U.S. patent application number 16/852158 was filed with the patent office on 2020-08-27 for modified release formulations of memantine oral dosage forms.
The applicant listed for this patent is Forest Laboratories Holdings Limited. Invention is credited to Wattanaporn Abramowitz, Mahendra G. Dedhiya, Shashank Mahashabde, Antonia Periclou, Niranjan Rao, Suneel K. Rastogi.
Application Number | 20200268685 16/852158 |
Document ID | / |
Family ID | 1000004824530 |
Filed Date | 2020-08-27 |
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United States Patent
Application |
20200268685 |
Kind Code |
A1 |
Rastogi; Suneel K. ; et
al. |
August 27, 2020 |
MODIFIED RELEASE FORMULATIONS OF MEMANTINE ORAL DOSAGE FORMS
Abstract
The present invention provides pharmaceutical compositions given
once daily containing at least one therapeutically active
ingredient selected from the group consisting of memantine and a
pharmaceutically acceptable salt of memantine, and a
pharmaceutically acceptable polymeric matrix carrier. The dosage
forms of the invention sustain the release of the therapeutically
active agent from about 4 to about 24 hours when said dosage form
is exposed to aqueous solutions. following entry of said form into
a use environment, wherein said dosage form has a dissolution rate
of more than about 80% after passage of about 6 hours to about 12
hours following said entry into said use environment.
Inventors: |
Rastogi; Suneel K.; (Island
Park, NY) ; Rao; Niranjan; (Belle Mead, NJ) ;
Periclou; Antonia; (Jersey City, NJ) ; Abramowitz;
Wattanaporn; (West Windsor, NJ) ; Dedhiya; Mahendra
G.; (Pomona, NY) ; Mahashabde; Shashank;
(Kendall Park, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Forest Laboratories Holdings Limited |
Hamilton |
|
BM |
|
|
Family ID: |
1000004824530 |
Appl. No.: |
16/852158 |
Filed: |
April 17, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15215456 |
Jul 20, 2016 |
10660868 |
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16852158 |
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14607526 |
Jan 28, 2015 |
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15215456 |
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14228944 |
Mar 28, 2014 |
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14607526 |
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13948438 |
Jul 23, 2013 |
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14228944 |
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13618014 |
Sep 14, 2012 |
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13948438 |
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13233381 |
Sep 15, 2011 |
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13618014 |
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11155330 |
Jun 16, 2005 |
8039009 |
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13233381 |
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60581242 |
Jun 17, 2004 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2009 20130101;
A61K 9/2013 20130101; A61K 9/2018 20130101; A61K 9/2077 20130101;
A61K 47/38 20130101; A61K 31/13 20130101; A61K 9/0053 20130101;
A61K 9/2054 20130101 |
International
Class: |
A61K 31/13 20060101
A61K031/13; A61K 9/20 20060101 A61K009/20; A61K 47/38 20060101
A61K047/38; A61K 9/00 20060101 A61K009/00 |
Claims
1. A modified release solid oral dosage form comprising: (a) at
least one therapeutically active ingredient selected from the group
consisting of memantine and a pharmaceutically acceptable salt of
memantine, and (b) a pharmaceutically acceptable polymeric carrier
substantially contributing to the modification of the release of
said active ingredient, said dosage form sustaining release of said
therapeutically active agent from about 4 hours to about 24 hours
following entry of said form into a use environment, wherein said
dosage form has a dissolution rate of more than about 80% after
passage of about 6 hours to about 12 hours following said entry
into said use environment.
2. The modified release solid oral dosage form according to claim
1, wherein said active ingredient is memantine hydrochloride.
3. The modified release solid oral dosage form according to claim
1, wherein the dissolution rate of more than about 80% is achieved
after about 12 hours.
4. The modified release solid oral dosage form of claim 3,
comprising the active ingredient in an amount within the range of
from about 1.0% w/w to about 20% w/w.
5. The modified release solid oral dosage form according to claim
1, wherein the dissolution rate of more than about 80% is achieved
after about 6 hours.
6. The modified release solid oral dosage form of claim 5, wherein
the active ingredient is present in amounts ranging from about 1.0%
w/w to about 35% w/w.
7. The modified release solid oral dosage form of claim 1, wherein
the polymeric carrier is a polymeric matrix.
8.-10. (canceled)
11. The modified release solid oral dosage form of claim 1, further
comprising a filler.
12. The modified release solid oral dosage form of claim 11,
wherein the filler is lactose monohydrate.
13. The modified release solid oral dosage form of claim 12,
wherein the dissolution rate of more than about 80% is achieved
after about 12 hours, and the lactose monohydrate is present in an
amount from about 5% w/w to about 50% w/w.
14. The modified release solid oral dosage form of claim 12,
wherein the dissolution rate of more than about 80% is achieved
after about 6 hours, and the lactose monohydrate is present in
amounts from about 5% w/w to about 75% w/w.
15. The modified release solid oral dosage form of claim 11,
wherein the filler is microcrystalline cellulose.
16. The modified release solid oral dosage form of claim 15,
wherein the microcrystalline cellulose is present in an amount from
about 5% w/w to about 80% w/w.
17. The modified release solid oral dosage form of claim 11,
wherein the filler is dicalcium phosphate.
18. The modified release solid oral dosage form of claim 17,
wherein the dicalcium phosphate is present in an amount from about
7% w/w to about 40% w/w.
19. The modified release solid oral dosage form of claim 1, further
comprising a lubricant.
20. The modified release solid oral dosage form of claim 19,
wherein the lubricant is magnesium stearate.
21. The modified release solid oral dosage form of claim 20,
wherein the dissolution rate of more than about 80% is achieved
after about 12 hours, and wherein the magnesium stearate is present
in an amount within the range from about 0.8% w/w to about 1.2%
w/w.
22. The modified release solid oral dosage form of claim 20,
wherein the dissolution rate of more than about 80% is achieved
after about 6 hours, and wherein the magnesium stearate is present
in an amount within the range from about 0.4% w/w to about 0.6%
w/w.
23. The modified release solid oral dosage form of claim 1, further
comprising one or more components selected from the group
consisting of carriers, excipients, anti-adherents, fillers,
stabilizing agents, binders, colorants, glidants, and
lubricants.
24. A modified release solid oral dosage form, comprising (a)
between about 2.5% w/w and about 20.0% w/w of memantine
hydrochloride; (b) between about 68% w/w and about 77% w/w of
hydroxypropyl methyl cellulose; (c) between about 6.9% w/w and
about 15% w/w of lactose monohydrate; (d) between about 0.8% w/w
and about 1.3% w/w of fumed silica; (e) between about 3.0% w/w and
about 5.0% w/w of talc; and (f) between about 0.9% w/w and about
1.1% w/w of magnesium stearate; wherein the dissolution rate of
memantine hydrochloride of more than about 80% is achieved after
about 12 hours.
25. A modified release solid oral dosage form, comprising: (a)
between about 5% w/w and about 35% w/w of memantine hydrochloride;
(b) between about 54% w/w and about 65% w/w of hydroxypropyl methyl
cellulose; (c) between about 7% w/w and about 24% w/w of lactose
monohydrate; (d) between about 0.8% w/w and about 1.3% w/w of fumed
silica; (e) between about 3.0% w/w and about 5.0% w/w of talc; and
(f) between about 0.4% w/w and about 0.6% w/w of magnesium
stearate; wherein the dissolution rate of memantine hydrochloride
of more than about 80% is achieved after about 6 hours.
26. A modified release solid oral dosage form, comprising: (a)
between about 5% w/w and about 35% w/w of memantine hydrochloride;
(b) between about 54% w/w and about 65% w/w of hydroxypropyl methyl
cellulose; (c) between about 7% w/w and 40% w/w of microcrystalline
cellulose; (d) between about 0.8% w/w and about 1.3% w/w of fumed
silica; (e) between about 3.0% w/w and about 5.0% w/w of talc; and
(f) between about 0.4% w/w and about 0.6% w/w of magnesium
stearate; wherein the dissolution rate of memantine hydrochloride
of more than about 80% is achieved after about 6 hours.
27. A modified release solid oral dosage form, comprising: (a)
between about 5% w/w and about 35% w/w of memantine hydrochloride;
(b) between about 54% w/w and about 65% w/w of hydroxypropyl methyl
cellulose; (c) between about 7% w/w and 40% w/w of dicalcium
phosphate; (d) between about 0.8% w/w and about 1.3% w/w of fumed
silica; (e) between about 3.0% w/w and about 5.0% w/w of talc; and
(f) between about 0.4% w/w and about 0.6% w/w of magnesium
stearate; wherein the dissolution rate of memantine hydrochloride
of more than about 80% is achieved after about 6 hours.
28. The modified release solid oral dosage form of claim 24 wherein
said modified release solid oral dosage form is a tablet.
29. The modified release solid oral dosage form of claim 1, wherein
the dissolution rate exhibited by said modified release solid oral
dosage form after about 1 hour is at least about 10% and up to
about 35%.
