
Febraury 3, 2015, which is a continuation of U.S. patent
application Ser. No. 13/863,140, filed Apr. 15, 2013, which is a
continuation of U.S. patent application Ser. No. 13/559,478, filed
Jul. 26, 2012, which is a continuation of U.S. patent application
Ser. No. 13/536,763, filed Jun. 28, 2012, now U.S. Pat. No.
8,338,486, issued Dec. 25, 2012, which is a continuation of U.S.
patent application Ser. No. 12/757,795, filed Apr. 9, 2010, now
U.S. Pat. No. 8,283,379, issued Oct. 9, 2012, which is a
continuation of U.S. patent application Ser. No. 11/399,879, filed
on Apr. 6, 2006, now U.S. Pat. No. 8,058,291, issued Nov. 15, 2011,
which claims priority to and incorporates by reference provisional
application 60/669,290, filed on Apr. 6, 2005, and is a
continuation-in-part of U.S. patent application Ser. No.
11/285,905, filed on Nov. 22, 2005, now U.S. Pat. No. 7,619,007,
issued Nov. 17, 2009, which it incorporates by reference in its
entirety; U.S. patent application Ser. No. 13/536,763 is also a
continuation-in-part of U.S. application Ser. No. 12/840,132, filed
Jul. 20, 2010, which is a continuation of Ser. No. 12/512,701,
filed Jul. 30, 2009, now U.S. Pat. No. 8,168,209, issued May 1,
2009, which is a division of U.S. application Ser. No. 11/285,905,
filed Nov. 22, 2005, now U.S. Pat. No. 7,619,007, issued Nov. 17,
2009, which claims priority to and incorporates by reference U.S.
Provisional Applications 60/630,885, filed Nov. 23, 2004,
60/635,365, filed Dec. 10, 2004, and 60/701,857, filed Jul. 22,
2005.
FIELD OF THE INVENTION
[0002] This invention relates to methods and compositions for
treating CNS-related conditions, such as Alzheimer's disease.
BACKGROUND OF THE INVENTION
[0003] Acute and chronic neurological and neuropsychiatric diseases
are among the leading causes of death, disability, and economic
expense in the world. Presently, Alzheimer's disease is the fourth
leading cause of death in the USA. Today there is no known cure for
this chronic degenerative ailment, which directly affects millions
of people throughout the world. Other diseases and disorders of the
central nervous system also result in substantial suffering and
cost for those afflicted by the ailments as well as their families
and providers.
[0004] Numerous drugs exist in the market today to treat the
symptoms or manage the progression of these diseases, but most have
modest or limited efficacy. Frequently, polypharmacy is employed to
optimize therapy to the specific needs of patients at different
stages of the disease. One of the key challenges in treating these
disorders is the high degree of interplay amongst the pathways that
control both normal and abnormal neuronal functions. The
therapeutic management of these functions is typically determined
such that the therapeutic effects are maximized while minimizing
the debilitating side effects of the therapies. This effort is
usually more complex when multiple therapeutics are employed.
[0005] Improved therapeutics for treatment of these diseases and
disorders are needed.
SUMMARY OF THE INVENTION
[0006] In general, the present invention provides methods and
compositions for treating and preventing CNS-related conditions,
such as neurodegenerative conditions (e.g., Alzheimer's disease and
Parkinson's disease) and pain, by administering to a subject in
need thereof a combination that includes an N-Methyl-D-Aspartate
receptor (NMDAr) antagonist and a second agent such as
acetylcholinesterase inhibitor (ACheI). The administration of the
combinations described herein results in the alleviation and
prevention of symptoms associated with or arising from CNS-related
conditions such as Parkinson's disease or Alzheimer's disease
including, for example, loss of memory, loss of balance,
hallucinations, delusions, agitation, withdrawal, depression,
communication problems, cognitive loss, personality change,
confusion and insomnia. The combinations of the present invention
may be used in the prevention or treatment of CNS-related
conditions associated with Alzheimer's disease and may also be
helpful for the treatment and prevention of headaches,
cerebrovascular diseases, motor neuron diseases, dementias,
neurodegenerative diseases, strokes, movement disorders, ataxic
syndromes, disorders of the sympathetic nervous system, cranial
nerve disorders, myelopathies, traumatic brain and spinal cord
injuries, radiation brain injuries, multiple sclerosis,
post-meningitis syndrome, prion diseases, myelitic disorders,
radiculitis, neuropathies, pain syndromes, axonic brain damage,
encephalopathies, chronic fatigue syndrome, psychiatric disorders,
glucose dysregulation, and drug dependence.
[0007] The NMDAr antagonist, the ACheI, or both agents may be
administered in an amount similar to that typically administered to
subjects. Optionally, the amount of the NMDAr antagonist, the
ACheI, or both agents may be administered in an amount greater than
or less than the amount that is typically administered to subjects.
If desired, the amount of the NMDAr antagonist in the
pharmaceutical composition is less than the amount of NMDAr
antagonist required in a unit dose to obtain the same therapeutic
effect for treating or preventing a CNS-related condition when the
NMDAr antagonist is administered in the absence of the ACheI.
Alternatively, the amount of the ACheI in the pharmaceutical
composition is less than the amount of the ACheI required in a unit
dose to obtain the same therapeutic effect for treating or
preventing a CNS-related condition when the ACheI is administered
in the absence of the NMDAr antagonist. Optionally, the NMDAr
antagonist, the ACheI, or both are present at a higher dose than
that typically administered to a subject for a specific condition.
For example, the amount of memantine (an NMDAr antagonist) required
to positively affect the patient response (inclusive of adverse
effects) may be 2.5-80 mg per day rather than the typical 10-20 mg
per day administered for presently approved indications i.e.
without the improved formulations described herein. A higher dose
amount of the NMDAr antagonist in the present invention may be
employed whereas a lower dose of the NMDAr antagonist may be
sufficient when combined with the ACheI to achieve a therapeutic
effect in the patient. Optionally, lower or reduced amounts of both
the NMDAr antagonist and the ACheI are used in a unit dose relative
to the amount of each agent when administered as a monotherapy. In
a preferred embodiment, the amount of the NMDAr antagonist in the
pharmaceutical composition is equal to or greater than the amount
typically administered to a subject for a specific condition as a
monotherapy and the amount of the ACheI in the pharmaceutical
composition is less than the amount typically administered to a
subject for a similar condition.
[0008] The invention also provides a pharmaceutical composition
that includes an NMDAr antagonist and an ACheI. Optionally, a
pharmaceutically acceptable carrier is included.
[0009] Although compositions comprising a NMDAr antagonist and a
second agent such as acetylcholinesterase inhibitor (ACheI) have
been disclosed (e.g. US 2004/0087658), the problem of providing
release of the NMDAr antagonist in a desired manner (e.g. in an
amount high enough to treat symptoms or damaging effects of an
underlying disease while avoiding undesirable side effects e.g. CNS
side effects) when present as a combined therapy has not been
addressed. In particular, the presently available dosage forms of
NMDAr antagonists need to be administered frequently and require
dose escalation at the initiation of therapy to avoid side effects
associated with initial exposure to the therapeutic agent. This
leads to difficulty in achieving adequate patient compliance, which
is further exacerbated by the complicated dosing schedules of
therapeutic modalities used for neurological or neuropsychiatric
disorders. This problem has not been addressed in the context of
providing an NMDAr antagonist as a combined therapy.
[0010] Providing a NMDAr antagonist in combination with an ACheI
requires careful formulation and the pharmacokinetic properties of
the two agents will need to be taken into account, for instance to
ensure that the amount and rate of release of each of the agents is
sufficient for a therapeutic benefit whilst minimizing or avoiding
undesired side effects. Further, not only do the pharmacokinetic
properties of each of the drugs (e.g. Tmax, drug half-life etc.)
need to be considered, but any interaction between the two agents
is a further complicating factor.
[0011] In one embodiment of the invention, the NMDAr antagonist,
the ACheI, or both agents may be provided in a controlled or
extended release form with or without an immediate release
component in order to maximize the therapeutic benefit of each,
while reducing unwanted side effects associated with each.
[0012] As used herein, "immediate release formulation" refers to a
formulation of an active pharmaceutical ingredient that releases
greater than 80 percent of the active pharmaceutical ingredient in
less than one hour in a USP dissolution method as described herein
or by the manufacturer for a commercial product. Typically, the
release of the active ingredient in an immediate release
formulation is greater than 80 percent in less than 30 minutes as
in FIGS. 1A and 2A.
[0013] When these drugs are provided in an oral form without the
benefit of controlled or extended release components, they are
released and transported into the body fluids over a period of
minutes to several hours. Thus, the composition of the invention
may contain an NMDAr antagonist and a sustained release component,
such as a coated sustained release matrix, a sustained release
matrix, or a sustained release bead matrix. In one example,
memantine (e.g., 5-80 mg) is formulated without an immediate
release component using a polymer matrix (e.g., Eudragit),
Hydroxypropyl methyl cellulose (HPMC) and a polymer coating (e.g.,
Eudragit). Such formulations are comprsessed into solid tablets or
granules. Optionally, a coating such as Opadry.RTM. or
Surelease.RTM. is used.
[0014] As used herein the terms "extended release dosage form",
"controlled release dosage form" and "sustained release dosage
form" and like expressions are used interchangeably and include
dosage forms where the active drug substance or substances are
released over an extended period of time. The term "extended"
release should be understood in contrast to immediate release and,
in particular, the term indicates that the formulation does not
release the full dose of the active ingredient immediately after
dosing. Such extended release dosage forms typically allow a
reduction in dosing frequency as compared to that presented by a
conventional dosage form such as a solution or an immediate release
dosage form. The extended release forms may or may not comprise an
immediate release component.
[0015] Optionally, the composition described herein is formulated
such that at least one of said NMDAr antagonist or said ACheI has
an in vitro dissolution profile less than 70% in one hour, less
than 90% in two hours, greater than 40% in six hours, and greater
than 85% in 12 hours as measured using a USP type 2 (paddle)
dissolution system at 50 rpm, at a temperature of 37.+-.0.5.degree.
with water as a dissolution medium.
[0016] As used herein, "C" refers to the concentration of an active
pharmaceutical ingredient in a biological sample, such as a patient
sample (e.g. blood, serum, and cerebrospinal fluid). The
concentration of the drug in the biological sample may be
determined by any standard assay method known in the art. The term
"Cmax" refers to the maximum concentration reached by a given dose
of drug in a biological sample. The term "Cmean" refers to the
average concentration of the drug in the sample over time. Cmax and
Cmean may be further defined to refer to specific time periods
relative to administration of the drug. The time required to reach
the maximal concentration ("Cmax") in a particular patient sample
type is referred to as the "Tmax." The agents of the combination
are administered in formulations that reduce the variability of the
ratio of the concentrations of the active agents over a period of
time, thereby maximizing the therapeutic benefit while minimizing
the side effects.
