Note: Descriptions are shown in the official language in which they were submitted.
:~3~2~
1 --
4 16168/=/CGC 1232
OSMOTIC CONTINUOUS DISPENSING ORAL DELIVERY SYSTE~I CONTAINING A
MODEl~TELY WATER-SOLUBL~ METOPROLOL SA T HAVING IMPROVED CORE
COMPOSITION AND VSE THEREOF
BACKGROUND OF TIIE INVENTION
Osmotic delivery systems Eor the oral administration of drugs are
well known in the art. These systems dispense -the active agent in a
controlled and continuous manner over a prolonged period of time to
produce a desired beneficial effect. Such systems are typically
represented by U.S. 3,845,770, U.S. 3,916,899, U.S. 4,016,880 and
the like.
Experimental osmotic delivery systems employlng metoprolol fumarate
contained within a semipermeable cellulosic wall and their in vivo
performance have been described in the literature, e.g. Theeuwes e-t
al., Br.J.Clin.Pharm. (1985), Vol. 19, pp. 69S~76S;
Godbillon et al., Br.J Clin.Pharm. (1985), Vol. 19, pp. 213S-2185
and Warrington et al., Br.J.Clin.Pharm. (1985), -Vol~ lg,
pp. 219S-224S.
Unfortunately, while experimental oral osmotic devices employing a
moderately water-soluble metoprolol salt such as metoprolol fumarate
(1:1) as the core ingredient can be prepared on a unit basis in the
laboratory by simple dip coating a compressed core oE the salt with,
for example, a cellulose acetate solution, to obtain a semi-
permeable membrane coated core, such a technique is unsuitable for
large scale production of uniform quality product. Due to the high
friability of the metoprolol salt, a compressed core thereof, alone
or with trace amounts of excipients such as poly-N-vinylpyrrolidone,
~3
~ ~3 ~
-- 2 --
is characteristically too fragile to employ in conventional air
suspension techniques, such as the Wurster Air suspes~sion technique
or the like.
Moreover, the addition of substantial amounts of excipients may be
expected to interfere with the release rate characteristlcs of the
active agent.
It has now been surprisingly discovered that the normal friability
of such cores can be substantially eliminated by employing between
about 7.5 and l5 percent by weight poly-N-vinylpyrrolidone in
combination with the moderately soluble pharmaceutically accsptable
salt of metoprolol.
OBJECTS OF THE INVENTION
It is acco}dingly an object of the invention to provide an osmotic
delivery system for a moderately water-601uble pharmaceutically
acceptable metoprolol salt comprising a semipermeable membrane wall
covering a core compartment containing an osmotically active solid
core composition comprising about 7.5 to about 15 percent by weight
poly-N-vinylpyrrolidone, up to about 5 percent by weight of a
tabletting lubricant; and about 92.5 to about 80 percent by weight
of said metoprolol salt, and at least one passageway in the wall,
for dispensing the metoprolol salt, in communication with said core
compartment and the external environment.
It is another object of the present invention to provide a method of
treatment of conditions responsive to beta1-adrenoreceptor blocking
agents in man in need of the same by orally administering to man an
effective unit dosage amount in the form of such a device.
These and other objects of the instant inventlon are more fully
described in the following detailed disclosure.
2 ~ ~ ~
DETAILED DESC~IPTION OF TH~ INVENTION
One embodiment of the present invention relates -to an osmotic
dispensing oral delivery system contalning a moderately water-
soluble pharmaceutically acceptable salt of metoprolol for a total
delivery of between about 50 and abou-t 500 mg of metoprolol, capable
of delivery, upon activation in the gastrointestinal tract, from
about 60 up to about 90 percent of said metoprolol salt at a
substantially continuous rate of about 5 to about 12 percent by
weight of the total weight of said metoprolol salt per hour com-
prising
a) a semipermeable shaped wall membrane substantially
impermeable to said salt and permeable to gastro-
intestinal fluid;
b) a core compartment within and defined by said wall,
said core being in the Eorm of a solid osmotically
active composition comprising about 7.5 to about
15 percent by weight poly-N-vinylpyrrolidone; up to
about 5 percent by weight of a tabletting lubricant;
and about 92.5 to about 80 percent by weight of said
metoprolol salt, all based on the core composition
weight; and
c) at least one passageway in the wall in communication
with the core compartment and the external environ-
ment for dispensing the metoprolol salt into said
gastrointestinal tract.