30. The modified release solid oral dosage form of claim 1, wherein
the dissolution rate exhibited by said modified release solid oral
dosage form after about 2 to about 6 hours is at least about 30%
and up to about 60%.
31. The modified release solid oral dosage form of claim 1, wherein
said modified release solid oral dosage form is administered
once-a-day.
32. 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
modified release solid oral dosage form of claim 1.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. .sctn. 119,
based on U.S. Provisional Application Ser. No. 60/581,242 filed
Jun. 17, 2004, which is hereby incorporated by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to pharmaceutical solid,
oral dosage forms which exhibit a modified release profile. The
invention is particularly suitable for once-a-day solid oral
pharmaceutical dosage forms in which the active ingredient is
memantine, releasing a therapeutically effective amount of the
active ingredient over an extended time period.
BACKGROUND OF THE INVENTION
[0003] Solid oral drug compositions or preparations have various
release profiles such as a modified or extended release profile as
referenced by USP XXIII (CDER, FDA, Rockville, Md.) or an immediate
release profile as referenced by FDA guidelines (Dissolution
Testing of Immediate Release Solid Oral Dosage Forms, issued August
1997, Section IV-A). For example, in the dissolution testing
guideline for modified release profiles, material dissolves over an
extended period and its dissolution is measured over time. A
minimum of three time points is recommended and should cover early,
middle and late stages of the dissolution profile. The last
measurement should be at a time point where at least 80% of the
drug is dissolved (Guidance for Industry, "Extended Release Oral
Dosage Forms: Development, Evaluation, and Application of In
Vitro/In Vivo Correlations", Food and Drug Administration, CDER,
September 1997, Page 17). Adequate sampling should be performed,
for example, at 1, 2 and 4 hours and every two hours thereafter
until 80% of the drug is released (Guidance for Industry, SUPAC-MR:
Modified Release Solid Oral Dosage Forms," Food and Drug
Administration, CDER, September 1997, Page 6). The preferred
dissolution apparatus is USP apparatus I (basket) or II (paddle),
used at compendially recognized rotation speeds, e.g., 100 rpm for
the basket and 50-75 rpm for the paddle (Guidance for Industry,
"Extended Release Oral Dosage Forms: Development, Evaluation, and
Application of In Vitro/In Vivo Correlations", Food and Drug
Administration, CDER, September 1997, Page 4).
[0004] Modified release solid oral dosage forms permit the
sustained release of the active ingredient over an extended period
of time in an effort to maintain therapeutically effective plasma
levels over similarly extended time intervals and/or to modify
other pharmacokinetic properties of the active ingredient.
Immediate release solid dosage forms permit the release of most or
all of the active ingredient over a short period of time, such as
60 minutes or less, and make rapid absorption of the drug possible.
A multiphase release profile (i.e., a composition containing at
least an immediate release formulation and at least one modified
release formulation) may be employed to attain one or more
combinations of release rates to attain more specific therapeutic
objectives such as a portion of drug releasing immediately,
followed by an extended release. However, modulation of the release
rate of an active ingredient does not necessarily ensure that
long-lasting effective blood level concentrations will be
consistently achieved or that the pharmacological effect will be
based solely on the release of the drug.
[0005] Sustained release formulations for drugs have become
increasingly available. This is true especially when the particular
drug is relatively soluble. Various formulation techniques have
been used for providing a sustained release formulation of soluble
drugs. In many such formulations, a drug-containing particle is
coated by one or more release retardant layers or films or is
dispersed within a continuous matrix such as a polymeric matrix.
The coating layer or the matrix comprises a relatively insoluble
material or materials, and the release of the drug is controlled by
means of the resistance of the coating layer or matrix against the
diffusion of the drug there through. The release of the drug from
such formulations is driven, e.g., by the gradient of the drug
concentration resulting from penetration of, e.g., gastric fluid,
by diffusion into the formulation.
[0006] One or more film-forming polymers may be employed to provide
sustained release of the active substance by controlling its rate
of diffusion across the film barrier(s). However, such an approach
is compromised if, during ingestion of the oral dosage form, the
film is prematurely breached, as by chewing, splitting or abrasion,
thereby releasing an excessive amount of active ingredient, which
can result in undesirable effects from excessive single-shot drug
release, and in failure of the dosage form to remain effective for
the required duration.
[0007] In the more common matrix-controlled release approach,
lipophilic substances, e.g., higher alcohols, waxes, or insoluble
thermoplastic materials, are employed. The release is controlled by
the rate of diffusion of the active ingredient into the surrounding
medium and, if the matrix itself is degradable, by the rate of its
degradation. One of the disadvantages is that a complete release of
drug from the matrix is frequently not achieved in practice.
Another drawback is that dose proportionality of the dosage forms
is not readily achieved, thus, requiring different compositions for
different strengths. Thus, the matrix composition to formulate a 20
mg sustained release dosage form may well be different from the
matrix composition to formulate a 40 mg sustained release dosage
form.
[0008] U.S. Pat. No. 5,382,601 provides solid pharmaceutical dosage
forms containing memantine, which exhibit an extended two-phase
release profile, with a portion of the drug being released
immediately, followed by a sustained release of the remainder. The
matrix of this formulation contains both a water-soluble and a
water-insoluble salt of casein, preferably sodium and calcium
caseinate. However, casein has an unpleasant taste; it is
associated with undesirable effect of exacerbating some side
effects as disclosed in U.S. Pat. No. 6,413,556; and displays
instability in varying pH. Another concern regarding casein is the
possibility of Bovine Spongiform Encephalitis (BSE) contamination
since casein is an animal-derived milk protein.
[0009] A general method of modified release for
N-methyl-D-aspartate (NMDA) receptor antagonists was described in
U.S. Pat. No. 6,194,000. This method also involves preparing an
instant release component and a modified release component to
arrive at the final formulation. The patent discloses a pellet (not
a bead) consisting of a coated core, the coating being any suitable
coating using organic solvent-based systems. However, not all NMDA
antagonists act in the same manner, and this patent does not
specifically disclose compositions containing memantine.
[0010] Currently, a dosing regimen of memantine of twice a day is
employed using immediate release tablets. This may be undesirable
because patient compliance decreases as the frequency of taking a
drug increases. Moreover, administration of an immediate-release
tablet can lead to greater frequency of adverse events due to a
faster rate of absorption. For pain treatment, it is very important
to maintain the pain relief without additional discomfort. There is
therefore an existing and continual need for a once a day modified
release formulation containing memantine or a pharmaceutically
acceptable salt of memantine with reliable slower absorption over a
targeted period of time.
SUMMARY OF THE INVENTION
[0011] According to the present invention, it has now been found
that memantine, and its salts, including the hydrochloride salt as
well as other pharmaceutically acceptable salts of memantine can be
formulated into a modified release form with anticipated
improvements in tolerability. The formulation of the present
invention includes memantine or a pharmaceutically acceptable salt
thereof, a pharmaceutically acceptable polymeric carrier (coating
and/or matrix) that substantially contributes to the modification
of the release of memantine, and one or more excipients to be
administered in a once-a-day oral dosage form.
[0012] Specifically, the present invention provides a dosage form
which slowly releases the active agent at a release rate of from at
least about 70% to about 80% in about 4 hours to about 24 hours
following entry of the dosage form into a use environment. In one
embodiment, the dosage form is released to this extent over 6 hours
from entry into the use environment, e.g., the gastric fluids.
Alternatively, the dosage form is released to this extent over 12
hours from entry into the use environment.
[0013] For a 12-hour release formulation, at least 70%, preferably
at least 80% of the active ingredient, e.g., memantine
hydrochloride, is released after about 12 hours following entry
into the use environment, but not before such time. In the 12-hour
oral dosage form of the present invention, the active ingredient is
usually present in amounts from about 1.0% w/w to about 20.0% w/w,
preferably from about 1.6% w/w to about 20.0% w/w, most preferably
from about 2.5% w/w to about 20% w/w. Alternatively, the active
ingredient may be measured as mg per tablet, ranging from about 5
to about 80 mg per tablet. Preferably, the tablets contain 7 mg, 10
mg, 20 mg, 28 mg, 40 mg or 80 mg active ingredient. Alternatively,
the active ingredient in the use of seeds may be up to 100 mg.
[0014] For a 6-hour release formulation, at least 70% preferably at
least 80% of the active ingredient is released after about 6 hours
following entry into the use environment, but not before such time.
In the 6-hour oral dosage form of the present invention, the active
ingredient is usually present in amounts from about 1.0% w/w to
about 35% w/w, preferably from about 1.6% w/w to about 35.0% w/w,
most preferably from about 5.0% w/w to about 35.0% w/w. The active
ingredient would therefore be present from about 5 mg to about 80
mg per tablet. Preferably, the tablets contain 7 mg, 10 mg, 20 mg,
28 mg, 40 mg, or 80 mg active ingredient.
