Note: Descriptions are shown in the official language in which they were submitted.
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Controlled Release KCI Tablet Formulations
Background of the Invention
There is a high incidence of severe potassium deficiency in patients treated
simultaneously with diuretics and carbenoxolone. In order to maintain the
extracellular and
intracellular concentrations of potassium within relatively narrow limits,
large doses of
potassium are required. These doses are released in the body in a controlled
release fashion
in order to avoid achieving life-threatening toxicity. The strengths of the
most dosage forms
available in the market place are 8 and 10 mEq KCl capsules or tablets. Since
a 20 mEq KCl
capsule formulation (exceeding 2 g in weight) is not feasible, there is a need
for a 20 mEq
KCl tablet formulation. There is a 20 mEq KCl tablet that is commercially
available under
the tradename, K-DUR 20, based on KCl granules coated with a coating
composition
comprising of ethyl cellulose (Ethocel Standard Premium 100 or Ethocel Medium
100 from
Dow Chemical) and hydroxypropyl cellulose (Klucel from Hercules) using a fluid
bed
granulator which is made under U.S. Patent 4,863,743 issued to C. Hsiao and T.
Chou of Key
Pharmaceuticals, Inc.
Summary of the Invention
An object of the present invention is to provide a method for manufacturing
pharmaceutically elegant KCl tablets having sustained release properties
(e.g., releasing not
more than 40% in one hr and not less than 80% over 8 hrs when tested in USP
Apparatus 2
(Paddles @ 50 rpm) in purified water. Another object is to provide tablets
with controlled
release characteristics, thereby providing treatments for potassium deficiency
in humans
while minimizing adverse side effects if possible. Since 20 mEq active is
equivalent to
almost 1500 mg Kcl, it is difficult to provide this dosage in a single tablet,
which can deliver
an effective daily dose of potassium without being unduly large for
swallowing. A more
particular but non-limiting further objective of the invention is to provide
tablets of total
tablet weight of about 2 g (preferably under 2 g) with acceptable hardness
(not less than 10
kP) and friability (not more than 1.5%).
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US Patent 5,422,122 teaches the art of making a pharmaceutical dosage forn~
by first forming KCl microcapsules by coacervation in a cyclohexane solution
of
ethylcellulose, overcoating the microcapsules with hydroxypropylcellulose and
compressing
the resulting microcapsules into 20 mEq KCl tablets. This patent is
incorporated here in its
entirety. Microencapsulated KCl granules produced by solvent coacervation of
ethylcellulose
are often Glassy hard granules with poor compactibility characteristics. In
order to improve
the compressibility/compactibility of the microcapsules, film coating with a
variety of
plasticized, pharnlaceutically acceptable polymeric materials was attempted.
Polymeric
materials found suitable for improving ethylcellulose coated KCl microcapsules
include
acacia, alginic acid or its salt, com starch, gelatin, xanthan gum,
polyvinylpyrrolidone (PVP),
sodium carboxymethylcellulose, methylcellulose, low molecular weight
ethylcellulose (EC)
and hydroxypropylmethyl cellulose (HPMC) alone or in combination. Different
plasticizers
such as triacetin, triethyl citrate, dibutyl sebacate, polyethylene glycol of
molecular weight
ranging from 200 to 8,000, were evaluated alone or in combination. These
attempts have
resulted in pharnlaceutically elegant 20mEq KCl capsule-shaped tablets
weighing about 2 g
(generally less) and having controlled release properties (releasing not more
than 40% in one
hr and not less than 80% over 8 hrs) when tested in USP Apparatus 2 (Paddles @
50 rpm) in
purified water.
Thus, one manifestation of the present invention is an improved 20 mEq KCl
controlled release dosage form prepared from a multiplicity of ethylcellulose
microencapsulated potassium chloride crystals, which are further coated with a
plasticized
water swellable/soluble polymer or a blend. These membrane coated granules are
capable of
being compressed into pharmaceutically elegant, easily swallowable 20 mEq KCl
tablets of
acceptable hardness and friability. Of course other KCl dosages are also
within the scope of
the invention. Another manifestation of the present invention is a method for
preparing
microencapsulated KCI crystals and a method for preparing a KCL tablet.
