Note: Descriptions are shown in the official language in which they were submitted.
CA 02550132 2006-06-30
RAPIDLY DISINTEGRATING METHYLCELLULOSE TABLETS
FIELD OF THE INVENTION
The present invention relates to an improved process for preparing
compressed methylcellulose containing tablets which meet USP disintegration
standards.
BACKGROUND OF THE INVENTION
The history of cellulose ethers, such as methylcellulose and
carboxymethylcellulose suggests that these agents are effective as bulk
laxatives.
Their mechanism of action involves increasing both the water content of, and
the
bulk content of the stool, as well as lubricating the stool; thereby relieving
constipation.
Cellulose ethers have been administered as bulk laxatives in dosage forms
comprising of tablets, suspensions, and bulk powders; the latter as sugar-free
or in
compositions containing high amounts of sugar.
Cellulose ethers administered as suspensions in water may contain high
concentrations of sucrose or other sugars and flavors. In such formulations,
the
sugar competes with the cellulose ether for available water, thereby
preventing the
cellulose ether from hydrating sufficiently to form a gel. The advantages of
using a
suspension formulation is that the cellulose ether is dispersed sufficiently
to avoid
any significant lumping in the digestive tract. However, these suspensions are
viscous, semi-gelatinous, and visually unappealing to the consumer. Another
disadvantage is the unpalatability of the suspensions due to the slimy mouth
feel and
extreme sweetness of such suspensions. Hence, these dosage forms have not
gained
significant consumer acceptance.
Bulk powders of cellulose ethers often exhibit lumping of individual
particles and gelation and thus, remain undissolved as they pass through the
digestive tract. Additionally, administration of bulk powders has caused
cramping,
CA 02550132 2006-06-30
L
nausea, and vomiting in some patients. Therefore, bulk powders are not the
preferred dosage form for cellulose ethers.
Palatable and visually appealing bulk powders have, however, been
accomplished by addition of water or another aqueous liquid to a dry powder
mix of
a water-soluble cellulose ether and a dispersing agent/sweetening component,
typically sugar. This technology is disclosed in South African patent No.
84,1044.
published Sept. 26, 1984. The pitfall with these compositions is that they
contain
about 400 calories of nutritive value per dose, primarily due to the high
sugar
content. This high caloric value is not acceptable to the average consumers or
to
users suffering from blood sugar disorders, including diabetics. Elderly
people are
normally, the common strata of the population that suffers from constipation
and the
more frequent users of laxatives, and are also commonly suffering with blood
sugar
disorders. The consumption of large quantities of sugar could aggravate blood
sugar
disorders.
Sugar encrusted cellulose ethers have been proposed as altematives to the
bulk powders containing high amounts of sugar. Such formulations have 1) less
sugar such as natural sugar or combination of sugars such as sucrose, glucose,
fructose or corn syrup solids; 2) lower caloric value; and 3) are readily
dispersed in
cold aqueous liquids.
Citrucel Orange Flavor, a bulk forming laxative containing methylcellulose
as its active ingredient, was first introduced into the market in 1986. This
product
contains 15 g of sucrose in a 19 g adult dose, which corresponds to a 2 g dose
of
methylcellulose. To decrease the sugar content of this product, a natural
flavored
formula lower in caloric value, and containing only 1 g sucrose, was developed
and
introduced in 1988. Additional patent protection for this product has focused
on
producing a sugar-free and virtually calorie-free powder. The product has a
sugar-
free sweetener, a dispersing agent, other excipients, and flavoring and was
marketed
in 1991 as Sugar Free Citrucel Orange Flavor.
There still remains a need in the art to develop a rapidly disintegrating
solid
dosage form of a bulk agent, preferably methylcellulose, which is convenient
to take
and transport, sugar free, and easily administered to the consumer having
blood
sugar disorders or diabetics, for instance.
-2-
CA 02550132 2009-03-18
,
-~ I
1
SUMMARY OF THE INVENTION
The present invention relates to an improved process for preparing
methylee(lulose tablets which are readily dispersible and meet United States
Pharmacopoeia standards for disintegration. The methylcellulose is compressed
into
tablets which contain an edible calcium salt, in preferred w/w ratios.
Preferably the
tablets rapidly disintegrate, in-vitro in 0. I N hydrochloric acid and water
at 37 ' 0.5 "C.
According to an aspect of the present invention, there is provided a rapidly
disintegrating tablet for oral administration comprising a methylcellulose
having a
viscosity of >1000 cps as the sole active ingredient; a diluent that is an
edible
calcium salt; and a disintegrating agent as an intragranular or extragranular
component, wherein the diluent and the disintegrating agent are separate
ingredients.
DETAILED DESCRIPTION OF THE INVENTION
There is a common belief that tabletted cellulose ethers do not readily
dissolve in the digestive tract because these cellulose ethers are highly
hygroscopic.
The outer portion of the tablet is said to form a gel-like hydrate that
prevents the
tablet from breaking up and greatly retards the hydration of the inner portion
of the
tablet. The present invention overcomes this art recognized problem and
involves
preparation of a novel composition , and process of making, by which a rapidly
disintegrating tablet of inethylcellulose is prepared.
The tablets are prepared by a novel process involving a high-shear wet
granulation method, followed by fluidized bed drying, milling, mixing with the
other
ingredients, and compression.
The present invention is to a methyicellulose tablet which comprises
methylcellulose having a viscosity of > 1000 centipoise, and at least one
excipient
selected from an edible calcium salt. It is recognized that the formulation
will also
include diluents and fillers well known to the skilled artisan.