[0015] In one embodiment of the present invention, the polymeric
carrier is a polymeric matrix. Preferably, the polymeric matrix is
a swellable matrix that contains hydroxypropyl methylcellulose. The
hydroxypropyl methylcellulose, in 12-hour formulations is present
in amounts from about 50% w/w to about 80% w/w, more preferably in
amounts from about 68% w/w to about 77% w/w. In 6-hour
formulations, the hydroxypropyl methylcellulose is present in
amounts from about 20% w/w to about 70% w/w, preferably from about
54% w/w to about 65% w/w.
[0016] The formulations of the present invention may further
comprise a filler. In one embodiment, the dosage forms contain the
lactose monohydrate as filler. In 12-hour formulations, the lactose
monohydrate is present in amounts from about 5% w/w to about 50%
w/w, more preferably from about 5% w/w to about 25% w/w, most
preferably from about 6.9% w/w to about 15% w/w. In 6-hour
formulations, the lactose monohydrate is present in amounts from
about 5% w/w to about 80% w/w, more preferably from about 5% w/w to
about 71% w/w, most preferably from about 7% w/w to about 24%
w/w.
[0017] In another embodiment, the dosage forms contain the
microcrystalline cellulose as filler in amounts from about 5% w/w
to about 80% w/w, more preferably from about 5% w/w to about 71%
w/w, most preferably from about 7% w/w to about 40% w/w.
[0018] In yet another embodiment, the dosage forms contain the
dicalcium phosphate dihydrate as filler in amounts from about 5%
w/w to about 80% w/w, more preferably from about 5% w/w to about
71% w/w, most preferably from about 7% w/w to about 40% w/w.
[0019] The formulations of the present invention may further
comprise a lubricant, preferably magnesium stearate. In 12-hour
formulations, the magnesium stearate is present in amounts ranging
from about 0.8% w/w to about 1.2% w/w, preferably from about 0.9%
w/w to about 1.1% w/w. In 6-hour formulations, the magnesium
stearate is present in amounts ranging from about 0.4% to about
0.6% w/w, preferably in an amount of about 0.5% w/w.
[0020] The formulations of the present invention may also contain
one or more additional carriers, excipients, fillers, stabilizing
agents, binders, colorants, glidants and lubricants.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 shows the dissolution rates for the scaled up batches
of 10, 20, and 40 mg memantine HCL tablets after six months of
storage conditions at 40.degree. C./75% RH. Dissolution is shown as
percent dissolved over time (hours). The open diamond represents
the 40 mg strength; the open square represents the 20 mg strength;
and the open triangle represents the 10 mg strength. These open
shapes represent measurements at 6 months. The corresponding filled
shapes represent the baseline measurements.
[0022] FIG. 2 shows the dissolution rates for the scaled up batches
of 10, 20, and 40 mg memantine HCl tablets after six months of
storage conditions at 40.degree. C./75% RH. Dissolution is shown as
percent drug released over time (hours). The open diamond
represents the 40 mg strength; the open square represents the 20 mg
strength; and the open triangle represents the 10 mg strength.
These open shapes represent measurements at 6 months. The
corresponding filled shapes represent the baseline
measurements.
[0023] FIG. 3 shows the stability of dissolution profiles for a 6
hour release formulation up to 6 months at 40.degree. C./75% RH.
The dissolution profiles show the percentage of drug dissolved for
various batches over time (hours). The age of each sample is
indicated in FIG. 3.
[0024] FIG. 4 shows the stability of dissolution profiles for a 12
hour release formulation up to 6 months at 40.degree. C./75% RH.
The dissolution profiles show the percentage of drug dissolved for
various batches over time (hours). The age of each sample is
indicated in FIG. 4.
[0025] FIG. 5 depicts the mean plasma concentrations of memantine
following administration of 20 mg modified release tablets in
comparison to two 10 mg immediate release tablets administered four
hour apart in young healthy male and female subjects over time
(hours). Treatment A (closed circle) represents the immediate
release formulation. Treatment B (open circle) represents a
modified release formulation. Treatment C (inverted triangle) also
represents a modified release formulation.
[0026] FIG. 6 depicts the mean plasma concentrations of memantine
following administration of 20 mg modified release tablets of the
present invention and two 10 mg immediate release tablets
administered four hours apart in young healthy male and female
subjects on a semi-log scale. Treatment A (closed circle)
represents the immediate release formulation. Treatment B (open
circle) represents a modified release formulation. Treatment C
(inverted triangle) also represents a modified release
formulation.
[0027] FIG. 7 depicts a truncated 24-hour profile of mean plasma
concentrations of memantine following administration of memantine
20 mg modified release tablets of the present invention in
comparison to two 10 mg immediate release formulation tablets
administered four hours apart in young healthy male and female
subjects. Treatment A (closed circle) represents the immediate
release formulation. Treatment B (open circle) represents a
modified release formulation. Treatment C (inverted triangle) also
represents a modified release formulation.
[0028] FIG. 8 shows the dose proportionality of drug dissolution
over time (hours) for 10 mg (X data points), 20 mg (circular data
points), and 40 mg (diamond data points) modified release memantine
tablets. The 10 mg tablet is a circular shaped tablet, whereas the
20 mg and 40 mg tablets are oval shaped tablets. The shape of the
tablet is critical to obtain the desired diffusion
characteristics.
[0029] FIG. 9 presents the dissolution data as percent drug
dissolved over time (hours) for using monohydrate and anhydrate
forms of lactose in 40 mg modified release memantine tablets.
[0030] FIG. 10 shows the dissolution profiles of modified release
memantine tablets prepared for doses 7 mg and 28 mg using three
different fillers--lactose monohydrate, dicalcium phosphate and
microcrystalline cellulose. The data show that each work about the
same dissolution. The shape of the data points for each composition
is indicated in FIG. 10.
DETAILED DESCRIPTION OF THE INVENTION
[0031] In accordance with the present invention, a pharmaceutical
composition is provided for the once-daily administration of
memantine or a pharmaceutically acceptable salt thereof, preferably
its HCl salt, or derivatives thereof, to a human or animal, where
the composition includes memantine in oral solid dosage forms,
preferably tablets.
[0032] In the present invention, the pharmaceutical compositions
comprise a therapeutically effective amount of memantine free base
or a pharmaceutically acceptable salt thereof, preferably the HCl
salt, one or more release modifiers in the form of polymeric
coatings and matrices, as well as, optionally, one or more
carriers, excipients, anti-adherants, fillers, stabilizing agents,
binders, colorants, glidants, and lubricants (all pharmaceutically
acceptable).
[0033] Memantine (1-amino-3,5-dimethyladamantane), which is an
analog of 1-amino-cyclohexane (disclosed, e.g., U.S. Pat. Nos.
4,122,193; 4,273,774; 5,061,703), is a systemically-active
uncompetitive NMDA receptor antagonist having low to moderate
affinity for the receptor and strong voltage dependency and rapid
blocking/unblocking kinetics. These pharmacological features allow
memantine to block sustained activation of the receptor under
pathological conditions and to rapidly leave the NMDA channel
during normal physiological activation of the channel. Memantine
and pharmaceutically acceptable salts thereof (e.g., the HCl salt,
MW 215.77) is approved in the U.S. for treatment of Alzheimer's
disease. Approval of memantine is currently sought for the
indication of neuropathic pain (wherein memantine has demonstrated
activity in in vitro models), and is currently approved outside the
United States as an oral formulation for both Alzheimer's and
Parkinson's Disease.
[0034] According to the invention, memantine may be used in the
form of a free base or a pharmaceutically acceptable salt. Suitable
salts of the compound include, but are not limited to, acid
addition salts, such as those made with hydrochloric,
methylsulfonic, hydrobromic, hydroiodic, perchloric, sulfuric,
nitric, phosphoric, acetic, propionic, glycolic, lactic pyruvic,
malonic, succinic, maleic, fumaric, maleic, tartaric, citric,
benzoic, carbonic cinnamic, mandelic, methanesulfonic,
ethanesulfonic, hydroxyethanesulfonic, benezenesulfonic, p-toluene
sulfonic, cyclohexanesulfamic, salicyclic, p-aminosalicylic,
2-phenoxybenzoic, and 2-acetoxybenzoic acid. In a preferred
embodiment, the salt is memantine hydrochloride
(C.sub.12H.sub.21N.HCl, MW 215.77). The term "salts" can also
include addition salts of free acids or free bases. All of these
salts (or other similar salts) may be prepared by conventional
means. All such salts are acceptable provided that they are
non-toxic and do not substantially interfere with the desired
pharmacological activity.
[0035] In addition, it is possible to use any salts and free base
form of memantine (collectively referred to as memantine),
including polymorphs, hydrates and solvates as well as amorphous
forms of memantine.
[0036] In a preferred embodiment of the invention, the active
ingredient is memantine hydrochloride.
[0037] In one embodiment, the memantine is formulated as a 12-hour
formulation, wherein the active ingredient has at least about
70-80% dissolution after about 12 hours. The active ingredient is
present in amounts ranging from about 1% w/w to about 20% w/w,
preferably from about 1.6% to about 20% w/w, most preferably from
about 2.5% w/w to about 20% w/w. In a preferred embodiment, the
active ingredient is present in amounts of about 10 mg to about 80
mg per tablet.