[0017] In a preferred embodiment, the dosage form is provided in a
non-dose escalating, twice per day or once per day form. In such
cases, the concentration ramp (or Tmax effect) may be reduced so
that the change in concentration as a function of time (dC/dT) is
altered to reduce or eliminate the need to dose escalate the drug.
A reduction in dC/dT may be accomplished, for example, by
increasing the Tmax in a relatively proportional manner.
Accordingly, a two-fold increase in the Tmax value may reduce dC/dT
by approximately a factor of 2. Thus, the NMDAr antagonist may be
provided so that it is released at a rate that is significantly
reduced over an immediate release (so called IR) dosage form, with
an associated delay in the Tmax. The pharmaceutical composition may
be formulated to provide a shift in Tmax by 24 hours, 16 hours, 8
hours, 4 hours, 2 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 certain embodiments, this is
accomplished by releasing less than 30%, 50%, 75%, 90%, or 95% of
the NMDAr antagonist into the circulatory or neural system within
one hour of such administration.
[0018] The provision of such non-dose escalating dosage forms are
particularly useful as they provide the drug at a therapeutically
effective amount from the onset of therapy further improving
patient compliance and adherence and enable the achievement of a
therapeutically effective steady-state concentration of the drug in
a shorter period of time. This results in an earlier indication of
effectiveness and increasing the utility of these therapeutic
agents for diseases and conditions where time is of the essence.
Furthermore, the compositions of the present invention, by virtue
of their design, allow for higher doses of the drug to be safely
administered, again increasing the utility of these agents for a
variety of indications.
[0019] If desired, the NMDAr antagonist or the ACheI of the
combination is released into a subject sample at a slower rate than
observed for an immediate release (IR) formulation of the same
quantity of the antagonist. The release rate is measured as the
dC/dT over a defined period within the period of 0 to Tmax for the
IR formulation and the dC/dT rate is less than about 80% of the
rate for the IR formulation. In some embodiments, the dC/dT rate is
less than about 60%, 50%, 40%, 30%, 20% or 10% of the rate for the
IR formulation. Similarly, the ACheI may also be released into a
patient sample at a slower rate than observed for an IR formulation
of the same quantity wherein the release rate is measured as the
dC/dT over a defined period within the period of 0 to Tmax for the
IR formulation and the dC/dT rate is less than about 80%, 60%, 50%,
40%, 30%, 20%, or 10%, of the rate for the IR formulation of the
same NMDAr antagonist over the first 1, 2, 4, 6, 8, 10, or 12
hours.
[0020] Optionally, the sustained release formulations exhibit
plasma concentration curves having initial (e.g., from 2 hours
after administration to 4 hours after administration) slopes less
than 75%, 50%, 40%, 30%, 20% or 10% of those for an IR formulation
of the same dosage of the same NMDAr antagonist. The precise slope
for a given individual will vary according to the NMDAr antagonist
being used, the quantity delivered, or other factors, including,
for some active pharmaceutical agents, whether the patient has
eaten or not. For other doses, e.g., those mentioned above, the
slopes vary directly in relationship to dose.
[0021] Using the sustained release formulations described herein,
the NMDAr antagonist or the ACheI reaches a therapeutically
effective steady state plasma concentration in a subject within the
course of the first five, seven, nine, ten, twelve, fifteen, or
twenty days of administration. For example, the formulations
described herein, when administered at a substantially constant
daily dose (e.g., memantine at a dose ranging between 15 mg and 80
mg and preferably between 20 and 45 mg) may reach a steady state
plasma concentration in approximately 70%, 60%, 50%, 40%, 30%, or
less of the time required to reach such plasma concentration when
using a dose escalating regimen.
[0022] The ratio of the concentrations of two agents in a
combination is referred to as the "Cratio," which may fluctuate as
the combination of drugs is released, transported into the
circulatory system or CNS, metabolized, and eliminated. An
objective of the present invention is to stabilize the Cratio for
the combinations described herein. In some embodiments, it is
preferred to reduce or even minimize the variation in the Cratio
(termed "Cratio,var"). Employing the methods described herein, the
release profiles of each active pharmaceutical ingredient may be
modified to produce nearly constant Cratios, thereby minimizing
Cratio, var. In cases where the Tmax and T1/2 of the NMDAr
antagonist and the ACheI are markedly different, e.g. by a factor
of two or more, the desired release profiles will likely be
dissimilar in order to minimize the relative variability of the
active agents between doses.
[0023] The present invention therefore features formulations of
combinations directed to dose optimization or release modification
to reduce adverse effects associated with separate administration
of each agent. The combination of the NMDAr antagonist and the
ACheI may result in an additive or synergistic response, as
described below.
[0024] In all foregoing aspects of the invention, at least 50%, 80,
90%, 95%, or essentially all of the NMDAr antagonist in the
pharmaceutical composition may be provided in a controlled release
dosage form. In some embodiments, at least 99% of the NMDAr
antagonist remains in the extended dosage form one hour following
introduction of the pharmaceutical composition into a subject. The
NMDAr antagonist may have a C.sub.max/C.sub.mean of approximately
2, 1.6, 1.5, 1.4, 1.3, 1.2 or less, approximately 2 hours to at
least 8, 12, 16, 24 hours after the NMDAr antagonist is introduced
into a subject. The ACheI may also be provided in a controlled
release dosage form. Thus, at least 50%, 60%, 70%, 80%, 90%, 95%,
or essentially all of the ACheI may be provided as a controlled
release formulation. If provided as such, the ACheI may have a
C.sub.max/C.sub.mean of approximately 2, 1.6, 1.5, 1.4, 1.3, 1.2 or
less, approximately 2 hours to at least 6, 8, 12, 16, or 24 hours
after the ACheI is introduced into a subject.
[0025] The active pharmaceutical agents may be administered to the
patient in a manner that reduces the variability of the ratio of
the concentrations of the active agents over a period of time,
thereby maximizing the therapeutic benefit while minimizing the
side effects. The present invention differs from prior studies by
providing novel combinations as well as formulations of
combinations directed to dose optimization or release modification
to reduce adverse effects associated with each agent.
[0026] Optionally, the Cratio,var of the NMDAr antagonist and the
ACheI is less than 100%, e.g., less than 70%, 50%, 30%, 20%, or 10%
after the agents have reached steady-state conditions. Optionally,
the Cratio,var of the NMDAr antagonist and the ACheI is less than
100%, e.g. less than 70%, 50%, 30%, 20%, or 10% during the first 24
hours post-administration of the agents. In some embodiments, the
Cratio,var is less than about 90% (e.g., less than about 75% or
50%) of that for IR administration of the same active
pharmaceutical ingredients over the first 4, 6, 8, or 12 hours
after administration.
[0027] In all foregoing aspects of the invention, the NMDAr
antagonist may be an aminoadamantine derivative including memantine
(1-amino-3,5-dimethyladamantane), rimantadine
(1-(1-aminoethyl)adamantane), or amantadine (1-amino-adamantane).
The ACheI, an acetylcholinesterase inhibitor, may be, e.g.,
donepezil/ARICEPT.RTM., rivastigmine/EXELON.RTM.,
galantamine/REMINYL.RTM., tacrine/COGNEX.RTM., metrifonate, or
huperzine-A. Thus, in some embodiments, the NMDAr antagonist is
memantine while the ACheI is donepezil, rivastigmine, galantamine,
tacrine, metrifonate, or huperzine-A.
[0028] In some embodiments, the NMDAr antagonist, the ACheI, or
both agents are formulated for oral, intravenous, topical,
intranasal, subtopical transepithelial, subdermal, or inhalation
delivery. Thus, the agents described herein may be formulated as a
suspension, capsule, tablet, suppository, lotion, patch, or device
(e.g., a subdermally implantable delivery device or an inhalation
pump). If desired, the NMDA antagonist and the ACheI may be admixed
in a single composition. Alternatively, the two agents are
delivered in separate formulations sequentially, or within one
hour, two hours, three hours, six hours, 12 hours, or 24 hours of
each other. If administered separately, the two agents may be
administered by the same or different routes of administration
three times a day, twice a day, once a day, or even once every two
days. Optionally, the two agents are provided together in the form
of a kit. Preferably, the NMDAr antagonist and the ACheI are
provided in a unit dosage form.
[0029] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the invention,
suitable methods and materials are described below. All
publications, patent applications, patents, and other references
mentioned herein are incorporated by reference in their entirety.
In the case of conflict, the present Specification, including
definitions, will control. In addition, the materials, methods, and
examples are illustrative only and not intended to be limiting. All
parts and percentages are by weight unless otherwise specified.
BRIEF DESCRIPTION OF THE FIGURES
[0030] FIG. 1A is a graph showing that the controlled release
formulation of memantine (Namenda) and sustained release
formulations of memantine (NPI-6601, NPI-6701, and NPI-6801). The
sustained release formulations contain 22.5 mg of memantine. These
dissolution profiles were obtained from a USP II Paddle system
using water as the medium.
[0031] FIG. 1B is a graph showing predicted plasma blood levels for
24 hours of dosing with an immediate release formulation of
memantine (Namenda) and sustained release formulations of memantine
(NPI-6601, NPI-6701, and NPI-6801), obtained using the Gastro-Plus
software package v.4.0.2. The sustained release formulations
contain 22.5 mg of memantine.
[0032] FIGS. 2A-2C show dissolution profiles of: FIG. 2A: Sustained
Release (SR) Memantine (fast)--Immediate Release (IR) Donepezil
(NPI-6170); FIG. 2B: SR Memantine (medium)--IR Donepezil
(NPI-6270); and FIG. 2C: SR Memantine (slow)--IR Donepezil
(NPI-6370).
[0033] FIGS. 3A-3C show dissolution profiles of: FIG. 3A: SR
Memantine (fast)--SR Donepezil (fast) (NPI-6171); FIG. 3B: SR
Memantine (medium)--SR Donepezil (fast) (NPI-6271); and FIG. 3C: SR
Memantine (slow)--SR Donepezil (fast) (NPI-6371).
[0034] FIGS. 4A-4C show dissolution profiles of: FIG. 4A: SR
Memantine (fast)--SR Donepezil (medium) (NPI-6172); FIG. 4B: SR
Memantine (medium)--SR Donepezil (medium) (NPI-6272); and FIG. 4C:
SR Memantine (slow)--SR Donepezil (medium) (NPI-6372).
[0035] FIGS. 5A-5C show dissolution profiles of FIG. 5A: SR
Memantine (fast)--SR Donepezil (slow) (NPI-6173); FIG. 5B: SR
Memantine (medium)--SR Donepezil (Slow) (NPI-6273); and FIG. 5C: SR
Memantine (slow)--SR Donepezil (slow) (NPI-6373).