-~-
CA 02550132 2009-03-18
The tablet formulations of the present invention are advantageous over other
dosage forms of methylcellulose because of their convenience of administration
and
rapid disintegration. This is in contrast to tablets of methylcellulose,
formulated as
100% w/w methylcellulose in a 0.5 gm caplet which have been found not to
disintegrate in 0.1 N HCI solution, using a conventional dissolution apparatus
even
after two hours. The present tablets should disintegrate in 0.1N HCI from
about 20
to about 30 minutes, preferably from about 10 to about 19 minutes, and more
preferably less than 10 minutes; and in water, the tablets should disintegrate
from
about 25 to about 30 minutes, preferably from about 15 to about 24 minutes,
and
more preferably less than 15 minutes.
-3a-
CA 02550132 2006-06-30
~ ~ .
It has been found that low molecular weight (mw) methylcellulose is less
effective for use as a laxative, and therefore is less desirable for use in a
rapidly
disintegrating tablet formulation. Higher molecular weight methylcellulose is
therefore
both desirable and necessary in the present invention. The fibers must have a
sufficient
viscosity to gel and retain water in the gut to provide the stool bulking and
softening for
laxation use.
By using the testing methods for methylcellulose under standard conditions,
such as those found in the USP XXII, p. 894, Apparent Viscosity method for
Methylcellulose, or as discussed in Handbook of Pharmaceutical Excipients,
APhA,
a preferred methylcellulose for use herein should have a viscosity of > 1000
centipoises (cps), preferably > 2000 centipoises, more preferably > 3000
centipoises,
and most preferably >4000 centipoise. Higher molecular weight methylcellulose
than those described is also desirable, however, the commercially availability
of this
grade of methylcellulose being the limiting feature. At present the upper
limit
commercially available is about 6000 cps, which is encompassed within the
scope of
this invention. One presently available methylcellulose product for use herein
is
TM
Methocel A4M, made by Dow Chemical Company, Midland Michigan as Dow
Methocel A4M, having a viscosity of about 3000 to about 5,600 cps, which is
within
75 to 140% of the desired target viscosity herein.
Some of the additional diluents or fillers for use in this formulation are
preferably swellable agents, and may include. but are not limited to, various
grades
TM
of microcrystalline cellulose, such as Avicel PH 101, Avicel PH 102, & Avicel
PH200; Corn starch; or Starch 1500.
The edible calcium salts suitable for use herein include but are not limited
to,
dibasic calcium phosphate dihydrate, calcium phosphate anhydrous, and tribasic
calcium phosphate; or mixtures thereof. A preferred edible calcium salt is the
dibasic calcium phosphate dihydrate salt, which salt also provides good
compressibility.
If microcrystalline cellulose is added, it is preferably from about 50 to 180
microns in size, more preferably about 50. Avicel PH 101 has a mean particle
size
of about 50; Avicel PH 102 has a mean particle size of about 100; and Avicel
PH
200 has a mean particle size of about 190 microns. Preferably the preferred
microcrystalline cellulose is Avicel PH 101.
-4-
CA 02550132 2006-06-30
- c ~
It is noted that the ratio of methylcellulose to edible calcium salt, and
additional diluents will depend upon the diluent chosen, and is within the
skill of the
art to determine with preciseness the necessary ratios.
Suitable ratios for particular diluents however, are described below:
For Methylcellulose:Dibasic calcium phosphate, dihydrate, from about 2 to
about
4:1, preferably from about 2.6-3.1:1;
For Methylcellulose:Calcium phosphate, anhydrous from about 2 to about 4:1,
preferably from about 3.1:1
Methylcellulose:Tribasic calcium phosphate, WG from about 2 to about 4:1,
preferably from about 3.1:1
For Methylcellulose: microcrystalline cellulose, from about 2:1 to about 14:1.
Preferably for Avicei PH 101 from about 2.2-13.5:1; for Avicel PH 102 from
about
2.4- 8.3:1; and for Avicel PH 200 from about 2.4-4:1.
For Methylcellulose:Corn starch from about 7.5 to about 15, preferably from
about
13.5:1;
For Methylcellulose:Starch 1500 , from about 2.0 to about 5.0:1, preferably
from
about 2.4:1;
TM
For Methylcellulose:Explotab, from about 5 to about 25:1, preferably from
about 8.1
to about 21.3:1.
It is recognized that with the edible calcium salt, the formulation must also
have an ingredient which keeps the granules together, i.e. a binding agent. A
preferred binding agent is PVP, or the alternative agents noted below.
In addition to the above noted edible calcium salt(s), optional diluents or
fillers, and binding agent(s), the formulation may also include additional
components such as, but are not limited to, a wetting agent,
(super)disintegrant(s), a
second binding agent(s), dye(s) or colouring agents, and lubricants, which are
-5-
CA 02550132 2008-01-28
preferably used to prepare a tablet that is wetted readily. and is rapidly
disintegrated
in 0.1N hydrochloric acid and water, the USP test standard test for
methylcellulose.
A preferred wetting agent is sodium lauryl sulfate.
A preferred lubricant is magnesium stearate.
TM
A prefen:ed binding agent is polyvinylpyrrolidone, or PVP, such as Povidone
29K/32. Preferably, the PVP is present in an amount of about 4 to about 6.5 %
w/w.
A preferred disintegrating agent is sodium starch glycolate, such as
Explotab . Preferably, the sodium starch glycolate is present in an amount of
about
3 to about 8% w/w.
As various excipents and diluents will be formulated together. and used in
combination herein, suggested % w/w ratios for various formulations are
presented
below. While not all of these ratios include the edible calcium salts, these
are
merely illustrative of the invention and the skilled artisan will readily
recognize how
to formulate the product of this invention with the addition of the edible
calcium
salts.
