Note: Descriptions are shown in the official language in which they were submitted.
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ORAL DOSAGE FORMULATIONS COMPRISING (ZS, 3S,5R)-2-(3,5-DIFLUOROPHENYL) -3,5-
DIMETHYL-2-MORPHOLINOL AND AN EFFECTIVE STABILIZING AMOUNT OF ALGINIC ACID
This invention relates to discrete oral dosage forms, such as tablets and
capsules, comprising (2S,3S,SR)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-
morpholinol
("active agent") or salts or solvates thereof.
The compound (2S,3S;SR)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-
morpholinol, is most typically prepared and isolated as its hydrochloride
salt, which
can be depicted as follows:
F
o
.."
F
",... ...,
H3C N CH3
H
HCl
This compound, along with certain pharmaceutical products prepared therefrom,
is
described in U.S. Patent No. 5,104,870 (Kelley et al.). In W099/25355 the use
of this
compound for the treatment of addiction to nicotine-containing products, and
especially tobacco products, is disclosed.
Alginic acid is described in the Handbook of Pharmaceutical Excipients, pp.
10-11 (American Pharmaceutical Association 2d Ed. 1994).
Briefly, in one aspect, the present invention provides a discrete oral dosage
form comprising a therapeutically effective amount of (2S,3S,SR)-2-(3,5-
difluorophenyl)-3,5-dimethyl-2-morpholinol or a physiologically acceptable
salt or
solvate thereof, or a solvate of said salt, and an effective stabilizing
amount of alginic
acid.
In another aspect, the present invention provides a method for preventing or
treating attention deficit hyperkinetic disorder or depression, comprising
administration of a discrete oral dosage form of this invention.
In another aspect, the present invention provides the use of a discrete oral
dosage form as defined above in the preparation of a medicament for the
prevention or
treatment of attention deficit hyperkinetic disorder or depression.
Depression states in the treatment of which the discrete oral dosage form of
the present invention is particularly useful are those classified as affective
disorders in
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the Diagnostic and Statistical Manual of Mental Disorders, Third Edition -
Revised,
American Psychiatric Association, Washington D.C. (1987) (DSM-III-R),
including
the mood disorders (DSM-III-R, 296.2X to 296.6X), other specific affective
disorders
(301.13 and 300.40) and bipolar and depressive disorders not otherwise
specified
(296.70 and 311.00).
In another aspect, the present invention provides a method for treating
addiction to nicotine-containing products, especially tobacco-containing
products,
comprising administration of a discrete oral dosage form of this invention.
In another aspect, the present invention provides the use of a discrete oral
dosage form as defined above in the preparation of a medicament for the
treatment of
addiction to nicotine-containing products, especially tobacco-containing
products.
Nicotine-containing products will include tobacco products (e.g. cigarettes,
cigars, pipe tobacco, chewing tobacco etc,) and nicotine replacement products,
such as
nicotine gums, sprays, patches and inhalers and the like. Treatment of
addiction to
I S such nicotine-containing products includes both partial and complete
alleviation of
addiction. Thus, in respect of tobacco products, as well as the cessation of
the
activity, for example smoking, this will also include reducing the level or
frequency of
such activity e.g. reduction of the number of cigarettes smoked in a given
period. In
respect of other nicotine-containing products, treatment will also involve
both
cessation of, and a reduction in the level of, usage of such products.
In another aspect, the present invention provides a method for treating other
conditions referred to in U.S. Patent No. 5,104,870, comprising administration
of a
discrete oral dosage form as defined above. Such conditions include the
following,
with classifications (where indicated) being those adopted in DSM-III-R:
anxiety
disorders, including phobic neuroses (300.00, 300.21, 300.22, 300.23 and
300.29),
anxiety neuroses (300.01, 300.02 and 300.30) and post-traumatic stress
disorder
(309.89); attention deficit disorders (314.00 and 314.01); eating disorders,
including
anorexia nervosa (307.10) and bulimia (307.51); personality disorders,
including
borderline personality disorder (301.83); sexual dysfunctions, including
hypoactive
sexual desire disorder (302.71), female sexual arousal disorder or male
erectile
disorder {302.72), inhibited female orgasm (302.73), inhibited male orgasm
(302.74),
premature ejaculation (302.75), dyspareunia (302.76), vaginismus (306.51) and
sexual
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3
dysfunction not otherwise specified (302.70); headaches, including migraine,
muscle
contraction and mixed (i.e. combination of migraine and muscle contraction)
headaches; and narcolepsy-cataplexy syndrome, a condition characterised by
excessive sleepiness (narcolepsy) often taking the form of sleep attacks,
episodes of a
seemingly irresistible need to sleep usually lasting for about fifteen minutes
or less,
together with brief (often lasting less than a minute) periods of loss of
muscle tone
(cataplexy) occurring in association with the expression of emotion.