[0036] FIGS. 6A-6E show plasma concentrations obtained using the
GastroPlus software package v.4.0.2 for the following compositions:
FIG. 6A: SR Memantine (fast)--IR Donepezil (NPI-6170); FIG. 6B: SR
Memantine (fast)--SR Donepezil (Slow) (NPI-6173; FIG. 6C: SR
Memantine (medium)--SR Donepezil (medium) (NPI-6272); FIG. 6D: SR
Memantine (Slow)--IR Donepezil (NPI-6370; and FIG. 6E: SR Memantine
(Slow) SR Donepezil (slow) (NPI-6373).
[0037] FIG. 7 shows plasma concentrations obtained using the
GastroPlus software package v.4.0.2 for an SR Memantine--SR
Donepezil forumulation (NPI-6272) and an IR Memantine--IR Donepezil
formulation.
[0038] FIG. 8 shows pharmacokinetic properties of various IR
formulations and SR formulations of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0039] The present invention provides methods and compositions for
treating or preventing CNS-related conditions, including
psychiatric disorders (e.g., panic syndrome, general anxiety
disorder, phobic syndromes of all types, mania, manic depressive
illness, hypomania, unipolar depression, depression, stress
disorders, PTSD, somatoform disorders, personality disorders,
psychosis, and schizophrenia), and drug dependence (e.g., alcohol,
psychostimulants (e.g., crack, cocaine, speed, and meth), opioids,
and nicotine), epilepsy, headache, acute pain, chronic pain,
neuropathies, cereborischemia, dementias (including Alzheimer's
type), movement disorders, and multiple sclerosis. The combination
includes a first agent that is an NMDAr antagonist and an ACheI
(e.g., donepezil/ARICEPT.RTM., rivastigmine/EXELON.RTM.,
galantamine/REMINYL.RTM., tacrine/COGNEX.RTM., metrifonate, or
huperzine-A). The combination is administered such that the
symptoms associated with CNS-related condition are alleviated or
prevented, or alternatively, such that progression of the
CNS-related condition is reduced. Desirably, either of these two
agents, or even both agents, is formulated for extended release,
thereby providing a concentration over a desired time period that
is high enough to be therapeutically effective but low enough to
reduce or avoid adverse events associated with excessive levels of
either agent in the subject. Preferably, the compositions of the
present invention are formulated to provide a concentration ratio
variability over the dosing interval that is less than that
observed or predicted for formulations where neither component or
only one component is in an extended release form.
NMDAr Antagonists
[0040] Any NMDAr antagonist can be used in the methods and
compositions of the invention, particularly those that are
non-toxic when used in the combination of the invention. The term
"nontoxic" is used in a relative sense and is intended to designate
any substance that has been approved by the United States Food and
Drug Administration ("FDA") for administration to humans or, in
keeping with established regulatory criteria and practice, is
susceptible to approval by the FDA or similar regulatory agency for
any country for administration to humans or animals.
[0041] The NMDAr antagonist may be an amino-adamantane compound
including, for example, memantine (1-amino-3,5-dimethyladamantane),
rimantadine (1-(1-aminoethyl)adamantane), amantadine
(1-amino-adamantane), as well as pharmaceutically acceptable salts
thereof. Memantine is described, for example, in U.S. Pat. Nos.
3,391,142; 5,891,885; 5,919,826; and 6,187,338. Amantadine is
described, for example, in U.S. Pat. Nos. 3,152,180; 5,891,885;
5,919,826; and 6,187,338. Additional aminoadamantane compounds are
described, for example, in U.S. Pat. Nos. 4,346,112; 5,061,703;
5,334,618; 5,382,601; 6,444,702; 6,620,845; and 6,662,845. All of
these patents are incorporated herein by reference.
[0042] Further NMDAr antagonists that may be employed include, for
example, ketamine, eliprodil, ifenprodil, dizocilpine, remacemide,
iamotrigine, riluzole, aptiganel, phencyclidine, flupirtine,
celfotel, felbamate, neramexane, spermine, spermidine, levemopamil,
dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) and its
metabolite, dextrorphan ((+)-3-hydroxy-N-methylmorphinan), a
pharmaceutically acceptable salt or ester thereof, or a metabolic
precursor of any of the foregoing.
[0043] The pharmaceutical composition may be formulated to provide
memantine in an amount ranging between 1 and 80 mg/day, 5 and 40
mg/day, or 10 and 20 mg/day; amantadine in an amount ranging
between 25 and 500 mg/day, 25 and 300 mg/day, or 100 and 300
mg/day; or dextromethorphan in an amount ranging between 1 and 5000
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 those
determined for adults. Representative dosing can be found in the
PDR by anyone skilled in the art.
[0044] Table 1 shows exemplary the pharmacokinetic properties
(e.g., Tmax and T1/2) of memantine, amantadine, and
rimantadine.
TABLE-US-00001 TABLE 1 Pharmacokinetics and Tox in humans for
selected NMDAr antagonists Human Dose PK (t1/2) Tmax in Normal
Dependent Compound in hrs hrs Dose Tox Memantine 60 3 10-20 mg/day,
Dose escalation starting at required, 5 mg hallucination Amantadine
15 3 100-300 mg/day Hallucination Rimantadine 25 6 100-200 mg/day
Insomnia
Acetylcholinesterase Inhibitor
[0045] The ACheI of the combination described herein is an
acetylcholinesterase inhibitor (e.g., donepezil/ARICEPT.RTM.,
rivastigmine/EXELON.RTM., galantamine/REMINYL.RTM.,
tacrine/COGNEX.RTM., metrifonate, or huperzine-A).
[0046] Donepezil, described in U.S. Pat. No. 4,895,841,
galantamine, described in U.S. Pat. No. 4,663,318, and
rivastigmine, described in U.S. Pat. No. 4,948,807, are all
presently approved by the United States FDA for the treatment of
mild to moderate Alzheimer's disease. The use of these ACheIs
commonly results in severe nausea, diarrhea, vomiting, and other
side effects, including cardiovascular side effects, most of which
are dose dependent. Furthermore, the interruption of therapy
typically requires re-titration of the dosing starting at the
lowest levels (Am. Fam. Phys. 68(7):136572 (2003)). Ultimately,
patients cannot tolerate chronic ACheI therapy.
[0047] The pharmaceutical composition may be formulated to provide
donepezil in an amount ranging between 1 and 10 mg/day, 2 and 5
mg/day, or 2 and 4 mg/day; rivastigmine in an amount ranging
between 1 and 12 mg/day, 2 and 6 mg/day, or 2 and 5 mg/day; or
galantamine in an amount ranging between 1 and 24 mg/day, 2 and 16
mg/day, or 2 and 12 mg/day. Pediatric doses will typically be lower
than those determined for adults. Representative dosing can be
found in the PDR by anyone skilled in the art.
[0048] Table 2 shows exemplary the pharmacokinetic properties
(e.g., Tmax and T1/2) of donepezil, rivastigmine, galantamine, and
Huperzine-A.
TABLE-US-00002 TABLE 2 Pharmacokinetics and Tox in humans for
selected AcheIs Main Dose- Human Dependent PK T1/2 Tmax Normal
Adverse Compound (hrs) (hrs) Dose Event ARICEPT .RTM./ 70 3-4.sup.
5-10 mg/day Nausea, Donepezil diarrhea, insomnia EXELON .RTM./ 1.5
1-2.5 6-12 mg/day Nausea, Rivastigmine vomiting REMINYL .RTM./ 7
1-2.5 16-24 mg/day Nausea, Galantamine vomiting, anorexia
HUPERZINE-A 4.8 1.3 100-400 .mu.g/day Nausea, hyper- activity,
dizziness
Making Controlled Release Formulations
[0049] A pharmaceutical composition according to the invention is
prepared by combining a desired NMDAr antagonist or antagonists
with one or more additional ingredients that, when administered to
a subject, causes the NMDAr antagonist to be released at a targeted
concentration range for a specified period of time. The NMDAr
antagonist may be provided so that it is released at a dC/dT that
is significantly reduced over an instant release (so called IR)
dosage form, with an associated delay in the Tmax. The
pharmaceutical composition may be formulated to provide a shift in
Tmax by 24 hours, 16 hours, 8 hours, 4 hours, 2 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 provided such that it is released at
rate resulting in a C.sub.max/C.sub.mean of approximately 2 or less
for approximately 2 hours to at least 8 hours after the NMDAr
antagonist is introduced into a subject.
[0050] In addition, the NMDAr antagonist may be provided such that
it is released at a rate resulting in a C.sub.max/C.sub.mean of
approximately 2 or less for approximately 2 hours to at least 8
hours after the NMDAr antagonist is introduced into a subject.
Optionally, the sustained release formulations exhibit plasma
concentration curves having initial (e.g., from 2 hours after
administration to 4 hours after administration) slopes less than
75%, 50%, 40%, 30%, 20% or 10% of those for an IR formulation of
the same dosage of the same NMDAr antagonist. The precise slope for
a given individual will vary according to the NMDAr antagonist
being used or other factors, including whether the patient has
eaten or not. For other doses, e.g., those mentioned above, the
slopes vary directly in relationship to dose. The determination of
initial slopes of plasma concentration is described, for example,
by U.S. Pat. No. 6,913,768, hereby incorporated by reference.
[0051] Optionally, the composition described herein is formulated
such the NMDAr antagonist has an in vitro dissolution profile less
than 70% in one hour, less than 90% in two hours, greater than 40%
in six hours, and greater than 85% in 12 hours as measured using a
USP type 2 (paddle) dissolution system at 50 rpm, at a temperature
of 37.+-.0.5.degree. with water as a dissolution medium.
[0052] Desirably, the compositions described herein have an in
vitro dissolution profile that is substantially identical to the
dissolution profile shown for the formulations shown in FIGS. 1A
and 2-5 and, upon administration to a subject at a substantially
constant daily dose, achieves a plasma concentration profile that
is substantially identical to those shown in FIGS. 1B,6, and 7.
[0053] A release profile, i.e., the extent of release of the NMDAr
antagonist over a desired time, can be conveniently determined for
a given time by calculating the C.sub.max/C.sub.mean for a desired
time range. For example, the NMDAr antagonist can be provided so
that it is released at C.sub.max/C.sub.mean of approximately 2 or
less for approximately 2 hours to at least 6 hours after the NMDAr
antagonist is introduced into a subject. One of ordinary skill in
the art can prepare combinations with a desired release profile
using the NMDAr antagonists and formulation methods described
below.
[0054] Optionally, the ACheI may also be prepared as a controlled
release formulation as described above for the NMDAr
antagonist.
[0055] Using the formulations described herein, therapeutic levels
may be achieved while minimizing debilitating side-effects that are
usually associated with immediate release formulations.
