Note: Descriptions are shown in the official language in which they were submitted.
10'~3~5~3
The present invention is concerned with a swstained release pharma-
ceutical formulation containing as the active ingredient a benzodia~epine
selected from the group consisting of chlordiazepoxide and diaæepam, one or
more antacid compounds or acetylsalicylic acid, said formulation being hydro-
dynamically balanced so that, upon contact with gastric fluid, said formula-
tion acquires and maintains a bulk density of less than 1 thereby being
buoyant in said fluid and remaining buoyant in the gastric fluid of the
stomach until substantially all of the active ingredient contained therein has
been released, said formulation comprising a homogeneous mixture of said ac-
tive ingredient; from 0 % to 80 % by weight of therapeutically iner~, pharma-
ceutically acceptable adjunct materials; from 0 ~ ~o 60 ~ by weight of a fatty
material haYing a specific gravity of less than 1 and from 20 % by weig~t to
75 % by weight of one or a mixture of hydrocolloids selected from the group
consisting of methyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl-
cellulose, hydroxyethylcellulose and sodium-carboxy~ethylcellulose to provide
upon contact wi~h gastric fluid, a water-impermeable barrier on the surface of
said formulation.
The convenience of administering a single dose of medica-
- 2 ~
1~'
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3~5~
tion which releases active ingredient over an extended period
of time as opposed to the administration of a number of single
doses at regular intervals has long been recognized in the
pharmaceutical art. T~e advantage to the patient and clinician
in ha~ing consistent and uniform blood levels of medication
over an extended period of time are likewise recognized. In
most sustained release preparations known to the pharmaceutical
D art, medicinal agents are either coated with varying
of some type of relatively insoluble material or are imbedded
into a rigid lattice of resinous material. In such preparations,
the object is to continuously provide drug for absorption into
the blood stream to replace the amount eliminated while the
dosage form is passing through the gastrointestinal tract of
the patient.
The conventional approaches to sustained release formula-
tion briefly outlined above can be disadvantageous in that
certain classes of active ingredients are not suited to
absorption during passage through the gastrointestinal tract
due to their physiochemical properties and/or favorable sites
of absorption. For example, most acidic medicaments are
principally absorbed from the stomach, whereas most basic
medicaments are absorbed primarily from the intestines. Most
medicaments will undergo varying degrees of change in solubility
by passage from the acutely acidic conditions of -the stomach to
the neutral to alkaline conditions of the intestines. For
example, ferrous salts are more soluble in the stomach than in
the intestines. Finally, there are medicaments, e.g., antacids,
':
107335~
which are intended to act in the stomach and therefore lose
most beneficial properties when they pass into the intestines.
It is readily apparent in view of the above considerations
that a large number of medicaments are not amenable to
conventional sustained release formulations which are not
retained in the stomach and which release medicament in the
intestines. It is equally apparent that a sustained release
formulation which is retained in the stomach and which slowly
releases medicament in the stomach over an extended period of
time would be eminently suited to such medicaments. Such a
sustained release formulation is provided by the present inven-
tion.
L~
C~/ar~c~e~ s
The principle of sustained release which-~k~e4ei~4
the pharmaceutical formulation of the subject invention is
~re~G~/~S
unique in the art, i.e., the formulation rem~in buoyant and
free floating in the gastric fluid for an extended period of
time, during which substantially all of the medicament is
released therefrom. Although many mechanisms of sustained
release are recognized in the art and the concept of a floating
formulation is recognized, there is no teaching which recognizes
the application of buoyancy to sustained release as is taught
by the subject invention.
For example, Davis U.S. Patent 3,418,999 teaches a tablet
which is buoyant. However, the buoyancy of the tablet is
disclosed as being merely an adjunct to swallowing and there is
.. : . ~ . ~ . . . ,~ . .
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~7335~
;- .