TM
Sodium lauryl sulfate:Explotab:Dibasic calcium phosphate, di hydrate: Povidone
29K/32:Magnesium stearate include: 0.38-0.40:3.5-7.9:20.6-24.8:4.0-6.5:0.5-1.0
Sodium lauryl sulfate:Explotab:Tribasic calcium phosphate WG : Povidone
29K/32:Magnesium stearate include: 0.40:3.5:21.6:6.4:1.0
Sodium lauryl sulfate:Explotab:Calcium phosphate, anhydrous: Povidone'"`
29K/32:Magnesium stearate include: 0.40:3.5:21.6:6.4:1.0
Methylcellulose:sodium lauryl sulfate (SLS), from about 60 to about 170:1,
preferably from about 155:1-170:1;
Methylcellulose:Povidone preferably PVP 29K/32, from about 8 to about 22:1,
preferably from about 10.4:1-16.7:1;
-6-
CA 02550132 2006-06-30
. s .
Methylcellulose:Magnesium stearate from about 50 to about 150;1, preferably
from
about 58-132:1;
Sodium lauryl sulfate:Explotab:Avicel PH 101 : Povidone 29K/32:Magnesium
stearate include: 0.35-0.46:3.05-6.17:4.38-27.13:4.38-6.66:0.76-1.14
Sodium lauryl sulfate:Explotab:Avicel PH 102 : Povidone 29K/32:Magnesium
stearate include: 0.35-0.46:4.9-6.17:9.21-25.53:4.38-6.66:0.76-1.14
Sodium lauryl sulfate:Avicel PH 200 : Povidone 29K/32:Magnesium stearate
include: 0.38-0.42:19.27-25.53:5.99-6.66:0.94-1.04
Sodium lauryl sulfate:Explotab:Corn starch: Povidone 29K132:Magnesium stearate
include: 0.36-0.38:3.66-7.07:4.35-4.68:4.35-4.68:0.88-0.95
Sodium lauryl sulfate:Explotab:Starch 1500 : Povidone 291CI32:Magnesium
stearate include: 0.36-0.38:3.66-7.07:24.05-25.89:4.35-4.68:0.88-0.95
Not wishing to be limited to the explicit excipients noted above, the
following alternative agents may also be used herein.
Alternatives lubricants to magnesiumNstearate include, but are not limited to,
rM
calcium stearate, sodium stearate, Cab-O-Sil, Syloid, stearic acid and talc.
Alternatives binding agents to PVP include but are not limited to,
hydroxypropylcellulose, hydroxypropyl methylcellulose, acacia, gelatin,
tragacanth,
pregelatinized starch and starch.
Alternatives disintegrants to Explotab include but are not limited to,
sodium carboxymethylcellulose, Ac-di-sol , carboxymethylcellulose, veegum,
alginates, agar, guar, tragacanth, locust bean, karaya, pectin, and
crospovidone.
Alternative wetting agents to sodium lauryl sulfate, include but are not
limited to, magnesium lauryl sulfate.
All of these formulations can be prepared with and without sugar. A sugar-
free formulation has the advantage that it can be administered easily to
consumers
with blood sugar disorders or to diabetics in need of such preparations.
-7-
CA 02550132 2006-06-30
. ,.
Another advantageous property of the present invention is that the
formulations contain calcium, such as dibasic calcium phosphate dihydrate.
These
fotmulations, for instance, will contain approximately an 80 mg/dose,
anticipating
formulating a 0.5gm/tablet X 2 tablets/dose of methylcellulose. If desired the
amount of calcium can be increased in these tablets to provide increased
therapeutic
value to the consumer.
The amount of methylcellulose present in each dose, as well as the number of
doses of laxative taken per day, will depend somewhat on the age, sex, size of
the
patient, severity of the patient's particular problem, the advice of the
treating
physician, if any, and the particular taste and habits of the patient.
Accordingly, the
tablets of this invention are advantageously administered in a single dose
which may
contain as much as 500 to 1000 mg of methyl cellulose tablet, or in a
plurality of
smaller doses containing as little as 250mg per tablet. Most preferably, for
laxative
effect, each tablet will contain about 500mg methylcellulose and the patient
may
take I to 2 tablets per dose. This dosage, of 1000mg should adequately provide
optimal laxative efficacy. Therefore, a preferred range of methylcellulose per
tablet
is optimally from about 450 to 550 mg, preferably about 500mg; or
alternatively
from about 200 to about 300mg for a smaller tablet, preferably about 250mg; or
even in increments of about 125mg tablet, i.e. 75 to 175mg per tablet.
While preferably the compressed tablets are uncoated, they may, if desired,
be coated with any suitable coating agent well known in the art. Suitably the
coating
agents are those used for immediate release purposes and will dissolve in the
gastric
juices. Such coating agents are well known to those skilled in the art and
include,
but are not limited to hydroxypropyl methylcellulose, or methyl cellulose, or
20%
TM
w/w Opadry II, orange in water.
As will readily be seen by the working examples, there are various
combinations
of intra and extragranular mixing which are possible using the ingredients
herein. All
are encompassed within the scope of this invention. Generally, the high
viscosity
methylcellulose, such as Methocel A4M, will first be granulated with a binder,
such as
povidone, a wetting agent, such as sodium lauryl sulfate, and a suitable
colouring agent
to form the intragranular mixture which is then granulated. These granular
components
are then admixed with additional wetting agents, and disintegrating agents and
finally
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CA 02550132 2006-06-30
blended with lubricant. This final granular mixture is then blended and
compressed into
the tablets of the present invention.
Therefore, an aspect of the present invention is a process for preparing a
tablet formulation which comprises
a) blending together to form an intragranular mixture high viscosity
methylcellulose of > 3000cps, a wetting agent, povidone or sodium starch
glycolate,
and an edible calcium salt; and
b) adding to the mixture of step (a) a PVP aqueous solution, or alternatively
spraying the mixture of step (a) with a PVP aqueous solution; and preparing
granulates; and
c) blending together an extragranular mixture of an edible calcium salt, a
wetting agent; a lubricating agent; povidone or sodium starch glycolate or a
mixture
thereof; and
d) compacting the granulates of step (b) with the extragranular mixture of
step (c).