In a preferred aspect, the present invention provides a method for preventing
or treating attention deficit hyperkinetic disorder, comprising administration
of a
discrete oral dosage form of this invention.
In another preferred aspect, the present invention provides the use of a
discrete
oral dosage form as defined above in the preparation of a medicament for the
prevention or treatment of attention deficit hyperkinetic disorder.
In another aspect the discrete oral dosage form may be further used in human
medicine: to alleviate symptoms of withdrawal consequent upon the cessation of
illicit
drug abuse; to potentiate the analgesia induced by morphine or a like opiate
analgesic,
for example in the care and treatment of terminally-ill cancer patients; to
prevent
functional impairment and drowsiness following administration of a drowsiness-
inducing benzodiazepine tranquillizer - suitable indications for concomitant
administration of a said compound or salt and such a benzodiazepine include a)
treatment of mixed anxiety and depression in situations where functional
impairment
or drowsiness is undesirable, and b) treatment of anxiety in situations where
functional impairment or drowsiness is undesirable; to prevent memory loss
following
administration of a benzodiazepine tranquillizer; to restore mental
functioning acutely
impaired consequent upon ethanol ingestion; to suppress prolactin release or
secretion, for example in the suppression of lactation post partum or in the
treatment
of galactorrhoea, hyperprolactinaemia, amenorrhoea resulting from
hyperprolactinaemia and prolactin-sensitive mammary cancer; or to treat memory
loss
and other memory deficits associated with benign senility.
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4
The discrete oral dosage form of this invention is typically a tablet or
capsule
and can be prepared by standard methods. For example, tablets of this
invention can
be prepared by wet granulation or direct compression.
The discrete oral dosage forms of this invention contain a therapeutically
effective amount of the active agent or a physic~logically acceptable salt or
solvate
thereof or a solvate of said salt. Generally, the amount needed to be
therapeutically
effective is calculated based on the weight of the active agent itself and not
any
associated counter ions or solvent. For example, the active agent is typically
prepared
as its hydrochloride salt, but the desired amount is usually based on the
amount of
active agent not including the weight of associated HCI.
The active agent (2S,3S,SR)-2-(3,S-difluorophenyl)-3,5-dimethyl-2-
morpholinol, as well as its hydrochloride salt, is known and can be prepared
by known
techniques, particularly as described in U.S. Patent No. 5,104,870 (Kelley et
al.).
Generally, the discrete oral dosage forms of this invention comprise at least
0.1 mg of active agent, or a salt or solvate thereof calculated to give at
least 0.1 mg of
active agent.
Generally, the discrete oral dosage forms of this invention comprise at least
0.1 % by weight of alginic based on total weight of the tablet or capsule,
preferably at
least 2 % by weight, and most preferably at least 5 % by weight alginic acid.
Particularly preferred alginic acid is alginic acid NF.
As used herein "% by weight", or "weight %", or "wt %", "% w/w", or like
terms, means a percentage by weight, based on the total weight of the
composition.
Unless otherwise indicated, percentages herein are given as percent by weight
of the
total weight of a discrete oral dosage form.
Alginic acid may be obtained from any suitable source, such as Mendell. In
general, the molecular weight is not critical, but is typically from 20,000 to
200,000.
Typically the pH of the alginic acid is 1.5 to 3.5 for a 3% weight/volume
aqueous
dispersion.
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Preferably, the discrete oral dosage forms of this invention further comprise
standard excipients such as binder, filler, lubricant, disintegrant, or
glidant. The
discrete oral dosage forms of this invention may also contain stabilizers in
addition to
the alginic acid.
Filler, sometimes also referred to as carrier, may be any suitable filler.
Preferably, the filler is selected from the group consisting of mannitol,
sucrose,
lactose, and microcrystalline cellulose fillers. Lactose, particularly lactose
monohydrate, is most preferred. Preferably the discrete oral dosage forms
contain
from 40 to 95 % by weight, more preferably from 55 to 90 % by weight, of
filler.