.
no suggestion therein of applying the buoyancy to sustained
release. The Davis tablets also must have an initial density
of less than 1, whereas the tablets of the subject invention
are not so restrictedl;l
The concept of a tablet which swells when in contact with
gastxic fluid is also recognized in the art. For example,
Johnson et al. U.S. Patent 3~574,820 teach tablets which swell
in contact with gastric fluids to a size such that they cannot
pass the pylorus and therefore are retained in the stomach. It
is readily apparent that such tablets are not buoyant since, if
they were, their size in relation to being able to pass the
pylorus would be of no consequence.
The incorporation of a swellable hydrocolloid in a
sustained release tablet is also recognized in the art. Playfair
U.S. Patent 3,147,187 teaches incorporation of a swelling gum
or proteinaceous material into a sustained release tablet to
r~ ~/5~egfa f~v~
aid in ~i~tintogration of the tablet and thus expose more
surface to digestion. There is no indication that the disclosed
tablets are intended to be buoyant. This is further evidenced
by the fact that all ingredients are combined into a melt
which is thereafter cooled and granulated. The hydrocolloid is
therefore formulated in the manner of a conventional tabletting
binder as opposed to being added to the formulation in a dry
prc?e*ce ";,S
particulate form as in the ~W;U~M~ of the subject invention
^ 25 whereby it functions to facilitate the buoyancy of the tablet.
.. ,. . . ., :. :
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335~
-- 6 --
Finally, Christenson et al. U.S. Patent 3rO65,143 teach
the use of a hydrocolloid in a sustained release tablet to form
a water impermeable barrier on the outer surface of the tablet
which gradually erodes and thus releases medicament over an
extended period of time. There is no suggestion, however, that
such phenomenon could be utilized to achieve a hydrodynamic
balance for a tablet such that it will remain floating on the
gastric fluid in the stomach for an e~tended period of time as
in the subject invention.
In accordance with the present invention, formulations
for the preparation of solid sustained release dosage forms for
oral administration are provided which are hydrodynamically
balanced to have a bulk density (specific gravity) of less than
one in contact with gastric fluid and which therefore will
remain floating in gastric fluid which has a specific gravity
of between 1.004 and 1.010. The sustained release formulations
of the present invention comprise a homogeneous mixture of
one or more medicaments with one or more hydrophilic hydro-
colloids which, in contact with gastric fluid at body tempera-
ture, will form a soft gelatinous mass on the surface of saidmixture, thus causing it to enlarge somenhat and to acqui~e a
bulk density (specific gravity) of less than one. The medica-
ment is slowly released from the surface of the gelatinous
mass which, due to its buoyancy, remains buoyant in the gastric
fluid. Ultimately, after substantially all of the medicaments
therein are released, the gelatinous mass disperses. The
sustained release formulation of this invention is orally
... . ..
:-:.: : : , :. , .. ~ ,
;. ~ ., . ' .
. . .
335~3
-- 7 --
administered in the form of tablets or capsules, e~g , hard or
soft gelatin capsules.
Upon oral ingestion of solid pharmaceutical dosage forms
prepared from the formulations of the present invention, the
capsule shell or the tablet film coating, if such is present,
dissolved leaving the contents in contact with gastric fluid.
Upon contact with ~astric fluid, the outermost hydrophilic
colloid hydrates to form an outside barrier which substantially
retains the shape of the capsule or tablet and therefore acts
to prevent the mass from disintegrating. The hydrated layer
thereafter slowly dissolved releasing medicament. There is also
a release of medicament by leaching action of or near the
surface of the mass. As new surface is exposed to gastric fluid
it becomes hydrated, thus maintaining the integrity of the
barrier. This process is continuously repeated until the
medicament is substantially leached out. Thereafter the
remaining matrix which is still buoyant in gastric fluid slowly
dissolves and is eliminated.