[0038] In an alternate embodiment, the memantine is formulated as a
6-hour formulation, wherein the active ingredient has at least
about 70-80% dissolution after about 6 hours. The active ingredient
is present in an amount ranging from about 1% w/w to about 35% w/w,
preferably from about 1.6% w/w to about 35% w/w, most preferably
from about 5% w/w to about 35% w/w. In another preferred
embodiment, the active ingredient is present in amounts of about 10
mg to about 80 mg per tablet.
[0039] To achieve the desired modified release rates, the modified
release dosage form may be formulated as a polymeric coating or
matrix. In one preferred embodiment, the modified release dosage
form is formulated as a matrix.
[0040] Depending upon the hydrophilic (erodable or non-erodable) or
hydrophobic nature of the matrix, the matrix may be a material that
swells upon contact with gastric fluid to a size that is large
enough to promote retention in the stomach while the subject is in
the digestive state. In addition to these diffusion based matrices,
the matrix may also be in an erodable form. The digestive state is
induced by food ingestion and begins with a rapid and profound
change in the motor pattern of the upper gastrointestinal (GI)
tract. The change consists of a reduction in the amplitude of the
contractions that the stomach undergoes and a reduction in the
pyloric opening to a partially closed state. The result is a
sieving process that allows liquids and small particles to pass
through the partially open pylorus while indigestible particles
that are larger than the pylorus are retropelled and retained in
the stomach. In other words, biological fluids migrate through the
matrix and dissolve the active ingredient which is released by
diffusion through the matrix which, simultaneously, modulates the
release rate. The controlled-release matrix in these embodiments of
the invention is therefore selected as one that can swell to a size
large enough to be retropelled and thereby retained in the stomach,
causing the prolonged release of the drug to occur in the stomach
rather than in the intestine. Disclosures of oral dosage forms that
swell to sizes that will prolong the residence time in the stomach
are found in U.S. Pat. Nos. 5,007,790, 5,582,837, and 5,972,389, as
well as International (PCT) Patent Application WO 98/55107 and WO
96/26718. Each of the documents cited in this paragraph is
incorporated herein by reference in its entirety.
[0041] In compositions comprising a hydrophilic matrix, the matrix
is composed of an insoluble hydrophilic polymer. This polymer is
chosen from cellulose esters, carboxyvinyl esters, or acrylic or
methacrylic esters. On contact with biological fluids, the matrix
becomes hydrated and swells, forming a network of polymers, through
which polymers the soluble active principles diffuse. Furthermore,
lipids, in particular glyceryl esters, can be added in order to
modulate, or lessen, the matrix swelling and rate of diffusion.
[0042] However, in the present invention, lipids are not needed to
modulate the diffusion of the matrix. Rather, the compositions of
the claimed invention work with the normal rate of gastric
diffusion, controlled in part by the thickness of the tablet. In
addition, compositions with lipids may include numerous adjuvants,
often expensive adjuvants, at high concentrations, which greatly
increases the cost of the composition. Furthermore, such
compositions are obtained by granulation and then compression of
the mixture formed of the polymer, active principles and various
adjuvants. These techniques often involve the use of organic
solvents, which it is subsequently essential to recover in order to
prevent them from dispersing into the atmosphere. In addition,
traces of toxic solvents can remain in the final product, which
traces necessarily have to be quantified.
[0043] In general, swellable matrices contain binders that are
water-swellable polymers, and suitable polymers are those that are
non-toxic, that swell in a dimensionally unrestricted manner upon
imbibitions of water, and that release the drug gradually over
time. Examples of polymers meeting this description include, but
are not limited to the following: cellulose polymers and their
derivatives including, but not limited to, hydroxymethyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, carboxymethylcellulose, and
microcrystalline cellulose polysaccharides and their derivatives,
polyalkylene oxides, polyethylene glycols, chitosan, poly(vinyl
alcohol), xanthan gum, maleic anhydride copolymers, poly(vinyl
pyrrolidone), starch and starch-based polymers, maltodextrins, poly
(2-ethyl-2-oxazoline), poly(ethyleneimine), polyurethane hydrogels,
crosslinked polyacrylic acids and their derivatives.
[0044] Further examples are copolymers of the polymers listed
above, including block copolymers and graft polymers. Specific
examples of copolymers are PLURONIC.RTM. and TECTONIC.RTM., which
are polyethylene oxide-polypropylene oxide block copolymers
available from BASF Corporation, Chemicals Div., Wyandotte, Mich.,
USA. Further examples are hydrolyzed starch polyacrylonitrile graft
copolymers, commonly known as "Super Slurper" and available from
Illinois Corn Growers Association, Bloomington, Ill., USA.
[0045] In the compositions comprising a hydrophobic matrix, the
matrix is composed of a lipid matrix agent of natural origin, for
example beeswaxes, which is highly innocuous. However, its
composition varies from one batch to another and its stability over
time is not very satisfactory. As above, these compositions are
generally obtained by granulation (wet or solvent), and then
compression, involving high proportions of each of the
constituents.
[0046] In the present invention, particularly preferred polymers
are poly(ethylene oxide), hydroxypropyl methyl cellulose, and
combinations of poly(ethylene oxide) and hydroxypropyl methyl
cellulose. Most preferred is hydroxypropyl methyl cellulose. In the
12-hour modified release formulations, the polymer is present in
amounts ranging from about 50% w/w to about 80% w/w, preferably
from about 68% to about 77% w/w. In the 6-hour modified release
formulations, the polymer is present in amounts ranging from about
20% w/w to about 70% w/w, preferably from about 54% w/w to about
65% w/w.
[0047] The prolongation in the time of maximum plasma concentration
values (T.sub.max) as compared to immediate release, is related to
the in vitro dissolution release rate of the drug. The in vitro
dissolution release rate of the drug depends on the composition of
the matrix. By using different cellulosic matrices, in-vitro
release rates (drug dissolution of more than about 70% to about
80%) can be manipulated anywhere from about 4 hours to 24 hours,
preferably about 6 to about 12 hours. The formulations have a time
of maximum plasma concentration (average T.sub.max) ranging from
between about 4 to about 24 hours, preferably from about 10 to
about 20 hours and an in vitro release rate of more than about 70%
to about 80% in about 6 to about 12 hours following entry to a use
environment. Preferably, the formulations have a release rate of
about 30% to about 60% in about 2 to about 6 hours. More
preferably, the formulations have a release rate of about 10% to
about 50% within the first hour following entry into a use
environment followed by extended release; more preferably, the
formulations have a release rate of about 10% to about 35% within
the first hour. All of the drug from the modified release
formulation does not release memantine immediately, such as not
more than 80% in about 15 to about 30 minutes within the first hour
following entry into a use environment. This is important so as to
prevent dose dumping.
[0048] 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 fabricated by direct
compression by punches and dics 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. This process is also preferred economically, because it
involves fewer unit operations involving inexpensive equipment.
Ordinarily, direct blending is a difficult process, and problems
such as blend segregation, low compressibility and low content
uniformity can occur. However, the formulations described in this
invention do not exhibit any such problems.
[0049] In the present invention, one or more fillers may be used
including but not limited to microcrystalline cellulose, dicalcium
phosphate, lactose, derivatives of cellulose, starch, other calcium
phosphates, gelatine, hydrated sugar alcohols (i.e., sorbite,
mannite), polyvinyl pyrrolidone, and collidone. Preferably, fillers
such as microcrystalline cellulose, dicalcium phosphate and lactose
are used to modify the dissolution pattern. When hydroxypropyl
methylcellulose or ethyl cellulose are used as the matrix material,
the dissolution rates can be much slower than the modified release
rate targeted. The slow release is because hydrophobic matrix
tablets release the drug by mechanism of polymer erosion. Since the
erosion from a hydrophobic matrix is very slow, the dissolution
rate of the readily soluble active ingredient is also slow. Fillers
are also important ingredients useful in improving the powder flow
and compressibility for memantine HCl tablets.
[0050] In one embodiment, the dosage forms contain the
microcrystalline cellulose as filler in amounts from about 5% w/w
to about 80% w/w, more preferably from about 5% w/w to about 71%
w/w, most preferably from about 7% w/w to about 40% w/w.
[0051] In another embodiment, the dosage forms contain dicalcium
phosphate dihydrate as one of many fillers or as the only filler in
amounts from about 5% w/w to about 80% w/w, more preferably from
about 5% w/w to about 71% w/w, most preferably from about 7% w/w to
about 40% w/w. In particular embodiments, the dosage forms are
lactose free.
[0052] In yet another embodiment, the dosage forms contain lactose
monohydrate as filler. For 12-hour release formulations, lactose
monohydrate is present in amounts ranging from about 5% w/w to
about 50% w/w, preferably from about 5% w/w to about 25% w/w, most
preferred from about 6.9% w/w to about 15% w/w. For 6-hour release
formulations, lactose monohydrate is present in amounts ranging
from about 5% w/w to about 75% w/w, preferably from about 5% w/w to
about 50% w/w, most preferred from about 7% w/w to about 24%
w/w.