Preferably, the discrete oral dosage forms of this invention contain from 1 to
10 percent of a disintegrant. Disintegrants may be any suitable disintegrant.
Preferred disintegrants are glucopyranose compounds. Suitable glucopyranose
compounds are typically a poly-a- or poly-(3-glucopyranose compound in which
some
of the hydroxyl groups have been converted to carboxy alkyl (e.g.,
carboxymethyl)
ether moieties. Some of the carboxy alkyl ether moieties may be in the form of
a
pharmaceutically acceptable salt (e.g., a sodium salt). Preferably, the
glucopyranose
compound is a sodium starch glycolate. Sodium starch glycolate is described in
the
Handbook of Pharmaceutical Excipients, pg. 462-466 (American Pharmaceutical
Association 2d Ed. 1994}. Most preferably, the glucopyranose compound is a low
pH
glucopyranose compound. By "low pH" is generally meant that a 3.3% aqueous
dispersion of the compound exhibits a pH of from 1 to S. The molecular weight
is not
critical, but is typically from 500,000 to 1,000,000. An example of a suitable
low pH
compound is available as EXPLOTAB~ LOW pH from Mendell (a Penwest
Company; 2981 Route 22, Patterson, NY, USA 12563-9970). See also,
EXPLOTAB~ Low pH Sodium Starch Glycolate Product Sheet (Mendell 1996).
Other suitable glucopyranose compounds include low pH croscarmellose sodium
(see,
for example, Handbook of Pharmaceutical Excipients, pg. 141 ).
Preferably, the discrete oral dosage forms of this invention contains from 0.1
to 5 percent of a lubricant. Lubricants that may be employed in carrying out
the
present invention include, but are not limited to, glyceryl behenate,
magnesium
stearate, and stearic acid. Glyceryl behenate and magnesium stearate are
preferred.
Magnesium stearate is particularly preferred.
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6
The discrete oral dosage form may be prepared by any suitable method of
pharmacy that includes the step of bringing into association the active agent,
the
alginic acid, and any other ingredients. Typically a filler or carrier is used
and is first
mixed with the alginic acid and one or more of the optional ingredients such
as
lubricant, stabilizer, and/or disintegrant. In general, the formulations of
the invention
are prepared by uniformly and intimately admixing the active agent
hydrochloride salt
with solid particulate carrier, alginic acid and optional ingredients, and
then, if
necessary, shaping the resulting mixture. For example, a tablet may be
prepared by
compressing or molding a powder or granules containing the active compound,
with
one or more optional ingredients. Compressed tablets may be prepared by
compressing, in a suitable machine, the compound in a free-flowing form, such
as a
powder or granules optionally mixed with a binder, lubricant, inert diluent,
and/or
surface active/dispersing agent(s). Molded tablets may be made by molding, in
a
suitable machine, the powdered compound moistened with an inert liquid binder.
Capsules may be prepared by filling a two piece hard gelatin capsule with the
active
agent, carrier, and accessory ingredients.
Oral dosage forms of the present invention are useful as antidepressants in
the
prevention or treatment of depression, obesity, and attention deficit
disorder, or aiding
in smoking cessation, in subjects, particularly humans, in need thereof, and
for all the
uses described in U.S. Patent No. S, I 04,870.
The present invention is illustrated in the following working examples, in
which "NF" means National Formulary grade and "mg" means milligrams.
EXAMPLES
The active agent hydrochloride salt can be prepared as described in the '870
patent.
The active agent, (2S,3S,SR)-2-(3,S-difluorophenyl)-3,5-dimethyl-2-
morpholinol, is unstable in the presence of common excipients used in the
production
of oral dosage forms. The rate of decomposition of the active agent can be
unacceptably rapid. Stability was determined by measuring ("assaying") the
amount
by weight of active ingredient, and the amount of impurities by the amount of
area
in an HPLC analysis. The % by weight of active remaining is referred to as "%
label
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7
claim" or "LC". Instability is generally indicated by assay values of less
than 90%
label claim, and impurity levels of 3% or higher. Preferably, formulations
will be
stable for more than 3 months, and most preferably, for more than 6 months.