Furthermore, as a result of the reduction in the time to obtain
peak plasma level and the potentially extended period of time at
the therapeutically effective plasma level, the dosage frequency
may be reduced to, for example, once or twice daily dosage, thereby
improving patient compliance and adherence. For example, side
effects including psychosis and cognitive deficits associated with
the administration of NMDAr antagonists may be lessened in severity
and frequency through the use of controlled-release methods that
shift the Tmax to longer times, thereby reducing the dC/dT of the
drug. Reducing the dC/dT of the drug not only increases Tmax, but
also reduces the drug concentration at Tmax and reduces the
Cmax/Cmean ratio providing a more constant amount of drug to the
subject being treated over a given period of time and reducing
adverse events associated with dosing. With regards to the ACheI,
the lower dC/dT and Cmean will result in a lower incidence of
cardiovascular or gastric side effects and other adverse
events.
[0056] In addition to the specific combinations disclosed herein,
combinations made of a first NMDAr antagonist and the ACheI may be
identified by testing the ability of a test combination of a
selected NMDAr antagonist and one or more ACheIs to lessen the
symptoms of a CNS-related disorder. Preferred combinations are
those in which a lower therapeutically effective amount of the
NMDAr antagonist and/or the ACheI is present relative to the same
amount of the NMDAr antagonist and/or the ACheI required to obtain
the same effect when each agent is tested separately.
[0057] The amounts and ratios of the NMDAr antagonist and the ACheI
are conveniently varied to maximize the therapeutic benefit and
minimize the toxic or safety concerns. The NMDAr antagonist may
range between 20% and 200% of its normal effective dose and the
ACheI may range between 20% to 200% of its normal effective dose.
The precise ratio may vary according to the condition being
treated. In one example, the amount of memantine ranges between 2.5
and 80 mg per day and the amount of donepezil ranges between 1 and
20 mg/day.
[0058] When the memantine is in a controlled-release form, the
preferred dosage range is 10 mg to 80 mg per day; daily doses of
about 22.5, 27.5, 32.5, 37.5, 42.5, 47.5, 52.5, 57.5, 62.5, 67.5,
72.5, 77.5 mg are particularly preferred. When the donepezil is in
a controlled-release form, the preferred dosage range lmg to 10 mg
per day; daily doses of about 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2,
2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8,
5.0 mg per day are particularly preferred. In a particularly
preferred embodiment the memantine dose is 30-45 mg per day, taken
in combination with a donepezil dose of 2-4 mg/day, administered as
a single dosage form, with no dose escalation over time. The
combination dosage form preferably has sustained release
formulations for memantine, donepezil or both, such that the
dissolution profile of the two drugs in the combination tablet are
"matched", especially with regards to the Tmax, dC/dT (normalized
for the dose of NMDAr antagonist and ACheI) in a human. For
memantine and donepezil, which have similar pharmacokinetic
properties, in vitro dissolution profiles will also be similar.
[0059] In a preferred embodiment of this invention, memantine and
donepezil are formulated into beads or pellets (as described
herein) with substantially similar dissolution profiles. More
preferably, beads or pellets of memantine are prepared with a
dissolution profiles similar to that shown for memantine in FIG. 4B
and, separately, beads or pellets of donepezil are prepared with a
dissolution profile similar to that shown for donepezil in the same
figure. The preferred pellets are approximately 0.4 mg each and
contain approximately 60 .mu.g memantine or donepezil and easily
characterized by known methods. The beads may be filled into
gelatin capsules by mass or number to achieve the preferred mass of
memantine of 30-45 mg per capsules and donepezil of 2-4 mg per
capsule. For example, a 42 mg memantine 3.6 mg donepezil
combination may be prepared by combining 700 memantine beads with
60 donepezil beads in each capsule, equivalent to 280 mg memantine
beads plus 24 mg donepezil beads per capsule.
[0060] Additionally, different release profiles for each active
pharmaceutical ingredient may be prepared and combined in
prescribed ratios to adjust the release profile for each of the
ingredients, enabling the more rapid development of formulations
for development purposes or specialized formulations for individual
products.
[0061] For a specified range a physician or other appropriate
health professional will typically determine the best dosage for a
given patient, according to his sex, age, weight, pathological
state, and other parameters. In some cases, it may be necessary to
use dosage outside of the range stated in pharmaceutical packaging
insert to treat a subject. Those cases will be apparent to the
prescribing physician or veterinarian.
[0062] In some embodiments, the combinations of the invention
achieve therapeutic levels while minimizing debilitating
side-effects that are usually associated with immediate release
formulations. Furthermore, as a result of the delay in the time to
obtain peak plasma level and the potentially extended period of
time at the therapeutically effective plasma level, the dosage
frequency may be reduced to, for example, once or twice daily
dosage, thereby improving patient compliance and adherence.
[0063] Accordingly, the combination of the invention allows the
NMDAr antagonist and the ACheI to be administered in a combination
that improves efficacy and avoids undesirable side effects of both
drugs. For example, side effects including psychosis and cognitive
deficits associated with the administration of NMDAr antagonists
may be lessened in severity and frequency through the use of
controlled-release methods that shift the Tmax to longer times,
thereby reducing the dC/dT of the drug. Reducing the dC/dT of the
drug not only increases Tmax, but also reduces the drug
concentration at Tmax and reduces the Cmax/Cmean ratio providing a
more constant amount of drug to the subject being treated over a
given period of time and reducing adverse events associated with
dosing. Similarly, side effects associated with the use of ACheIs
may also be reduced in severity and frequency through controlled
release methods.
[0064] In certain embodiments, the combinations provide additive
effects. Additivity is achieved by combining the active agents
without requiring controlled release technologies. In other
embodiments, particularly when the pharmacokinetic profiles of the
combined active pharmaceutical ingredients are dissimilar,
controlled release formulations optimize the pharmacokinetics of
the active pharmaceutical agents to reduce the variability of the
Cratio over time. Reduction of Cratio variability over a defined
time period enables a concerted effect for the agents over that
time, maximizing the effectiveness of the combination. The Cratio
variability ("Cratio.var") is defined as the standard deviation of
a series of Cratios taken over a given period of time divided by
the mean of those Cratios multiplied by 100%. The Cratio for the
controlled release formulation of drugs with significantly
different pharmacokinetic properties is more consistent than for
the IR administration of the same drugs over any significant time
period, including shortly after administration and at steady
state.
Modes of Administration
[0065] The combination of the invention may be administered in
either a local or systemic manner or in a depot or sustained
release fashion. The two agents may be delivered in an oral,
transdermal or intranasal formulation. In a preferred embodiment,
the NMDAr antagonist, the ACheI of the combination, or both agents
may be formulated to provide controlled, extended release (as
described herein). For example, a pharmaceutical composition that
provides controlled release of the NMDAr antagonist, the ACheI, or
both may be prepared by combining the desired agent or agents with
one or more additional ingredients that, when administered to a
subject, causes the respective agent or agents to be released at a
targeted rate for a specified period of time. The two agents are
preferably administered in a manner that provides the desired
effect from the first and second agents in the combination.
Optionally, the first and second agents are admixed into a single
formulation before they are introduced into a subject. The
combination may be conveniently sub-divided in unit doses
containing appropriate quantities of the first and second agents.
The unit dosage form may be, for example, a capsule or tablet
itself or it can be an appropriate number of such compositions in
package form. The quantity of the active ingredients in the unit
dosage forms may be varied or adjusted according to the particular
need of the condition being treated.
[0066] Alternatively, the NMDAr antagonist and the ACheI of the
combination may not be mixed until after they are introduced into
the subject. Thus, the term "combination" encompasses embodiments
where the NMDAr antagonist and the ACheI are provided in separate
formulations and are administered sequentially. For example, the
NMDAr antagonist and the ACheI may be administered to the subject
separately within 2 days, 1 day, 18 hours, 12 hours, one hour, a
half hour, 15 minutes, or less of each other. Each agent may be
provided in multiple, single capsules or tablets that are
administered separately to the subject. Alternatively, the NMDAr
antagonist and the ACheI are separated from each other in a
pharmaceutical composition such that they are not mixed until after
the pharmaceutical composition has been introduced into the
subject. The mixing may occur just prior to administration to the
subject or well in advance of administering the combination to the
subject.
[0067] If desired, the NMDAr antagonist and the ACheI may be
administered to the subject in association with other therapeutic
modalities, e.g., drug, surgical, or other interventional treatment
regimens. Accordingly, the combination described herein may be
administered simultaneously or within 14 days, 7 days, 5 days, 3
days, one day, 12 hours, 6 hours, 3 hours, or one hour of
additional therapeutic modalities. Where the combination includes a
non-drug treatment, the non-drug treatment may be conducted at any
suitable time so long as a beneficial effect from the co-action of
the combination and the other therapeutic modalities is achieved.
For example, in appropriate cases, the beneficial effect is still
achieved when the non-drug treatment is temporally removed from the
administration of the therapeutic agents, perhaps by days or even
weeks.
[0068] The preparation of pharmaceutical or pharmacological
compositions are known to those of skill in the art in light of the
present disclosure. General techniques for formulation and
administration are found in "Remington: The Science and Practice of
Pharmacy, Twentieth Edition," Lippincott Williams & Wilkins,
Philadelphia, Pa. Tablets, capsules, pills, powders, granules,
dragees, gels, slurries, ointments, solutions suppositories,
injections, inhalants and aerosols are examples of such
formulations.
[0069] In some embodiments, the first agent and second agent of the
combination described herein are provided within a single or
separate pharmaceutical compositions. "Pharmaceutically or
Pharmacologically Acceptable" includes molecular entities and
compositions that do not produce an adverse, allergic or other
untoward reaction when administered to an animal, or a human, as
appropriate. "Pharmaceutically Acceptable Carrier" includes any and
all solvents, dispersion media, coatings, antibacterial and
antifungal agents, isotonic and absorption delaying agents and the
like. The use of such media and agents for pharmaceutical active
substances is well known in the art. Except insofar as any
conventional media or agent is incompatible with the active
ingredient, its use in the therapeutic compositions is
contemplated. Supplementary active ingredients can also be
incorporated into the compositions. "Pharmaceutically Acceptable
Salts" include acid addition salts and which are formed with
inorganic acids such as, for example, hydrochloric or phosphoric
acids, or such organic acids as acetic, oxalic, tartaric, mandelic,
and the like. Salts formed with the free carboxyl groups can also
be derived from inorganic bases such as, for example, sodium,
potassium, ammonium, calcium, or ferric hydroxides, and such
organic bases as isopropylamine, trimethylamine, histidine,
procaine and the like.
Formulations for Oral Administration
[0070] Combinations can be provided as pharmaceutical compositions
that are optimized for particular types of delivery. For example,
pharmaceutical compositions for oral delivery are formulated using
pharmaceutically acceptable carriers that are well known in the art
and described further below. The carriers enable the agents in the
combination to be formulated, for example, as a tablet, pill,
capsule, solution, suspension, powder, liquid, or gel for oral
ingestion by the subject.