[0053] When tablets are made by direct compression, the addition of
lubricants may be helpful and is sometimes important to promote
powder flow and to prevent or lessen "capping" (the breaking off of
a portion of the tablet) when the pressure is relieved. Useful
lubricants include magnesium stearate, and hydrogenated vegetable
oil (preferably hydrogenated and refined triglycerides of stearic
and palmitic acids). In a preferred embodiment, the lubricant is
magnesium stearate. For the 12-hour release formulations, the
magnesium stearate is present in amounts ranging from about 0.8%
w/w to about 1.2% w/w, preferably from about 0.9% w/w to about 1.1%
w/w. For the 6-hour release formulations, the magnesium stearate is
present in amounts ranging from about 0.4% w/w to about 0.6% w/w,
preferably about 0.5% w/w. Additional excipients may be added to
enhance tablet hardness, powder flowability, and tablet friability
and to reduce adherence to the die wall.
[0054] In accordance with the present invention, a modified release
pharmaceutical composition is provided for the once daily
administration of memantine or a pharmaceutically acceptable salt
thereof, preferably its HCl salt, to a human or animal subject. The
memantine formulations of the invention are suitable for the
treatment of CNS diseases, including but not limited to the
treatment of Alzheimer's disease, Parkinson's disease, AIDS
dementia (U.S. Pat. No. 5,506,231, see also Parsons et al.,
Neuropharmacology 1999 June; 38(6):735-67), neuropathic pain (U.S.
Pat. No. 5,334,618), cerebral ischemia (U.S. Pat. No. 5,061,703),
epilepsy, glaucoma, hepatic encephalopathy, multiple sclerosis,
stroke, depression (U.S. Pat. No. 6,479,553), tardive dyskinesia,
malaria, Borna virus, Hepatitis C (U.S. Pat. Nos. 6,034,134 and
6,071,966). Additional pathologies for treatment of which memantine
is suitable are disclosed in U.S. Pat. Nos. 5,614,560 and
6,444,702. Of particular interest is the ability to provide
uninterrupted pain relief. Accordingly, the present invention
further provides a method for the therapeutic or prophylactic
treatment of CNS disorders in a human or animal subject, the method
including administering to the subject, a composition in accordance
with the present invention.
[0055] For purposes of the present invention, "sustained release or
modified release" means that the release of the therapeutically
active agent occurs over an extended period of time leading to
lower peak plasma concentrations (C.sub.max) and a prolonged
T.sub.max as compared to "immediate release." The "dissolution
requirements" and "disintegration requirements" referred to above
are conducted using the equipment and tests specified in the USP
XXIV and conducted pursuant to the individual Official Monographs
of USP XXIV (U.S. Pharmacopoeia and National Formulary, USP XXIV/NF
19, Chapter 1088, pages 2051-2056, 2000), incorporated herein by
reference, for the particular therapeutically active agent(s)
included in the tablet core.
[0056] A "therapeutically effective amount" means the amount of a
compound that, when administered to a mammal for treating a state,
disorder or condition is sufficient to effect such treatment. The
"therapeutically effective amount" will vary depending on the
compound, the disease and its severity and the age, weight,
physical condition and responsiveness of the mammal to be treated.
According to the instant invention, in one embodiment, a
therapeutically effective amount of memantine is an amount
effective to treat CNS disorders, including Alzheimer's disease or
Parkinson's disease. In another embodiment, a therapeutically
effective amount is an amount effective to treat neuropathic pain,
or other painful conditions such as visceral hypersensitivity.
Other uses include, but are not limited to, the treatment of
dementia and depression. The effective amount of the drug for
pharmacological action, and therefore the tablet strength, depends
on the disease itself, e.g., in Alzheimer's disease, the patient is
initially given a 5 mg dose and the dosage is progressively
increased to 10 mg twice a day. Additional doses evaluated in
clinical trials include 40 mg/day.
[0057] The term "pharmaceutically acceptable" means biologically or
pharmacologically compatible for in vivo use in animals or humans,
and preferably means approved by a regulatory agency of the Federal
or a state government or listed in the U.S. Pharmacopeia or other
generally recognized pharmacopeia for use in animals, and more
particularly in humans.
[0058] As used herein, the term "treat" is used herein to mean to
relieve or alleviate at least one symptom of a disease in a
subject, including for example, pain, Alzheimer's disease, vascular
dementia, or Parkinson's disease. The term "treat" may mean to
relieve or alleviate the intensity and/or duration of a
manifestation of disease experienced by a subject in response to a
given stimulus (e.g., pressure, tissue injury, cold temperature,
etc.). For example, in relation to dementia, the term "treat" may
mean to relieve or alleviate cognitive impairment (such as
impairment of memory and/or orientation) or impairment of global
functioning (activities of daily living, ADL) and/or slow down or
reverse the progressive deterioration in ADL or cognitive
impairment. Within the meaning of the present invention, the term
"treat" also denotes to arrest, delay the onset (i.e., the period
prior to clinical manifestation of a disease) and/or reduce the
risk of developing or worsening a disease. The term "protect" is
used herein to mean prevent delay or treat, or all, as appropriate,
development or continuance or aggravation of a disease in a
subject. Within the meaning of the present invention, the dementia
is associated with a CNS disorder, including without limitation
neurodegenerative diseases such as Alzheimer's disease (AD), Down's
Syndrome and cerebrovascular dementia (VaD).
[0059] The term "about" or "approximately" means within an
acceptable error range for the particular value as determined by
one of ordinary skill in the art, which will depend in part on how
the value is measured or determined, i.e., the limitations of the
measurement system. For example, "about" can mean within 1 or more
than 1 standard deviations, per practice in the art. Alternatively,
"about" with respect to the compositions can mean plus or minus a
range of up to 20%, preferably up to 10%, more preferably up to 5%.
Alternatively, particularly with respect to biological systems or
processes, the term can mean within an order of magnitude,
preferably within 5-fold, and more preferably within 2-fold, of a
value. Where particular values are described in the application and
claims, unless otherwise stated the term "about" means within an
acceptable error range for the particular value. For example, when
referring to a period of time, e.g., hours, the present values
(.+-.20%) are more applicable. Thus, 6 hours can be, e.g., 4.8
hours, 5.5 hours, 6.5 hours, 7.2 hours, as well as the usual 6
hours.
[0060] The term "similarity factor" or "f2 factor" as used herein
refers to one way of comparing dissolution profiles of two
different products. (Multisource Pharmaceutical Products:
Guidelines on Registration Requirements to establish
Interchangeability, Quality Assurance and Safety: Medicines,
Essential Drugs and Medicines Policy, World Health Organization,
1211 Geneva 27, Switzerland, pages 11-12, 2004, incorporated herein
by reference). This model-independent mathematical approach
compares the dissolution profile of the two products: test and
reference (or two strengths, or pre- and post-approved products
from the same manufacturer). Tests are recommended to be performed
under the same test conditions. The dissolution time points for
both the profiles should be the same, for example for immediate
release products e.g. 10, 15, 30, 45, 60 minutes and for extended
release products, e.g., 1, 2, 3, 5 and 8 hours. Only one time point
should be considered after 85% dissolution of the reference
product. An f2 value of 50 or greater (50-100) ensures sameness or
equivalence of the two curves, and thus the performance of the two
products. The similarity factor f2 should be computed using the
equation:
f.sub.2=50 log
{[1+(l/n).sub.t=l.sup.n(R.sub.t-T.sub.t).sup.2].sup.-0.5100}
where Rt and Tt are the cumulative percentage of the drug dissolved
at each of the selected n time points of the comparison (reference)
and (test) product respectively. For products which are very
rapidly dissolving, i.e. more than 85% dissolution in 15 minutes or
less, a profile comparison is not necessary. For extended release
beaded capsules, where the strength differs only in the number of
beads containing active moiety, dissolution profile comparison
(f2>50) under one recommended test condition is sufficient for
biowaivers. A biowaiver is a waiver by regulatory authority of a
requirement for bioequivalence of a new formulation compared to a
previous one. Whereas for extended release tablets, as in the
present invention, when the drug product is in the same dosage form
but in a different strength, and is proportionally similar in its
active and inactive ingredients and has the same drug release
mechanism, a lower strength can be granted a biowaiver if it
exhibits similar dissolution profiles, f2>50, in three diverse
pH buffers (between pH 1.2 and 7.5) by the recommended test
method.
[0061] The term "dissolution stability" as used herein refers to
the similarity of dissolution profiles (similarity factor greater
than 50, in comparison to initial) obtained at different periods of
storage at varying temperature and humidity conditions.
[0062] The term "substantially the same dissolution stability"
means similarity factor f2 of greater than 50 as compared to a
reference dissolution profile.
[0063] The term "entry into a use environment" means contact of a
formulation of the invention with the gastric fluids of the patient
to whom it is administered, or with a fluid intended to simulate
gastric fluid.
