PHARMACEUTICAL COMPOSITIONS OF MEMANTINE
Cross-Reference to Related Applications
[0001] This application claims the benefit of U.S. Provisional Application Nos.
61/683,875, filed August 16, 2012; and 61/833,348, filed June 10, 2013; both of which are
herein incorporated by reference in their entirety.
Field of the Invention
[0002] The present invention relates to oral dosage forms comprising Memantine or a
pharmaceutically acceptable salt thereof, pharmaceutical formulations comprising the oral
dosage forms, and methods for treating comprising the oral dosage forms and formulations.
Background of the Invention
[0003] Memantine is reportedly an orally active NMDA receptor antagonist. The reported
IUPAC name for memantine hydrochloride is 3,5-dimethyladamantan-l-amine
hydrochloride. Memantine HC1 has the structure,
[0004] Memantine HCI is currently marketed by Forest in the form of film coated tablets
under the trade name NAMENDA®. In Europe, memantine hydrochloride is marketed by
Merz (AXURA®) and Lundbeck (EBIXA®). Memantine 10 mg twice daily is the FDAapproved
regimen for the treatment of moderate to severe Alzheimer's disease.
[0005] NAMENDA XR™ (memantine hydrochloride) was approved by the U.S. Food
and Drug Administration for the treatment of moderate to severe dementia of the Alzheimer's
type. NAMENDA XR is a 28 mg once-daily extended-release formulation of NAMENDA.
[0006] Immediate release pharmaceutical formulations comprising memantine are
described in various publications including, inter alia, US 2006/198884 and US 2010/028427.
[0007] Modified release pharmaceutical formulations comprising memantine are
described in various publications including, inter alia, US 5,382,601, US 6,194,000, US
7,619,007, US 8,039,009 US 8,168,209, US 2007/065512 and US 2010/266684.
[0008] Alzheimer's disease is a progressive, degenerative brain disease. As the disease
progresses, patients and caregivers face increasing problems with medication adherence.
Given Alzheimer's relentlessly progressive nature, newer and more effective therapies for
Alzheimer's disease are needed.
Summary of the Invention
[0009] The present invention provides modified release solid oral dosage forms
comprising a distinguishably high amount of memantine or a pharmaceutically acceptable
salt thereof while avoiding undesirable side effects, particularly CNS side effects. The high
doses in the solid oral dosage forms of the present invention are adapted to achieve
therapeutically effective steady-state concentrations at a greater interval between dosing than
presently employed, while maintaining safety requirements and improving patient
compliance.
[0010] The present invention provides modified release solid oral dosage forms
comprising a therapeutically effective amount of memantine or a pharmaceutically acceptable
salt thereof, and at least one pharmaceutically acceptable rate controlling excipient.
[001 1] In particular, the present invention provides a modified release solid oral dosage
form comprising a therapeutically effective amount of memantine or a pharmaceutically
acceptable salt thereof, and at least one pharmaceutically acceptable rate controlling
excipient, wherein the solid oral dosage form is adapted for administering with an interval
between doses of 5 days or above 5 days to a patient in a need thereof, and wherein the solid
oral dosage form:
(a) provides an in vivo plasma profile at steady state comprising a Cmax of about 160
ng/ml or less, a Cm of more than about 30 ng/ml, and an AUCtau of more than
about 14,000 ng h/ml, and/or
(b) has a dissolution profile of: not more than 45% at 24 hours, not more than 70% at
48 hours, and not more than 80% at 55 hours.
[0012] The modified release solid oral dosage forms of the present invention provide an in
vivo plasma profile at steady state comprising Cmax of about 160 ng/ml or less, Cmi of more
than about 30 ng/ml, AUCtau of more than about 14,000 ng h/ml, and Tmax of at least about 36
hours.
[0013] The amount of memantine or a pharmaceutically acceptable salt thereof in the
modified release solid oral dosage forms of the present invention is preferably up to 200 mg.
Preferably, the amount is at least 112 mg, at least 140 mg, at least 160 mg, at least 170 mg, at
least 180 mg, or at least about 190 mg of memantine or a pharmaceutically acceptable salt
thereof. More preferably, the amount is from about 112 mg to about 200 mg, from about 140
mg to about 200 mg, from about 160, 170, 180 or 190 mg to about 200 mg. In another
preferred embodiment, the amount is from about 160 mg to about 190 mg or from about 170
mg to about 190 mg.
[0014] The present invention further provides modified release solid oral dosage forms
comprising at least about 112 mg, e.g. about 140 mg of memantine or a pharmaceutically
acceptable salt thereof, and at least one pharmaceutically acceptable rate controlling
excipient, wherein the solid oral dosage form is adapted for administering once weekly to a
patient in a need thereof, and wherein the solid oral dosage form provides an in vivo plasma
profile at steady state comprising a Cmax of about 160 ng/ml or less.
[0015] In a preferred dosage form of the invention, the memantine or pharmaceutically
acceptable salt thereof is present in both immediate release form and extended release form,
and may be in the form of coated beads. According to this aspect, of the invention, the
dosage form comprises: (i) an immediate release component comprising immediate release
memantine or a pharmaceutically acceptable salt thereof, and (ii) an extended release
component comprising extended release memantine or a pharmaceutically acceptable salt
thereof. Preferably, the immediate release component (i) is in the form of beads comprising
immediate release memantine or a pharmaceutically acceptable salt thereof, and the extended
release component (ii) is in the form beads comprising extended release memantine or a
pharmaceutically acceptable salt thereof, wherein beads comprise an extended-release coating
containing at least one rate controlling excipient, i.e. the formulation contains two
populations (IR and ER) of memantine or a pharmaceutically acceptable salt thereof. These
dosage forms may be in the form of capsules or tablets.
[0016] Alternatively, another preferred dosage form of the present invention comprises
memantine or pharmaceutically acceptable salt thereof, wherein the memantine is provided in
a matrix comprising a mucoadhesive agent. In this embodiment, the mucoadhesive agent
functions as the rate controlling excipient as well as enabling the dosage form to be retained
in the body for an extended period of time. Preferably the dosage forms are monolithic, i.e.
do not contain layers, and more preferably, the dosage form is a tablet.
[0017] The present invention provides methods for treating mild, moderate or severe
Alzheimer's dementia, or neuropathic pain, wherein the method comprises administering a
modified release solid oral dosage form or pharmaceutical formulation according to the
present invention to a patient in need thereof.
[00 18] The present invention provides modified release solid oral dosage forms or
pharmaceutical formulations according to the present invention for use in the treatment of
mild, moderate or severe Alzheimer's dementia, or neuropathic pain.
[0019] The present invention provides modified release solid oral dosage forms or
pharmaceutical formulations according to the present invention for use in the manufacture of
a medicament for treating mild, moderate or severe Alzheimer's dementia, or neuropathic
pain.
Brief Description of the Drawings
[0020] Figure 1 shows the dissolution profile of a 168 mg dose with 5%IR/95%ER (with
30% polymer) population administered once weekly (QW).
[0021] Figure 2 shows the concentration over time curve following administration of 140
mg of memantine QW with a zero order release rate. The P5 and P95 refer the 5% and 95%
confidence limits for a 28 mg QD dose.
[0022] Figure 3 shows the concentration over time curve following administration of 168
mg of memantine QW with 10IR/90(ER 30%) population compared to 28 mg QD. The P5
and P95 refer the 5% and 95% confidence limits for a 28 mg QD dose.
[0023] Figure 4 shows the concentration over time curve following administration of 168
mg of memantine QW with 5IR/95(ER 30%) population compared to 28 mg QD. The P5 and
P95 refer the 5% and 95% confidence limits for a 28 mg QD dose.
[0024] Figure 5 shows the concentration over time curve following administration of 196
mg of memantine QW with 10IR/90(ER 30%) population compared to 28 mg QD. The P5
and P95 refer the 5% and 95% confidence limits for a 28 mg QD dose.
[0025] Figure 6 shows the concentration over time curve following administration of 196
mg of memantine QW with 5IR/95(ER 30%) population compared to 28 mg QD. The P5 and
P95 refer the 5% and 95% confidence limits for a 28 mg QD dose.
Detailed Description of the Invention
[0026] Unless stated otherwise, the following terms and phrases as used herein are
intended to have the following meanings.
[0027] As used herein, the term "C" refers to the plasma/serum/blood concentration of an
active pharmaceutical ingredient, or drug, such as memantine or a pharmaceutically
acceptable salt thereof, in a biological sample, such as a patient sample (e.g., blood, plasma,
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 C includes such
concentrations measurements as the Cmi , Cmax, AUC, and Css (steady state concentration).
Typically the term C refers to the plasma, serum or blood concentration.
[0028] As used herein, the term "Cmax" refers to the maximum plasma, serum or blood
concentration of a drug, such as memantine or a pharmaceutically acceptable salt thereof, in a
biological sample reached over one dosing interval at steady state. Accordingly, Cmax is the
maximum concentration at steady state, Cmax_ss-
[0029] As used herein, the term "Cm " refers to the minimum plasma, serum or blood
concentration of a drug, such as memantine or a pharmaceutically acceptable salt thereof, in a
biological sample reached over one dosing interval at steady state.
[0030] As used herein, the term "Tmax" refers to the time required to reach the maximal
plasma, serum or blood concentration ("Cmax") of the drug, such as memantine or a
pharmaceutically acceptable salt thereof, in a particular patient sample type.
[003 1] As used herein, the term "AUC" refers to the area under the plasma, serum or
blood concentration versus time curve.
[0032] As used herein, the term "AUC tau" refers to the area under the curve for a plasma,
serum or blood concentration versus time curve of a drug, such as memantine or a
pharmaceutically acceptable salt thereof, reached by a given dose over one dosing interval at
steady state. The area under the curve is measured for a time tau at steady state, where tau is
the length of the dosing interval. The term AUC tau measures the total exposure at steady state
for the dosing interval.
[0033] As used herein, the term "immediate release" or "IR" means that the escape or
release of a drug, such as memantine or a pharmaceutically acceptable salt thereof, from a
dosage form (tablet, capsule, pellet, etc.) occurs immediately or as quickly as possible after
administration, usually in a few minutes to hours. The drug is released in a single action and
the time of action of the drug is limited.