Detailed Description of the Invention
A plurality of potassium chloride crystals, preferably from about 20 mesh to
about 70 mesh, more preferably from about 30 mesh to about 50 mesh, are coated
with two
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distinct layers. rl'he first layer applied to the crystals is composed of
ethylcellulose.
Utilization of a high viscosity ethylcellulose such as one with a viscosity of
from about 90 to
about 110 cp, e.g., Ethocel 100 (Dow Chemical Corp.) allows the crystals to
retain their
diffusion controlling characteristics even after compression into a tablet
form. The
ethylcellulose may be applied by any suitable technique known in the art, but
is preferably
applied by coacervation using polyethylene as a phase separator as described
in U. S. Patent
5,422,122. If coacervation is used, trace amounts of the phase separator may
be present in
the first layer, preferably in an amount less than about one percent by weight
of the
ethylcellulose coated crystals.
The ethylcellulose layer is preferably applied to the KCl crystals in an
amount of about 8 to about 20 percent, more preferably from about 11 to about
15 percent, of
the total weight of the uncoated potassium chloride crystals. This first layer
controls the
release of the potassium chloride over time, total release time being
proportionally dependent
upon the thickness of ethylcellulose. After application of the ethylcellulose,
a drying step
should preferably be carried out for such a time period and at such
temperatures so that the
microencapsulated crystals do not adhere to one another. The resultant
ethylcellulose
encapsulated potassium chloride microcapsules are preferably of such a size
that less than
5% are greater than 20 mesh.
A second, discrete layer of at least one hydrophilic (water swellable/soluble)
polymer coating, is applied over the first layer of ethylcellulose.
Hydrophilic polymer
coatings include, but are not necessarily limited to acacia, alginic acid or
its salt, corn starch,
gelatin, xanthan gum, polyvinylpyrrolidone (PVP), sodium
carboxymethylcellulose,
methylcellulose, low molecular weight ethylcellulose (Ethocel with a viscosity
from about 4
to 20 cps) and hydroxypropylmethyl cellulose (HPMC) such as Methocel ES or l~.
These
hydrophilic polymers can be used alone or in combination.
In accordance with the invention the hydrophilic polymer layer is plasticized.
Suitable plasticizers include triacetin, triethyl citrate, dibutyl sebacate
(DBS), polyethylene
glycol (PEG) of molecular weight ranging from 200 to 8,000 (e.g., a blend of
PEG 400 and
PEG 4000). The plasticizers can be used alone or in combination. The
plasticizer is
typically used in an amount of about 2 to 30% based on the combined weight of
the
hydrophillic polymer and plasticizer. The amount will vary with the type of
plasticizer and
the nature of the hydrophillic polymer. For example for HPMC and PEG400 the
ratio can
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vary ti-om about 7U/3U to 9U/lU. With PVP, DBS or triethyl citrate can be used
as the
plasticizer in a ratio of 94/6 to 97/3.
The plasticized hydrophilic layer is applied by conventional techniques, such
as from an aqueous solution using a fluidized bed coater, to the preformed
layer of
ethylcellulose. The hydrophilic polymer coating layer inclusive of the
plasticizer is applied
in an amount of about 0.5 to 5% w/w (preferably about 1 to 3% w/w and still
more typically
2% w/w) of the weight of the ethylcellulose coated crystals.
The hydrophilic polymer does not significantly diffuse into the
ethylcellulose,
but rather forms a distinct second layer. The first membrane of ethylcellulose
coacervated in
the absence of any plasticizer can be easily distinguishable from the
plasticized polymeric
membrane by microscopic/spectroscopic techniques. As this layer is soluble to
gastric fluids,
the hydrophilic polymer coating dissolves following ingestion of the resultant
tablet. For all
practical purposes, it does not contribute to the controlled release of
potassium chloride.
Rather, the hydrophilic polymer coating is present primarily as a binder
material so that a
high dosage rate tablet can be formed with a minimal amount of conventional
excipients and
low compaction pressures to allow minimal disruption of the rate controlling
ethylcellulose
membrane. In addition, this formulation allows the microencapsulated potassium
chloride to
be dispersed essentially intact over a wide area, reducing the risk of gastric
irritation.