EXAMPLES
[0064] The present invention will be better understood by reference
to the following Examples, which are provided as exemplary of the
invention, and not by way of limitation.
Example 1: Preparation of Memantine HCl Modified Release
Tablets
[0065] The present example describes the process of developing
memantine hydrochloride modified release tablets in 7, 10, 20, 28,
40 mg and 80 mg dosages.
[0066] The following tables provide the exemplary makeup of
modified release tablets including the active components, polymeric
matrix, and other excipients for the specified dosage forms with
specific the target release time periods.
TABLE-US-00001 TABLE 1 mg per tablet % w/w 10 mg 20 mg 40 mg 80 mg
10 mg 20 mg 40 mg 80 mg 12 Hour Formulation STRENGTH: Memantine
Hydrochloride 10 20 40 80 2.5% 5.0% 10.0% 18.1% HPMC (Synchron KF)
306 306 306 306 76.5% 76.5% 76.5% 69.6% Lactose 60 50 30 30 15.0%
12.5% 7.5% 6.9% Fumed Silica (Cab-O-Sil) 4 4 4 4 1.0% 1.0% 1.0%
0.9% Talc 16 16 16 16 4.0% 4.0% 4.0% 3.6% Magnesium Stearate 4 4 4
4 1.0% 1.0% 1.0% 0.9% Total 400 400 400 440 100.0% 100% 100.0%
100.0% 6 Hour Formulation STRENGTH: Memantine Hydrochloride 10 20
40 80 5.0% 10.0% 20.0% 33.3% HPMC (Synchron KF) 130 130 130 130
65.0% 65.0% 65.0% 54.2% Lactose 48 38 18 18 24.0% 19.0% 9.0% 7.5%
Fumed Silica (Cab-O-Sil) 2 2 2 2 1.0% 1.0% 1.0% 0.8% Talc 9 9 9 9
4.5% 4.5% 4.5% 3.8% Magnesium Stearate 1 1 1 1 0.5% 0.5% 0.5% 0.4%
Total 200 200 200 240 100.0% 100.0% 100.0% 100.0%
[0067] The following tables illustrate the composition of modified
release tablets including the active components, polymeric matrix,
and microcrystalline cellulose and/or dicalcium phosphate
fillers.
TABLE-US-00002 TABLE 2 6 Hour Formulation mg per tablet % w/w
STRENGTH: 7 mg 28 mg 7 mg 28 mg 7 mg 28 mg 7 mg 28 mg Memantine
Hydrochloride 7 28 7 28 3.2 12.7 3.2 12.7 HPMC (Synchron KF) 130
130 130 130 59.1 59.1 59.1 59.1 Microcrystalline Cellulose 71 50 0
0 32.3 22.7 0.0 0.0 Dicalcium Phosphate 0 0 71 50 0.0 0.0 32.3 22.7
Fumed Silica (Cab-O-Sil) 2 2 2 2 0.9 0.9 0.9 0.9 Talc 9 9 9 9 4.1
4.1 4.1 4.1 Magnesium Stearate 1 1 1 1 0.5 0.5 0.5 0.5 Total 220
220 220 220 100.0 100.0 100.0 100.0
Test batches of each of the tablets were prepared according to the
process outlined below.
[0068] Preparation of Blend for Tabletting.
[0069] The memantine HCl, HPMC (hydroxypropyl methyl cellulose,
Synchron oral carrier vehicle, type KF), lactose monohydrate, NF
and colloidal silicon dioxide, NF, (Cab-O-Sil.RTM.) are mixed in a
V-Blender for 10 minutes. Talc (an anti-adherant component) is
added to the above mixture and mixed for 5 minutes. Finally,
magnesium stearate is added to the mixture and mixed for 5 minutes.
The blend is discharged in a container lined with double
polyethylene bag liners and labeled as "Final Blend for
Compression".
[0070] Compression of Tablets.
[0071] The blend is compressed using a rotary tablet press. The
tablet shape for 12 hrs dissolution tablets is circular and the
target average tablet weight is about 400 mg. The diameter of the
tablets is 0.4375 inch. The tablet shape for 6 hrs dissolution
tablets is circular and the target average tablet weight is about
200 mg. The diameter of the tablets is 0.3125 inch.
[0072] During compression, the following controls are performed
periodically: tablet weight, tablet hardness, and tablet thickness.
In addition, dissolution tests were conducted on the 10 mg, 20 mg,
and 40 mg tablets for the 6 hour release formulations, as well as
the 20 mg for the 12 hour release formulation. For dissolution
tests, tablets of different hardness were tested using USP
Apparatus 11 using 900 ml of pH 1.2 buffer. (U.S. Pharmacopoeia and
National Formulary, USP XXIV/NF 19, Chapter 711, pages 1941-1943,
2000). The data are presented in Table 3 below.
TABLE-US-00003 TABLE 3 Time (hrs) 6 hr release 12 hr release 10 mg
20 mg 40 mg 20 mg Hardness 7.2-8.5 kp 7.3-8.4 kp 7.2-8.3 kp
7.8-11.0 kp 0 0 0 0 0 1 32 32 28 19 2.5 54 52 49 35 4 69 68 64 47 6
83 81 78 58 8 91 91 89 67 12 98 98 99 81
[0073] The formulations for the Memantine HCl tablets for strengths
10, 20 and 40 mg were scaled up. These batches showed excellent
stability after storage at 40 C/75% RH in HDPE bottles without
desiccant after two months and six months. See FIGS. 1 and 2 for
dissolution results, wherein all tablets performed satisfactorily,
at or close to the baseine value. In addition, 20 mg tablets were
tested for stability of dissolution of the 6 hour and 12 hour
release formulations. Dissolution profiles for the batches (01074H
6 hour and 01075H 12 hour) up to 6 months at 40 C/75% RH are shown
in FIGS. 3 and 4. The dissolution profiles of modified release
memantine tablets prepared for doses 7 mg and 28 mg using three
different fillers--lactose monohydrate, dicalcium phosphate and
microcrystalline cellulose are provided in FIG. 10.
Example 2: Pharmacokinetic Study of Memantine
[0074] The present example demonstrates the bioavailability of
immediate release memantine tablets as compared to modified release
memantine tablets.
Materials and Methods
[0075] The study design in the present example was a 57-day
single-center, open-label study in 24 young healthy subjects, ages
ranging from 18 to 35 years old. Subjects underwent a screening
evaluation consisting of a complete medical history, complete
physical examination with vital signs, 12-lead ECG, clinical
laboratory evaluations, consisting of a CBC (including
differential), clinical chemistry, urinalysis, RPR/VDRL, Anti HIV 1
and 2 tests, drugs of abuse screen (including alcohol and
nicotine), Anti-HCV and HbsAg. Female subjects had a .beta.-hCG
serum pregnancy test performed at screening and a urine pregnancy
test on Day -1.
[0076] Inclusion criteria included informed consent, normal
physical examination, healthy adults between 18 and 35 years of
age, non-smokers, within 15% of ideal body weight in relation to
height, and a sitting pulse rate of not less than 50 beats per
minute by palpitation, and a heart rate of not less than 50 beats
per minute as recorded by ECG. Exclusion criteria included
hypersensitivity to memantine or other NMDA antagonists, presence
of any clinically significant disease, sitting systolic blood
pressure greater than 180 mmHg or less than 100 mmHg or a sitting
diastolic blood pressure greater than 100 mmHg or less than 60 mmHg
at screening, significant ECG abnormalities, history of alcohol or
substance abuse, positive tests to drugs of abuse, consumption of
caffeine within 48 hours or alcohol within 72 hours prior to
testing, participation in other clinical investigation within 30
days of study, clinical conditions associated with memantine,
concomitant medications, or females breastfeeding.
[0077] There were three treatment regimens including an immediate
release memantine HCl 10 mg tablet (30 minutes dissolution,
Treatment A), a modified release memantine HCl 20 mg tablet
(formulation 1, 6 hour dissolution, Treatment B), and a second
modified release memantine HCl 20 mg tablet (formulation II, 12
hour dissolution, Treatment C). The subjects received three
treatments on study days 1, 22, and 43 in a crossover manner
separated by a 21-day washout period based on randomized treatment
sequences. The immediate release treatment was administered twice a
day, at 0800 and 1200 hours, for one day. The modified release
treatments were administered once a day at 0800 hours. Formulation
A is discussed in detail in co-pending application filed
simultaneously with the present application, Attorney Docket no.
03269/100M544-US1.
[0078] Subjects were admitted into a non-smoking environment at
approximately 1900 hours on Days -1, 21, and 42. There were a total
of six overnight stays for each subject (Days -1, 1, 21, 22, 42 and
43). Subjects were subjected to diet and fluid control and received
no concomitant medications.