Comparative Example C1
Tablets were prepared containing the equivalent of 1 mg of active agent. The
active agent hydrochloride salt was weighed so as to give a calculated amount
of 1 mg
per tablet of free base. The tablets were prepared by sifting each component
except
magnesium stearate and silicon dioxide through a # 20 mesh screen. The sifted
components were added to a V-shell blender and mixed for 1 S minutes. The
magnesium stearate and silicon dioxide were sifted through a # 20 mesh screen
and
added to the V-shell blender. The contents were mixed for a period of 5
additional
minutes. The blend was compressed on a rotary tablet press fitted with 8.6mm
round
tooling, uppers scored and lowers, plain, at approximately 250 mg per tablet.
The
1 S composition of the tablets is summarized below in Table 1.
Table 1
Component Amount pcr tablet,
wt
Active agent, HCl 0.463
Anhydrous Lactose 76.9
Microcrystalline Cellulose20.0
PH 102
Magnesium Stearate 0.400
Crospovidone 2.00
Silicon Dioxide 0.200
The tablets were tested for % label claim and impurities initially and after
one
month at three conditions: 30°C, 40°C with75% relative humidity,
and 50°C. The
results of the stability testing are summarized below in Table 2.
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Table 2
Testing Timepoint Label Claim, weight % Total Impurities, area
Initial 95.7 1.9
30°C 90.8 6.5
40°C/75%RH 76.5 17,7
50°C 78.8 15.0
The data show that the stability of these tablets is unacceptable.
Comparative Examples C2 and C3
Tablets containing 1.25 mg of active agent were prepared as in Comparative
Example C 1 except stearic acid and sodium starch glycolate were used as the
lubricant
and disintegrant, respectively and Comparative Example C2 contained 4.8 wt% of
ascorbic acid and Comparative Example C3 contained 4.8 wt % of citric acid.
The
theory was that the pH and/or antioxidant effects of these carboxylic acids
would
stabilize the formulations. The results of stability testing are summarized
below in
Table 3.
Table 3
Testing Comparative Example C2 Comparative Example C3
Timepoint
Label Claim Total Impurities Label Claim Total Impurities
Weight % Area% Weight % Area
Initial 85.2 2.96 90. I 2.89
As the data show, the stability at the initial test point was poor enough that
there was no need to stare tablets at accelerated conditions. These
compositions were
actually less stable than the composition with no carboxylic acid.
Examples 1-4
Tablets were made containing 4 different amounts of active agent. The active
agent HCl was weighed so as too deliver 0.25 mg, 0.5 mg, 1.25 mg, and 5 mg, of
active agent per tablet for Examples 1-4 respectively, based on conversion
from active
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agent HCl to active agent base. Each of the tablets contained 5% by weight of
alginic
acid.
The active agent hydrocloride salt ("active agent HC1") was first sieved
through a US Standard 30 mesh hand screen to remove any large lumps from the
S article. Next, the active agent HCl was milled with centrifugal mill fitted
with a 0.5
mm screen.
The desired amount of milled active agent HCl was then sieved with a
vibratory screener fitted with a US Standard 14-mesh stainless steel screen.
The
active agent HCI was then charged to V-blender. A 5 cubic foot blender was
used in
the manufacture of the 1.25 mg tablets, whereas a 3 cubic foot blender was
used in the
manufacture of the 0.25 mg and 0.5 mg tablets strengths. A one cubic foot
blender
was used to blend the S mg tablets. The desired amounts of lactose
monohydrate,
modified spray dried, alginic acid and sodium starch glycolate, low pH were
also
sieved with the vibratory screener fitted with a US Standard 14 mesh stainless
steel
screen and added to the blender. The V-blender was then rotated for 20
minutes. The
proper amount of glyceryl behenate was screened with a vibratory screener
fitted with
a US Standard 14 mesh stainless steel screen and added to the blender. The V-
blender
was rotated for an additional 5 minutes.
The active agent HCl tablets were compressed on a rotary tablet press. Round,
S mm diameter, plain-face, standard concave, tooling was used for the
compression.
The target compression weight was 75 mg. Finally, the tablets were dedusted.
The
composition of the tablets is summarized below in Table 4.