After the hydrophilic polymer coating layer is applied, the now twice coated
crystals are subjected to a final drying step. The resultant coated potassium
chloride
microcapsules are preferably of such a size that less than 15%, are greater
than 20 mesh. The
coated crystals may then be formed into tablets by compression using
conventional
techniques. Preferably a minimal amount of excipients, no more than about 15%
more
preferably no more than 12%, and most preferably no more than 7% by weight
based on the
weight of the final dosage tablet, is added to the coated crystals prior to
compression. The
terns "excipients," as used herein, refers to any additional pharmaceutically
acceptable
ingredients which may be used in a tablet. These excipients include, but are
not limited to,
ingredients such as diluents or binders, disintegrants, wetting agents, and
lubricating agents.
Representative binders include, but are not limited to, Klucel Registered LF
(hydroxypropylcellulose) and Avicel Registered (microcrystalline cellulose).
Disintegrants
include, but are not limited to, cornstarch, lactose, mannitol, sucrose,
Avicel Registered
(microcrystalline cellulose), Primogel Registered (sodium carboxymethyl
starch,
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~;mcompress Registered (dibasic catcmm phosphate dihydrate), Crospovidone
Registered
(cross linked polyvinyl pyrrolidone), and tricalcium phosphate. Wetting agents
include, but
are not limited to sodium lauryl sulfate. Lubricating agents include, but are
not limited to
stearates (e.g. magnesium, calcium, and sodium), stearic acid, Sterotex
Registered, talc,
waxes, and Stearowet Registered.
In a particular embodiment of the invention, the ethylcellulose KCl
microcapsules coated with a plasticized polymer coating solution are blended
with a diluent,
preferably microcrystalline cellulose, optionally a disintegrant and/or a
lubricant, and
compressed into capsule shaped tablets. In one embodiment, a disintegrant such
as
crosslinked PVP (Crospovidone) or sodium starch glycolate at a level of 0.2 to
2% w/w
and/or a lubricant/surfactant such as sodium lauryl sulfate is optionally
blended with the
compression mix. In the course of these investigations, it was discovered that
sodium lauryl
sulfate, widely used as a surfactant produce strong tablets with low
friability. It was also
discovered that microcapsules fluid bed coated with the plasticized polymeric
systems
discussed in this patent application could be compressed into strong tablets
with low
friability without a lubricant (magnesium stearate) or a surfactant (sodium
lauryl sulfate).
The final tablets will contain a pharmaceutically acceptable amount of
potassium chloride. Acceptable daily dosages may be found in The Physicians'
Desk
Reference, 45th ed. ( 1991 ), e.g., 20-200 mEq/day thereof, preferably from
about 8 mEq to
about 20 mEq. The pharmaceutically elegant 20 mEq Microcaps KC1 tablets will
exhibit
sustained release properties (releasing not more than 40% in one hr and not
less than 80%
over 8 hrs when tested in USP Apparatus 2 (Paddles @ 50 rpm) in purified
water, thereby
providing treatments for potassium deficiency in humans with minimal adverse
side effects.
Typical formulations are given in Example 1-3. Unless otherwise indicated all
parts are by weight.
Ingredients Example 1 Example 2 Example 3
Film Coating
Microcaps KCI 1714.3 1714.3 1714.3
HPMC ES 6.2 30.8 31.5
PEG 400 2.6 13.2
1 / 1 PEG 400/PEG 4000 3.5
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Compression Mix
Film coated 1723.1 1758.3 1749.3
KCl
Microcryst. 186.2 200.9 174.9
Cellulose
Crosslinked 39.2 19.9
PVP
Sod. Lauryl 9.8 9.9
sulfate
Total Tablet 1960.2 1989.0 1943.2
weight
Example 1
Microcaps KCl granules (KC1 crystals microencapsulated in ethylcellulose)
with a 87.5 KC1 content were coated with an aqueous solution of
hydroxypropylmethyl
cellulose (HPMC) and polyethylene glycol 400 (PEG 400) at a ratio of 77/23 to
achieve a
weight gain of 0.5% w/w. The film coated granules were blended with
microcrystalline
cellulose (MCC), crosslinked PVP and sodium lauryl sulfate in an amounts of at
9.5%, 2.0%
and 0.5% w/w, respectively and compressed into tablets weighing 1960 mg on a
rotary tablet
press. These tablets containing 1500 mg of Microcaps KCl release slowly over a
period of
hrs when dissolved in O.1N HCl using USP Apparatus 2.