It has been found that the release pattern and resulting
blood levels attained with the sustained release formulation .;
of the invention has advantages over other sustained release
mechanisms known in the art, particularly wherein the medica r
ment contained therein is principally absorbed and/or exerts
S~sf~ L
~_J its therapeutic activity in the stomach or duodenum~=~
release formulations prepared in accordance with the present
invention unexpectedly produce optimum blood levels with
. ~,,; .,. 1, .
- ' ` ':' '' ' ~ ;"' ,,
. ....
:10~3358
certain medicaments, e.g., chlordiazepoxide. ~he results with chlordiaæepox-
ide were superior to known sustained release formulation previously tried,
each of which had failed to produce satisfactory blood levels. In addition,
the sustained release formulation of the present invention ~mexpectedly pro-
vides an excellent means for administering antacid substances over a prolong-
ed period of time.
In order to successfully practice the present invention, the hydro-
colloids utilized must hydrate in acidic medium, e.g., gastric fluid with a
pH equivalent to 0.1~ hydrochloric acid,
-- 8 --
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- 10~33S~
_ g _.
n6'f e/y
i.e., a pH of i~UK~Y~4~1.2. Furtermore, although the
initial bulk density of the formulation of the invention may
initially be greater than one, it is essential that the formu-
lation be hydrodynamically balanced to have a bulk density of
less than one when in contact with gastric fluids to assure
buoyancy. There are a number of methods whereby the rate of
release of medication from the sustained release formulation
of the present invention can be adjusted. First, the choice of
a particular hydrocolloid or mixture of hydrocolloids can affect
the release rate, e.g., high viscosity hydrocolloids, e.g.,
methylcellulose 60 HG, 4000 cps, hydrate more slowly and
maintain a soft mass for a longer time than low viscosity
hydrocolloids, e.g., methylcellulose 60 HG, 10 cps. Further,
edible, pharmaceutically inert, fatty materials having a
specific gravity of less than one can be added to the formula-
tion to decrease the hydrophilic property of the formulation
and therefore increase buoyancy. Examples of such materials
include: a purified grade of beeswax; fatty acids; long chain
fatty alcohols such as, for example, cetyl alcohol, myxistyl
alcohol, stearyl alcohol, glycerides such as glyceryl esters
of fatty acids or hydrogenated aliphatic acids such asl for
example, glyceryl monostearate, glyceryl distearate, glyceryl
esters of hydrogenated castor oil and the like; oils such as
mineral oil and the like.
There may also be incorporated into the sustained release
formulations of the present invention additional edible non-
toxic ingredients recognized in the art of pharmaceutical
; , . , ~ ,~ .
. : , , - , :. ,
.
: .
~ ' ". . ,
- :L0~335~
compounding such as excipients, preservatives, stahilizexs, table~ting lubri-
cants and the like. The choice o~ such matarials and the amounts to be util-
ized are considered to be within the purview of one skilled in the art. It is
to be borne in mind, however, that such conventional pharmaceutical adjuncts
which might adversely affect the hydrodynamic balance of the sustained release
formulation of the present invention are not suitable for use therein.
The a unt of the active medicament or mixtures thereof in the sus-
tained release for~ulation of the present invention can vary over a wide
range, i.e., from about 0.1% by weight to about 90~ by weight. ~he a~oun~ of
active substances present is usually between about 5% by weight and 50~ by
weight. Factors which govern the amount of active substance present in the
sustained release for~ulations of the present invention are, for example, the
a~ount required to yive full therapeutic dosage, the bulk density thereof,
the hydrophilic or hydrophobic properties thereof, the stability thereof and
the like. These proper~ies are known or are easily ascertainable by a person
skilled in the art and the formulation adjustments required to incorporate
any given therapeutically active substance into a sustained release formula-
tion in accordance with the present invention are considered to be within the
purview of the art. The am.ount of the hydrocolloid
- 10 -
~' .
... .. .
i: :
.
.
. , . ~ .
1~733S~3
ingredient to be utilized will vary in relation to the amounts and properties
of the active ingredient and inert pharmaceutical adjuncts utilized.