[0071] The NMDAr antagonist, the ACheI of the invention, or both
agents may be provided in a controlled, extended release form. In
one example, at least 50%, 90%, 95%, 96%, 97%, 98%, 99%, or even in
excess of 99% of the NMDAr antagonist is provided in an extended
release dosage form. A release profile, i.e., the extent of release
of the NMDAr antagonist or the ACheI over a desired time, may be
conveniently determined for a given time by calculating the
C.sub.max/C.sub.mean for a desired time range to achieve a given
acute or chronic steady state serum concentration profile. Thus,
upon the administration to a subject (e.g., a mammal such as a
human), the NMDAr antagonist has a Cmax/Cmean of approximately 2.5,
2, 1.5, or 1.0 approximately 1, 1.5, 2 hours to at least 6, 8, 9,
12, 18, 21, or 24 hours following such administration. If desired,
the release of the NMDAr antagonist may be monophasic or
multiphasic (e.g., biphasic). Moreover, the ACheI may be formulated
as an extended release composition, having a C.sub.max/C.sub.mean
of approximately 2.5, 2, 1.5, or 1.0, approximately 1, 1.5, 2 hours
to at least 6, 8, 9, 12, 18, 21, or 24 hours following
administration to a subject. One of ordinary skill in the art can
prepare combinations with a desired release profile using the NMDAr
antagonists and the ACheI and formulation methods known in the art
or described below.
[0072] As shown in Tables 1 and 2, the pharmacokinetic half-lives
of the drugs of both classes vary from about 1.5 hours to 70 hours.
Thus, suitable formulations may be conveniently selected to achieve
nearly constant concentration profiles over an extended period
(preferably from 8 to 24 hours) thereby maintaining both agents in
a constant ratio and concentration for optimal therapeutic benefits
for both acute and chronic administration. Preferred Cratio,var
values may be less than about 30%, 50%, 75%, 90% of those for IR
administration of the same active pharmaceutical ingredients over
the first 4, 6, 8, or 12 hours after administration. Preferred
Cratio,var values are less than about 100%, 70%, 50%, 30%, 20%,
10%.
[0073] Formulations that deliver this constant, measurable profile
also allow one to achieve a monotonic ascent from an acute ratio to
a desired chronic ratio for drugs with widely varying elimination
half-lives. Compositions of this type and methods of treating
patients with these compositions are embodiments of the invention.
Numerous ways exist for achieving the desired release profiles, as
exemplified below.
[0074] In some embodiments, the first agent and second agent of the
combination described herein are provided within a single or
separate pharmaceutical compositions. "Pharmaceutically or
Pharmacologically Acceptable" includes molecular entities and
compositions that do not produce an adverse, allergic or other
untoward reaction when administered to an animal, or a human, as
appropriate. "Pharmaceutically Acceptable Carrier" includes any and
all solvents, dispersion media, coatings, antibacterial and
antifungal agents, isotonic and absorption delaying agents and the
like. The use of such media and agents for pharmaceutical active
substances is well known in the art. Except insofar as any
conventional media or agent is incompatible with the active
ingredient, its use in the therapeutic compositions is
contemplated. Supplementary active ingredients can also be
incorporated into the compositions. "Pharmaceutically Acceptable
Salts" include acid addition salts and which are formed with
inorganic acids such as, for example, hydrochloric or phosphoric
acids, or such organic acids as acetic, oxalic, tartaric, mandelic,
and the like. Salts formed with the free carboxyl groups can also
be derived from inorganic bases such as, for example, sodium,
potassium, ammonium, calcium, or ferric hydroxides, and such
organic bases as isopropylamine, trimethylamine, histidine,
procaine and the like.
[0075] Suitable methods for preparing combinations in which the
first agent, ACheI, or both agents are provided in extended
release-formulations include those described in U.S. Pat. No.
4,606,909 (hereby incorporated by reference). This reference
describes a controlled release multiple unit formulation in which a
multiplicity of individually coated or microencapsulated units are
made available upon disintegration of the formulation (e.g., pill
or tablet) in the stomach of the animal (see, for example, column
3, line 26 through column 5, line 10 and column 6, line 29 through
column 9, line 16). Each of these individually coated or
microencapsulated units contains cross-sectionally substantially
homogenous cores containing particles of a sparingly soluble active
substance, the cores being coated with a coating that is
substantially resistant to gastric conditions but which is erodable
under the conditions prevailing in the small intestine.
[0076] The combination may alternatively be formulated using the
methods disclosed in U.S. Pat. No. 4,769,027, for example.
Accordingly, extended release formulations involve prills of
pharmaceutically acceptable material (e.g., sugar/starch, salts,
and waxes) may be coated with a water permeable polymeric matrix
containing an NMDAr antagonist and next overcoated with a
water-permeable film containing dispersed within it a water soluble
particulate pore forming material.
[0077] One or both agents of the combination may additionally be
prepared as described in U.S. Pat. No. 4,897,268, involving a
biocompatible, biodegradable microcapsule delivery system. Thus,
the NMDAr antagonist may be formulated as a composition containing
a blend of free-flowing spherical particles obtained by
individually microencapsulating quantities of memantine, for
example, in different copolymer excipients which biodegrade at
different rates, therefore releasing memantine into the circulation
at a predetermined rates. A quantity of these particles may be of
such a copolymer excipient that the core active ingredient is
released quickly after administration, and thereby delivers the
active ingredient for an initial period. A second quantity of the
particles is of such type excipient that delivery of the
encapsulated ingredient begins as the first quantity's delivery
begins to decline. A third quantity of ingredient may be
encapsulated with a still different excipient which results in
delivery beginning as the delivery of the second quantity beings to
decline. The rate of delivery may be altered, for example, by
varying the lactide/glycolide ratio in a
poly(D,L-lactide-co-glycolide) encapsulation. Other polymers that
may be used include polyacetal polymers, polyorthoesters,
polyesteramides, polycaprolactone and copolymers thereof,
polycarbonates, polyhydroxybuterate and copolymers thereof,
polymaleamides, copolyaxalates and polysaccharides.
[0078] In one embodiment of the invention, the NMDAr antagonist,
the ACheI, or both agents may be provided in a controlled or
extended release form with or without an immediate release
component in order to maximize the therapeutic benefit of each,
while reducing unwanted side effects associated with each. When
these drugs are provided in an oral form without the benefit of
controlled or extended release components, they are released and
transported into the body fluids over a period of minutes to
several hours. Thus, the composition of the invention may contain
an NMDAr antagonist and a sustained release component, such as a
coated sustained release matrix, a sustained release matrix, or a
sustained release bead matrix. In one example, memantine (e.g.,
5-80 mg) is formulated without an immediate release component using
a polymer matrix (e.g., Eudragit), Hydroxypropyl methyl cellulose
(HPMC) and a polymer coating (e.g., Eudragit). Such formulations
are compressed into solid tablets or granules or formed into
pellets for capsules or tablets. Optionally, a coating such as
Opadry.RTM. or Surelease.RTM. is used.
[0079] Separately prepared pellets, preferably release controlling
pellets, combined in any manner provide the flexibility of making
ratios of NMDAr antagonist to ACheI containing compositions ranging
from 0.1:100 to 100:0.1, more preferably from 1:100 to 100:1, most
preferably 1:10 to 10:1 by mass or by numbers of pellets (see
Example 7), and at the desired release profiles for each of the
active ingredients. Optionally, the NMDAr antagonist, the ACheI, or
both agents are prepared using the OROS.RTM. technology, described
for example, in U.S. Pat. Nos. 6,919,373, 6,923,800, 6,929,803,
6,939,556, and 6,930,128, all of which are hereby incorporated by
reference. This technology employs osmosis to provide precise,
controlled drug delivery for up to 24 hours and can be used with a
range of compounds, including poorly soluble or highly soluble
drugs. OROS.RTM. technology can be used to deliver high drug doses
meeting high drug loading requirements. By targeting specific areas
of the gastrointestinal tract, OROS.RTM. technology may provide
more efficient drug absorption and enhanced bioavailability. The
osmotic driving force of OROS.RTM. and protection of the drug until
the time of release eliminate the variability of drug absorption
and metabolism often caused by gastric pH and motility
[0080] Alternatively, the combination may be prepared as described
in U.S. Pat. No. 5,395,626 features a multilayered controlled
release pharmaceutical dosage form. The dosage form contains a
plurality of coated particles wherein each has multiple layers
about a core containing an NMDAr antagonist and/or the ACheI
whereby the drug containing core and at least one other layer of
drug active is overcoated with a controlled release barrier layer
therefore providing at least two controlled releasing layers of a
water soluble drug from the multilayered coated particle.
[0081] By way of example, extended release oral formulation can be
prepared using additional methods known in the art. For example, a
suitable extended release form of the either active pharmaceutical
ingredient or both may be a matrix tablet composition. Suitable
matrix forming materials include, for example, waxes (e.g.,
carnauba, bees wax, paraffin wax, ceresine, shellac wax, fatty
acids, and fatty alcohols), oils, hardened oils or fats (e.g.,
hardened rapeseed oil, castor oil, beef tallow, palm dil, and soya
bean oil), and polymers (e.g., hydroxypropyl cellulose,
polyvinylpyrrolidone, hydroxypropyl methyl cellulose, and
polyethylene glycol). Other suitable matrix tabletting materials
are microcrystalline cellulose, powdered cellulose, hydroxypropyl
cellulose, ethyl cellulose, with other carriers, and fillers.
Tablets may also contain granulates, coated powders, or pellets.
Tablets may also be multi-layered. Multi-layered tablets are
especially preferred when the active ingredients have markedly
different pharmacokinetic profiles. Optionally, the finished tablet
may be coated or uncoated.
[0082] The coating composition typically contains an insoluble
matrix polymer (approximately 15-85% by weight of the coating
composition) and a water soluble material (e.g., approximately
15-85% by weight of the coating composition). Optionally an enteric
polymer (approximately 1 to 99% by weight of the coating
composition) may be used or included. Suitable water soluble
materials include polymers such as polyethylene glycol,
hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
polyvinylpyrrolidone, polyvinyl alcohol, and monomeric materials
such as sugars (e.g., lactose, sucrose, fructose, mannitol and the
like), salts (e.g., sodium chloride, potassium chloride and the
like), organic acids (e.g., fumaric acid, succinic acid, lactic
acid, and tartaric acid), and mixtures thereof. Suitable enteric
polymers include hydroxypropyl methyl cellulose, acetate succinate,
hydroxypropyl methyl cellulose, phthalate, polyvinyl acetate
phthalate, cellulose acetate phthalate, cellulose acetate
trimellitate, shellac, zein, and polymethacrylates containing
carboxyl groups.