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Table 4
Component Example
4
Active agent per Tablet (mg) 0.25 0.5 1.25 5
Active agent HCI, Milled (wt 0.383 0.767 1.92 7,67
%)
Lactose Monohydrate, NF, 87.61 87.23 86.08 80.33
Modified Spray Dried (wt %)
Aiginic Acid, NF (wt %) 5 5 5 5
Sodium Starch Glycolate, NF, 5 5 5 5
(Low pH)
(wt %)
Glyceryl Behenate, NF (wt %) 2 2 2 2
The stability of the tablets was evaluated at three conditions, 25°C
with 60%
relative humidity ("RH"), 40°C with 75% RH, and 50°C with
ambient humidity
5 ("AMB"). The results of the stability evaluation are summarized below in
Table 5. In
Table S, the data for L.C. are wt % and the data for Total Impurity are area
%.
Table 5
Example Example Example Example
1 2 3 4
25C, 60%RH Total L.C. Total L.C. Total L.C. Total L.C.
Impurity Impurity Impurity impurity
Initial 0.53 99.0 0.44 100.00.27 98.0 0.18 98.0
I month 0.73 98.9 NT NT 0.29 98.5 0.18 98.3
3 month 0.68 98.9 NT NT 0.30 98.5 0.25 98.3
5 month NT NT NT NT 0.21 97.8 0.19 98.1
6 month 0.46 99.1 NT NT 0.25 97.3 0.24 98.7
9 month 0.45 96.9 NT NT 0.20 97.4 0.18 97.4
40C, 75%RH
Initial 0.53 99.0 0.44 100.00.27 98.0 0.18 98.0
I month 0.31 98.5 NT NT 0.19 97.5 0.15 97.2
3 month 0.28 97.9 NT NT 0.21 97.7 0.25 99.7
6 month 0.20 99.3 NT NT 0.30 98.2 0.16 97.7
50C, AMB
Initial 0.53 99.0 0.44 100.00.27 98.0 0.18 98.0
I month 0.28 97.7 NT NT 0.18 96.8 0.47 98.9
3 month 0.22 97.7 NT NT 0.19 98.2 0.20 98.4
m ~ - m a i amcu
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11
The data show that alginic acid stabilizes the active agent HCl in these
tablets
at a variety of active agent strengths and at a variety of temperature and
humidity
conditions.
Examples 5 and 6
Tablets were made containing 2 different amounts of active agent. The active
agent HCl was weighed so as to deliver 0.25 mg and S mg, of active agent per
tablet
for Examples 5 and 6 respectively. Each of the tablets contained 10% by weight
of
alginic acid.
Tablets were prepared as in Examples 1-4 except the tablets were film coated
using standard techniques. The film-coating was Opadry, White, YS-1-18034. A
tablet weight of 75 mg was used. The composition of the tablets is summarized
below
in Table 6.
Table 6
Component Example
5 6
Active agent per Tablet (mg) 1.25 S
Active agent HCI, Milled (wt %) 0.383 7.66
Lactose Monohydrate, NF, Modifies Spray Dried (wt %) 87.61 80.84
Alginic Acid, NF (wt %) 10 10
Glyceryl Behenate, NF (wt %) 2 1.5
The stability of the tablets was evaluated initially, after 2 weeks, and after
one
month, each at 40°C and 75% RH. Both lots were packaged in foil/foil
blisters.
Stability was assessed by determination of the total impurity levels and
active agent
content of both formulations. The results of the stability testing are
summarized
below in Table 7, the data for L.C. are wt % and the data for Total Impurity
are area
%.
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Table 7
Example 5 Example
6
40CJ75%RH TotallmpurityL.C. Total L.C.
Impurity
Initial 0.21 107 0.19 100
2 weeks 0.60 110 0.26 99
1 month 1.48 105 0.33 99
Examples 7 and 8
Tablets were made containing 2 different amounts of active agent. The active
agent HCl was weighed so as to deliver 10 mg and 5 mg, of active agent per
tablet far
Examples 7 and 8 respectively. Each of the tablets contained 2.5% by weight of
alginic acid.
Tablets were manufactured as in Examples 1-4 except the tablet diameter was
increased to 6.5 mm, and the tablet weight was increased to 150 mg and 135 mg
for
formulations 7 and 8, respectively. These tablets were not film-coated. The
composition of the tablets is summarized below in Table 8.
Table 8
Component Example
7 8
Active agent per Tablet (mg) 10 5
Active agent HCI, Milled (wt %) 7.66 4.26
Lactose Monohydrate, NF, Modifies 83.84 57.74
Spray Dried (wt %)
Microcrystalline Cellulose PH 113, 0 30
NF (wt %)
Alginic Acid, NF (wt %) 2.5 2.5
Sodium Starch Glycolate, NF, (Low S 5
pH) (wt %)
Magnesium Stearate, NF (wt %) 1 0.5
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Tablets were stored in open and closed vials to assess stability in both
configurations. Stability results are summarized below in Table 9, the data
for L.C.
are wt % and the data for Total Impurity are area %..