[0034] As used herein, the term "modified release" or "MR" means that the escape or
release of a drug, such as memantine or a pharmaceutically acceptable salt thereof, from the
dosage form (tablet, capsule, pellet, etc.) has been modified so that the release rate is slower
than that in an unmodified or immediate release dosage form. Drug release takes place some
time after administration and/or for a prolonged period after administration or to a specific
target in the body. Drug release may occur over several hours or over several days in order to
maintain a therapeutically effective plasma concentration of the drug. Modified release
encompasses delayed release (release at a time other than immediately after administration),
extended release (release over a prolonged time period), sustained release (rate of drug
release is sustained over a period of time), and controlled release (rate of drug release is
controlled to get a particular drug concentration in the body) or a combination thereof.
[0035] As used herein, the term "rate controlling excipient" refers to an excipient or a
combination of excipients present in such amounts sufficient to control the release rate of the
drug in the dosage form, for example to reduce the dose-dependent toxicity of a drug, such as
memantine or a pharmaceutically acceptable salt thereof. A rate controlling excipient or a
combination thereof controls the rate of drug release from a dosage form.
[0036] As used herein, the term "at least one pharmaceutically acceptable rate controlling
excipient" refers to the presence of one, two, three, four, or more rate controlling excipients
in the dosage form. Preferably, one or two rate controlling excipients are employed.
[0037] As used herein, the term "memantine" refers to memantine free base. In certain
embodiments, memantine also includes any pharmaceutically acceptable salt, such as the HC1
salt. Preferably, in any embodiments of the invention as described herein, the memantine is
in the form of its hydrochloride salt. More preferably, in any embodiment of the invention as
described herein, reference to the amounts and dosage ranges of memantine in the solid oral
dosage forms are to the amounts and dosage ranges of memantine hydrochloride.
[0038] As used herein, the term "QW" refers to a dosage form suitable for once weekly
administration.
[0039] As used herein, the term "once weekly" means administering a dose once every
seven days. The interval between administrations for once weekly is six days if
administration of a dose occurs on the same day each week.
[0040] As used herein, the term "QD" refers to a dosage form suitable for once daily
administration.
[0041] As used herein, the term "Cav" refers to average concentration during a dosing
interval. It can be calculated as (AUC(0-t au))/tau.
[0042] As used herein, the term "DFL" refers to degree of fluctuation. It can be calculated
as 100*(C x-Cmi l)/Cav.
[0043] As used herein, reference to a total weight of a dosage form refers to the total
weight of a tablet (excluding any non functional coating such as cosmetic coating), and in the
case of a capsule, refers to the total weight of the capsule contents, excluding the weight of
the capsule itself.
[0044] As used herein, unless otherwise indicated, references to percentages refer to
weight percent.
[0045] Capsule sizes refer to standard sizes known to those skilled in the art. For
example, a capsule size of -00- refers to a capsule with a volume of from about 0.9 ml to
about 1 ml, typically about 0.95 ml; a capsule size of -0- refers to a capsule with a volume of
from about 0.6 ml to about 0.7 ml, typically about 0.68 ml; and a capsule size of -1- refers to
a capsule with a volume of from about 0.4 ml to about 0.6 ml, typically about 0.5 ml.
[0046] As used herein, the term "bioavailability" refers to the rate and extent to which an
active pharmaceutical ingredient is absorbed from a dosage form and becomes available at
the site of action.
[0047] The present invention provides modified release solid oral dosage forms
comprising a therapeutically effective amount of memantine or a pharmaceutically acceptable
salt thereof, and at least one pharmaceutically acceptable rate controlling excipient, wherein
the solid oral dosage forms are adapted for administering with an interval between doses of 5
days, or more e.g. 6-8 days, preferably 6, 7 or 8 days and more preferably 6 days, to a patient
in a need thereof, and wherein the solid oral dosage forms provide an in vivo plasma profile at
steady state comprising a Cmax of about 160 ng/ml or less, a Cmi of more than about 30
ng/ml, and an AUCtau of more than about 14,000 ng h/ml. For example, it will be appreciated
that an interval of 6 days between doses would enable the drug to be administered weekly to
the patient, on the same day of the week.
[0048] The present invention further provides modified release solid oral dosage forms
comprising at least about 112 mg, e.g., about 140 mg of memantine or a pharmaceutically
acceptable salt thereof, and at least one pharmaceutically acceptable rate controlling
excipient, wherein the solid oral dosage forms are adapted for administering once weekly to a
patient in a need thereof, and wherein the solid oral dosage form provides an in vivo plasma
profile at steady state comprising a Cmax of about 160 ng/ml or less.
[0049] The present invention further provides modified release solid oral dosage forms
comprising at least about 112 mg, or at least about 140 mg of memantine or a
pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable rate
controlling excipient, wherein the solid oral dosage form is adapted for administering once
weekly, most preferably on the same day every week, to a patient in a need thereof, and
wherein the solid oral dosage form provides an in vivo plasma profile at steady state
comprising a Cmax of about 160 ng/ml or less, a Cmi of more than about 30 ng/ml, Tmax of at
least about 36 hours, and an AUCtau of more than about 14,000 ng h/ml.
[0050] In one embodiment, the present invention provides a modified release solid oral
dosage form comprising at least about 112 mg, preferably at least about 140 mg, and more
preferably at least about 160 mg of memantine or a pharmaceutically acceptable salt of
memantine, and at least one pharmaceutically acceptable rate controlling excipient, wherein
the solid oral dosage form provides an in vivo plasma profile at steady state comprising a
Cmax of about 160 ng/ml or less.
[005 1] The amount of memantine or a pharmaceutically acceptable salt thereof in the
modified release solid oral dosage forms of the present invention is up to 200 mg. Preferably,
the amount is of at least 112 mg, at least 140 mg, at least 160 mg, at least 170 mg, at least 180
mg, or at least about 190 mg of memantine or a pharmaceutically acceptable salt thereof.
More preferably, the amount is from about 112 mg to about 200 mg, from about 140 mg to
about 200 mg, from about 160, 170, 180 or 190 mg to about 200 mg, for example, 168mg,
176mg, 182mg, 188mg and 196mg.
[0052] A pharmacokinetic parameter or combinations of such parameters indicate the
bioavailability of an active pharmaceutical ingredient, such as, memantine or a
pharmaceutically acceptable salt thereof. Such pharmacokinetic parameters are known to the
person skilled in the art. Examples of such parameters include: T 2 (half-life), Cmi , Cmax,
AUC, AUC tau , Tmax, and Css (steady state concentration).
[0053] In preferred embodiments, the modified release solid oral dosage forms of the
present invention comprise the following in vivo plasma profile concentrations, at steady
state: a Cmax of about 145 ng/ml or less or about 135 ng/ml or less, more preferably about 125
ng/ml or less; a Cmi of more than about 30 ng/ml, more preferably greater than about 40
ng/ml, and even more preferably a Cmi of more than about 50 ng/ml.
[0054] In a specific embodiment of the present invention, the modified release solid oral
dosage forms provide an in vivo plasma profile at steady state comprising an AUC tau of more
than about 14,000 ng h/ml, preferably more than about 15,000 ng h/ml, most preferably, more
than about 16,000 ng h/ml. Optionally, the modified release solid oral dosage forms provide
an in vivo plasma profile at steady state comprising an AUC tau of more than about 17,000 ng
h/ml.
[0055] The solid oral dosage forms of the present invention comprise the following in vivo
plasma profile concentrations at steady state: a Cmax from about 100 ng/ml to about 170
ng/ml, preferably from about 100 ng/ml to about 140 ng/ml or from about 100 ng/ml to about
130 ng/ml; a Cmi from about 20 ng/ml to about 125 ng/ml, preferably from about 30 ng/ml to
about 125 ng/ml or from about 40 ng/ml to about 125 ng/ml or from about 50 ng/ml to about
125 ng/ml; and an AUC tau from about 10,000 ng h/ml to about 25,000 ng h/ml, preferably
from about 12,000 ng h/ml to about 25,000 ng h/ml or from about 14,000 ng h/ml to about
25,000 ng h/ml or from about 15,000 ng h/ml to about 25,000 ng h/ml or from about 16,000
ng h/ml to about 25,000 ng h/ml or from about 17,000 ng h/ml to about 25,000 ng h/ml.
[0056] The solid oral dosage forms of the present invention solve the problem of
providing a unit dose of memantine for low frequency administration i.e., more than 5 day
intervals (preferably 6 day intervals, i.e. preferably once weekly that also provides a
therapeutically effective amount of memantine and with minimal side effects, preferably not
more than the side effects associated with Namenda XR®(28mg, capsule), most preferably
not more than the side effects associated with of Namenda® (lOmg, tablet) when these are
administered at the recommended dosages (for example once daily for Namenda XR® 28 mg
and twice per day for Namenda® 10 mg). Compositions for low frequency administration, for
example, once weekly, require higher amounts of memantine. Compositions with higher
amounts of memantine would increase undesirable side effects and toxicity because the
memantine would be released and transported into the bodily fluids immediately or over a
very short period of time after administration. In addition, a therapeutically effective amount
of memantine would not be present in the bodily fluids during the prolonged interval between
administrations. In order to achieve a desirable combination of pharmacokinetic parameters,
higher dose memantine compositions are formulated to control the release of memantine so
that a therapeutically effective amount is available in the bodily fluids.
[0057] Currently available formulations for memantine, such as those for NAMENDA®
and Namenda XR™ which are intended for daily administration, are not suitable for lower
frequency administration, for example, for once weekly administration. For example, these
formulations do not contain the required amount of memantine or the sufficiently prolonged
release characteristics to enable a longer interval between doses. For example, varying the
amount of memantine in such formulations in order to provide an acceptable Cmi to be
therapeutically effective, would also increase the Cmax to a level that is toxic. Lowering the
ma to non-toxic levels in such formulations would result in a Cmi that are too low to be
therapeutically effective throughout the interval between administrations. Even if an
acceptable Cmax and Cmin can be provided, the total exposure (AUC) to memantine during the
interval between administration would be too low so that there would be too little memantine
in the systemic circulation to achieve appropriate therapeutic activity.
[0058] The dosage forms of the present invention solve the problems of providing a
desirable combination of pharmacokinetic parameters by modifying the release of memantine
by increasing the dose of memantine and including excipient that control the release of
memantine. The rate controlling excipients reduce the rate of release of memantine so that
the total amount of memantine is not released all at once, but is prolonged over the interval
between administrations.