[0083] The coating composition may be plasticised according to the
properties of the coating blend such as the glass transition
temperature of the main agent or mixture of agents or the solvent
used for applying the coating compositions. Suitable plasticisers
may be added from 0 to 50% by weight of the coating composition and
include, for example, diethyl phthalate, citrate esters,
polyethylene glycol, glycerol, acetylated glycerides, acetylated
citrate esters, dibutylsebacate, and castor oil. If desired, the
coating composition may include a filler. The amount of the filler
may be 1% to approximately 99% by weight based on the total weight
of the coating composition and may be an insoluble material such as
silicon dioxide, titanium dioxide, talc, kaolin, alumina, starch,
powdered cellulose, MCC, or polacrilin potassium.
[0084] The coating composition may be applied as a solution or
latex in organic solvents or aqueous solvents or mixtures thereof.
If solutions are applied, the solvent may be present in amounts
from approximate by 25-99% by weight based on the total weight of
dissolved solids. Suitable solvents are water, lower alcohol, lower
chlorinated hydrocarbons, ketones, or mixtures thereof. If latexes
are applied, the solvent is present in amounts from approximately
25-97% by weight based on the quantity of polymeric material in the
latex. The solvent may be predominantly water.
[0085] The pharmaceutical composition described herein may also
include a carrier such as a solvent, dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption
delaying agents. The use of such media and agents for
pharmaceutically active substances is well known in the art.
Pharmaceutically acceptable salts can also be used in the
composition, for example, mineral salts such as hydrochlorides,
hydrobromides, phosphates, or sulfates, as well as the salts of
organic acids such as acetates, proprionates, 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 agents, or pH buffering agents.
Liposomes, such as those described in U.S. Pat. No. 5,422,120, WO
95/13796, WO 91/14445, or EP 524,968 Bl, may also be used as a
carrier.
[0086] Additional methods for making controlled release
formulations are described in, e.g., U.S. Pat. Nos. 5,422,123;
5,601,845; 5,912,013; and 6,194,000, all of which are hereby
incorporated by reference.
Formulations for Other Routes of Administration
[0087] Alternatively, the compositions of the present invention may
be administered transdermally. Preparation for delivery in a
transdermal patch can be performed using methods also known in the
art, including those described generally in, e.g., U.S. Pat. Nos.
5,186,938; 6,183,770; 4,861,800; 4,284,444 and WO 89/09051. A patch
is a particularly useful embodiment in cases where the therapeutic
agent has a short half-life or requires reduction in dC/dT. Patches
can be made to control the release of skin-permeable active
ingredients over a 12 hour, 24 hour, 3 day, and 7 day period. In
one example, a 2-fold daily excess of an NMDAr antagonist is placed
in a non-volatile fluid along with the opiate narcotic agent,
non-steroidal anti-inflammatory agent, or anesthetic. Given the
amount of the agents employed herein, a preferred release will be
from 12 to 72 hours.
[0088] Transdermal preparations of this form will contain from 1%
to 50% active ingredients. The compositions of the invention are
provided in the form of a viscous, non-volatile liquid. Preferably,
both members of the combination will have a skin penetration rate
of at least 10.sup.-9 mole/cm.sup.2/hour. At least 5% of the active
material will flux through the skin within a 24 hour period. The
penetration through skin of specific formulations may be measures
by standard methods in the art (for example, Franz et al., J.
Invest. Derm. 64:194-195 (1975)).
[0089] Pharmaceutical compositions containing the NMDAr antagonist
and/or ACheI of the combination may also be delivered in an aerosol
spray preparation from a pressurized pack, a nebulizer or from a
dry powder inhaler. Suitable propellants that can be used in a
nebulizer include, for example, dichlorodifluoro-methane,
trichlorofluoromethane, dichlorotetrafluoroethane and carbon
dioxide. The dosage may be determined by providing a valve to
deliver a regulated amount of the compound in the case of a
pressurized aerosol.
[0090] Compositions for inhalation or insufflation include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. The liquid
or solid compositions may contain suitable pharmaceutically
acceptable excipients as set out above. Preferably the compositions
are administered by the oral, intranasal or respiratory route for
local or systemic effect. Compositions in preferably sterile
pharmaceutically acceptable solvents may be nebulized by use of
inert gases. Nebulized solutions may be breathed directly from the
nebulizing device or the nebulizing device may be attached to a
face mask, tent or intermittent positive pressure breathing
machine. Solution, suspension or powder compositions may be
administered, preferably orally or nasally, from devices that
deliver the formulation in an appropriate manner.
[0091] In some embodiments, for example, the composition may be
delivered intranasally to the cribriform plate rather than by
inhalation to enable transfer of the active agents through the
olfactory passages into the CNS and reducing the systemic
administration. Devices used for this route of administration are
included in U.S. Pat. No. 6,715,485. Compositions delivered via
this route may enable increased CNS dosing or reduced total body
burden reducing systemic toxicity risks associated with certain
drugs.
[0092] Additional formulations suitable for other modes of
administration include rectal capsules or suppositories. For
suppositories, traditional binders and carriers may include, for
example, polyalkylene glycols or triglycerides; such suppositories
may be formed from mixtures containing the active ingredient in the
range of 0.5% to 10%, preferably 1%-2%.
[0093] The combination may optionally be formulated for delivery in
a vessel that provides for continuous long-term delivery, e.g., for
delivery up to 30 days, 60 days, 90 days, 180 days, or one year.
For example the vessel can be provided in a biocompatible material
such as titanium. Long-term delivery formulations are particularly
useful in subjects with chronic conditions, for assuring improved
patient compliance, and for enhancing the stability of the
combinations. Formulations for continuous long-term delivery are
provided in, e.g., U.S. Pat. Nos. 6,797,283; 6,764,697; 6,635,268,
and 6,648,083.
[0094] If desired, the agents may be provided in a kit/as a
combined preparation. The kit/combined preparation can additionally
include instructions for use. In some embodiments, the kit/combined
preparation includes in one or more containers the NMDAr antagonist
and, separately, in one or more containers, the ACheI described
herein. The NMDAr antagonist and ACheI may be mixed together prior
to administration or may be administered separately to the subject.
Where they are administered separately to the patient they may be
administered at the same time as separate formulations, at
different times and over different periods of time, which may be
separate from one another or overlapping. The NMDAr antagonist and
ACheI may be administered in any order.
[0095] In other embodiments, the kit/combined preparation provides
a combination with the NMDAr antagonist and the ACheI mixed in one
or more containers. The kits/combined preparations include a
therapeutically effective dose of an agent for treating dementia or
other CNS-related condition.
[0096] Preparation of a pharmaceutical composition for delivery in
a subdermally implantable device can be performed using methods
known in the art, such as those described in, e.g., U.S. Pat. Nos.
3,992,518; 5,660,848; and 5,756,115.
Indications Suitable for Treatment with the Combination
[0097] Any subject experiencing or at risk of experiencing a
CNS-related disorder including dementia (e.g., Alzheimer's disease,
Parkinson's disease, Picks disease, fronto-temporal dementia,
vascular dementia, normal pressure hydrocephalus, HD, and MCI),
neuro-related conditions, dementia-related conditions, such as
epilepsy, seizure disorders, acute pain, chronic pain, chronic
neuropathic pain may be treated using the combinations and methods
described herein. Epileptic conditions include complex partial,
simple partial, partials with secondary generalization,
generalized--including absence, grand mal (tonic clonic), tonic,
atonic, myoclonic, neonatal, and infantile spasms. Additional
specific epilepsy syndromes are juvenile myoclonic epilepsy,
Lennox-Gastaut, mesial temporal lobe epilepsy, nocturnal frontal
lobe epilepsy, progressive epilepsy with mental retardation, and
progressive myoclonic epilepsy. The combinations of the invention
are also useful for the treatment and prevention of pain caused by
disorders including cerebrovascular disease, motor neuron diseases
(e.g., ALS, Spinal motor atrophies, Tay-Sach's, Sandoff disease,
familial spastic paraplegia), neurodegenerative diseases (e.g.,
familial Alzheimer's disease, prion-related diseases, cerebellar
ataxia, Friedrich's ataxia, SCA, Wilson's disease, RP, ALS,
Adrenoleukodystrophy, Menke's Sx, cerebral autosomal dominant
arteriopathy with subcortical infarcts (CADASIL); spinal muscular
atrophy, familial ALS, muscular dystrophies, Charcot Marie Tooth
diseases, neurofibromatosis, von-Hippel Lindau, Fragile X, spastic
paraplesia, psychiatric disorders (e.g., panic syndrome, general
anxiety disorder, phobic syndromes of all types, mania, manic
depressive illness, hypomania, unipolar depression, depression,
stress disorders, PTSD, somatoform disorders, personality
disorders, psychosis, and schizophrenia), and drug dependence
(e.g., alcohol, psychostimulants (eg, crack, cocaine, speed, meth),
opioids, and nicotine), Tuberous sclerosis, and Wardenburg
syndrome), strokes (e.g., thrombotic, embolic, thromboembolic,
hemmorhagic, venoconstrictive, and venous), movement disorders
(e.g., PD, dystonias, benign essential tremor, tardive dystonia,
tardive dyskinesia, and Tourette's syndrome), ataxic syndromes,
disorders of the sympathetic nervous system (e.g., Shy Drager,
Olivopontoicerebellar degeneration, striatonigral degenration, PD,
HD, Gullian Barre, causalgia, complex regional pain syndrome types
I and II, diabetic neuropathy, and alcoholic neuropathy), Cranial
nerve disorders (e.g., Trigeminal neuropathy, trigeminal neuralgia,
Menier's syndrome, glossopharangela neuralgia, dysphagia,
dysphonia, and cranial nerve palsies), myelopethies, traumatic
brain and spinal cord injury, radiation brian injury, multiple
sclerosis, Post-menengitis syndrome, prion diseases, myelities,
radiculitis, neuropathies (e.g., Guillian-Barre, diabetes
associated with dysproteinemias, transthyretin-induced
neuropathies, neuropathy associated with HIV, neuropathy associated
with Lyme disease, neuropathy associated with herpes zoster, carpal
tunnel syndrome, tarsal tunnel syndrome, amyloid-induced
neuropathies, leprous neuropathy, Bell's palsy, compression
neuropathies, sarcoidosis-induced neuropathy, polyneuritis
cranialis, heavy metal induced neuropathy, transition metal-induced
neuropathy, drug-induced neuropathy), axonic brain damage,
encephalopathies, and chronic fatigue syndrome. All of the above
disorders may be treated with the combinations and methods
described herein.