Table 9
Example Example Example Example
7, 7, 8, 8,
O en Closed Open Closed
P
40C Total L.C. Total L.C. Total L.C. Total L.C.
75%RH Impurity Impurity Impurity Impurity
Initial 0.39 100.1 0.39 100.1 0.51 99.7 0.51 99.7
2 weeks 0.34 99.3 0.44 99.3 0.36 99.6 0.48 100.0
1 month 0.31 99.9 0.45 99.8 0.35 99.7 0.53 97.8
3 month 0.35 98.9 0.46 99.7 0.37 99.7 0.64 98.8
~ ~ ~
I
Examples 9 and 10
Tablets were made containing 2 different amounts of microcrystalline
cellulose. The active agent HCl was weighed so as to deliver 7.5 mg, of active
agent
per tablet for Examples 9 and 10. Each of the tablets contained S% by weight
of
alginic acid.
Tablets were manufactured as listed above the tablet diameter was 6.5 mm and
the tablet weight was 135 mg. These tablets were not film-coated. The
compositions
of the tablets are summarized below in Table 10.
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Table 10
Component Example
9 10
Active agent per Tablet (mg) 7.5 7.5
Active agent HC1, Milled (wt %) 6.39 6.39
Lactose Monohydrate, NF, Modifies Spray78.11 73.11
Dried (wt %)
Microcrystalline Cellulose PH 102, 5 10
NF (wt %)
Alginic Acid, NF (wt %) 5 5
Sodium Starch Glycolate, NF, (Low pH) 5 5
(wt %)
Magnesium Stearate, NF (wt %) 0.5 0.5
Tablets were stored in open and closed vials to assess stability in both
configurations. Results of stability testing are summarized below in Table 11,
the
data for L.C. are wt % and the data for Total Impurity are area %.
Table 11
Example Example Example Example
9, 9, 10, 10,
Open Closed Open Closed
40C Total L.C. Total L.C. Total L.C. Total L.C.
75%RH Impurity Impurity Impurity Impurity
Initial 0.04 100.9 0.04 100.90.06 98.9 0.06 98.9
1 month 0.05 100.0 0.08 100.40.05 97.3 0.07 98.7
3 month 0.12 99.5 0.13 100.60.14 98.8 0.19 98.5
Examples 11 and 12
Tablets were made containing 2 different amounts of microcrystalline
cellulose. The active agent HCl was weighed so as to deliver 1.25 mg, of
active agent
per tablet for Examples 11 and 12. Each of the tablets contained 5% by weight
of
alginic acid.
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Tablets were .manufactured as listed above except the tablet diameter was 6.5
mm and the tablet weight was 135 mg. These tablets were not film-coated. The
compositions of the tablets are summarized below in Table 12.
S Table 12
Component Example
11 12
Active agent per Tablet (mg) 1.25 1.25
Active agent HCI, Milled (wt %) 1.06 I
.06
Lactose Monohydrate, NF, Modifies 83.44 78.44
Spray Dried (wt %)
Microcrystalline Cellulose PH 102, S 10
NF (wt %)
Alginic Acid, NF (wt %) 5 5
Sodium Starch Glycolate, NF, (Low 5 5
pH) (wt %)
Magnesium Stearate, NF (wt %) 0.5 0.5
Tablets were stored in open and closed vials to assess stability in both
configurations. The results of stability testing are summarized below in Table
13, the
data for L.C. are wt % and the data for Total Impurity are area %.
Table 13
Example Example Example Example
11, 11, 12, 12,
Open Closed Open Closed
40C Total L.C. Total L.C. Total L.C. Total L.C.
75%RH Impurity Impurity Impurity Impurity
Initial 0.05 98.0 0.05 98.0 0.05 98.8 0.05 98.8
1 month 0.04 99.3 0.19 98.3 0.06 99.8 0.16 98.4
3 month 0.10 98.2 0.28 97.6 0.11 96.3 0.32 98.6
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The foregoing is illustrative of the present invention, and is not to be
construed
as limiting thereof. The invention is defined by the following claims, with
equivalents
of the claims to be included therein.
