Note: Descriptions are shown in the official language in which they were submitted.
CA 02309542 2000-OS-08
WO 99IZ4017 PCTIUS98I24102
NOVEL ORAL DOSAGE FORM FOR CARVEDILOL
Field of the Invention
The present invention relates to a novel formulation containing carvedilol, or
a
pharmaceutically acceptable salt thereof, and to its use in the treatment
and/or prophylaxis
of certain disorders.
Background of the Invention
U.S. Patent No 4,503,067 describes a compound which is known as carvedilol.
This compound is a novel multiple action drug useful in the treatment of mild
to moderate
hypertension. Carvedilol is known to be both a competitive non-selective (3-
adrenoceptor
antagonist and a vasodilator. The vasodilatory actions of carvedilol result
primarily from
al-adrenoceptor blockade, whereas the ~i-adrenoceptor blocking activity of the
drug
prevents reflex tachycardia when used in the treatment of hypertension. These
multiple
actions of carvedilol are responsible for the antihypertensive efficacy of the
drug. Also,
carvedilol, as a consequence of its antioxidant action in attenuating oxygen
free radical-
initiated lipid peroxidation, is useful in organ protection, in particular,
cardioprotection.
Additionally, carvedilol is useful in the treatment of congestive heart
failure.
The current formulation of carvedilol is a conventional swallow tablet, taken
twice
daily. This formulation is in immediate release form; that is to say the
nature of the
formulation is such that by the time carvedilol leaves the stomach, it is
either in solution or
it is in the form of a suspension of fine particles, i.e., a form from which
carvedilol can be
readily absorbed.
It has now been found that controlled release and delayed release formulations
containing carvedilol give rise to a once daily formulation. These
formulations are able to
extend the duration of action of carvedilol, thus improving the
bioavailability of this drug.
Summary of the Invention
The present invention provides a controlled release or delayed release
formulation
containing carvedilol or a pharmaceutically acceptable salt thereof.
Detailed Description of the Invention
The present invention provides a controlled release or delayed release
formulation
comprising carvedilol, which is (1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)-
ethyl]amino]-2-propanol), of the formula (I):
-1-
CA 02309542 2000-OS-08
WO 99124017 PCTIUS98/24102
OCH 3
O~N-~O w
OH H
N
H ~I)
or a pharmaceutically acceptable salt thereof, in an oral dosage unit form.
The present invention also provides for a matrix formulation comprising
carvedilol
in an oral dosage unit form and for an enteric coated formulation comprising
carvedilol in
an oral dosage unit form.
Carvedilol may be conveniently prepared as described in U.S. Pat. No.
4,503,067.
Reference should be made to said patent for its full disclosure, the entire
disclosure of
which is incorporated herein by reference.
According to the formulation of the instant invention, carvedilol is suitably
in the
form of the free base or a pharmaceutically acceptable salt thereof.
Preferably, carvedilol is
in the form of the free base.
By controlled release is meant any formulation that achieves slow release of
drug
over an extended period of time. In the controlled release formulations of the
instant
invention, a portion of the carvedilol in the formualtion is made available as
a priming dose
and the remainder is released in a sustained fashion. An example of a
controlled release
system is a matrix formulation.
By delayed release is meant any formulation that utilizes repetitive,
intermittent
dosings of carvedilol from one or more immediate release units incorporated
into a single
dosage form. Examples of delayed release systems include repeat action tablets
and
capsules, and enteric-coated tablets where timed release is achieved by a
barrier coating.
Examples of controlled release formulations which are suitable for
incorporating
carvedilol are described in:
Sustained Release Medications, Chemical Technology, Review No. 177, Ed. J.C.
Johnson, Noyes Data Corporation (1980); and
Controlled Drug Delivery, Fundamentals and Applications, 2nd Edition, Eds.
J.R.
Robinson, V.H.L. Lee, Mercel Dekkes Inc., New York (1987).
Examples of delayed release formulations which are suitable for incorporating
carvedilol are described in:
Remington's Pharmaceutical Sciences, 16th Edition, Ed. A. Osol, Mack
Publishing
Company ( 1980).
-2-
CA 02309542 2000-OS-08
WO 99/Z4017 PCTIUS98/24102
Other examples of controlled release formulations which are suitable for
incorporating carvedilol are described in U. S. Patent No. 4,839,177, issued
June 13, 1989,
and U. S. Patent No. 5,422,123, issued June 6, 1995. Matrix controlled release
formulations for carvedilol are detailed in U. S. Patent No. 4,389,393, issued
June 21, 1983,
and U. S. Patent No. 4,968,508, issued November 6, 1990.
Additionally, the controlled release formulations containing carvedilol may be
in
the form of a non-compressed pellet, having an enteric coat or a sustained
release coat
permeable to gastrointestinal juices. These controlled release formulations
are prepared,
for example, as described in U. S. Patent No. 4,524,060, issued June 18, 1985,
and U. S.
Patent No. 4,983,401, issued January 8, 1991. Other controlled release
formulations are
described in U. S. Patent No. 4,880,830, issued November 14, 1989, and U. S.
Patent No.
5,068,112, issued November 26, 1991.