[0079] Vital signs and adverse events were recorded over the course
of the study. Blood samples for the determination of memantine were
obtained from each subject during the course of the study 1, 22,
and 43 on study day after the 0800 hour drug administration at the
following times: 0.0 hour (pre-dose), every hour for the first 12
hours, 14, 24, 36, 48, 72, 96, 144, 192, 240, 288 and 336 hours
post dose. A number of blood samples were subjected to
pharmacokinetic analysis for the determination of memantine
concentration.
[0080] Approximately 5 mL of blood were collected per sample
following dosing on Days 1, 22, and 43. Blood samples were
centrifuged and the plasma for each sample was harvested. The
samples were then flash frozen in an isopropyl alcohol/dry ice bath
and stored in a -70.degree. C. freezer.
[0081] Bioanalytical Procedures.
[0082] The bioanalytical procedure used to measure the plasma
memantine concentrations was validated to demonstrate accuracy,
linearity, reproducibility, and precision of the analytical
procedures. An LC/MS/MS (liquid chromatography/mass spec/tandem
mass spec) method was developed for the determination of memantine
in human plasma. After the addition of 10 ng of [.sup.2H.sub.6]
memantine internal standard and 0.5 M sodium carbonate buffer to
plasma standards and samples, the compounds were extracted with
ethyl acetate. The organic layer was isolated and dried at room
temperature under the vacuum in a sample concentrator (Savant). The
dry residue was analyzed after reconstitution in mobile phase. The
components of the reconstituted samples were separated on a Zorbax
SB-C8 column (150.times.4.6 mm, 3.5 .mu.m) and detected by
atmospheric pressure chemical ionization (APCI) with a selected
reaction monitoring (SRM) positive ion mode. The SRM used
precursor.fwdarw.positive product ions of m/z 180.fwdarw.163 and
m/z 186.fwdarw.169 to monitor memantine and its internal standard,
respectively. The protonated molecular ions of memantine and
[2H.sub.6] memantine are the precursor ions for the SRM mode. The
peak height ratio of memantine product ion to that of its internal
standard was the response used for quantification. The plasma
standards of the method validation showed accuracy within .+-.8.2%
deviation and precision did not exceed 7.6% CV. Accuracy for the
determination of memantine in plasma quality controls was within
.+-.8.8% deviation with a precision not exceeding 9.8% CV. The
lower limit of quantification of the method was 0.5 ng/mL.
[0083] Pharmacokinetic Analysis.
[0084] Pharmacokinetic parameters were estimated using WinNonlin
(version 3.3, Pharsight Corporation, Mountain View, Calif.). The
following parameters were determined from the plasma concentrations
of memantine following single dose administration: the area under
the plasma concentration time curve (AUC.sub.0-t, AUC.sub.0-24, and
AUC.sub.0-.infin.), maximum plasma concentration (C.sub.max), time
of maximum plasma concentration (T.sub.max), elimination half-life
(T.sub.1/2) and mean residence time (MRT). Maximum plasma
concentrations (C.sub.max) and the time of the maximum
concentration (T.sub.max) for memantine were determined by
observation.
[0085] The first-order rate constant, .lamda..sub.2, describing the
terminal decline in plasma was estimated by WinNonlin (version 3.3)
using log-linear regression of the terminal linear phase of the
mean plasma concentration-time curves of memantine.
[0086] Estimates of terminal elimination half-life (Tin) in hours
were calculated with equation 1:
T 1 / 2 = 0 . 6 9 3 .lamda. s Eq . 1 ##EQU00001##
[0087] The area under the plasma concentration versus time curve up
to the last measurable concentration at time t (AUC.sub.0-t) or at
24 hours (AUC.sub.0-24) was estimated by numerical integration
using the linear trapezoidal rule (Equation 2).
AUC 0 - t = i = 2 0.5 ( C i + C i - 1 ) ( t i - t i - 1 ) Eq . 2
##EQU00002##
where C.sub.i was the plasma concentration at the corresponding
sampling time point t.sub.i.
[0088] Area under the plasma concentration-time curve up to time
infinity (AUC.sub.0-.infin.) of memantine was computed using the
following (Equation 3):
A U C 0 - .infin. = A U C 0 - t + C last .lamda. z Eq . 3
##EQU00003##
where C.sub.last is the last measurable concentration in the
concentration-time profile.
[0089] MRT was calculated using the following (Equation 4):
MRT = AUMC A U C 0 - .infin. Eq . 4 ##EQU00004##
where AUMC is the area under the first moment curve.
[0090] Descriptive statistics for the memantine pharmacokinetic
parameters C.sub.max, t.sub.max, AUC.sub.0-t, AUC.sub.0-24,
AUC.sub.0-.infin., t.sub.1/2, and MRT were provided for subjects
who completed the study. Between-treatment comparisons were made
using ANOVA appropriate for a 3-way crossover design.
Results
[0091] Adverse Events.
[0092] There were no serious adverse events reported. Nineteen
(82.6%) of the twenty-three subjects reported a total of 42
treatment emergent adverse events following administration of
Treatments A, B, and C. There were no significant differences in
the number of adverse events observed with any treatment. A total
of 14, 12, and 16 adverse events were observed following Treatments
A, B, and C, respectively. The most common adverse events (i.e.,
occurring in 3 or more subjects) were headache, dizziness,
flatulence, and infection.
[0093] Pharmacokinetic Results.
[0094] The mean plasma concentrations of memantine are illustrated
in FIG. 5 (linear scale) and in FIG. 6 (semi-log scale). FIG. 7
presents mean plasma concentrations of memantine during the first
24 hours post-dose. Peak memantine concentration was highest
following administration of the IR formulation (Treatment A) and
lowest following administration of the MR formulation II (Treatment
C).
[0095] The mean (.+-.SD) pharmacokinetic parameters of memantine
following Treatments A, B and C are listed below.
TABLE-US-00004 TABLE 4 Treatment A Treatment B Treatment C IR
Formulation I MR Formulation I MR Formulation II Parameter (n = 20)
(n = 20) (n = 20) C.sub.max 24.92 .+-. 4.82 20.37 .+-. 3.83 17.4
.+-. 4.60 (ng/mL) T.sub.max (h) 8.2 .+-. 2.0 12.1 .+-. 2.1 19.3
.+-. 7.3 AUC.sub.0-24 435.7 .+-. 87.0 367.2 .+-.66.8 303.3 .+-.
78.2 (ng h/mL) AUC.sub.0-t 1898.2 .+-. 453.0 1755.7 .+-. 468.9
1653.8 .+-. 589.8 (ng h/mL) AUC.sub.0-.infin. 1969.0 .+-. 455.8
1828.0 .+-. 489.9 1730.1 .+-. 609.4 (ng h/mL) T.sub.1/2 (h) 57.4
.+-. 14.2 59.6 .+-. 15.4 59.1 .+-. 15.5 MRT (h) 83.9 .+-. 17.8 87.4
.+-. 19.4 89.0 .+-. 20.2
[0096] Statistical comparisons of memantine parameters are
presented below in Table 5.
TABLE-US-00005 TABLE 5 Treatment B vs. Treatment A Treatment C vs.
Treatment A Least- 90% Least- 90% Squares Confidence Squares
Confidence Parameter Means Ratio Interval Means Ratio Interval
C.sub.max 81 76.65-85.75 70 65.93-73.77 AUC.sub.0-24 84 80.23-87.79
69 66.00-72.22 AUC.sub.0-t 91 83.90-99.10 84 77.15-91.14
AUC.sub.0-.infin. 92 84.29-99.04 85 78.06-91.73
[0097] Absorption of memantine from the modified release tablets
was delayed as compared to the immediate release tablet. The rate
and extent of absorption of memantine were reduced following
administration of the modified release formulations as compared to
the immediate release formulation. Importantly, the rate of
absorption (T.sub.max) was delayed from 8.2 hours for the IR tablet
(i.e., about 4 hours after the administration of the second tablet)
to 12.1 hours and 19.3 for the two MR formulations. While the
moderate release had slower rate and extent of absorption, there
was better tolerability of the moderate release dose. No
differences were observed in the terminal elimination half-life
between treatments.
[0098] The 90% confidence intervals for the comparison of the
log-transformed C.sub.max, AUC.sub.0-24, AUC.sub.0-t, and
AUC.sub.0-.infin. for Treatment B (MR Formulation i) versus
Treatment A (IR tablet) showed a significant reduction in mean
C.sub.max value of the MR Formulation I but not in the AUC
parameter values as compared to the IR tablet. The 90% confidence
intervals for the comparison of the log-transformed C.sub.max,
AUC.sub.0-24, AUC.sub.0-t and AUC.sub.0-.infin. for Treatment C (MR
Formulation II) versus Treatment A (IR tablet) showed significant
reductions in mean C.sub.max and AUC values of MR Formulation II as
compared to the IR tablet.
DISCUSSION
[0099] In this study, single daily doses of 20 mg memantine,
administered as two 10 mg doses of an immediate release tablet,
separated by a 4-hour interval, were found to be safe and
well-tolerated. There were no serious adverse events observed in
this study.
[0100] The rate and extent of absorption of memantine was highest
following administration of the immediate release tablets.