[0059] However, the inventors have found that prolonging the release of memantine
creates the problem that too little memantine is released early during the interval between
administration. As a result, a therapeutically effective amount is not achieved. By including
a portion of the total memantine in immediate release form and another portion in extended
release form in accordance with the present invention, the inventors have found that it is
possible to achieve a sustained release formulation for low frequency administration whilst
enabling a therapeutically effective amount of memantine to be achieved soon after
administration. The amount of memantine in the immediate release form is a sufficient
amount that does not produce a spike in the plasma concentration versus time curve, that is,
does not produce a too high Cmax that increases toxicity.
[0060] The dosage forms of the present invention as described above may further include
one or more mucoadhesives to slow the passage of the dosage form through the body e.g.
gastrointestinal tract, so that the dosage form remains in the body sufficiently long for all the
memantine to be released in the body.
[0061] According to a second aspect of the present invention, a sustained release
formulation for low frequency administration can also be produced by formulating
memantine as a mucoadhesive dosage form, e.g. as a matrix formulation which releases
memantine over an extended period while remaining in the gastrointestinal tract. These
dosage forms include at least one mucoadhesive excipient providing the required sustained
release characteristics to enable low frequency administration as described above. The
mucoadhesive dosage forms according to this aspect of the present invention are preferably
monolithic, i.e. do not comprise layers.
[0062] Treatments of acute and chronic neurological and neuropsychiatric diseases have
the problem of treatment compliance because the patient or caretaker may forget to
administer the medication. This is especially applicable to the treatment of Alzheimer's
disease. The modified release dosage forms of the present invention have the advantage that
they can be administered less often and therefore improves compliance.
[0063] Accordingly, the oral dosage forms of the present invention provide advantages
over other known oral dosages. For example, the oral dosage forms of the present invention
can be administered less frequently yet still provide a therapeutic effective amount of
memantine and steady state blood levels. The oral dosage forms of the present invention
provide reduced pill burden for patients who resist treatment, increase convenience for
caregivers who can only check the patient on a weekly basis leading to greater compliance
and less burden on family members. In addition, the oral dosage forms of the present
invention can be taken with or without food, and for patients who cannot swallow capsules,
the oral dosage forms can be sprinkled on applesauce or other food and the entire contents
consumed.
[0064] The dosage forms described herein are formulated such that the memantine or a
pharmaceutically acceptable salt thereof present in the dosage form has an in vitro dissolution
profile that is slower than that for an immediate release (IR) formulation as well as slower
than that for the 28 mg of memantine extended release NAMENDA XR™ (inactive
ingredient are sugar spheres, polyvinylpyrrolidone, hypromellose, talc, polyethylene glycol,
ethylcellulose, ammonium hydroxide, oleic acid, and medium chain triglycerides in hard
gelatin capsules). The dosage forms of the present invention may contain immediate release,
sustained or extended release or delayed release components, or combinations thereof.
Preferably, the dosage forms of the present invention comprise a combination of an
immediate release component and a sustained or extended release component.
[0065] The memantine or a pharmaceutically acceptable salt thereof, in the solid oral
dosage forms of the first aspect of the present invention can be provided in a modified release
form such as controlled or extended release (ER) form, with an immediate release (IR)
component. Thus, the solid oral dosage forms of this aspect of the present invention
comprise both an IR (immediate release) component and an ER (extended release)
component. In a preferred embodiment, the solid oral dosage form of the invention contains
at least 90% of the memantine or a pharmaceutically acceptable salt thereof in an extended
release form and the remaining memantine or pharmaceutically acceptable salt thereof in an
immediate release form. Another specific embodiment of the invention is a modified release
solid oral dosage form, wherein at least 95% of the memantine or a pharmaceutically
acceptable salt thereof is in an extended release form and the remaining memantine or
pharmaceutically acceptable salt thereof is in an immediate release form.
[0066] In one preferred embodiment, the solid oral dosage forms of the present invention
comprise about 5% to about 20% of the memantine or a pharmaceutically acceptable salt
thereof in immediate release form and about 80% to about 95% of the memantine or a
pharmaceutically acceptable salt thereof in extended release form. In a more preferred
embodiment, the solid oral dosage forms of the present invention comprise about 5% to about
10%, about 5% to about 15% of the memantine or a pharmaceutically acceptable salt thereof
in immediate release form and about 85% to about 95%, about 90% to about 95% of the
memantine or a pharmaceutically acceptable salt thereof in extended release form.
[0067] The immediate release component of the dosage forms of the present invention can
comprise a core coated with layer containing memantine or with a pharmaceutically
acceptable salt thereof. The IR component can comprise a sugar sphere, which is coated with
a layer containing IR memantine or a pharmaceutically acceptable salt thereof. The IR
memantine layer can comprise memantine or a pharmaceutically acceptable salt thereof and a
binder (preferably hydroxypropyl methyl cellulose, preferably Methocel E-5 PR).
Alternatively, instead of a core (e.g. a sugar sphere) coated with a memantine (and optionally
a binder) layer, the IR component can be formed as a core comprising IR memantine, for
example, memantine or a pharmaceutically acceptable salt thereof, preferably in combination
with a filler (preferably microcrystalline cellulose, e.g. Avicel PH101).
[0068] The extended release component of the dosage forms of the present invention can
be prepared by coating the beads forming the immediate release component, as defined
above, with a controlled release layer. Preferably the controlled release layer comprises a
rate controlling excipient optionally with a plasticizer and/or a pore former. More preferably,
the controlled release layer comprises a rate controlling excipient together with a plasticizer.
Particularly preferred controlled release layers include: (1) at least one rate controlling
polymer (preferably ethyl cellulose, more preferably ethyl cellulose 7cPS, hydroxypropyl
methylcellulose, preferably HPMC 6 cPs, or a combination thereof) and at least one
plasticiser (preferably triethyl citrate), and (2) a polyacrylate dispersion (preferably an
aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate
such as Eudragit NE 30D) and at least one pore former and/or an anti-tacking agent
(preferably talc). The talc in the latter formulation, as well as functioning as a pore former,
may also function as an anti-tacking agent for the controlled release layer.
[0069] The controlled release excipient is preferably present in an amount of about 10 to
about 50 wt% relative to the weight of the ER memantine component in the dosage form,
more preferably about 15 to about 45 wt% and most preferably about 18 to about 38 wt%
relative to the weight of the ER memantine component in the dosage form.
[0070] Preferably the weight ratio of control release excipient(s) to plasticizer in the ER
memantine component of the dosage form ranges from about 10:1 to about 3:1, more
preferably about 8:1 to about 4:1, and most preferably about 6:1 to about 5:1.
[0071] The amount of the controlled release layer components (e.g. controlled release
polymer and plasticizer) relative to the total weight of the ER memantine component of the
dosage form is preferably from about 15 to about 50 wt%, more preferably from about 20 to
about 35 wt% and particularly from about 20 to about 30 wt%.
[0072] Preferably, the weight ratio of the controlled release excipient to memantine or
pharmaceutically acceptable salt thereof in the ER memantine component of the dosage form
is about 1 : 1 to about 1 : 5, more preferably about 1 : 1 to about 1 : 4, and particularly about
1 : 1 to about 1 : 3, especially about 1 : 1.5 to about 1 : 2.5.
[0073] Preferably the weight ratio of the controlled release layer components (e.g.
controlled release polymer and plasticizer) relative to the remaining components in the ER
memantine component of the dosage form is about 1 : 5 to about 1: 1, more preferably about
1 : 4 to about 1 : 2, and particularly about 1 : 3.8 to about 1 : 3.
[0074] Solid oral dosage forms of the present invention comprising both an IR and ER
component can be made by mixing an IR component with an ER component. For example,
dosage forms having 10% IR and 90% ER, or 5% IR and 95% ER (designated 10IR/90ER
and 5IR/95ER) can be made by mixing corresponding portions of IR and ER. The mixture
can be filled into a capsule, or compressed into a tablet. Where the dosage form is a tablet,
the IR and ER components can be mixed together, optionally with further excipients (e.g.
lubricant, filler and optionally a mucoadhesive, as defined herein - preferably magnesium
stearate, lactose, starch, and polyethylene oxide) before being compressed into tablets.
[0075] Modified release dosage forms can be made by, but not limited to, making pellets
of different thicknesses so that the thinnest release the drug first and the thickest last,
including a slow dissolving matrix or coating, including a non-dissolving coating around a
tablet or capsule with small holes to let the drug out (by diffusion or solvation), controlling
release of the drug by diffusion through a coating or matrix or by erosion of the matrix or
coating by a process dependent on, for example, a particular condition such as the presence of
enzymes or a particular pH. Modified release dosage forms have higher amounts of the drug
than the amount present in an unmodified or immediate release dosage form.
[0076] The dissolution rate of the dosage forms of the present invention are typically of
not more than 35% at 24 hours, not more than 70% at 48 hours, or not more than 80% at 55
hours. In a preferred embodiment, the modified release solid oral dosage forms provide a
dissolution rate of not more than 70% at 50 hours, or a dissolution rate of more than 70% at
72 hours or a dissolution rate of more than about 80%> at about 96 hours. As used herein,
dissolution rates are measured using a USP type 1 (basket) dissolution system at 100 rpm,
900ml, 0.2% NaCl in 0.1N HC1 pH=1.2, at a temperature of 37±0.5° C.
[0077] Desirably, a specific dosage form described herein has an in vitro profile that is
substantially identical to the dissolution profile shown in Figure 1. For example, the modified
release solid oral dosage forms provide a dissolution rate of:
(i) about 15% to about 25% after 10 hours, about 35% to about 45% after 24
hours and about 55%> to about 65%> after 48 hours
(ii) preferably about 30%> to about 40%> after 20 hours, about 50%> to about 60%>
after 40 hours and about 65%> to about 80%> after 60 hours,
(iii) more preferably about 10% to about 20% after 5 hours, about 40% to about
50% after 30 hours and about 65% > to about 75% > after 60 hours.
[0078] In preferred embodiments, the modified release solid oral dosage forms of the
present invention provide in vivo plasma profiles at steady state which are further
characterized by a memantine or a pharmaceutically acceptable salt thereof Tmax of at least
about 36 hours, more preferably a memantine or a pharmaceutically acceptable salt thereof
ma of about 36 to 96 hours. Most preferably, the memantine or a pharmaceutically
acceptable salt thereof Tmax is of about 48 to 72 hours.
[0079] The modified release solid oral dosage forms of the present invention can be
adapted for administration with an interval between doses of above 5 days (preferably, of 6
days) to a patient in a need thereof. Preferably, the dosage form is adapted for administration
once every 7 days. In a preferred embodiment, the interval between administrations is 5
days, 6 days or 7 days. For example, administration once every 7 days (i.e. with an interval
of 6 days) enables administration of the drug on the same day of the week, thus facilitating
patient compliance.