The metoprolol salt containing devlce i8 suitable for treating those
conditions in mammals, including man, responsive to beta1-adreno-
receptor blocking agents. Preferred indicat:Lons include the treat-
ment of those indications for whlch metoprolol and its pharmaceuti-
cally acceptable salts are known to be useful, including hyperten-
sion, angina pectoris, cardiac arrhythmlas, and in the treatment of
hemodynamically stable patients with myocardial infarction to reduce
cardiovascular mortality.
~2~ ~
Conventional commercially available metoprolol tartrate has an
immediate release profile and is not in a rate controlled continuous
dispensing form. On multiple dosing, such non-continuous forms
produce fluctuations between peaks and troughs in terms of blood
plasma levels as well as the degree of beta-blockade. While more
frequent administration of such conventional forms can reduce these
fluctuations, it is burdensome to some patients and may lessen
compliance. While single daily doses of the conventional metoprolol
salt are adequate if the only aim is to reduce blood pressure, a
three-times-a-day regimen is advisable for the maintenance phase for
the respective indications of myocardial infarction and angina
pectoris.
The instant device advantageously provides a once-a-day regimen for
all of the above indications for the total release, per unit dose,
of between about 60 and about 500 mg of metoprolol wherein Erom
about 50 up to about 90 percent of metoprolol is released at a
substantially continuous rate of about 5 to about 12 percent by
weight per hour.
The pharmaceutically acceptable salt of metoprolol is advantageously
moderately water-soluble, such that the salt dissolves in the
aqueous environment upon activation in the envlronment oE use, i.e.
the gastrointestinal tract, by aqueous fluid being imbibed by
diffusion through the semipermeable shaped wall into the core
compartment to continuously form a concentrated osmotically active
solution of dissolved metoprolol salt. The concentrated salt, or
solute, solution exhibits an osmotic pressure gradient against the
aqueous gastrointestinal fluid and is released through one or more
passageways in the wall in communication with both the core compart-
ment and the external environment, to dispense the metoprolol salt
at a controlled, preferably generally constant rate Izero orderJ.
The influx rate of aqueous Eluid from the aqueous environment
through the semipermeable wall is controlled by the continuous
dissolution of the metoprolol salt containing composition in the
~ 3 ~
core of the device. Accordingly, the metoprolol salt chosen is
advantageously one which processes only limited or moderate solubi-
lity in the imbibed aqueous fluid, such that the metop}olol salt is
released in a slow and continuous manner a prolonged time by
maintaining the rate of internal dissolution of the core composi-
tion.
Preferably, the pharmaceutically acceptable metoprolol salt exhibits
useful properies for formulations in oral osmotic systems ad has a
solubility in water between about 0.1 to about 0.6 grams per cubic
centimeter in water at about 37~C and the solubility can be deter-
mined simply by placing the salt in water and diluting until
complete solution. Suitable metoprolol salts include lower alka-
noate salts of metoprolol salts and mono-or di-metoprolol salts of
lower alkylene dicarboxylates, especially metoprolol fumarate (1:1)
and metoprolol maleate (1:1). Most preferred is the metoprolol
fumarate (1:1).
The semipermeable wall membrane is prepared from a material which
can form films and is inert to the metoprolol salt drug or host, is
pharmaceutically acceptable and is permeable to the external
gastrointestinal fluid while essentially being impermeable to the
metoprolol salt drug in the device. This selectively permeable
membrane forming the wall is insoluble in the gastrointestinal tract
and non-erodible or it can be bioerodible after a predetermined
period with bioerosion corresponding to the end of the active drug
release period. In each instance it is permeable to the gastro-
intestinal solvent but not to the metoprolol salt solute and is
suitable for construction of the osmotic powered device. Typical
materials for forming the wall include membranes known to the art as
present in osmosis and reverse osmosis membranes7 such as commer-
cially available unplasticized cellulose acetate, plastici~ed
cellulose triacetate, agar acetate, amylose triacetate, beta glucan
acetate, beta glucan triacetate cellulose acetate ethyl carbamate7
cellulose acetate phthalate7 cellulose acetate methyl carbamate,
cellulose acetate succinate, cellulose acetate dimethylaminoacetate,
~ 3 ~
cellulose acetate ethyl carbonate, cellulose acetate methyl sulfonate,
cellulose acetate butyl sulfonate, cellulose ethers, cellulose acetate
propionate, poly(vinyl methyl) ether polymers, cellulose acetate octate,
cellulose acetate laurate, methyl cellulose, triacetate oE locust bean
gum, cellulose acetate with acetylated hydroxyethyl cellulose,
hydroxylated ethylenevinylacetate, osmotic membranes made from polymeric
epoxides, alkylene oxide-alkyl glycidyl ethers, polyurethanes, polyglolic
acid, and polycation-polyanion membranes known in the art. Generally such
membranes have a fluid permeability of between about 0.01 to lO cm3/cm2 x
hour or day or higher at atmospheric pressure against a saturated product
solution at about 30C, and simultaneously possess a high degree of
impermeability to the metoprolol salt solution.