Wherein one or a mixture of fatty materials in present in the SU5-
tained release formulations of the invention, such material comprises up to
about 60% by weight of the total formulation. In general, wherein the formu~
lations do contain a fatty material, such material is present in from about
5% by weight to about 30~ by weight. ~he amount of fatty material utilized
is governed by the amounts and physical characteristics of both the active
ingredient and the hydrocolloid with the object being to achieve a hydro-
dynamically balanced formulation, i.e., a formulation which acquires a bulk
density (specific gravity) of less than one in gastric fluids.
The amount of edible, inert pharmaceutical adjunct materials whichmay be present in the sustained release formulations of the present invention
will also vary in accordance with the amounts and physical properties of ~he
other ingredients. Such materials which themselves have a bulk density of
less than one will enhance the buoyancy of the formulation. ~ore importantly,
it is possible to utilize the selection of inert pharmaceutical adjunct
materials to
,
,:
.
~733~8
- 12 -
modify the rate of release of the formulati~n. For example,
soluble excipients, e.g., lactose, mannitol and the like, will
increase the rate of release whereas insoluble excipients e.g.,
dicalcium phosphate, terra alba and the like, will decrease
solubility. Wherein such pharmaceutical adjunct material are
included in the formulations of the invention, they can be
present in up to 80~ by weight of the final Eormulation.
Generally, such conventional pharmaceutical adjuncts are
present in from about 5% by weight to about 60% by weight of
the formulation. The inclusion of and choice of such materials
is again considered to be within the purview of the art
utilizing the principles of the present invention.
7~ re/ease
V The hydrodynamically balanced sustained ~C~2 dosage
formulations of the present invention are prepared by
techniques well established in the art. Wherein the formu-
lations of the invention are to be administered in the form
of capsules, all that is required is the thorough mixing of
all ingredients and milling or comminuting to form a
homogeneous mixture of relatively fine particle size.
Occasionally, however, the conventional pharmaceutical
techniques of slugging, wet granulating or extruding may be
required to achieve proper fill weight in the capsule. The
resulting mixture is then filled into suitable pharmaceutical
carsules with hard gelatin capsules being preferred. The capsule
should be completely filled. Adjustments in the formulation
,,
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.
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1~335~3
- 13
necessary to achieve this end are within the skill of the art.
Wherein the formulations of the present invention are
~ 5~er~
ad~i-ne&ter-c~ in the form o~ tablets, such tablets are prepared
by conventional techniques. In most instances it is necessary
to utilize the technique of wet granulation followed by
compression into tablets. However, where the physical properties
of the ingredients will permit, tablets may be prepared by
direct compression of a homogeneous mixture of the
ingredients. Such tablets contain conventional tabletting
lubricants and may also contain other pharmaceutical adjunct
materials in accordance with the criteria set forth herein.
It is to be noted that many of the hydrocolloids utilized
in the practice of the invention are conventionally used in
pharmaceutical compounding as tablet binders and as such, are
incorporated into the tablet formulation in the form of a
solution or dispersion in a suitable solvent.
In the practice of the invention, however, the hydro-
colloid ingredient is incorporated into the formulation in dry
form, thus excluding it from wet granulation techniques where
they are utilized. However, a small percentage o~ the hydro-
colloid ingredient may be utilized in accordance with
convention techniques as a tablet binder. Wherein a hydro-
colloid such as described herein is utilized conventionally
as a tablet binder and is combined into the formulation in
. .
: . '' ;' ' '
- , . -
:`
~33S~3
-- 14 --
the presence of a solvent, such hydrocolloid does not function
to facilitate the buoyancy of the tablets prepared therefrom.