[0080] The solid oral dosage forms of the present invention include all pharmaceutically
acceptable salts of memantine. Preferably, the memantine is in its hydrochloride salt form or
in its sulfate salt form. More preferably the memantine is in the form of memantine
hydrochloride.
[0081] The modified release solid oral dosage form of the present invention is suitable for
administration in a one unit dosage form. Oral dosage forms for the purpose of the present
invention include capsules, tablets, pellets, granules, powders and combinations thereof.
Preferably, oral dosage forms of the present invention are in the form of capsules, tablets,
pellets or granules. Particularly preferred are oral dosage forms in the form of capsules or
tablets. Optionally, if the dosage form is a capsule, the memantine or a pharmaceutically
acceptable salt thereof is provided in the form of coated beads. Typically, if the modified
release solid oral dosage form is in a capsule form, the dosage form comprises from about
15% to about 25% by weight of memantine or a pharmaceutically acceptable salt of
memantine. Capsule size of the present invention is preferably smaller than -00-, more
preferably, -0- or smaller, most preferably -1- or smaller.
[0082] Typically, if the modified release solid oral dosage form is in a tablet form, the
dosage form comprises from about 10%> to about 20%> by weight (preferably about 10%> to
about 18 wt%), or about 15% to about 35% by weight of memantine or a pharmaceutically
acceptable salt of memantine. In other embodiments, the modified release solid oral dosage
form comprises memantine or the pharmaceutically acceptable salt thereof from about 15% to
about 25% by weight of the total dosage form. Typically for dosage forms of the present
invention in capsule form, the dosage form comprises from about 20%> to about 60%>,
preferably from about 25% to about 50%, and more preferably from about 28% to about
50%, by weight of memantine or a pharmaceutically acceptable salt of memantine.
[0083] The pharmaceutically acceptable rate controlling excipient of the modified release
solid oral dosage form according to the first aspect of the present invention can be a
polymeric material or combinations of one or more polymeric materials. Preferably, the
polymeric material is selected from a group consisting of: polyethylene oxide, ethyl cellulose
(e.g., preferably ethylcellulose having a viscosity of about 4 to about 10 cPs, particularly
about 7 cPs), hydroxypropyl methylcellulose (HPMC, preferably having a viscosity of about
4 to about 9 cPs, more preferably about 5 to about 8 cPS, and most preferably about 5 to
about 7 cPs and particularly about 6 cPs), polyvinyl alcohol (PVA, preferably polyvinyl
alcohol 205, 523, 540, 203S, 205S, 523S and 540S), polyvinylpyrrolidone (PVP, preferably
Povidone K 12, Povidone K 17, Povidone K 25, Povidone K 30 and Povidone K 90, more
preferably Povidone K 25, Povidone K 30 and Povidone K 90). These polymeric materials
are preferably combined with a plasticizer to form the controlled (extended) release layer.
Suitable plasticizers include those selected from the group consisting of: polyethylene glycol,
triethyl citrate, tributyl citrate, glycerine, dibutyl sebacate, triacetin and diethylphthalate.
Other suitable rate controlling excipients include polyacrylates, polymethacrylates, ethyl
acrylate-methyl methacrylate copolymers (such as Eudragit RS or NE), hydroxypropyl
cellulose (HPC, preferably having a viscosity of about 4 to about 9 cPs, more preferably
about 5 to about 8 cPS, and most preferably about 5 to about 7 cPs) and a mixture thereof. A
particularly preferred rate controlling excipient is a copolymer of ethyl acrylate and methyl
methacrylate, for example an aqueous dispersion of a neutral copolymer based on ethyl
acrylate and methyl methacrylate (e.g. Eudragit, preferably Eudragit NE30D, which is a 30%
aqueous dispersion of the above).
[0084] Preferably, the pharmaceutically acceptable rate controlling excipient is selected
from a group consisting of: polyethylene oxide, ethyl cellulose (e.g. ethylcellulose having a
viscosity of about 4 to about 10 cPs), hydroxypropyl methylcellulose (HPMC), ethyl acrylatemethyl
methacrylate copolymers (Eudragit®), and a mixture thereof. In certain preferred
embodiments, the rate controlling excipient is a combination of at least two polymeric
materials. For example, in some preferred embodiments, the rate controlling excipient is a
combination of ethyl cellulose (preferably having a viscosity of about 4 to about 10 cPs, and
more preferably about 6 to about 8 cPs), and hydroxylpropylmethyl cellulose (preferably
having a viscosity of about 4 to about 9 cPs, more preferably about 5 to about 8 cPS, and
most preferably about 5 to about 7 cPs). In some preferred embodiments, the
pharmaceutically acceptable rate controlling excipient is a combination of polyethylene oxide
and Eudragit , a combination of ethyl cellulose (having a viscosity of about 4 to about 10
cPs), hydroxypropyl methylcellulose (having a viscosity of about 4 to about 9 cPs) and
triethyl citrate, or a combination of polyethylene oxide.
[0085] The total amount of the rate controlling excipient, i.e., the polymeric material and
other rate controlling excipient, is about 8% to about 60% of the total weight of the dosage
form. In a preferred embodiment, the total amount of the rate controlling excipient is from
about 8% to about 50% of the total weight of the dosage form, or from about 8% to about
40% of the total weight of the dosage form, or from about 8% to about 30% of the total
weight of the dosage form, or from about 8% to about 20%> of the total weight of the dosage
form, or from about 50% to about 60% of the total weight of the dosage form. Preferable,
total amount of the rate controlling excipient is about 19% to about 40% of the total weight of
the dosage form, or from about 19%> to about 30%> of the total weight of the dosage form, or
from about 19% to about 25% of the total weight of the dosage form, or from about 30% to
about 60% of the total weight of the dosage form, or from about 30% to about 50% of the
total weight of the dosage form, or from about 30% to about 40% of the total weight of the
dosage form, or from about 40% to about 60% of the total weight of the dosage form, or from
about 50% to about 60% of the total weight of the dosage form. Preferably, in the ER
memantine component, the memantine or pharmaceutically acceptable salt thereof is present
in an amount of about 8 to about 60 wt%, preferably about 10 to about 50 wt%, relative to the
ER component. The amount of the rate controlling polymer is about 60% to about 100%,
about 70 to about 90%, about 70% to about 80% of the weight of the ER component of the
dosage form.
[0086] The amount of the rate controlling polymer in the controlled release layer, i.e. not
including extragranular part is about 60%> to about 100%, about 70 to about 90%>, about 70%>
to about 80% of the total weight of the controlled release layer.
[0087] In the ER component of the dosage form, the amount of the plasticizer is about
10% to about 20%, about 12% to about 16%, about 14% to about 15% of the weight of the
controlled release layer (e.g. controlled release polymer and plasticizer).
[0088] In a preferred embodiment, the ratio of the amount by weight of memantine or a
pharmaceutically acceptable salt thereof to the total amount by weight of the rate controlling
excipient in the ER component of the dosage form is from about 1:0.3 to about 1:5.0.
Preferably, the ratio is from about 1:0.4 to about 1:0.8, or from about 1:2.5 to about 1:4.0.
[0089] Preferably, in the dosage forms of the present invention having an immediate
release memantine component and an extended release memantine component, the ER
memantine component preferably comprises about 30% to about 40%, preferably about 35%
by weight of the other parts of the ER memantine component (e.g. core and drug layer) . Such
dosage forms are designated, for example, as 10IR/90 (ER 30%) or lOIR/90 (ER 35%).
[0090] The solid oral dosage forms of the first aspect of the present invention can further
comprise one or more mucoadhesives as described below.
[0091] As indicated above, a second aspect of the invention provides a solid oral dosage
form which comprises memantine or a pharmaceutically acceptable salt thereof in an
extended release form in which the memantine or pharmaceutically acceptable salt thereof is
formulated with at least one mucoadhesive. Thus, in the dosage forms of this aspect of the
present invention, the mucoadhesive functions as both the rate controlling excipient and
further enables the dosage form to be retained in the body for an extended time. In particular,
the memantine or a pharmaceutically acceptable salt thereof is present in a matrix containing
a mucoadhesive. The modified release solid oral dosage forms of the present invention can
comprise at least one mucoadhesive with or without an immediate release component or an
extended release component as described above. For example, the dosage forms of the
present invention can comprise at least one mucoadhesive with only an extended release
component, or only immediate release component without controlled release layer.
[0092] Alternatively according to a second aspect of the present invention, the memantine
may be formulated in a matrix with a mucoadhesive. Preferably the dosage form of this
aspect of the present invention is in the form of a monolithic tablet.
[0093] Mucoadhesives slow the passage of the dosage form through the body so that the
dosage form is inside the body during the interval between administrations so that memantine
or a pharmaceutically acceptable salt thereof is released in the body. Mucoadhesives are
substances that adhere to a biological tissue for an extended period of time by interfacial
forces. The biological tissue is a mucous membrane. Mucoadhesion occur when a
mucoadhesive contacts and adheres to a membrane by wetting of the mucoadhesive surface
or from the swelling of the mucoadhesive. Further adhesion occurs when the mucoadhesive
penetrates into the crevice of the membrane surface or when the chains of the mucoadhesive
interact with those of the mucus on the membrane. Suitable mucoadhesive are polymers that
are water soluble or water insoluble hydrophilic polymers, polymers that have swellable
networks, hydrogels, and polymers with groups that can cross-link with other polymers or
with a mucous membrane. For example, mucoadhesives can be polyethylene oxide when
used in the matrix with the drug.
[0094] In the second aspect of the present invention, where the memantine or
pharmaceutically acceptable salt thereof is formulated as a matrix with at least one
mucoadhesive, the mucoadhesive may be present from about 20% to about 60%>, about 30%>
to about 60%, about 40%> to about 60%>, and particularly about 50 to about 60 wt%>, of the
total weight of the dosage form.
[0095] The ratio of the amount by weight of memantine or the pharmaceutically
acceptable salt thereof to the amount by weight of the mucoadhesive is from about 1:2 to
about 1:4, preferably about 1:4.
[0096] In preferred embodiments of the formulations of the present invention wherein the
dosage form comprises an IR memantine component and an ER memantine component
(wherein the ER component contains memantine coated with an ER layer), polyethylene
oxide may be included as an extra-granular layer in the ER component, i.e., not in the core or
in the designated controlled release layer. When polyethylene oxide is in the extra-granular
layer, it functions as a rate controlling excipient, i.e., the release rate is controlled by both the
rate controlling excipients in the controlled release layer and in an extra-granular layer.