Administration of the Compositions
[0098] Immediate release formulations of memantine (e.g., Namenda)
are typically administered at low doses (e.g., 5 mg/day) and
progressively administered at increasing frequency and dose over
time to reach a steady state serum concentration that is
therapeutically effective. According to the manufacturer's
recommendation, Namenda, an immediate release formulation of
memantine, is first administered to subjects at a dose of 5 mg per
day. After a period of time, subjects are administered with this
dose twice daily. Subjects are next administered with a 5 mg and 10
mg dosing per day and finally administered with 10 mg Namenda twice
daily. Using this approved dosing regimen, a therapeutically
effective steady state serum concentration may be achieved within
about thirty days following the onset of therapy. Using a sustained
release formulation (at a constant daily dose of 22.5 mg, for
example), a therapeutically effective steady state concentration
may be achieved substantially sooner, without using a dose
escalating regimen. Such concentration is predicted to be achieved
within 13 days of the onset of therapy. Furthermore, the slope
during each absorption period for the sustained release formulation
is less (i.e. not as steep) as the slope for Namenda. Accordingly,
the dC/dt of the sustained release formulation is reduced relative
to the immediate release formulation even though the dose
administered is larger than for the immediate release formulation.
Based on this model, a sustained release formulation of memantine
may be administered to a subject in an amount that is approximately
the full strength dose (or that effectively reaches a
therapeutically effective dose) from the onset of therapy and
throughout the duration of treatment. Accordingly, a dose
escalation would not be required. Similarly, the controlled release
methods described herein may be employed to reduce the dC/dT for
other NMDAr antagonists or ACheIs enabling the administration of
the combinations without the requirement for dose escalation.
[0099] Treatment of a subject with the combination may be monitored
using methods known in the art. The efficacy of treatment using the
combination is preferably evaluated by examining the subject's
symptoms in a quantitative way, e.g., by noting a decrease in the
frequency of adverse symptoms, behaviors, or attacks, or an
increase in the time for sustained worsening of symptoms. In a
successful treatment, the subject's status will have improved
(i.e., frequency of relapses will have decreased, or the time to
sustained progression will have increased).
[0100] The invention will be illustrated in the following
non-limiting examples.
Example 1
In Vivo Method for Determining Optimal Steady-State Concentration
Ratio (C.sub.ratio,ss)
[0101] A dose ranging study is performed using, for example, the
dementia model (APP23 mouse model described by Van Dam et al. (See
Psychopharmacology 2005, 180(1):177-190), or the Tg2576 model
described by Dong et al (Psychopharmacology 2005, 181(1):145-152).
An isobolic experiment ensues in which the drugs are combined in
fractions of their EDXXs to add up to ED100 (e.g., ED50:ED50 or
ED25:ED75). The plot of the data is constructed. The experiment
points that lie below the straight line between the ED50 points on
the graph are indicative of synergy, points on the line are
indicative of additive effects, and points above the line are
indicative of 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 of validated animal models.
Example 2
Combinations of an NMDAr Antagonist and an ACheI
[0102] Representative combination ranges and ratios are provided
below for compositions of the invention. The ranges given in Table
3 are based on the formulation strategies described herein.
TABLE-US-00003 TABLE 3 Adult Dosage and Ratios for Combination
Therapy AcheI Quantity, mg/day/ACheI:NMDA Ratio Range) NMDA drug
Donepezil/ Rivastigmine/ Galantmine/ Tacrine/ mg/day ARICEPT .RTM.
EXELON .RTM. REMINYL .RTM. COGNEX .RTM. Huperzine-A Metrifonate
Memantine/ 1-20 1-24 3-48 8-160 0.02-0.8 8-80 2.5-80 (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 0.02-0.8 8-80 50-400 (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 0.02-0.8 8-80 50-200 (0.005-0.4)
(0.005-0.48) (0.015-0.96) (0.04-3.2) (0.0001-0.016) (0.04-1.6)
Example 3
Release Profile of Memantine and Galantamine
[0103] Release proportions are shown in Table 4 below for a
combination of memantine and galantamine. The cumulative fraction
is the amount of drug substance released from the formulation
matrix to the serum or gut environment (e.g., U.S. Pat. No.
4,839,177) or as measured with a USP II Paddle system using water
as the dissolution medium.
TABLE-US-00004 TABLE 4 Release profile of memantine and donepezil
MEMANTINE GALANTAMINE T1/2 = 60 hrs T1/2 = 7 hrs Time cum. fraction
A cum. fraction B 1 0.2 0.2 2 0.3 0.3 4 0.4 0.4 8 0.5 0.5 12 0.6
0.6 16 0.7 0.7 20 0.8 0.8 24 0.9 1.0
Example 4
Tablet Containing a Combination of Memantine and Galantamine
[0104] An extended release dosage form for administration of
memantine and galantamine is prepared as three individual
compartments. Three individual compressed tablets are prepared,
each having a different release profile, are encapsulated into a
gelatin capsule which is then closed and sealed. The components of
the three tablets are as follows.
TABLE-US-00005 TABLE 5 Immediate Release Dosage form Component
Amount TABLET 1 (immediate release): Function per tablet Memantine
Active agent 0 mg Galantamine HBr Active agent 10.25 mg Dicalcium
phosphate dihydrate Diluent 26.6 mg Microcrystalline cellulose
Diluent 26.6 mg Sodium starch glycolate Disintegrant 1.2 mg
Magnesium Stearate Lubricant 0.6 mg
TABLE-US-00006 TABLE 6 Delayed Release (3-5 hours) Dosage form
Component Amount TABLET 2 (3-5 hour release): Function per tablet
Memantine Active agent 10 mg Galantamine HBr Active agent 10.25 mg
Dicalcium phosphate dihydrate Diluent 26.6 mg Microcrystalline
cellulose Diluent 26.6 mg Sodium starch glycolate Disintegrant 1.2
mg Magnesium Stearate Lubricant 0.6 mg Eudragit RS30D Delayed 4.76
mg release Talc Coating 3.3 mg component Triethyl citrate Coating
0.95 mg component
TABLE-US-00007 TABLE 7 Delayed Release (7-10 hours) Dosage form
Component TABLET 3 (Release delayed Amount 7-10 hours): Function
per tablet Memantine Active agent 12.5 mg Galantamine HBr Active
agent 5.125 mg Dicalcium phosphate dihydrate Diluent 26.6 mg
Microcrystalline cellulose Diluent 26.6 mg Sodium starch glycolate
Disintegrant 1.2 mg Magnesium Stearate Lubricant 0.6 mg Eudragit
RS30D Delayed 6.5 mg release Talc Coating 4.4 mg component Triethyl
citrate Coating 1.27 mg component
[0105] The tablets are prepared by wet granulation of the
individual drug particles and other core components as may be done
using a fluid-bed granulator, or are prepared by direct compression
of the admixture of components. Tablet 1 (Table 5) is an immediate
release dosage form, releasing the active agents within 1-2 hours
following administration. It contains no memantine to avoid the
dC/dT effects of the current dosage forms. Tablets 2 (Table 6) and
3 (Table 7) are coated with the delayed release coating material as
may be carried out using conventional coating techniques such as
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, fillers, coatings,
and the like.
[0106] Oral administration of the capsule to a patient will result
in a release profile having three pulses, with initial release of
galantamine from the first tablet being substantially immediate,
release of the memantine and galantamine from the second tablet
occurring 3-5 hours following administration, and release of the
memantine and galantamine from the third tablet occurring 7-10
hours following administration.
Example 5
Pellets Containing Memantine or Donepezil
[0107] Memantine HCl (or Donepezil HCl) containing pellets were
prepared by wet massing. Memantine HCl (or Donepezil HCl) was
weighed and sieved through a No. 20 screen into the bowl of low
shear planetary mixer. To this, microcrystalline cellulose was
weighed and added through No. 20 screen and blended with Memantine
HCl (or Donepezil HCl) using a spatula, then in a planetary mixer
on low speed. Eudragit NE 400, accurately weighed was incrementally
added to the powder blend, allowing sufficient time between
additions for complete distribution. To avoid accumulation at the
bottom and to loosen the material, the bottom was periodically
scraped. Purified water was blended into the mixture in 10 mL
increments (the first of which was used to rinse the beaker
containing Eudragit NE 40D) until a uniform blend appropriate for
extrusion was obtained. 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-US-00008 TABLE 8 Pellets containing Memantine HCl Percent Wt.
solid Target Wt. Actual Wt. in per Batch per Batch per Batch
Component Supplier Formula.sup.1 (grams) (g) (g) Memantine 20.0%
50.0 50.0 50.00 HCl Eudragit Degussa 30.0% 75.0 187.5 187.50 NE 40D
Micro- FMC 50.0% 125.0 125.0 125.00 crystalline Corp Cellulose
(Avicel PH 101) Purified N/A N/A 50.0 10.0 Water TOTAL 100.0% 250.0
N/A N/A .sup.1based on solid in the final product
TABLE-US-00009 TABLE 9 Pellets containing Donepezil HCl Percent Wt.
solid Target Wt. Actual Wt. in per Batch per Batch per Batch
Component Supplier Formula.sup.1 (grams) (g) (g) Donepezil 20.0%
40.0 40.0 39.98 HCl Eudragit Degussa 30.0% 60.0 150.0 150.05 NE 40D
Micro- FMC 50.0% 100.0 100.0 100.00 crystalline Corp Cellulose
(Avicel PH 101) Purified N/A N/A 50.0 10.0 Water TOTAL 100.0% 200.0
N/A N/A .sup.1based on solid in the final product
Example 6
Memantine HCl/Donepezil HCl Formulations
[0108] Formulations of Sustained Release (SR) Memantine HCl (or
Donepezil HCl), fast and medium, were obtained by applying a
subcoat of Opadry (2% final pellet weight) followed by a functional
coating of Surelease (15% dispersion prepared from 25% Surelease)
to 20% Memantine HCl (or Donepezil HCl) pellets.
[0109] Formulations of Sustained Release (SR) Memantine HCl (or
Donepezil HCl), slow, were obtained by applying a subcoat of Opadry
(10% final bead weight), functional coating of plasticized Eudragit
RS (35% final pellet weight) and triethylcitrate (plasticizer, 10%
of the functional coating) to 20% Memantine HCl (or Donepezil HCl)
pellets.