Another aspect of the present invention is a process for the manufacture of a
pharmaceutical tablet, which process comprises mixing
a) granulates comprising high viscosity methylcellulose of > 3000cps, a
wetting
agent, povidone or sodium starch glycolate, an edible calcium salt; and
b) blending together an extragranular mixture of an edible calcium salt, a
wetting agent; a lubricating agent; povidone or sodium starch glycolate or a
mixture
thereof; and
c) compacting the granulates of step (b) with the granular mixture of step
(a); and
d) compressing into a tablet.
Another aspect of the present invention is the method of relieving
constipation by increasing the water content of the stool, or by providing a
lubricating effect on the stool in a mammal in need thereof, which method
comprises
administering to said mammal, an effective amount of a high viscosity
methylcellulose compressed into a tablet with a suitable diluent.
METHODS OF PREPARATION
The following examples illustrates the invention but is not intended to limit
the scope thereof. All parts and percentages are by weight unless otherwise
indicated.
The disintegration time of the formulations described in the Tables below were
obtained by using a conventional disintegration apparatus.
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CA 02550132 2006-06-30
EXAMPLE 1
TABLE I
Swallowable Methytcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 67.27
Dibasic Calcium phosphate, dihydrate 0.0370 4.98
Sodium lauryl sulfate 0.0015 0.20
Dye/Colouring agent 0.0010 0.13
Povidone 29K/32 0.0480 6.46*
DI water q.s. q.s.
Phase B
Phase A 0.5875 79.04
Sodium lauryl sulfate 0.0015 0.20
Sodium starch glycolate 0.0260 3.50
Dibasic Calcium phosphate, dihydrate 0.1245 16.75
Magnesium stearate 0.0038 0.51
TOTAL 0.7433 100.00
The process of preparing the rapidly disintegrating tablet of methylcellulose
is carried out using specified quantities of ingredients, such as those
mentioned in
TABLE I above, using the following steps:
1. Preparation of Povidone K29/32 (PVP) Solution
The specified amount of PVP was weighed and added to the weighed
quantity of water and stirred till all the PVP was dissolved completely.
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CA 02550132 2006-06-30
2. Preparation of Phase A
Accurately weighed amounts of Methocel A4M, calcium phosphate, dibasic
dihydrate, sodium lauryl sulfate, and colouring agent, such as any suitable
FD&C
Aluminium lake, were transferred to a Key Hi-shear granulator and mixed for
about
10 minutes with impellor speed at 135 rpm and chopper speed at 10%. The PVP
solution was sprayed onto the mixture in the granulator at a rate of approx.
>200
mUmin. Once addition of PVP solution was complete, the chopper was stopped.
The mixing was continued in the granulator till resistance reads about 130-135
watts
and the time noted to reach that wattage. A sample was withdrawn from the wet
granulation to record loss on drying (% LOD). The moist granules were dried in
the
Aeromatic Fluid bed dryer in portions till the % LOD reading approximated 1.0-
3.0%. The temperature of the air in the fluid bed dryer was maintained at
approx.
90-95 "C and the sample was found to be dry at an outlet air temperature of
approx.
32-52 C. The dried granules were milled through a 12# screen in the Fitz Mill
at a
high speed. The granules were weighed and percent yield calculated. The
moisture
content was measured for the dry granules. A sample from the granules was
withdrawn and analyzed for particle size distribution, bulk and tap density,
flow
index, and moisture studies. The granules were weighed and ingredients of
Phase B
were calculated based on the weight of remaining granules.
3. Preparation of the Final Blend
To the weighed milled granules produced in Phase A above, specified
amounts of sodium lauryl sulfate, sodium starch glycolate (Explotab ), and
dibasic
calcium phosphate, dihydrate were added into the V-blender and mixed about 10
minutes. Magnesium stearate was then added to the blend and mixed for an
additional 3 minutes or so. Samples from different sections of the V-blender
were
drawn and submitted for analyzing blend uniformity. A sample from the final
blend
was analyzed for particle size distribution, bulk and tap density, flow index,
and
moisture studies. The granules were then weighed.
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CA 02550132 2006-06-30
4. Compression of methylcellulose tablets
The final blend was charged into the hopper of a Stokes single punch `F'
tablet press and compressed into caplets with a suitable tooling. Target
hardness
de~ired is between 10 and 25, preferably 8-12 SCU, a preferred target weight
of each
tablet of less than 750 mg; an estimated friability of less than 2.0%, more
preferably
less than 1.0%, and target disintegration times below 30 minutes in water and
acid
(shorter disintegration times, less than 10 minutes, more preferably less than
8
minutes, in 0.1 N HCI and less than 15 minutes in water, more preferably about
8
minutes, are preferred). The tablets were packaged in Ziplock bags. The
tablets
were tested for weight variation, hardness, disintegration in acid and water,
friability,
moisture (% LOD), thickness, viscosity, and content uniformity.
The formulation in TABLE I exhibited a disintegration time of less than 5
minutes in 0.1 N HCl and less than 9 minutes in water by the conventional USP
method using Disintegration Apparatus with disks.
The disintegration time for the formulation of Table 1, Example 1, was less
than 5 minutes in 0.1 N HCI was less than 9 minutes in water.
It is noted that Examples 2 to 6, and 11 to 15 are Avicel based formulations,
and Examples 7 to10 are strach based formulations which do not contain an
edible
calcium salt excipients. These are merely for illustration purposes, and may
be
formulated to include the edible calcium salts as desired using the teachings
of this
invention and working examples 1, and 16 to 23.