C.sub.max values averaged 24.92, 20.37 and 17.48 ng/mL for the
immediate release tablet (Treatment A), the modified release tablet
formulation I (Treatment B) and the modified release tablet
formulation II (Treatment C), respectively. AUC.sub.0-.infin.
averaged 1969, 1827 and 1730 ng-h/mL for the immediate release
tablet (Treatment A), the modified release tablet formulation I
(Treatment B) and the modified release tablet formulation II
(Treatment C), respectively. Mean T.sub.max was 8.2 hours, 12.1
hours and 19.3 hours, for Treatments A, B and C, respectively.
[0101] The 90% confidence intervals for the comparison of the
log-transformed C.sub.max, AUC.sub.0-24, AUC.sub.0-t and
AUC.sub.0-.infin. for Treatment B (MR Formulation I) versus
Treatment A (IR tablet) showed a significant reduction in mean
C.sub.max value of MR Formulation I but not in the AUC parameter
values relative to the IR tablet. The 90% confidence intervals for
the comparison of the log-transformed C.sub.max, AUC.sub.0-24,
AUC.sub.0-t and AUC.sub.0-.infin. for Treatment C (MR Formulation
II) versus Treatment A (IR tablet) showed significant reductions in
mean C.sub.max and AUC values of MR Formulation II relative to the
IR tablet.
[0102] No differences were observed in the terminal elimination
half-life of memantine across the different treatments. There were
no statistically significant differences in mean elimination
half-life or mean weight-adjusted C.sub.max, AUC.sub.0-t and
AUC.sub.0-.infin. values between male and female subjects following
administration of the IR or MR formulations.
[0103] In conclusion, the delayed T.sub.max for the two
modified-release formulations is indicative of the slower
absorption rate compared to the immediate-release tablets and
demonstrates that the desired release characteristics were
obtained. Both formulations delayed T.sub.max and are therefore
acceptable. Treatment B (6 Hour formulation) had greater
bioavailability than Treatment C (12 hour formulation).
Example 3: Dissolution Rates of Dose-Proportional Modified Release
Memantine
[0104] The present example demonstrates the different dissolution
rates for dose proportional 6 hour release formulations of 10 mg,
20 mg, and 40 mg memantine hydrochloride.
[0105] The following table provides the makeup of modified release
tablets including the active components, polymeric matrix, and
other excipients for the specified dosage forms with specific the
target release time periods.
TABLE-US-00006 TABLE 6 Batch # REF PK Batch A B C Memantine HCl 20
10 20 40 Syncrhon KF 130 65 130 260 Lactose 38 19 38 76 Monohydrate
Cab-O-Sil .RTM. 2 1 2 4 Talc 9 4.5 9 18 Mg Stearate 1 0.5 1 2 Total
200 100 200 400 Tooling 0.3125 0.2500 0.2500 .times. 0.4900 .times.
Dimension 0.5918 0.7500 Tablet 0.1689 0.1371 0.1227 0.1280
Thickness (in) Tablet Shape Circular Circular Oval Oval Calculated
31.56 31.56 31.56 Area/Vol (inch.sup.-1) Maximum 17.6 11.7 10.0 6.7
Hardness Obtained
[0106] Dissolution of Dose Proportional Formulation.
[0107] 10 mg as compared to 40 mg formulations do not have
proportional dissolution rates, i.e., 40 mg is slower than 10 mg.
Note that the area to volume ratios are kept constant. In the
erosion/diffusion type matrix system, it is important to keep this
parameter constant to provide same erosion and diffusional flux.
The dose proportionality data, shown in FIG. 8, demonstrate the
varied rates. In FIG. 8, the 10 mg tablet is circular shape, and
the 20 mg and 40 mg tablets are oval shaped tablets. The shape of
the tablets is critical to achieve the desired diffusion
characteristics.
Example 4: Modified Release Memantine
[0108] The present example demonstrates exemplary 6 hour and 12
hour release formulations of memantine hydrochloride.
[0109] 40 mg (6 hour) formulations with total 300 to 600 mg fill
weight were developed. The total weight was 200 mg for "6 Hour"
formulation used in the pharmacokinetic study. The study optimized
flow and compression properties of the tablet formulation. A series
of batches were prepared with varying amount of lactose monohydrate
as filler to study its effect on flow and compression properties.
The specific objectives of this series of batches are as follows:
[0110] To study the effect of level of lactose monohydrate on the
powder flow and compression properties, 400 mg, 500 mg and 600 mg
tablet weight. [0111] To study the effect of increase in amount of
lactose on dissolution profiles, 400 mg, 500 mg and 600 mg tablet
weight. [0112] To study the effect of tablet shape on dissolution
profile: circular and oval. [0113] To investigate if the
formulations are dose proportional at higher levels of lactose at
400 mg and 600 mg tablet weight. [0114] To study the effect of
storage conditions on the product performance.
[0115] The following Table shows the 6 hour formulations:
TABLE-US-00007 TABLE 7 Item A B C D Memantine HCl 40 40 40 40
Synchron KF 130 130 130 130 Lactose 112 206 300 394 Monohydrate
Cab-O-Sil .RTM. 3 4 5 6 Talc 13.5 18 22.5 27 Mg stearate 1.5 2 2.5
3 Total 300 400 500 600
These lots were subdivided further. The reasons for subdivision are
given in the table below.
TABLE-US-00008 TABLE 8 Tablet weight Strength Hardness Purpose of
Sublots Shape Dimension (mg) (mg) (kP) experiment A Circular
11/32'' 300 40 10.6-12.8 BA Circular 11/32'' 400 40 9.5-15.9 To
test dose BB Circular 11/32'' 200 20 10.2-11.8 proportionality at
BC Circular 5/16'' 100 10 3.6-4.6 lower fill wt BD Oval 0.296''
.times. 0.57'' 400 40 11.8-12.3 Effect of tablet shape on 40 mg CA
Circular 7/16'' 500 40 3.7-4.8 Effect of tablet CB Circular 7/16''
500 40 12.1-12.6 hardness CC Circular 7/16'' 500 40 19.1-19.6 DA
Circular 7/16'' 600 40 11.7-13.5 To test dose DB Circular 11/32''
300 20 11.0-12.8 proportionality at DC Circular 5/16'' 150 10
8.2-9.7 Higher fill wt
[0116] The powder properties of the final blends for compression
were evaluated. During compression, excellent powder flow through
the hopper was visually observed. The following Table presents the
results of powder testing.
TABLE-US-00009 TABLE 9 Lot # Compressibility Flowability Index A 12
57.5 B 10 58.0 C 10 62.0 D 15 59.0
[0117] The results above indicate that when the level of lactose
was increased from 112 to 394 mg (Tablet weight from 300 mg to 600
mg), there was no significant change in the powder properties. For
all the studied blends, the flow and compression properties are
good.
[0118] The final tablets for each sublots had good hardness and
friability values.
[0119] The effect of different types of lactose and the final
weight on compression processes and dissolution was also studied.
The current formulation study was executed to optimize compression
process, flow and compression properties of the tablet formulation.
A series of batches were prepared with varying amount of lactose,
both grades anhydrous and monohydrate. The following Table details
the formulations.
TABLE-US-00010 TABLE 10 Item A B C D E Memantine HCl 40 40 40 40 40
Synchron KF 130 130 130 130 130 Lactose Monohydrate 18 65 112 -- --
Lactose Anhydrous -- -- -- 65 112 Cab-O-Sil 2 2.5 3 2.5 3 Talc 9
11.25 13.5 11.25 13.5 Mg stearate 1 1.25 1.5 1.25 1.5 Total
weight/tablet 200 250 300 250 300 All weights in mg
[0120] No significant differences in compressibility were observed
between blend with lactose monohydrate compared to those with the
anhydrate. The dissolution data are shown in FIG. 9. The data show
no significant difference between the dissolution profiles for
monohydrate and anhydrate forms of lactose. Increase in amount of
lactose does not affect the release rate. It is concluded that
release rate is dependent on the amount of Synchron KF for these
formulations.
[0121] With respect to the flow and compression properties of
memantine HCl, Synchron KF and lactose, it was observed that
memantine itself has poor flow properties and flowability index is
23.5. This was attributed to the needle shaped particles of the
drug. The flow property of lactose (both forms) was visually
observed to be excellent. Microscopic examination revealed that the
lactose monohydrate particles are larger and are more spherical in
shape. The anhydrate yielded irregular shape agglomerates. Based on
these results, the monohydrate form is preferred.
[0122] The present invention is not to be limited in scope by the
specific embodiments described herein. Indeed, various
modifications of the invention in addition to those described
herein will become apparent to those skilled in the art from the
foregoing description and the accompanying figures. Such
modifications are intended to fall within the scope of the appended
claims.
[0123] It is further to be understood that all values are
approximate, and are provided for description.
[0124] Patents, patent applications, publications, product
descriptions, and protocols are cited throughout this application,
the disclosures of which are incorporated herein by reference in
their entireties for all purposes.
* * * * *