[0097] The modified release solid oral dosage forms of the present invention may further
comprise one or more pharmaceutically acceptable carriers or excipients.
[0098] Examples of pharmaceutical acceptable excipients are fillers, binders, glidants,
lubricants and bases.
[0099] Suitable binders include, for example, cellulose polymers (e.g.
hydroxypropylmethyl cellulose, hydroxypropylcellulose, methylcellulose and hydroxyethyl
cellulose and METHOCEL™), polyvinylpyrrolidone, polyvinyl alcohol, and mixtures
thereof. The amount of binder is about 10% to about 20% of the total weight of the dosage
form.
[00100] Suitable fillers (diluents) include, for example, microcrystalline cellulose (e.g.
Avicel), lactose, sorbitol, dextrose, sucrose, mannitol, dibasic calcium phosphate, starch, and
mixtures thereof. The amount of the filler is about 15% to about 60% of the total weight of
the dosage form, or about 15% to about 50% of the total weight of the dosage form, or about
15% to about 30% of the total weight of the dosage form.
[00101] Suitable glidants include, for example colloidal silicon dioxide, magnesium
stearate, talc, sodium stearyl fumarate, magnesium carbonate, starch and mixtures thereof.
Preferably the glidant is colloidal silicon dioxide. The amount of the glidant is about 0.1% to
about 5% of the total weight of the dosage form, about 0.1% to about 3% of the total weight
of the dosage form or about 0.1% to about 1% of the total weight of the dosage form.
[00102] Suitable lubricants include, for example, sodium stearyl fumarate, stearic acid,
magnesium stearate, calcium stearate, zinc stearate, talc, glyceryl behenate, and mixtures
thereof. Preferably, the lubricant is magnesium stearate, talc, and mixtures thereof. The
amount of the lubricant is about 0.5% to about 5% of the total weight of the dosage form, or
about 2% to about 4% of the total weight of the dosage form.
[00103] Suitable bases include sodium carbonate.
[00104] Tablets in accordance with this invention can be prepared by conventional mixing,
comminution, and tabletting techniques that are well known in the pharmaceutical
formulations industry. The modified release tablet, for example, may be obtained by direct
compression by punches and dies fitted to a rotary tabletting press, ejection or compression
molding, granulation followed by compression, or forming a paste and extruding the paste
into a mold or cutting the extrudate into short lengths. Preferably, the process used for
preparing tablets is direct compression of the blend.
[00105] Compression can be accomplished using conventional equipment. Typically, the
blend of active ingredients and excipients is passed through a roller apparatus for compaction.
However, other means for compacting the API mixture, e.g., compaction into slugs (or
"slugging"), may be used.
[00106] To achieve the desired modified release rates, the modified release dosage form
may be formulated as a polymeric coating or matrix.
[00107] In other embodiments, the present invention provides an oral dosage form
comprising a plurality of beads, each bead comprising a core comprising an active ingredient
and, in the case of the ER memantine component, a rate controlling excipient layer. The
modified release beads in accordance with the present invention may be prepared initially as
IR beads, with a core, layer of active ingredient, and a seal (i.e. a cosmetic) coating.
Alternatively, the IR beads may be formed of a core containing memantine and optionally a
filler. The IR beads may then be coated with a modified release component in the form of a
rate controlling excipient dispersion and preferably an additional topcoat of polymer (i.e. a
cosmetic coat) for aesthetic, handling or stability purposes. The final dosage form, such as a
capsule, may contain a different amount of beads depending on the desired dose of the
composition.
[00108] The beads or bead mixtures may be used, for example, in suspensions, filled into
capsules or compressed into tablets. One or more types of modified release beads can be
mixed together and encapsulated.
[00109] In one embodiment of the invention, the beads are formulated into capsules with
the use of an encapsulation machine.
[001 10] Alternatively, if the dosage form is to be a tablet, the IR and ER beads may
optionally be mixed with further excipients (e.g. lubricant, filler and a mucoadhesive, as
defined herein - preferably magnesium stearate, lactose, starch, and polyethylene oxide)
[001 11] The present invention further provides a method for treating a disorder selected
from the group consisting of mild, moderate and severe Alzheimer's dementia, and
neuropathic pain, wherein the method comprises administering a therapeutically effective
amount of a modified release solid oral dosage form of the invention.
[001 12] The present invention provides modified release solid oral dosage form or
pharmaceutical formulation according to the present invention for use in the treatment of
mild, moderate or severe Alzheimer's dementia, or neuropathic pain.
[001 13] The present invention provides modified release solid oral dosage forms or
pharmaceutical formulations according to the present invention for use in the manufacture of
a medicament for treating mild, moderate or severe Alzheimer's dementia, or neuropathic
pain.
[001 14] The present invention is illustrated by the following examples, which are not
intended to limit the scope of the invention. It will be appreciated that various modifications
are within the spirit and scope of the invention.
Examples
[001 15] The pharmacokinetic model used in the examples below can be represented as
follows.
PK Model For ER Simulation
Example 1: Exposure Following Administration Of 140 Mg Of Memantine Once
Weekly.
[001 16] Plasma concentration over time was obtained by convoluting actual (in vitro)
dissolution data with observed plasma concentration versus time data. The obtained Plasma
concentration over time was simulated using a Monte Carlo simulation with a 1-compartment
model in NONMEM v 7.1 for 1000 subjects. Phoenix WinNonLin (6.1) was used to perform
non-compartmental analysis on the simulated plasma concentration over time.
Pharmacokinetic parameters were calculated from the simulated data and are listed below for
exposures for once weekly administration of 140 mg of memantine for 7 doses.
[001 17] The concentration over time curve following 140 mg of memantine QW
administration with a zero order release rate compared to 28 mg QD is shown in Figure 2.
Example 2 : Exposure Following Administration Of Less Than 140 Mg Of Memantine
Once Weekly.
[00 118] Following the procedure in Example 1, pharmacokinetic parameters were
calculated for once weekly administration of 28 mg, 56 mg, 84 mg and 112 mg of
memantine. The parameters are listed below for exposures to 7 doses.
Example 3 : Exposure Following Administration Of More Than 140 Mg Of Memantine
Once Weekly.
[001 19] Following the procedure in Example 1, pharmacokinetic parameters were
calculated for once weekly administration of 168 mg and 196 mg of memantine. The
parameters are listed below for exposures to 7 doses.
Example 4 : Exposure Following Administration Of 168 Mg Of Memantine Once
Weekly.
[00120] Plasma concentration over time was obtained by convoluting actual (in vitro)
dissolution data with observed plasma concentration versus time data. The obtained Plasma
concentration over time was simulated using a Monte Carlo simulation with a 2-compartment
model in NONMEM v 7.1 for 1000 subjects. Phoenix WinNonLin (6.1) was used to perform
non-compartmental analysis on the simulated plasma concentration over time.
Pharmacokinetic parameters were calculated from the simulated data and are listed below for
exposures for once weekly administration of 168 mg of memantine QW for 11 doses.
[00121] The concentration over time curve following administration of 168 mg of
memantine QW with 10 IR / 90 (ER 30%) population compared to 28 mg QD is shown in
Figure 3.
Example 5: Exposure Following Administration Of 168 Mg Of Memantine Once
Weekly.
[00122] Following the procedure in Example 4, pharmacokinetic parameters were
calculated for once weekly administration of 168 mg of memantine with 5IR/95(ER 30%)
population. The parameters are listed below for exposures to 11 doses.
[00123] The concentration over time curve following administration of 168 mg of
memantine QW with 5IR/95(ER 30%) population compared to 28 mg QD is shown in Figure
4.
Example 6: Exposure Following Administration Of 196 Mg Of Memantine Once
Weekly.
[00124] Following the procedure in Example 4, pharmacokinetic parameters were
calculated for once weekly administration of 196 mg of memantine with 10IR/90(ER 30%)
population. The parameters are listed below for exposures to 11 doses.
[00125] The concentration over time curve following administration of 196 mg of
memantine QW with 10IR/90(ER 30%) population compared to 28 mg QD is shown in
Figure 5.
Example 7: Exposure Following Administration Of 196 Mg Of Memantine Once
Weekly.
[00126] Following the procedure in Example 4, pharmacokinetic parameters were
calculated for once weekly administration of 196 mg of memantine with 5IR/95(ER 30%)
population. The parameters are listed below for exposures to for 11 doses.
[00127] The concentration over time curve following administration of 196 mg of
memantine QW with 5IR/95(ER 30%) population compared to 28 mg QD is shown in Figure
6.
Example 8: Exposure Following Administration Of 176 Mg, 182 Mg And 188 Mg Of
Memantine Once Weekly.
[00128] Following the procedure in Example 4, pharmacokinetic parameters were
calculated for once weekly administration of 176 mg, 182 mg and 188 mg of memantine with
10IR/90(ER 30%) and 5IR/ 5(ER 30%) populations. The parameters are listed below for
exposures to 11 doses.
10IR/90(ER 30%) population
5IR/95(ER 30%) population
[00129] The following Examples 9, 10, 11, 13, 14, 15 and 17 illustrate the extended release
component of the dosage forms according to the first aspect of the present invention, i.e.
wherein the memantine is coated with an extended or controlled release coating. It will be
appreciated that the final dosage form can be prepared by mixing the extended release
component with an immediate release component, in the appropriate proportions as required,
and either encapsulated, e.g. as illustrated in Example 18, or mixed with tableting excipients
and compressed, e.g. as illustrated in Example 19. The immediate release components can be
made in the same way as the extended release component, but omitting the controlled release
layer.
[00130] Examples 12 and 16 illustrate dosage forms according to the second aspect of the
present invention, i.e. wherein the memantine is provided in a matrix with a mucoadhesive.
Example 9: Coated Spheres (Extrusion/Spheronized) Filled Into Capsules.
[0013 1] Memantine Hydrochloride and microcrystalline cellulose are mixed into a blend
with a high shear mixer. The blend is further granulated with gradual addition of water for a
few minutes. The resulting wet mass is extruded through a 0.6-1 .0 mm screen, and then
spheronized in a spheronizer to create spheroids. The spheroids are dried in a Fluid bed Glatt
Dryer till the moisture content is less than about 2%, and optionally sieved to provide
particles in a selected size range. The resulting spheroids are coated in a Wurster-equipped
Fluidized Bed coater (bottom-spray technology) with Control release layer.