Tablets prepared in accordance with the present
invention can be manufactured on conventional tabletting
equipment. However, it is critical that they are not
compressed to a degree of hardness such that they will not
acquire a bulk ~ of less than one in contact with
gastric fluids. In accordance with the present invention,
tablets which initially have a density greater than one will
be buoyant in gastric fluids. This buoyancy results from a
combination of an increase in the bulk volume of the tablet
when it contacts gastric fluids due to the hydration and
swelling of the hydrocolloid particles on the tablet surface
and the internal voids in the tablet center remaining dry due
to the barrier formed by the hydrocolloid particles. Therefore,
it is critical that the tablets are not compressed to a
degree of hardness such that the porosity is materially
reduced and the hydrocolloid particles on the tablet surface
are compacted so tightly that rapid hydration is retarded. It
will be appreciated that the maximum hardness to which a tablet
having an initial density greater -than one can be compressed
will vary both with the initial density of the tablet and the
size of the tablet~ The hardness for any tablet will lie
between the maximum at which a buoyant tablet can be produced
in accordance with the teachings herein and a minimum re~uired
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3~
for tablets to meet basic pharmaceutical tests of stability during shipment,
and the like. This range of hardness can be easily determined ~y standard
pharmaceutical hardness measurements combined with te!3ting of the buoyancy of
samples of tablets di~ferent hardness in gastric fluid. Such determinations
are considered to be within the skill of the skilled artisan.
- 15 -
. . .
. .,
., ~.
3:~58
It is reported in the lit0rature that the irritation of the stomach caused by
aspirin is the resul~ of contact of this very acidic substance with the
stomach walls. m erefore, it will be appreciated that the formulations of
the invention axe particularly advantageous for the administratlon of aspirin
since they remain buoyant in gastric fluid.
Medicaments co which the sustained release formulation of the sub-
ject invention is particularly amenable are chlordiazepoxide and diazepam.
It is noteworthy that, after a number o~ sustained release mechanisms known
to the art proved unsuccessful, superior results were obtained with chlordiaz-
epoxide utilizing the formulations of the subject invention. For the ben~o-
diazepines the formulation according to the present invention is preferably
brought in the form of a capsule.
The sustained release ~ormulations of the present invention are also
particularly amenable to the administration of
~ 16 -
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~L~;173358
antacids such as the oxides, hydroxides and carbonates of magnesium aluminu~
hydroxide, magnesium txisilicate and the like. Whexein such substances gener-
ate carbon dioxide, bubbles will become entrapped by the hydrated outer layer
thus enhancing the buoyancy of the formulation. Amo~mts of carbon dioxide
generating bases can also be utilizad in non-antacid formulations to enhance
buoyancy. It is further within the scope of the present invention to adminis-
ter the formulations hydrodyn~mically balanced in accordance with the inven- r
tion as one layer of a two layer tablet. The remaining layer contains medica-
ment in a conventional formulation free of sus~ained release ingredients.
m is unique tablet, upon ingestion, provides an immediate release of medica-
mant and a buoyant layer which continues to release medicament o~er a period
of time while being retained in the stomach. Such unique two-layered tablets
are particularly advantageous for the administration of antacid substances.
me sustained release formulation of the present invention has been
found to remain buoyant in gastric fluid despite the presence of surfactants
or food. me efficacy of madicaments administered utilizing ~he sustained
release formulation of the presen~ invention has been found to be independent
of the site of absorption of the particular medicament. Utilizing dogs which
had ingested capsules containing barium sulfate in the formulation in accord-
ance
- 17 -
,l
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,
.
,
,
3~5~
- 18 -
with the present invention, it has been demonstrated by the
use of x-ray techniques that the formulati.on remains buoyant
in the gastric fluid and does not adhere t:o the walls of the
stomach.
The following examples illustrate the invention.