Preferred semipermeable membrane materials include polyurethanes, methyl
cellulose, cellulose acetate, e-thyl cellulose, and cellulose acetate
butyrate. Most preferred is cellulose acetate.
Suitable tabletting lubricants include, for example, those lubricants
known in the art such as silica, talc, magnesium stearate and high
molecular weight polyethylene glycol. Preferred is magnesium stearate.
The preferred amount is between about l and about 5, most praferably
between about 2 and about 4, percent by weight, based upon the total core
weight.
The poly-N-vinylpyrrolidone (PVP, Povidone) constituent is well known in
the art, water soluble and has an average molecular weight between about
10,000 and about 700,000, preEerably between 10,000 and 100,000. Prefer-
red is povidone USP, commercially available through GAF Corp. under the
tradename Plasdone~. The amount oE poly-N-vinylpyrrolidone, as stated
above, is between about 7.5 and about 15 percent by weight, based upon
the total core weight.
~L 3 ~
Preferably, the amount of poly-N-vinylpyrrolidone present in the
core formulation is about 8.5 and about 13 percent by weight.
Preferably~ PLASDONE K-30 (GAF Corp.) of a molecular welght of
40,000 ls used.
The amount of the metoprolol salt, as metoprolol present in the
core, can vary widely but is preferably between about 50 to about
SOO mg per unit tablet device. Most preferably, the core contains
between about 60 to about 200 mg of metoprolol salt.
The core compartment i8 advantageously in the form of a tablet which
is film coated with the semipermeable membrane to form the wall. The
core composition is advantageously prepared by combining the
moderately water-soluble ~alt of metoprolol with the poly-N-vinyl-
pyrrolidone, either by d{y blending and granulating in the presence
of a water-ethanol mixture or by mixing said salt with an aqueous
ethanolic solution of poly-N-vinylpyrrolidone, and subsequently
granulating the mixture, and then drying the granulation and milling
the same and optionally blending the dried milled granules with a
tabletting lubricant, and compressing the resulting granules into
tablets to form the core. The cores have advantageous properties
useful for formulation such as hardness between about 8-25 S.C.U.
units (Strong Cobb Units) and Eragibility being less than 1.5 %,
aspecially less than 1 %.
The core tablat is than subsequently coated with a semipermeable
film-forming solution by using conventional coating methods, e.g.
air suspension techniques, such as the Wurster Air suspension
technique, to obtain a core tablet coated with the semipermeable
wall material. The resulting device is provided with at least one
passageway to osmotically release the metoprolol salt, as a concen-
trated or saturated solution, from the core to tha gastrointestinal
tract at a controlled rate. The passageway(s) can be formed, in
situ, by using a heterogeneous solution to coat the core tablet
~ 3 ~
containing the semipermeable membrane film-forming solution and a
water or gastrointestinal fluid soluble material, whereby in the
environment of use passageways are formed by erosion with aqueous
solvent in situ, or the semipermeable shaped wall can be drilled,
either mechanically or by use of a laser, to form the passageway or
passageways.
The passageway orifice siæe will vary depending upon the size of the
core 7 exact desired releaso profile, and the number of passageways.
Where one passageway is present, the orifice size can vary, for
example, between about 0.1 mm and about 0.8 mm.