Formulation of Beads by Extrusion
Component Weight (mg)
Core
Microcrystalline cellulose (Avicel PH 101) 210.0
Memantine HC1 140.0
Control Release Layer
Ethylcellulose 7 cPs 73.5
Hydroxypropylmethyl cellulose 6 cPs 15.75
Triethyl citrate 15.75
Total weight 455.0
Example 10: Coated Spheres (DL Coating) Filled Into Capsules.
[00132] Sugar spheres are coated with Drug Layer (DL) containing Memantine HC1 and
HPMC as a binder dissolved in hydro alcoholic solution in a Wurster-equipped Fluidized Bed
coater (bottom-spray technology). The second Control Release coating is also performed in
Wurster-equipped Fluidized Bed coater.
Example 11: Coated Spheres (DL Coating/Extrusion) Compressed Into Tablets.
[00133] Memantine Hydrochloride and microcrystalline cellulose are mixed into a blend
with a high shear mixer. The blend is further granulated with gradual addition of water for a
few minutes. The resulting wet mass is extruded through a 0.6-1 .0 mm screen, and then
spheronized in a spheronizer to create spheroids. The spheroids are dried in a Fluid bed Glatt
Dryer till the moisture content is less than about 2%, and optionally sieved to provide
particles in a selected size range. Alternatively, Memantine HC1 pellets can be obtained by
Drug Layer (DL) coating as in Example 10. The resulting spheroids are coated in a Wursterequipped
Fluidized Bed coater (bottom-spray technology) with Control release layer. The
extended release coated beads are further mixed with a spray-dried compound consisting of
85% alpha-lactose monohydrate and 15% maize starch dry matter (StarlacTM), a non-ionic
polyethylene oxide polymer (Polyox WSR- 301) and magnesium stearate and then
compressed into tablets.
Example 12: Extended Release Matrix Tablets.
[00134] Memantine Hydrochloride, non-ionic polyethylene oxide polymer (Polyox WSR-
301), microcrystalline cellulose, Lactose, Colloidal silicon dioxide, Sodium Carbonate and
Magnesium Stearate are mixed in dry mix and then compressed into tablets. Alternatively,
this process can be performed by wet granulation when polyethylene oxide polymer (Polyox
WSR- 301) Colloidal silicon dioxide, Sodium Carbonate and Magnesium Stearate are added
as ex-granular.
Example 13: Beads by Extrusion Spheronization Having Higher Strength.
[00135] Memantine Hydrochloride and microcrystalline cellulose are mixed into a blend
with a high shear mixer. The blend is further granulated with gradual addition of water for a
few minutes. The resulting wet mass is extruded through a 0.6-1 .0 mm screen, and then
spheronized in a spheronizer to create spheroids. The spheroids are dried in a Fluid bed Glatt
Dryer till the moisture content is less than about 2%, and optionally sieved to provide
particles in a selected size range. The resulting spheroids are coated in a Wurster-equipped
Fluidized Bed coater (bottom-spray technology) with Control release layer.
Example 14: Beads by DL Technology Having Higher Strength.
For both Formulation A and Formulation B:
[00136] Sugar spheres are coated with Drug Layer (DL) containing Memantine HC1 and
HPMC as a binder dissolved in hydro alcoholic solution in a Wurster-equipped Fluidized Bed
coater (bottom-spray technology). The second Control Release coating is also performed in
Wurster-equipped Fluidized Bed coater.
Formulation of Beads by DL Coating (Formulation A)
Component Weight (mg)
Core
Sugar spheres 57.5
Drug Layer Coating
Memantine HC1 161.0
(METHOCEL E-5 PR.(HYPROMEL.USP 57.5
Control Release Layer
Ethylcellulose 7 cPs 56.03
Hydroxypropylmethyl cellulose 6 cPs 12.00
Triethyl citrate 12.00
Total weight 346.84
Formulation of Beads by DL Coating (Formulation B)
Component Weight (mg)
Core
Sugar spheres 67.85
Drug Layer Coating
Memantine HC1 190.0
(METHOCEL E-5 PR.(HYPROMEL.USP 67.85
Control Release Layer
Ethylcellulose 7 cPs 66.1 1
Hydroxypropylmethyl cellulose 6 cPs 13.80
Triethyl citrate 13.80
Total weight 409.27
Example 15: Compressed Tablets Formulation.
[00137] Memantine Hydrochloride and microcrystalline cellulose are mixed into a blend
with a high shear mixer. The blend is further granulated with gradual addition of water for a
few minutes. The resulting wet mass is extruded through a 0.6-1 .0 mm screen, and then
spheronized in a spheronizer to create spheroids. The spheroids are dried in a Fluid bed Glatt
Dryer till the moisture content is less than about 2%, and optionally sieved to provide
particles in a selected size range. Alternatively, Memantine HC1 pellets can be obtained by
Drug Layer (DL) coating as in Example 10. The resulting spheroids are coated in a Wursterequipped
Fluidized Bed coater (bottom-spray technology) with Control release layer. The
extended release coated beads are further mixed with a spray-dried compound consisting of
85% alpha-lactose monohydrate and 15% maize starch dry matter (StarlacTM), a non-ionic
polyethylene oxide polymer (Polyox WSR- 301) and magnesium stearate and then
compressed into tablets.
Formulation of Beads compressed into tablets
Component Weight (mg)
Core
Microcrystalline cellulose (Avicel PH 101) 285.6
Memantine HC1 190.0
Control Release Layer
Polyacrylate dispersion (EUDRAGIT NE 30D) 116.8
Talc extra fine 18.4
Ex-granular
Polyethylene oxide (Polyox WSR-301) 408.0
STARLAC™ 408.0
Magnesium stearate 13.6
Total weight 1442.0
Example 16: Extended Release Matrix Tablets.
[00138] Memantine Hydrochloride, non-ionic polyethylene oxide polymer (Polyox WSR-
301), microcrystalline cellulose, Lactose, Colloidal silicon dioxide, Sodium Carbonate and
Magnesium Stearate are mixed in dry mix and then compressed into tablets. Alternatively,
this process can be performed by wet granulation when polyethylene oxide polymer (Polyox
WSR- 301) Colloidal silicon dioxide, Sodium Carbonate and Magnesium Stearate are added
as ex-granular.
Example 17:
[00139] Sugar spheres are coated with Drug Layer (DL) containing Memantine HC1 and
HPMC as a binder dissolved in hydro alcoholic solution in a Wurster-equipped Fluidized Bed
coater (bottom-spray technology). The second Control Release coating is also performed in
Wurster-equipped Fluidized Bed coater. The final coated beads are then encapsulated.
Example 18: Capsule Dosage form containing IR and ER memantine components
[00140] Sugar spheres are coated with Drug Layer (DL) containing Memantine HC1 and
HPMC as a binder dissolved in hydro alcoholic solution in a Wurster-equipped Fluidized Bed
coater (bottom-spray technology). A 95% portion of the IR beads is then coated by additional
ER coating. The second Control Release coating is also performed in Wurster-equipped
Fluidized Bed coater. Both portions are then mixed and encapsulated.
Example 19: Tablet dosage form containing IR and ER memantine components
[00141] The IR and ER memantine components of Example 18 are mixed with
Polyethylene oxide (Polyox WSR-301), STARLAC™ and Magnesium stearate, and
compressed into tablets.
Example 20: Dissolution Procedure.
CLAIMS
We claim:
1. A modified release solid oral dosage form comprising a therapeutically effective
amount of memantine or a pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable rate controlling excipient, wherein the solid oral dosage
form is adapted for administering with an interval between doses of 5 days or above 5
days to a patient in a need thereof, and wherein the solid oral dosage form:
(c) provides an in vivo plasma profile at steady state comprising a Cmax of about 160
ng/ml or less, a Cmi of more than about 30 ng/ml, and an AUC tau of more than
about 14,000 ng h/ml, and/or
(d) has a dissolution profile of: not more than 45% at 24 hours, not more than 70% at
48 hours, and not more than 80% at 55 hours.
2. A modified release solid oral dosage form according to Claim 1 adapted for
administering once weekly to a patient in need thereof.
3. The modified release solid oral dosage form according to Claim 1 or Claim 2, wherein
the dosage form comprises memantine or a pharmaceutically acceptable salt thereof in
an amount of at least about 112 mg, at least about 140 mg, at least about 160 mg, at
least about 170 mg, or at least about 190 mg.
4. The modified release solid oral dosage form according to Claim 1 or Claim 2, wherein
the dosage form comprises memantine or a pharmaceutically acceptable salt thereof in
an amount of about 140 to about 190 mg, about 160 to about 190 mg, about 170 mg to
about 190 mg, or about 140 to about 200 mg, about 160 to about 200 mg, about 170 to
about 200 mg or about 190 to about 200 mg.
5. A modified release solid oral dosage form comprising at least about 112 mg, or at least
about 140 mg of memantine or a pharmaceutically acceptable salt of memantine, and at
least one pharmaceutically acceptable rate controlling excipient, wherein the solid oral
dosage form:
(a) provides an in vivo plasma profile at steady state comprising a Cmax of about 160
ng/ml or less, and/or
(b) has a dissolution profile of: not more than 45% at 24 hours, not more than 70% at
48 hours, and not more than 80% at 55 hours.
A modified release solid oral dosage form according to Claim 5 adapted for
administering once weekly to a patient in a need thereof.
A modified release solid oral dosage form according to Claim 6, and wherein the solid
oral dosage form:
(a) provides an in vivo plasma profile at steady state comprising a Cmax of about 160
ng/ml or less, a Cmi of more than about 30 ng/ml, Tmax of at least about 36, and
an AUC tau of more than about 14,000 ng h/ml, and/or
(b) has a dissolution profile of: not more than 45% at 24 hours, not more than 70% at
48 hours, and not more than 80% at 55 hours.
The modified release solid oral dosage form according to any of Claims 5, 6 or 7,
wherein the dosage form comprises memantine or a pharmaceutically acceptable salt
thereof in an amount of at least about 160 mg, at least about 170 mg, or at least about
190 mg.
The modified release solid oral dosage form according to any of Claims 5, 6, 7 or 8,
wherein the dosage form comprises memantine or a pharmaceutically acceptable salt
thereof in an amount of about 140 to about 190 mg, about 160 to about 190 mg, about
170 mg to about 190 mg, or about 140 to about 200 mg, about 160 to about 200 mg,
about 170 to about 200 mg or about 190 to about 200 mg.