: ,: .. , - . :
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73351!~
\
-- 19 --
Example l
Sustained release capsules containing chlordiazepoxide
were prepared as follows:
Ingredient mg/ca~sule
Chlordiazepoxide 30.6
Hydroxypropylmethylcellulose, 4000 cps 100.4
Lactose Anhydrous 30.0
.1
'~ ` Sterotex K* 58.0
Talc 50 0
Magnesium Stearate
Total 275.0
*A hydrogenated cottonseed oil manufactured by Capital City
Products, Colubus, Ohio.
~-~ The chloridazepoxide, methylcellulose and lactose were
~ f',l e~
homogeneously blended in a suitable blender a~er which the
mixture was passed through a Comminuting Machine at high speed
utilizing a No. 2B screen with knives forward. The Sterotex K,
talc and magnesium stearate were then added to the mixture and
the whole blended for an additional five minutes. The mixture
was then passed through a Comminuting Machine at high speed
utilizinga No. O plate, knives forward. The blending and
milling procedures were repeated and the mixture was filled
into No. 2 size pink opaque capsules.
~ 'rr~J~marK
.
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~10~33S8
, ~
- 20 -
The thus-formed capsules were tested for in vitro
release rates by the rotating bottle technique in simulated
gastric fluid. The results of these tests are set forth in
Table I.
TABLE I
Percent of Active Ingredient Released
Time (hours) Gastric Fluid (pH 1.2)
O O
1 39
2 61
3.5 86
94
7 100
Accelerated chemical stability tests at 55C., in a light
chamber and at 37 C./85~i R.H., both-in amber and polyethylene
bottles with a silica plug showed the capsules to have
acceptable stability.
Samples of the above capsules were tested in vivo in
man in comparison with three commercial capsules each
containing 10 mg. chloridazepoxide administered at 0, 4 and
8 hours. The results are set forht in Table II.
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33~i8
-- 21 --
h ~1
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a
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td
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335~3
It is eYident from the abo~e data that the sustained release capsules ~atch
very well with the regimen of single dose capsules.
~ 22 -
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~0~3~S~
~3
L~ 1., :
Example ~
Sustained release antacid capsules were prepared asfollows:
Ingredient m~/capsule
FMA-ll* 254.7
Magnesium Oxide, Light 127.0
Lactose, hydrous 20.3
Hydroxypropylmethylcellulose, 4000 cps 63.0
Gum Karaya, Stein Hall 31.0
Talc, tablet grade 24.0
Magnesium Stearate 5.0
Total 525.0
*Aluminum Hydroxide-Magnesium carbonate co-precipitate - Reheis
Co., Berkley Heights, New Jersey.
lL 15 The FMA-11, light magnesium oxide, lactose and
magnesium stearate were blended in a suitable mixer for
10 minutes and then passed through a Comminuting Maching
using a No. 1 plate at medium speed, knives forward. The
mixture was then slugged on a suitable press using 3/4" F.F.
punch and the slugs milled on a Comminuting Machine at medium
speed using a No. 1 plate, knive forward. The resulting
granules were thoroughly mixed with the remaining ingredients
and filled into No. O capsules utilizing conventional capsule
~r~JemA~K
:
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~llO~33~
,51.. ~i
filling equipment.
As the Federal Register does not give a specific method
for testing a sustained release antacid preparation, the
capsules were tested by the following method. A capsule is
placed in 300 ml. of O.lN hydrochloric acid in a stoppered
flask rotated at 40 rpm. A 50 ml. sample is withdrawn at a
specified time and titrated with O.lN NaOH to pH 3.5 which
is the neutralization point given in the Federal Register
for acid neutralizing capacity. The amount of acid consumed
was calculated from the sample. The results are given in
Table IV. The capsules remained floating throughout the test.
TABLE IV
T _ Antacid Release
1st hour 42.1%
2nd hour 96.7%
3rd hour 104%
. . , . ., : ; :, .:
~33 ~ /
`D
Exam~le ~
Sustained release aspirin capsules were prepared as
follows:
Ingredient _~./ca~sule
Acetylsalicyclic Acid, Micronized 400
Dicalcium Phosphate, anhydrous 20
Hydroxypropylcellulose 40
Tragacanth 100
Total 560
All ingredients except tragacanth were thoroughly mixed
and passed through a Comminuting Machine using a No. 00 plate,
knives forward. The mixture was granulated with anhydrous
ethanol, dried and milled. The tragacanth was then blended
with the mixture and the whole filled into No. 0 capsules.