TABLE-US-00010 TABLE 10 Memantine SR Products SR Memantine SR
Memantine SR Memantine Pellets Pellets Pellets Product (Fast)
(Medium) (Slow) "Label 0.164 Blend of 40% 0.100 Claim" "Fast" and
60% (mg "Slow" active/ mg pellets) Sample 134.6 136.2 207.9 208.9
weight (mg pellets) 16 hr 23.41 23.44 17.97 18.24 "Assay" Value (mg
released) "Assay" 0.174 0.172 0.0864 0.0873 Value (mg active/ mg
pellets) Average 0.173 0.0869 Assay Value (mg active/mg pellets)
Amount of 130.0 52.0 155.4 259.0 pellets for 22.5 mg dose (mg)
TABLE-US-00011 TABLE 11 Donepezil Immediate Release (IR) Product
Product IR Donepezil HCl "Label Claim" (mg active/mg granulation)
0.0357 Sample weight (mg pellets) 140.6 143.7 "Assay" Value (mg
released) 4.25 4.28 "Assay" Value (mg active/mg granulation) 0.0302
0.0298 Average Assay Value (mg active/mg gran) 0.030 Amount of
granulation for 5 mg dose (mg) 166.7
TABLE-US-00012 TABLE 12 Donepezil SR Product Product SR Donepezil
SR Donepezil HCl Pellets HCl Pellets SR Donepezil HCl (Fast)
(Medium) Pellets (Slow) "Label Claim" (mg 0.180 0.166 0.156
active/mg pellets) Sample weight (mg 113.8 113.9 135.6 135.5 128.8
128.3 pellets) 16 hr "Assay" Value 20.03 20.00 23.26 23.46 19.27
19.86 (mg released) "Assay" Value (mg 0.176 0.176 0.172 0.173 0.150
0.155 active/mg pellets) Average Assay Value 0.176 0.172 0.152 (mg
active/mg pellets) Amount of pellets for 5 mg 28.4 29.0 32.8 dose
(mg)
Example 7
Dosage Formulation of Memantine-Donepezil Combination
[0110] Various combinations of memantine and donepezil were
prepared by filling the respective pellets in hard gelatin capsules
as shown in Table 13. The separately prepared pellets provide the
flexibility of making ratios of memantine to donepezil pellets
ranging from 0.1:100 to 100:0.1, more preferably from 1:100 to
100:1, most preferably 1:10 to 10:1.
TABLE-US-00013 TABLE 13 Memantine-Donepezil Dosage Combinations
Product Memantine Donepezil Wt. Wt. solid/dosage solid/dosage Unit
(in mg) Formulation Unit (in mg) Formulation NPI-6170 130.0 SR
(Fast) 166.7 IR NPI-6270 52.0 SR (Fast) 166.7 IR 155.4 SR (Slow)
NPI-6370 259.0 SR (Slow) 166.7 IR NPI-6171 130.0 SR (Fsst) 28.4 SR
(Fast) NPI-6271 52.0 SR (Fast) 28.4 SR (Fast) 155.4 SR (Slow)
NPI-6371 259.0 SR (Slow) 28.4 SR (Fast) NPI-6172 130.0 SR (Fast)
29.0 SR (medium) NPI-6272 52.0 SR (Fast) 29.0 SR (medium) 155.4 SR
(Slow) NPI-6372 259.0 SR (Slow) 29.0 SR (medium) NPI-6173 130.0 SR
(Fast) 32.8 SR (Slow) NPI-6273 52.0 SR (Fast) 32.8 SR (Slow) 155.4
SR (Slow) NPI-6373 259.0 SR (Slow) 32.8 SR (Slow) SR = Sustained
Release, IR = Immediate Release
Example 8
Dissolution Profiles
[0111] The dissolution profiles of the various memantine-donepezil
combinations (as shown in Example 7) were obtained from USP II
(paddle) dissolution system at 50 rpm, at a temperature of
37.0.+-.0.5.degree. C., using water as the medium (FIGS. 2A-2C,
3A-3C, 4A-4C and 5A-5C).
[0112] For the dissolution analysis, 10 mL dissolution solutions of
memantine and donepezil were diluted with 3 mL of 0.1% formic acid.
Standards of memantine or donepezil were also prepared and diluted
with 3 mL of 0.1% formic acid. A 1 mL aliquot of the diluted
solution or standard was transferred into an HPLC vial. A 10 .mu.L
aliquot of the solution or standard was injected onto the LC/MS/MS
for analysis. A C18 reversed phase column (Phenomenex, Luna 5.mu.,
Phenyl-Hexyl 50.times.2 mm) was used for analysis. Memantine and
donepezil were separated from endogenous interfering substances and
subsequently eluted from the HPLC column by a mobile phase of 33%
acetonitrile, 33% methanol and 34% formic acid for mass
quantification. A mass spectrometer set at mass-to-charge ratios
(m/z) of 180.51>162.70 and 380.14>288.18 was used to detect
and quantify memantine and donepezil, respectively. Data were
processed and calculated by an automated data acquisition system
(Analyst 1.2, Applied Biosystems, Foster City, Calif.).
Example 9
Release Profiles of IR and SR Memantine-Donepezil Formulations
[0113] The in vivo release profiles were obtained using the
Gastro-Plus software package v.4.0.2 (FIGS. 6A-6E, 7). Exemplary
human PK release profiles are shown in FIG. 7. The release profiles
and pharmacokinetic properties for a controlled release combination
product made according to 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 manufacturers' recommendation (5 mg memantine q.d.,
incremented on a weekly basis to 5 mg BID, 10 mg in the morning and
5 mg in the evening, and 10 mg memantine b.i.d. thereafter; 5 mg
donepezil q.d. for two weeks, increasing to 10 mg donepezil q.d.
thereafter). For the SR formulation NPI-6272, the 22.5 mg memantine
and 10 mg donepezil are provided in a controlled release oral
delivery formulation releasing the active agents as shown in FIG.
4B. The SR product dC/dT is considerably lower than the IR form for
a similar dose for both memantine and donepezil. As measured, the
dC/dT for memantine at 22.5 mg is comparable to that for a 5 mg IR
dosage form. Thus, the SR formulations provide a more gradual
increase in the drug during each patient dose.
[0114] In addition to achieving the desired release profile, this
combination formulation will exhibit a preferred decrease
Cmax/Cmean, even with a higher dose of the NMDAr antagonist and
ACheI, thus the present invention may provide greater doses for
increased therapeutic effect without escalation that might
otherwise be required. Furthermore, the increased dosing allows
less frequent administration of the therapeutic agents.
Example 10
A Patch Providing Extended Release of Memantine and
Rivastigmine
[0115] As described above, extended release formulations of an
NMDAr antagonist are formulated for topical administration.
Memantine transdermal patch formulations are prepared as described,
for example, in U.S. Pat. Nos. 6,770,295 and 6,746,689.
[0116] For the preparation of a drug-in-adhesive acrylate, 5 g of
memantine and 1 g of rivastigmine are dissolved in 10 g of ethanol
and this mixture is added to 20 g of Durotak 387-2287 (National
Starch & Chemical, U.S.A.). The drug gel is coated onto a
backing membrane (Scotchpak 1012; 3M Corp., U.S.A.) using a coating
equipment (e.g., RK Print Coat Instr. Ltd, Type KCC 202 control
coater). The wet layer thickness is 400 p.m. The laminate is dried
for 20 minutes at room temperature and then for 30 minutes at
40.degree. C. A polyester release liner is laminated onto the dried
drug gel. The sheet is cut into patches and stored at 2-8.degree.
C. until use (packed in pouches). The concentration of memantine in
the patches ranges between 5.6 and 8 mg/cm.sup.2, while
rivastigmine ranges between 1.1 and 1.6 mg/cm.sup.2. The nearly
continuous infusion of the components provides a much more
consistent Cratio over time maximizing the additive or synergistic
effects of the combinations of the present invention to achieve the
optimal therapeutic effects.
Example 11
Multiple Dose Safety Study in Alzheimer's Patients with an Extended
Release Memantine, Extended Release Donepezil Combination
[0117] A study to determine safety and pharmacokinetics of an
extended release combination formulation of memantine and donepezil
is described below. The study results are expected to assess the
frequency of adverse events as well as evaluate the pharmacokinetic
parameters at higher doses.
TABLE-US-00014 Purpose To determine the safety and pharmacokinetics
of repeated doses of drug. Dosage: Based on previous single
ascending dose (SAD) study, either e.g. 22.5 mg memantine SR + 4 mg
donepezil SR, 45 mg memantine SR + 4 mg donepezil SR, or 45 mg
memantine SR + 8 mg donepezil SR, QD for 30 days Concurrent
memantine IR or memantine IR plus donepezil IR Controls (both dosed
as per manufacturers' labels) Route: Oral Subject Males or females
diagnosed with dementia of the Population: Alzheimer's type. (Age
range 50-80?) Structure: 4 arm Study Sites: TBD Blinding: Patients
blinded Method of Random with equal number of males and females in
Subject each group and equal age distributions within Assignment:
groups Total Sample 24 Subjects 6 per dosing arm Size: Primary None
Efficacy Endpoint: Adverse Monitored at least twice daily for
behavioral, Events: cardiovascular, and gastrointestinal effects
reported for high doses of memantine or donepezil (including
dizziness, headache, confusion, constipation, hypertension,
coughing, nausea, diarrhea, vomiting). Blood By canula through
first day of study period then Collection 2-4 times daily for rest
of study Analysis Assays to measure memantine, donepezil, and
potentially other physiological parameters, adverse events
Example 12
Treatment of Alzheimer's Patients with an Extended Release
Memantine, Extended Release Donepezil Combination
[0118] A study to determine effectiveness of two extended release
combination formulations of memantine and donepezil is described
below. The study results are expected to establish a more rapid
onset of efficacy without increase in adverse effects (confirming
tolerability of a non-dose escalating dosing regimen (i.e.,
administration of substantially identical doses of memantine and
donepezil throughout the term of dosing)).
TABLE-US-00015 Purpose To determine the efficacy of combination
therapy, non-dose escalated Study 22.5 mg memantine SR + 4 mg
donepezil SR, 45 mg Dosages: memantine SR + 4 mg donepezil SR
Concurrent memantine IR (Namenda) or memantine IR plus Controls
donepezil IR (Aricept) both per manufacturers' dosing labels (as of
2004). Route: Oral Subject Males or females diagnosed with dementia
of the Population: Alzheimer's type. (Age range 50-80) Structure: 4
arm Study Sites: Multi-center Blinding: Patients blinded Method of
Random with equal number of males and females in Subject each group
and equal age distributions within Assignment: groups Total Sample
400 subjects, 100 per arm Size: Primary Improvement of ADAS-Cog,
SIBIC, HAM-D in or Efficacy neuropsychiatric index at 7, 14, 21,
42, 63, 84 Endpoint: days. Efficacy Monitored twice per week for
first 4 weeks, then Monitoring: weekly thereafter. Adverse
Monitored at least twice daily for behavioral, Events:
cardiovascular and gastrointestinal effects reported for high doses
of memantine or donepezil (including dizziness, headache,
confusion, constipation, hypertension, coughing, nausea, diarrhea,
vomiting). Blood By canula at the following time points:
Collection: Day 1: 0, 4, 8, 12 hours Days 2, 4, 6, 8, 10, 12, 14,
17, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 pre-dose trough
Analysis: Efficacy, adverse events, and laboratory assays measuring
study drugs.
* * * * *