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CA 02550132 2006-06-30
EXAMPLE 2
A formulation containing both Avicel PH 1010 and Explotab , intra and
extragranularly as shown in TABLE II below, exhibited an average
disintegration
time of less than 1 minute in 0.1 N HCI at 37 = 0.5"C using the automated
disintegration apparatus.
TABLE 11
Swallowable Methylcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 60.31
Avicel PH 1010 0.0370 4.46
Sodium lauryl sulfate 0.0015 0.18
Povidone 29K/32 0.0370 4.46
Explotab 0.0300 3.62
DI water q.s. q.s.
Phase B
Phase A 0.6055 73.03
Sodium lauryl sulfate 0.0017 0.21
Sodium starch glycolate 0.0253 3.05
Avicel PH 101 0.1880 22.67
Magnesium stearate 0.0086 1.04
TOTAL 0.8291 100.00
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CA 02550132 2006-06-30
EXAMPLE 3
A formulation containing Avicel PHIO1 intragranularly, extragranular Avicel
PH
102 and Explotabt9, intra and extragranularly, as shown below in TABLE 1II
exhibited an average disintegration time of less than 3 minutes in 0.1 N HCI
at 37 '
0.5 C using the automated disintegration apparatus.
TABLE III
Swallowable Methylcellulose Tablets
Formula g/tablet (% w!w)
Ingredient
Phase A
Methocel A4M 0.5000 59.24
Avicel PH 1010 0.0370 4.38
Sodium lauryl sulfate 0.0015 0.18
Povidone 29K/32 0.0370 4.38
Explotab 0.0300 3.56
Dye/colouring agent 0.0040 0.47
DI water q.s. q.s.
Phase B
Phase A 0.6095 72.21
Sodium lauryl sulfate 0.0015 0.18
Sodium starch glycolate 0.0220 2.61
Avicel PH 102@ 0.2035 24.11
Magnesium stearate 0.0075 0.89
TOTAL 0.8440 100.00
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CA 02550132 2006-06-30
EXAMPLE 4
A formulation containing Avicel PH I Oi intragranularly, extragranular
Avicel PH
102 and Explotab intra and extragranularly as shown in TABLE IV below
exhibited
an average disintegration time of less than 2 minutes in 0. i N HCl at 37 0.5
"C using
the automated disintegration apparatus.
TABLE IV
Swallowable Methylcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 59.52
Avicel PH 101 0.0370 4.41
Sodium lauryl sulfate 0.0015 0.18
Povidone 29K/32 0.0370 4.41
Explotab 0.0300 3.57
DI water q.s. q.s.
Phase B
Phase A 0.6055 72.08
Sodium lauryl sulfate 0.0015 0.18
Sodium starch glycolate 0.0220 2.62
Avicel PH 102@ 0.2035 24.23
Magnesium stearate 0.0075 0.89
TOTAL 0.8400 100.00
In an alternative embodiment of Example 4 a coated version of the formulation
shown in TABLE IV was tested for disintegration time. The coating solution
used was
20% w/w Opadry II, Orange in water. The average disintegration time of coated
tablets
was less than one minute in 0.1N HCI at 37 ' 0.5 C using the automated
disintegration
apparatus.
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CA 02550132 2006-06-30
EXAMPLE 5
A formulation containing Avicel PH101 intragranularly, extragranular
Avicel PH 102 and Explotab intra and extragranularly as shown in TABLE V
exhibited an average disintegration time of less than one minute in 0.1N HCI
at 37 '
0.5 C using the automated disintegration apparatus.
TABLE V
Swallowable Methylcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 60.24
Avicel PH 1010 0.0370 4.46
Sodium lauryl sulfate 0.0015 0.18
Povidone 29K/32 0.0370 4.46
Explotab 0.0300 3.62
D1 water q.s. q.s.
Phase B
Phase A 0.6055 72.95
Sodium lauryl sulfate 0.0015 0.18
Sodium starch glycolate 0.0110 1.33
Avicel PH 102 0.2045 24.64
Magnesium stearate 0.0075 0.90
TOTAL 0.8300 100.00
-16-
CA 02550132 2006-06-30
EXAMPLE 6
A formulation containing Avicel PH101 intragranularly, extragranular
Avicel PH102 and no Explotab as shown in TABLE VI below, exhibited an
average disintegration time of less than 3 minutes in 0.1 N HCI and less than
2
minutes at 37 = 0.5 "C using the automated disintegration apparatus. The
disintegration times using the conventional apparatus were about 1 minute in
acid
and less than 2 minutes in water.
TABLE VI
Swallowable MethYlcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 67.94
Avicel PH 1010 0.0370 5.03
Sodium lauryl sulfate 0.0015 0.20
Povidone 29K/32 0.0370 5.03
Dye/Colouring Agent 0.0010 0.14
DI water q.s. q.s.
Phase B
Phase A 0.5765 78.34
Sodium lauryl sulfate 0.0011 0.15
Avicel PH 102 0.1527 20.75
Magnesium stearate 0.0056 0.76
TOTAL 0.7359 100.00
-17-
CA 02550132 2006-06-30
EXAMPLE 7
A formulation containing corn starch intragranularly, extragranular Starch
1500 and no Explotab as shown in TABLE VII exhibited an average
disintegration
time of less than 16 minutes in 0.1N HCI at 37 = 0.5 C using the automated
disintegration apparatus.
TABLE VII
Swallowable Methylcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 63.29
Corn starch 0.0370 4.68
Sodium lauryl sulfate 0.0015 0.19
Povidone 29K/32 0.0370 4.68
Dye/Colouring Agent 0.0010 0.13
DI water q.s. q.s.