0. The modified release solid oral dosage form according to any preceding claim, wherein
the dosage form comprises at least about 160 mg of memantine or a pharmaceutically
acceptable salt of memantine.
1. The modified release solid oral dosage form according to any preceding claim, wherein
the dosage form comprises at least about 170 mg of memantine or a pharmaceutically
acceptable salt thereof.
12. The modified release solid oral dosage form according to any preceding claim, wherein
the dosage form comprises at least about 190 mg of memantine or a pharmaceutically
acceptable salt of memantine.
13. The modified release solid oral dosage form according to any preceding claim, wherein
the dosage form comprises up to about 200 mg or memantine or a pharmaceutically
acceptable salt of memantine.
14. The modified release solid oral dosage form according to any preceding claim, wherein
the solid oral dosage form provides an in vivo plasma profile at steady state comprising
a Cmax of about 100 ng/ml to about 145 ng/ml, about 100 ng/ml to about 135 ng/ml, or
about 100 ng/ml to about 125 ng/ml.
15. The modified release solid oral dosage form according to any of Claims 1-13, wherein
the solid oral dosage form provides an in vivo plasma profile at steady state comprising
a Cmin of about 30 ng/ml to about 125 ng/ml, about 40 ng/ml to about 125 ng/ml, or
about 50 ng/ml to about 125 ng/ml.
16. The modified release solid oral dosage form according to any preceding claim wherein
the solid oral dosage form provides an in vivo plasma profile at steady state comprising
a Cmax of about 145 ng/ml or less or about 135 ng/ml or less.
17. The modified release solid oral dosage form according to any of Claim 1-13, wherein
the solid oral dosage form provides an in vivo plasma profile at steady state comprising
a Cmax of about 125 ng/ml or less.
18. The modified release solid oral dosage form according to any of Claims 1-13 wherein
the solid oral dosage form provides an in vivo plasma profile at steady state comprising
a Cmin of more than about 30 ng/ml.
19. The modified release solid oral dosage form according to Claim 18, wherein the solid
oral dosage form provides an in vivo plasma profile at steady state comprising a Cmi of
more than about 40 ng/ml.
20. The modified release solid oral dosage form according to Claim 19, wherein the solid
oral dosage form provides an in vivo plasma profile at steady state comprising a Cmi of
more than about 50 ng/ml.
2 1. The modified release solid oral dosage form according to any preceding claim, wherein
the solid oral dosage form provides an in vivo plasma profile at steady state comprising
an AUC tau of more than about 14,000 ng h/ml.
22. The modified release solid oral dosage form according to Claim 21, wherein the solid
oral dosage form provides an in vivo plasma profile at steady state comprising an
AU au of about 14,000 ng h/ml to about 25,000 ng h/ml.
23. The modified release solid oral dosage form according to any preceding claim, wherein
the solid oral dosage form provides an in vivo plasma profile at steady state comprising
an AUC tau of 15,000 ng h/ml or more, and preferably more than about 15,000 ng h ml.
24. The modified release solid oral dosage form according to Claim 23, wherein the solid
oral dosage form provides an in vivo plasma profile at steady state comprising an
AU au of about 15,000 ng h/ml to about 25,000 ng h/ml or about 16,000 ng h/ml to
about 25,000 ng h/ml.
25. The modified release solid oral dosage form according to any preceding claim, wherein
the solid oral dosage form provides an in vivo plasma profile at steady state comprising
an AUC tau of more than about 16,000 ng h/ml.
26. The modified release solid oral dosage form according to any preceding claim, wherein
the solid oral dosage form provides a dissolution rate of not more than 70% at 48 hours,
preferably not more than 70% at 72 hours, and more preferably wherein more than
about 80% is achieved after about 96 hours.
27. The modified release solid oral dosage form according to any of claims 1-25, wherein
the solid oral dosage form provides a dissolution profile of not more than 70% at 50
hours, not more than 75% at 60 hours, and more than about 80% after about 96 hours.
28. The modified release solid oral dosage form according to any preceding claim, wherein
the in vivo plasma profile at steady state is further characterized by a memantine Tmax of
at least about 36 hours, and preferably a memantine Tmax of about 36 to 96 hours.
29. The modified release solid oral dosage form according to any preceding claim, wherein
the in vivo plasma profile at steady state is further characterized by a memantine Tmax of
about 36 to 96 hours or about 48 to 72 hours.
30. The modified release solid oral dosage form according to any preceding claim, wherein
the dosage form is adapted for administration with an interval between doses of 5 days
or above 5 days, preferably 6 days, to a patient in a need thereof, or for administration
once every 7 days to a patient in a need thereof.
31. The modified release solid oral dosage form according to any of Claims 1-30, wherein
the pharmaceutically acceptable salt of memantine is hydrochloride salt or sulfate salt.
32. The modified release solid oral dosage form according to any of Claims 1-31, wherein
memantine is in the form of the hydrochloride salt.
33. The modified release solid oral dosage form according to any of Claims 1-32, wherein
the dosage form is a one unit dosage form.
34. The modified release solid oral dosage form according to any of Claims 1-33, wherein
the dosage form is in the form of a capsule.
35. The modified release solid oral dosage form according to Claim 34, wherein the
capsule size is -00- or smaller, -0- or smaller, or -1- or smaller.
36. The modified release solid oral dosage form according to any of Claims 1-33, wherein
the dosage form is in the form of a tablet.
37. The modified release solid oral dosage form according to any preceding claim, wherein
the memantine or pharmaceutically acceptable salt thereof is provided in the form of
coated beads.
38. The modified release solid oral dosage form according to Claim 37, wherein the
memantine or pharmaceutically acceptable salt thereof is present in both immediate
release form and extended release form.
39. The modified release solid oral dosage form according to Claim 38, wherein the dosage
form comprises:
(i) an immediate release component comprising immediate release memantine or
a pharmaceutically acceptable salt thereof, and
(ii) an extended release component comprising extended release memantine or a
pharmaceutically acceptable salt thereof.
40. The modified release solid oral dosage form according to Claim 38 or Claim 39
wherein: the immediate release component (i) is in the form of beads comprising
immediate release memantine or a pharmaceutically acceptable salt thereof, and the
extended release component (ii) is in the form beads comprising extended release
memantine or a pharmaceutically acceptable salt thereof, wherein beads comprise an
extended-release coating containing at least one rate controlling excipient.
4 1. The modified release solid oral dosage form according to Claim 39 or Claim 40,
wherein (i) comprises an inert core, preferably a sugar sphere, coated with memantine
or a pharmaceutically acceptable salt thereof, and optionally a binder.
42. The modified release solid oral dosage form according to Claim 41, wherein the binder
is selected from the group consisting of: cellulose polymers, hydroxypropylmethyl
cellulose, hydroxypropylcellulose, methylcellulose, hydroxyethyl cellulose,
polyvinylpyrrolidone, polyvinyl alcohol and mixtures thereof, and preferably wherein
the binder is hydroxypropylmethyl cellulose.
43. The modified release solid oral dosage form according to any of Claims 39-40, wherein
(i) comprises a core formed from memantine or a pharmaceutically acceptable salt
thereof, and optionally a filler.
44. The modified release solid oral dosage form according to Claim 43, wherein the filler is
selected from the group consisting of: microcrystalline cellulose, lactose, sorbitol,
dextrose, sucrose, mannitol, dibasic calcium phosphate, starch and mixtures thereof,
and preferably wherein the filler is microcrystalline cellulose.
45. The modified release solid oral dosage form according to any of Claims 40 to 44,
wherein the extended release component (ii) is prepared by coating the immediate
release beads of component (i) as defined in any of Claims 40 or 4 1 with at least one
rate controlling excipient.
46. The modified release solid oral dosage form according to any of Claims 1-45, wherein
at least 90% by weight of the memantine or a pharmaceutically acceptable salt thereof
is in extended release form.
47. The modified release solid oral dosage form according to Claim 46, wherein at least
95% by weight of the memantine or a pharmaceutically acceptable salt thereof is in
extended release form.
48. The modified release solid oral dosage form according to any of Claims 46 or 47,
wherein the remaining memantine or pharmaceutically acceptable salt thereof is in
immediate release form.
49. The modified release solid oral dosage form according to any of Claims 1-48, wherein
the rate controlling excipient is a polymeric material.
50. The modified release solid oral dosage form according to Claim 49, wherein the
polymeric material is selected from polyethylene oxide, ethyl cellulose (e.g., preferably
ethylcellulose having a viscosity of about 4 to about 10 cPs, particularly about 7 cPs),
hydroxypropyl methylcellulose (HPMC, preferably having a viscosity of about 4 to
about 9 cPs, more preferably about 5 to about 8 cPS, and most preferably about 5 to
about 7 cPs and particularly about 6 cPs), polyvinyl alcohol (PVA, preferably polyvinyl
alcohol 205, 523, 540, 203S, 205S, 523S and 540S), polyvinylpyrrolidone (PVP,
preferably Povidone K 12, Povidone K 17, Povidone K 25, Povidone K 30 and
Povidone K 90, more preferably Povidone K 25, Povidone K 30 and Povidone K 90),
polyacrylates, polymethacrylates, ethyl acrylate-methyl methacrylate copolymers
(preferably Eudragit RS or NE), hydroxypropyl cellulose (HPC, preferably having a
viscosity of about 4 to about 9 cPs, more preferably about 5 to about 8 cPS, and most
preferably about 5 to about 7 cPs) and a mixture thereof.
51. The modified release solid oral dosage form according to Claim 49 or Claim 50,
wherein the rate controlling excipient is a combination of two polymeric materials,
preferably wherein rate controlling excipient is a combination of ethyl cellulose
(preferably having a viscosity of about 5 to about 9 cPs, and more preferably about 6 to
about 8 cPs), and hydroxylpropylmethyl cellulose (preferably having a viscosity of
about 4 to about 9 cPs, more preferably about 5 to about 8 cPS, and most preferably
about 5 to about 7 cPs).
52. The modified release solid oral dosage form according to any of Claims 49-5 1, further
comprising a plasticizer.
53. The modified release solid oral dosage form according to Claim 52, wherein the
plasticizer is selected from a group consisting of: polyethylene glycol, triethyl citrate,
tributyl citrate, glycerin, dibutyl sebacate, triacetin, diethylphthalate and mixtures
thereof, and preferably wherein the plasticizer is triethyl citrate.