The capsules were found to remain buoyant in the gastric
fluid.
..
': :'' .' ` . , :
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: ~
:` ~~33513
,2~
. ~ s~
Exam~le ~
Sustained release aspirin tablets containing 7.5 grains
aspir~n were prepared from the following granulations:
Granulation A Mg.
Acetylsalicyclic Acid 500
Hydroxypropylmethylcellulose, 400 cps 125
Hydroxypropylmethylcellulose, 15 cps 3
Total 628
Granulation B
Calcium Carbonate, precipitated 65
Magnesium Carbonate 20
Mannitol 10
Carboxymethylcellulose 2
Total 97
The two granulations were homogeneously mixed with
5 mg. talc and compressed using capsule-shaped punches to a
hardness of 5 to 6 S.C.U. Hardness should not exceed 11 S.C.U.
for tablet to remain buoyant.
.. .. . . ........
.- .: . ",
335
~7
Example ~
Sustained release two-layered antacid tablets were
prepared as follows:
Layer A-Immediate Release
In~redient ms/tablet
FMA-ll* 160.0
Methylcellulose 5.8
Magnesium Oxld~ 80.0
Primojel** 10.0
Magnesium Stearate 2.5
Total 258.3
* Aluminum hydroxide-magnesium carbonate co-precipitate -
Reheis Co.
** Sodium carboxymethyl starch - E. Mendel & Co.; Carmel,
New York
The FMA-ll and magnesium oxide were mixed in a suitable
mixer. The resulting mixture was granulated utilizing a 2.5%
by weight solution of the methylcellulose in a mixture of equal
parts water and ethyl alcohol. The granulation was dried
overnight at 60C. The dried granulation was then milled,
combined with the Primojel and magnesium stearate and mixed
for five minutes. The resulting homogeneous mixture was then
compre~sed on a conventional two-layer tablet press.
,~ ~ Tr~em~r~cs
.
. ~: , .:, ~:;
3351
;28
D
Layer B-Sustained Release
Ingredient mg/tahlet
; ) FMA-ll 170
Magnesium Oxide 85
Methylcellulose 4000 cps (dry) 90
Methylcellulose 4000 cps (wet) 6
Ethylcellulose 90
Direct Compression Grade Starch 35
Syloid* 30
Magnesium Stearate 23
Total 529
*Purified silicon dioxide - W. R. Grace & Co., Baltimore,
Maryland
~mA
The ~-11 and the magnesium oxide were mixed in a
suitable mixer. The resulting mixture was granulated with a
solution of the methylcellulose (wet) in a mixture of equal
parts water and ethyl alcohol and the granulation dried
overnight at 60C. The resulting granulation was combined
with the methylcellulose (dry), ethylcellulose, direct
compression grade starch and Syloid and thoroughly mixed for
about 10 minutes. The magnesium stearate was added and the
mixture mixed for an additional five minutes. This mixture
was then compressed on a conventional two-layer tabletting
machine with Layer A to a standard concave capsule shape
3/4"x5/16". The acceptable hardness of the tablets was between
~ rr~Jem~K
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35~3
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12 and 14 s.c.u. and it was found that the hardness could
not exceed 16 s.c.u.
A sample of the two-layer antacid tablets thus formed
was placed in a beaker containing gastric fluid and
equipped with a magnetic stirrer running at slow speedO It
was observed that the immediate release layer separated and
sank to the bottom of the beaker in fine particulate form. The
sustained release layer remained floating for two hours
slowly releasing medication.
...
:.. : .
,~ .: .,. - : : .