Phase B
Phase A 0.5765 72.97
Sodium lauryl sulfate 0.0015 0.19
Starch 1500 0.2045 25.89
Magnesium stearate 0.0075 0.95
TOTAL 0.7900 100.00
-18-
CA 02550132 2006-06-30
EXAMPLE 8
A formulation containing corn starch intragranularly, extragranular Starch
1500 and intragranular Explotab as shown in TABLE VIII exhibited an average
disintegration time of less than 14 minutes in 0. I N HCI at 37 = 0.5 "C using
the
automated disintegration apparatus.
TABLE VIII
Swallowable Methylcellulose Tablets
Formula g/tablet (% wlw)
Ingredient
Phase A
Methocel A4M 0.5000 61.00
Corn starch 0.0370 4.51
Sodium lauryl sulfate 0.0015 0.18
Povidone 29K/32 0.0370 4.51
Explotab 0.0300 3.66
Dye/Colouring Agent 0.0010 0.12
DI water q.s. q.s.
Phase B
Phase A 0.6065 73.98
Sodium lauryl sulfate 0.0015 0.18
Starch 1500 0.2045 24.93
Magnesium stearate 0,0075 0.91
TOTAL 0.8200 100.00
- 19-
CA 02550132 2006-06-30
EXAMPLE 9
A formulation containing corn starch intragranularly, extragranular Starch
1500 and intra as well as extragranular Explotab as shown in TABLE IX
exhibited
an average disintegration time of less than 13 minutes in 0.1 N HCI at 37 =
0.5 "C
using the automated disintegration apparatus.
TABLE IX
Swallowable Methylcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 59.88
Corn starch 0.0370 4.43
Sodium lauryl sulfate 0.0015 0.18
Povidone 29K/32 0.0370 4.43
Explotab 0.0300 3.59
Dye/Colouring Agent 0.0010 0.12
DI water q.s. q.s.
Phase B
Phase A 0.6065 72.63
Sodium lauryl sulfate 0.0015 0.18
Starch 1500 0.2045 24.49
ExplotabtlD 0.0150 1.80
Magnesium stearate 0.0075 0.90
TOTAL 0.8350 100.00
-20-
CA 02550132 2006-06-30
EXAMPLE 10
A formulation containing com starch intragranularly, extragranular Starch
1500 and intra as well as extragranular Explotab (in higher amounts than
shown
above in Example 9, TABLE IX) as shown in TABLE X exhibited an average
disintegration time of less than 11 minutes in 0.1 N HCI and less than 18
minutes in
water at 37 = 0.5 "C using the automated disintegration apparatus.
TABLE X
Swallowable Methylcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 58.82
Corn starch 0.0370 4.35
Sodium lauryl sulfate 0.0015 0.18
Povidone 291U32 0.0370 4.35
Explotab 0.0300 3.53
Dye/Colouring Agent 0.0010 0.12
DI water q.s. q.s.
Phase B
Phase A 0.6065 71.35
Sodium lauryl sulfate 0.0015 0.18
Starch 1500 0.2045 24.05
Explotab 0.0300 3.54
Magnesium stearate 0.0075 0.88
TOTAL 0.8500 100.00
-21 -
CA 02550132 2006-06-30
EXAMPLE 1 I
Various formulation containing Avicel PH 101 intragranularly and different
levels of extragranular Avicel PH 102 (as shown in Examples 6, 7, and 8
above)
were made to observe their effect on disintegration time of the tablets.
The formulation in TABLE XI, below, exhibited an average disintegration
time of less than one minute in 0.1 N HCI and less than 2 minutes in water at
37 ' 0.5
"C using the automated disintegration apparatus. The conventional
disintegration
apparatus yielded less than 1 minute in both acid and water.
TABLE XI
Swallowable Methylcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 62.42
Avicel PH 101 0.0370 4.62
Sodium lauryl sulfate 0.0015 0.19
Povidone 29K/32 0.0480 5.99
Dye/Colouring Agent 0.0010 0.12
DI water q.s. q.s.
Phase B
Phase A 0.5875 73.34
Sodium lauryl sulfate 0.0015 0.19
Avicel PH 102 0.2045 25.53
Magnesium stearate 0.0075 0.94
TOTAL 0.8010 100.00
-22-
CA 02550132 2006-06-30
EXAMPLE 12
The formulation in TABLE XII exhibited an average disintegration time of
less than 5 minutes in 0.1 N HCI and less than 7 minutes in water at 37 ' 0.5
"C using
the automated disintegration apparatus. The conventional disintegration
apparatus
yielded less than 5 minutes in acid and less than 8 minutes in water.
TABLE XII
Swallowable Methylcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 69.35
Avicel PH l01 0.0370 5.13
Sodium lauryl sulfate 0.0015 0.21
Povidone 29K/32 0.0480 6.66
Dye/Colouring Agent 0.0010 0.14
Dt water q.s. q.s.
Phase B
Phase A 0.5875 81.48
Sodium lauryl sulfate 0.0015 0.21
Avicel PH 102 0.1245 17.27
Magnesium stearate 0.0075 1.04
TOTAL 0.7210 100.00
-23-
CA 02550132 2006-06-30
EXAMPLE 13
The formulation in TABLE XIII exhibited an average disintegration time of
less than 10 minutes in 0.1 N HCI and less than 14 minutes in water at 37 =
0.5 "C
using the automated disintegration apparatus. The conventional disintegration
apparatus yielded less than 14 minutes in acid and less than 22 minutes in
water.
TABLE XIII
Swallowable Methylcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 76.10
Avicel PH 101 0.0370 5.63
Sodium lauryl sulfate 0.0015 0.23
Povidone 29K/32 0.0480 7.31
Dye/coloring agent 0.0010 0.15
DI water q.s. q.s.