54. The modified release solid oral dosage form according to any of Claims 1-50, wherein
the rate controlling excipient is an ethyl acrylate-methyl methacrylate copolymer
(preferably Eudragit, and more preferably Eudragit NE30D, which is a 30% aqueous
dispersion of a copolymer of ethyl acrylate and methyl methacrylate).
55. The modified release solid oral dosage form according to Claim 54, further comprising
talc.
56. The modified release solid oral dosage form according to any of Claims 1-55, wherein
the total amount of the rate controlling excipients to the total weight of the dosage form
is from about 8% to about 60%; from about 8% to about 50%; from about 8% to about
40%; from about 8% to about 30%; from about 8% to about 20%; from about 50% to
about 60%>; from about 19%> to about 40%>; from about 19%> to about 30%>; from about
19% to about 25%; from about 30%> to about 60%>; from about 30%> to about 50%>; from
about 30% to about 40%>; from about 40%> to about 60%>; or from about 50%> to about
60%.
57. The modified release solid oral dosage form according to any of Claims 39-56, wherein
the amount of rate controlling excipient is about 10 to about 50 wt%, preferably about
10 to about 45 wt% and more preferably about 15 to about 40 wt% of the extended
release component of the dosage form.
58. The modified release solid oral dosage form according to any of Claims 39-57, wherein
the extended release layer is about 10 to about 40 wt%>, preferably about 15 to about 35
wt% and more preferably about 20 to about 30 wt% of the extended release component
of the dosage form.
59. The modified release solid oral dosage form according to any of Claims 39-58, wherein
the amount of memantine or a pharmaceutically acceptable salt of memantine in the
extended release component is about 10 to about 60 wt%>, preferably about 10 to about
55 wt% and more preferably about 10 to about 50 wt% relative to the weight of the
extended release component.
60. The modified release solid oral dosage form according to any of Claims 39-59, wherein
in the extended release component, the weight ratio of the rate controlling excipient(s)
to memantine or the pharmaceutically acceptable salt thereof is from about 1:0.2 to
about 1:5.0, preferably from about 1:0.3 to about 1:3.0, and more preferably about 1:0.3
to about 1:2.8.
6 1. The modified release solid oral dosage form according to any of Claims 52-60, wherein
in the extended release component, the weight ratio of the plasticizer to rate controlling
excipient(s) is from about 1:2 to about 1:10, preferably from about 1:3 to about 1:8, and
more preferably about 1:4 to about 1:7.
62. The modified release solid oral dosage form according to any of Claims 37-61 in the
form of a capsule.
63. The modified release solid oral dosage form according to Claim 62, wherein the
immediate release component is as defined in Claim 41, and the extended release
component (ii) comprises a sugar sphere coated with memantine or a pharmaceutically
acceptable salt thereof and optionally a binder, which extended release component is
further coated with at least one rate controlling excipient and optionally a plasticizer.
64. The modified release solid oral dosage form according to any of Claims 37-61 in the
form of a compressed tablet.
65. The modified release solid oral dosage form according to Claim 63 wherein the
immediate release component (i) is as defined in Claim 43, and the extended release
component (ii) comprises a core formed from memantine or a pharmaceutically
acceptable salt thereof, which extended release component is coated with at least one
rate controlling excipient.
66. The modified release solid oral dosage form according to any of Claims 64 and 65,
further comprising a lubricant, preferably wherein the lubricant is selected from the
group consisting of: sodium stearyl fumarate, stearic acid, magnesium stearate, calcium
stearate, zinc stearate, talc, glyceryl behenate and mixtures thereof, and more preferably
magnesium stearate.
67. The modified release solid oral dosage form according to any of Claims 1-66 further
comprising a mucoadhesive.
68. The modified release solid oral dosage form according to Claim 67, wherein the
mucoadhesive is selected from the group consisting of water soluble or water insoluble
hydrophilic polymers, polymers that have swellable networks, hydrogels, and polymers
with groups that can cross-link with other polymers or with a mucous membrane, and
preferably wherein the mucoadhesive is polyethylene oxide.
69. The modified release solid oral dosage form according to Claim 67 or Claim 68,
wherein the mucoadhesive is present in an amount of about 5 to about 60 wt%, about 5
to about 50 wt%, about 5 to about 40wt%, about 5 to about 20 wt%, about 5 to about 15
wt% and most preferably about 5 to about 10 wt%, of the total weight of the dosage
form.
70. The modified release solid oral dosage form according to any of Claims 67 to 69,
wherein the weight ratio memantine or the pharmaceutically acceptable salt thereof to
the mucoadhesive is from about 1:2 to about 1:4, preferably about 1:4.
7 1. The modified release solid oral dosage form according to any of Claims 1-36 wherein
the memantine or pharmaceutically acceptable salt thereof is provided in a matrix
comprising a mucoadhesive agent.
72. The modified release solid oral dosage form according to Claim 71, wherein the
mucoadhesive is selected from the group consisting of water soluble or water insoluble
hydrophilic polymers, polymers that have swellable networks, hydrogels, and polymers
with groups that can cross-link with other polymers or with a mucous membrane, and
preferably wherein the mucoadhesive is polyethylene oxide.
73. The modified solid oral dosage form according to Claim 7 1 or Claim 72, wherein the
amount of mucoadhesive in the dosage form is from about 20 to about 80 wt%, about
30 to about 70 wt%, and more preferably about 40 to about 60 wt%, and even more
preferably about 50 to about 60 wt%.
74. The modified solid oral dosage form according to any of Claims 71-73, wherein the
amount of memantine or pharmaceutically acceptable salt thereof in the dosage form is
from about 5 to about 40 wt%, preferably about 5 to about 30 wt%, and more
preferably about 10 to about 20 wt%.
75. The modified solid oral dosage form according to any of Claims 7 1 to 74, wherein the
ratio of the memantine or pharmaceutically acceptable salt thereof to mucoadhesive in
the dosage form is from about 1:1 to about 1:10, preferably from about 1:2 to about 1:7,
and more preferably from about 1:2 to about 1:5.
76. The modified solid oral dosage form according to any of Claims 7 1 to 75, further
comprising at least one excipient selected from a filler, a glidant, a lubricant, and a
base.
77. The modified solid oral dosage form according to Claim 76 further comprising a filler,
glidant, lubricant and a base.
78. The modified solid oral dosage form according to any of Claims 76 or Claim 77,
wherein the filler is selected for the group consisting of: microcrystalline cellulose (e.g.
Avicel), lactose, sorbitol, dextrose, sucrose, mannitol, dibasic calcium phosphate,
starch, and mixtures thereof, preferably microcrystalline cellulose or lactose, or
mixtures thereof.
79. The modified solid oral dosage form according to any of Claims 76-78, wherein the
glidant is selected from the group consisting of: colloidal silicon dioxide, magnesium
stearate, talc, sodium stearyl fumarate, magnesium carbonate, starch and mixtures
thereof, and preferably colloidal silicon dioxide.
80. The modified solid oral dosage form according to any of Claims 76-79, wherein the
lubricant is selected from the group consisting of: sodium stearyl fumarate, stearic acid,
magnesium stearate, calcium stearate, zinc stearate, talc, glyceryl behenate, and
mixtures thereof, and preferably magnesium stearate.
81. The modified solid oral dosage form according to any of Claims 76-80, wherein the
base is sodium carbonate.
82. The modified solid oral dosage form according to any of Claims 76-81, in the form of a
monolithic tablet.
83. A method for treating mild, moderate or severe Alzheimer's dementia, or neuropathic
pain, wherein the method comprises administering a modified release solid oral dosage
form or pharmaceutical formulation of any of Claims 1-82 to a patient in need thereof.
84. A modified release solid oral dosage form or pharmaceutical formulation according to
any of Claims 1-82 for use in the treatment of mild, moderate or severe Alzheimer's
dementia, or neuropathic pain.
85. The modified release solid oral dosage form, pharmaceutical formulation or method
according to any of Claims 1-84, wherein the dosage form has a dissolution profile of:
not more than 45% at 24 hours, not more than 70% at 48 hours, and not more than 80%
at 55 hours.
86. The modified release solid oral dosage form, pharmaceutical formulation or method
according to any of Claims 1-84, wherein the dosage form has a dissolution rate of not
more than 35% at 24 hours, not more than 70% at 48 hours, or not more than 80% at 55
hours.
87. The modified release solid oral dosage form, pharmaceutical formulation or method
according to any of Claims 1-84, wherein the dosage form has a dissolution rate of not
more than 70% at 50 hours, or a dissolution rate of more than 70% at 72 hours or a
dissolution rate of more than about 80% at about 96 hours.
88. The modified release solid oral dosage form, pharmaceutical formulation or method
according to any of Claims 1-87, wherein the dosage form comprise the following in
vivo plasma profile concentrations at steady state: a Cmax from about 100 ng/ml to about
145 ng/ml, about 100 ng/ml to about 140 ng/ml, about 100 ng/ml to about 135 ng/ml,
about 100 ng/ml to about 130 ng/ml, about 100 ng/ml to about 125 ng/ml, about 100
ng/ml to about 170 ng/ml, preferably from about 100 ng/ml to about 140 ng/ml or from
about 100 ng/ml to about 130 ng/ml; a Cmi from about 20 ng/ml to about 125 ng/ml,
preferably from about 30 ng/ml to about 125 ng/ml or from about 40 ng/ml to about
125 ng/ml or from about 50 ng/ml to about 125 ng/ml; and an AUCtau from about
10,000 ng h/ml to about 25,000 ng h/ml, preferably from about 14,000 ng h/ml to about
25,000 ng h/ml or from about 15,000 ng h/ml to about 25,000 ng h/ml or from about
16,000 ng h/ml to about 25,000 ng h/ml or from about 17,000 ng h/ml to about 25,000
ng h/ml.
89. The modified release solid oral dosage form, pharmaceutical formulation or method
according to any of Claims 1-88, wherein the amount of memantine or a
pharmaceutically acceptable salt thereof in the dosage form is up to 200 mg, at least
112 mg, at least 140 mg, at least 160 mg, at least 170 mg, at least 180 mg, at least about
190 mg, from about 112 mg to about 200 mg, from about 140 mg to about 200 mg, or
from about 160, 170, 180 or 190 mg to about 200 mg.
90. The modified release solid oral dosage form, pharmaceutical formulation or method
according to any of Claims 1-89, wherein the pharmaceutically acceptable salt of
memantine is hydrochloride salt or sulfate salt.
91. The modified release solid oral dosage form, pharmaceutical formulation or method
according to any of Claims 1-90, wherein the memantine is in the form of its
hydrochloride salt.