Example 2
Microcaps KCl granules (KCl crystals microencapsulated in ethylcellulose)
with a 87.5 KCl content were coated to achieve a weight gain of 2.5% w/w with
an aqueous
solution of HPMC and PEG 400 at a ratio of 77/23. The film coated granules
were blended
with microcrystalline cellulose and crosslinked PVP at 10.0 and 1.0% w/w,
respectively and
compressed into tablets weighing 1989 mg on a rotary tablet press. These
tablets containing
1500 mg active as Microcaps KCl release slowly over a period of 10 hrs when
dissoluted in
0.1 N HCL using USP Apparatus 2.
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IlJxample 3
Microcaps KCl granules (KCl crystals microencapsulated in ethylcellulose)
with a 87.5 KCl content were coated with an aqueous solution of HPMC and PEG
400 at a
ratio of 77/23 to achieve a weight gain of 1.0% w/w. The film coated granules
were blended
with microcrystalline cellulose, crosslinked PVP and magnesium stearate at
9.5%, 2.0 and
0.5% w/w, respectively and compressed into tablets weighing 1968 mg on a
rotary tablet
press. These pharmaceutically elegant tablets containing 1500 mg active as
Microcaps KCl
release slowly over a period of 10 hrs when dissoluted in O.1N HC1 using USP
Apparatus 2.
Ingredients Example 4 Example 5 Example 6
Film Coating
Microcaps KCl 1714.3 1714.3 1714.3
PVP (K-30) 31.5 31.5
1 / 1 Ethocel/PVP 31.5
1/1 PEG 400/PEG 4000 3.5
Tri-ethyl citrate 3.5
Dibutyl sebacate 3.5
Compression Mix
Film coated KCl 1749.3 1749.3 1749.3
Microcryst. Cellulose194.4 196.6 194.3
Crosslinked PVP 19.6
Total Tablet weight1943.7 1965.5 1943.7
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Example 4
Microcaps KCl granules (KC1 crystals microencapsulated in ethylcellulose) with
a 87.5 KCI
content were coated with an aqueous solution of polyvinylpyrrolidone (PVP K-
30)
containing 1:1 PEG 400/PEG 4000 at 10% w/w to achieve a weight gain of 2.0%
w/w. The
film coated granules were blended with microcrystalline cellulose at 10.0% w/w
and
compressed into tablets weighing 1944 mg on a rotary tablet press. These
tablets containing
1500 mg active as Microcaps KCl release slowly over a period of 10 hrs when
dissoluted in
O.1N HCl using USP Apparatus 2.
Example
Microcaps KCl granules (KCl crystals microencapsulated in ethylcellulose) with
a 87.5 KCl
content were coated to achieve a weight gain of 2.0% w/w with an aqueous
solution of PVP
and tri-ethyl citrate at a ratio of 97/03. The film coated granules were
blended with
microcrystalline cellulose and crosslinked PVP at 10.0 and 1.0% w/w,
respectively and
compressed into tablets weighing 1965 mg on a rotary tablet press. These
tablets containing
1500 mg active as Microcaps KCl release slowly over a period of 10 hrs when
dissoluted in
O.1N HCl using USP Apparatus 2.
Example 6
Microcaps KCl granules (KCl crystals microencapsulated in ethylcellulose) with
a 87.5 KC1
content were coated with an IPA/acetone solution of PVP/Ethocel/DBS at a ratio
of 48/48/04
to achieve a weight gain of about 2.0% w/w. The film coated granules were
blended with
microcrystalline cellulose at 10% w/w and compressed into tablets weighing
1944 mg on a
rotary tablet press. These pharmaceutically elegant tablets containing 1500 mg
active as
Microcaps KC1 release slowly over a period of 10 hrs when dissoluted in O.1N
HCl using
USP Apparatus 2.
_g_
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The above examples are provided to show how to practice the present
invention and are not intended to be exhaustive or to include all obvious
modifications and
variations which will become apparent to those skilled in formulation
development.
However, all these modifications are within the scope of the present invention
and by the
following claims:
What is claimed is:
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