Phase B
Phase A 0.5875 89.42
Sodium lauryl sulfate 0.0015 0.23
Avicel PH 102 0.0605 9.21
Magnesium stearate 0.0075 1.14
TOTAL 0.6570 100.00
-24-
CA 02550132 2006-06-30
EXAMPLE 14
Two formulations containing Avicel PH101 intragranularly with different
levels of extragranular Avicel PH 200 (shown in TABLE XIV and XV below)
were made to observe the effect on disintegration time of tablets.
The formulation in TABLE XIV exhibited an average disintegration time of
less than 7 minutes in 0.1 N HCI and less than 9 minutes in water at 37 ' 0.5
"C using
the automated disintegration apparatus. The conventional disintegration
apparatus
yielded less than 8 minutes in acid and less than 13 minutes in water.
TABLE XIV
Swallowable MethYlcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 62.42
Avicel PH 101 0.0370 4.62
Sodium lauryl sulfate 0.0015 0.19
Povidone 29K/32 0.0480 5.99
Dye/Coloring Agent 0.0010 0.12
DI water q.s. q.s.
Phase B
Phase A 0.5875 73.34
Sodium lauryl sulfate 0.0015 0.19
Avicel PH200 0.2045 25.53
Magnesium stearate 0.0075 0.94
TOTAL 0.8010 100.00
- 25
CA 02550132 2006-06-30
EXAMPLE 15
The formulation in TABLE XV exhibited an average disintegration time of
less than 4 minutes in 0.1 N HCI and less than 7 minutes in water at 37 = 0.5
"C using
the automated disintegration apparatus. The conventional disintegration
apparatus
yielded less than 5 minutes in acid and less than 9 minutes in water.
TABLE XV
Swallowable Methylcelfulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 69.35
Avicel PH101 0.0370 5.13
Sodium lauryl sulfate 0.0015 0.21
Povidone 29K/32 0.0480 6.66
Dye/Coloring Agent 0.0010 0.14
DI water q.s. q.s.
Phase B
Phase A 0.5875 81.48
Sodium lauryl sulfate 0.0015 0.21
Avicel PH2000 0.1245 17.27
Magnesium stearate 0.0075 1.04
TOTAL 0.7210 100.00
-26-
CA 02550132 2006-06-30
EXAMPLE 16
A formulation containing a calcium source from the intragranular and
extragranular excipient, dibasic calcium phosphate, dihydrate with
extragranular
Explotab is shown in TABLE XVI.
The formulation in TABLE XV1 exhibited an average disintegration time of
less than 6 minutes in O.IN HCl and less than 9 minutes in water at 37 ' 0.5
C using
the automated disintegration apparatus. The conventional disintegration
apparatus
yielded less than 5 minutes in acid and less than 12 minutes in water.
TABLE XVI
Swallowable Methylcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 66.93
Dibasic Calcium phosphate, dihydrate 0.0370 4.95
Sodium lauryl sulfate 0.0015 0.20
F, D, and C Yellow #6 0.0010 0.13
Povidone 29K/32 0.0480 6.43
DI water q.s. q.s.
Phase B
Phase A 0.5875 78.65
Sodium lauryl sulfate 0.0015 0.20
Sodium starch glycolate 0.0260 3.48
Dibasic Calcium phosphate, dihydrate 0.1245 16.67
Magnesium stearate 0.0075 1.00
TOTAL 0.7470 100.00
-27-
CA 02550132 2006-06-30
EXAMPLE 17
A formulation containing a calcium source from the intra and extragranular
excipient, dibasic calcium phosphate, dihydrate with a higher amount of
extragranular Explotab than in Example 17, is shown below in TABLE XVII.
The formulation in TABLE XVII exhibited an average disintegration time of
less than 9 minutes in 0.1 N HCI and less than 14 minutes in water at 37 ' 0.5
"C
using the automated disintegration apparatus. The conventional disintegration
apparatus yielded less than 6 minutes in acid and less than 12 minutes in
water.
TABLE XVII
Swallowable Methylcellulosc Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 65.19
Dibasic Calcium phosphate, dihydrate 0.0370 4.82
Sodium lauryl sulfate 0.0015 0.20
F,D,andCYellow#6 0.0010 0.13
Povidone 29K/32 0.0480 6.26
DI water q.s. q.s.
Phase B
Phase A 0.6105 79.60
Sodium lauryl sulfate 0.0015 0.20
Sodium starch glycolate 0.0230 3.00
Dibasic Calcium phosphate, dihydrate 0.1245 16.23
Magnesium stearate 0.0075 0.97
TOTAL 0.7670 100.00
-28-
CA 02550132 2006-06-30
EXAMPLE 18
Formulations containing a calcium source from the intra and extragranular
excipient, dibasic calcium phosphate, dihydrate with different levels of
extragranular
Explotab , in combination with similar amount of intragranular Explotab , are
shown below in TABLE XVIII and XIX (Example 19).
The formulation in TABLE XVIII exhibited an average disintegration time
of less than 6 minutes in 0.1 N HCl and less than 11 minutes in water at 37
0.5 "C
using the automated disintegration apparatus.
TABLE XVIII
Swallowable Methylcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0,5000 65.19
Dibasic Calcium phosphate, dihydrate 0.0370 4.82
Sodium lauryl sulfate 0.0015 0.20
Sodium starch glycolate 0.0230 3.00
F, D, and C Yellow #6 0.0010 0.13
Povidone 29K/32 0.0480 6.26
DI water q.s. q.s.
Phase B
Phase A 0.6105 79.60
Sodium lauryl sulfate 0.0015 0.20
Sodium starch glycolate 0.0230 3.00
Dibasic Calcium phosphate, dihydrate 0.1245 16.23
Magnesium stearate 0.0075 0.97
3o TOTAL 0.7670 100.00
-29-
CA 02550132 2006-06-30
EXAMPLE 19
The formulation in TABLE XIX exhibited an average disintegration time of
less than 9 minutes in 0. ! N HCI and less than 14 minutes in water at 37 =
0.5 "C
using the automated disintegration apparatus.