Generally, the film-forming semipermeable wall material is applied
to the tablet core in the form of an organic solvent containing
solution. Suitable solvents include, for example, dioxane, diethyl
ether, lower alkanols, such as methanol or ethanol, and halogenated
lower alkanes, such as chloroform, methylchloride and methylene
chloride, or mlxtures thereof. The amount of semipermeable membrane
material employed per unit dose will vary dependent upon, for
example, the permeability characteristics of the membrane material.
For example, using cellulose acetate as the film-forming material,
between about 4 and about 20 percent by weight, preferably between
about 10 and about 20 percent by weight based upon the total weight
of the device, may be employed.
The following examples are merely illustrative of the present
invention and should not be considered as limiting the scope of the
present invention. All parts ~re by weight unless otherwise speci-
fied.
xample 1:
To 95.37 parts by weight metoprolol fumarate (1:1) there is added
8.10 parts by weight povidone USP and the mixture is milled to a
powder and granulated with an ethanol/water mixture (70t30). The
granulation mixture is then dried9 sized and 1.53 parts by weight
magnesium stearate NF mixed therewith. The resulting particulate
- 9 -
product is compressed into core tablets containing a total weight
per tablet of 105 mg, containing 7.7 weight percent povidone,
1.5 weight percent magnesium stearate, and remainder metoprolol
fumarate (1:1). The core tablets exhibited the following
charactsristics:
Hardness (SC~: 9-11
Friability (percentage of tablets broken): 0.2
Disintegration time (min): 9
Example 2:
To illustrate the fragility of core tablets containing insuEficient
amounts of poly-N-vinylpyrrolidone, the following composition was
prepared in identical fashion with Example 1 but with a reduced
amount of povidone USP:
Parts by Weight Weight %
Metoprolol fumarate (1:1) 95.37 93.5
Povidone ~SP 5.10 5
Magnesium Stearate NF 1.53 1.5
The core tablets exhibited the following comparative characteristcs.
Ilardness (SCU) : 7-9
Friability (%) : ~.2
Disintegration (min) : 8
Example 3:
Employing the procedure of Example 1, the following core tablets
were prepared (parts by weight):
-- 10 --
Example 3 4 5 6
Metoprolol Fumarate (1:1) 95.37g5.37 95.37 95.37
Povidone, USP 10.1013.108.1011.10
Magnesium Stearate NF1.53 1.532.53 2.53
% Povidone 9-4 12.0 7.610.2
% Magnesium Stearate 1.~ 1.4 2.4 2.3
Hardness (SCU) 14-15 ll-lo 9-11 8-11
Friability (%) 0.3 0.2 0.2 0.2
Disintegration (min) 7 8 18 15
Example 7:
Core tablets are prepared according to Example 1, containing per
tablet 95 mg metoprolol fumarate (1:1), 2.90 mg magnesium
stearate NF, and 11.10 mg povidone USP, having a hardness (SCU) of
8-11, a friability of 0.2 % and a disintegration time of about
15 minutes. The core tablets are film coated by air suspension with
a methyl alcohol/mathylene chloride solution of cellulose acetate
containing about 16 mg cellulose acetate per tablet. The coated
tablets are drilled to provide an exit passage orifice having a
diameter of about 0.5 mm.
Example 8-
Coated tablets are prepared and drilled according to Example 7, but
containing tbe following composition per tablet: metoprolol
fumarate (1:1), 190.74 mg; povidone USP, 22.20 mg; magnesium
stearate, 5.06 mg having a core composition hardness (SCU) of 11-16,
a friability of O.Z % and a disintegration time of 27 minutes, which
is then coated with approximately 29 mg cellulose acetate and the
dried coated tablet drilled to provide an ex:Lt passageway having a
diameter of about 0.5 mm. Upon placement in simulated gastric fluid
without en~ymes at 37"C, in a U.S.P basket, s~7herein the fluld is
stirred at 100 rpm, the ollowing release characteristics are
observed:
Average Hoully Average
Time IntervalRelease Rate Cumulative Release
(Hour~) (mglh) (Percent)
-- . _
0 - 2 17.8 t 2.7 18.7
2 - 4 21.4 + 1.6 1~1.2
4 - 6 19.0 + 0.9 6l.2
6 - 8 17.0 -~ 1.6 79.0
8 - 10 8.3 ~ 1.4 87.7
10 - 12 4.5 ~ 0.7 92.5