TABLE XIX
Swallowable Methylcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 63.86
Dibasic Calcium phosphate, dihydrate 0.0370 4.73
Sodium lauryl sulfate 0.0015 0.19
Sodium starch glycolate 0.0230 2.94
F, D, and C Yellow #6 0.0010 0.13
Povidone 29K/32 0.0480 6.13
DI water q.s. q.s.
Phase B
Phase A 0.6105 77.97
Sodium lauryl sulfate 0.0015 0.19
Sodium starch glycolate 0.0390 4.98
Dibasic Calcium phosphate, dihydrate 0.1245 15.90
Magnesium stearate 0.0075 0.96
TOTAL 0.7830 100.00
-30-
CA 02550132 2006-06-30
,
EXAMPLE 20
Formulations containing a calcium source from the intra and extragranular
excipient, dibasic calcium phosphate, dihydrate with extragranular Explotab
are
shown in TABLE XX and XXI (Example 21) below.
The formulation in TABLE XX exhibited an average disintegration time of
less than 5 minutes in 0.1 N HCl and less than 13 minutes in water at 37 ' 0.5
"C
using the automated disintegration apparatus.
TABLE XX
Swallowable Methylcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 66.89
Dibasic Calcium phosphate, dihydrate 0.0370 4.95
Sodium lauryl sulfate 0.0015 0.20
F, D, and C Yellow #6 0.0010 0.13
Povidone 29K/32 0.0300 4.01
DI water q.s. q.s.
Phase B
Phase A 0.5695 76.19
Sodium lauryl sulfate 0.0015 0.20
Sodium starch glycolate 0.0445 5.95
Dibasic Calcium phosphate, dihydrate 0.1245 16.66
Magnesium stearate 0.0075 1.00
TOTAL 0.7475 100.00
-31-
CA 02550132 2006-06-30
EXAMPLE 21
The formulation in TABLE XXI exhibited an average disintegration time of
less than 7 minutes in 0.1N HCl and less than 9 minutes in water at 37 0.5 C
using
the conventional disintegration method.
TABLE XXI
Swallowable Methylcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 64.52
Dibasic Calcium phosphate, dihydrate 0.0370 4.77
Sodium lauryl sulfate 0.0015 0.19
F, D, and C Yellow #6 0.0010 0.13
Povidone 29K/32 0.0480 6.19
DI water q.s. q.s.
Phase B
Phase A 0.5875 75.81
Sodium lauryl sulfate 0.0015 0.19
Sodium starch glycolate 0.0235 3.03
Dibasic Calcium phosphate, dihydrate 0.1550 20.00
Magnesium stearate 0.0075 0.97
TOTAL 0.7750 100.00
-32-
CA 02550132 2006-06-30
~ .
EXAMPLE 22
A formulation containing a calcium source from the intra and extragranular
excipient, calcium phosphate, anhydrous with extragranular Explotab is
indicated
in TABLE XXII.
The formulation in TABLE XXII exhibited an average disintegration time of
less than 11 minutes in 0.1 N HCI and less than 19 minutes in water at 37 '
0.5 "C
using the conventional disintegration apparatus.
TABLE XXII
Swallowable Methylcellulose Tablets
Formula g/tablet (% w/w)
Ingredient
Phase A
Methocel A4M 0.5000 66.93
Calcium phosphate, Anhydrous 0.0370 4.95
Sodium lauryl sulfate 0,0015 0.20
F, D, and C Yellow #6 0.0010 0.13
Povidone 29K/32 0.0480 6.43
DI water q.s. q.s.
Phase B
Phase A 0.5875 78.65
Sodium lauryl sulfate 0.0015 0.20
Sodium starch glycolate 0.0260 3.48
Calcium phosphate, Anhydrous 0.1245 0.67
Magnesium stearate 0.0075 1.00
TOTAL 0.7470 100.00
-33-
CA 02550132 2006-06-30
EXAMPLE 23
A formulation containing a calcium source from the intra and extragranular
excipient, tribasic calcium phosphate WG with extragranular ExplotabCR is
indicated in TABLE XXIII.
The formulation in TABLE XXIII exhibited an average disintegration time
of less than 13 minutes in 0.1 N HCI and less than 24 rninutes in water at 37
= 0.5 "C
using the conventional disintegration apparatus.
TABLE XXIII
Swallowable Methylcellulose Tablets
Formula g/tablet (% w!w)
Ingredient
Phase A
Methocel A4M 0.5000 66.93
Tribasic Calcium phosphate, WGU 0.0370 4.95
Sodium lauryl sulfate 0.0015 0.20
F,D,andCYellow#6 0.0010 0.13
Povidone 29K/32 0.0480 6.43
DI water q.s. q.s.
Phase B
Phase A 0.5875 78.65
Sodium lauryl sulfate 0.0015 0.20
Sodium starch glycolate 0.0260 3.48
Tribasic Calcium phosphate, WG 0.1245 16.67
Magnesium stearate 0.0075 1.00
TOTAL 0.7470 100.00
-34-
CA 02550132 2009-03-18
The above description fully discloses the invention including preferred
embodiments thereof. Modifications and improvements of the embodiments
specifically disclosed herein are within the scope of the following claims.
Without
further elaboration, it is believed that one skilled in the art can, using the
preceding
description, utilize the present invention to its fullest extent. Therefore
the
Examples herein are to be construed as merely illustrative and not a
limitation of the
scope of the present invention in any way. The embodiments of the invention in
which an exclusive property or privilege is claimed are defined as follows.
-35-