Such controlled release formulations are preferably formulated in a manner
such
that release of carvedilol is affected predominantly during the passage
through the stomach
and the small intestine, and delayed release formulations are preferably
formulated such
that release of the carvedilol is avoided in the stomach and is affected
predominantly during
passage through the small intestine
Said formulations are preferably formulated such that the release of the
carvedilol
is predominantly 11/z to 3 hours post ingestion.
The small intestine is suitably the duodenum, the ileum or the jejunem.
The formulations of the present invention allow for once-a-day dosing.
Preferred formulations for carvedilol are enteric coated tablets or caplets,
wax or
polymer coated tablets or caplets or time-release matrices, or combinations
thereof. The
oral route of administration of the formulation of the present invention is
preferred.
According to the instant invention, the controlled release formulation may be
a
matrix formulation. This formulation may comprise a plurality of matrix cores
containing
carvedilol, said matrix cores having different release rates of the drug. The
preferred
formulation comprises an immediate release phase of carvedilol, as well as a
sustained
release phase. The sustained release phase matrix core may be uncoated or
coated.with a
release-delaying substance. Preferably, when the matrix core is coated with a
release-
delaying substance, the release-delaying substance is present in an amount of
from 2 to
30% (w/w) relative to the matrix core. More preferably, the release-delaying
substance is
present in an amount of from 5 to 25% (w/w).
The release-delaying substance of the present invention is a coating agent or
a
blend of agents thereof, which protects carvedilol from immediate degradation
in the
stomach. The overcoating, depending on the release rate desired, may allow for
continual
release, or slow release, or delayed release. A preferred release-delaying
substance is
-3-
CA 02309542 2000-OS-08
WO 99/24017 PCTIUS98/24102
enteric coating, i.e., a medicinal preparation treated to pass through the
stomach unaltered,
which disintegrates in the intestines.
The matrix formulations of the present invention may be prepared using three
types
of materials: insoluble plastics, hydrophilic polymers or fatty compounds.
Plastic matrices
include methyl acrylate-methacrylate, polyvinyl chloride and polyethylene.
Hydrophilic
polymers include methylcellulose, hydroxypropylmethylcellulose (HMPC) and
sodium
carboxymethylcellulose. Fatty compounds include various waxes such as carnauba
wax
and glyceryl tristearate. The most common method of preparation is to mix
carvedilol with
the matrix material and then compress the mixture into tablets. In the case of
wax matrices,
carvedilol is generally dispersed in molten wax, which is then congealed,
granulated and
compressed into cores. In the matrix formulation containing carvedilol, the
priming dose
(the portion of the carvedilol that is immediately available in the
formulation) is placed in a
coat of the tablet. The coat can be applied by press coating or by
conventional pan or air
suspension coating.
In one embodiment of the invention, the carvedilol matrix tablet formulation
comprises a mixture of HMPC and Carbopol. In a further embodiment of the
invention, the
carvedilol matrix tablet formulation comprises a mixture of HMPC, Carbopol and
mannitol.
The flow diagram hereinafter summarizes the manufacturing process foc the
preparation of
controlled release tablets containing carvedilol.
-4-
CA 02309542 2000-OS-08
wo 99naom QcTius9snaioa
Carvedilol
Mann'ttol
Hydroxypropyt methy~ellulose Blend
PUrilied Water ~ ~ Granulate
I Wet Screen I
I Dry Granules I
Screen
Carbomer 941 ~Scree~~ &end
AAegnesium Stearate IScreen---
Compression Nix
Compress Cores
Opadry Wh'tte ~Mx Spray
PUr~ied Water
Opadry Clear ~~x~ Spray
Purified Wate ~r
Carve~lol Controlled
Release Tabbts
According to the instant invention, carvedilol, mannitol, and HPMC is
granulated
with purified water, wet screened, and then dried. The dry granules are
screened. The
resultant internal granulation is blended with pre-screened Carbomer 941 until
homogeneous. Pre-screened magnesium stearate is mixed with the blend to create
the
compression mix. Tablets are compressed as round cores and are coated to an
approximate
3 % weight gain with an Opadry~ white solution, followed by an approximate 0.5
%
weight gain with an Opadry~ clear solution.
-5-
CA 02309542 2000-OS-08
WO 99/24017 PCT/US98I24102
The present invention also provides for various combinations of immediate
release
and controlled release forms. For example, the uncoated sustained release
matrix core may
be in combination with an immediate release form of carvedilol and/or a coated
matrix
form. The matrix core may be comprised of a multitude of pellets coated
independently
with different release-delaying substances, all of which may be combined with
uncoated or
immediate release forms of carvedilol.
Delayed release formulations containing carvedilol may be prepared either by
coating particles or granules of carvedilol with varying thicknesses of slowly
soluble
polymers, or by microencapsulation. In formulations employing
microencapsulation, a
hydrophilic substance acts as the coating material around a microcapsule. The
hydrophilic
substance can be selected from a variety of natural and synthetic polymers
including
shellacs, waxes, starches, cellulose acetate phthlate or butyrate,
polyvinylpyrrolidone and
polyvinyl chloride. Once the coating material dissolves, all the carvedilol in
the
microcapsule is immediatley available for dissolution and absorption. Thus,
the release of
carvedilol can be controlled by adjusting the thickness and the dissolution
rate of the coat.
The thickness can be varied from less than 1 micromolar to 200 micromolar by
changing
the amount of coating material from 3 to 30% of the total weight. If only a
few different
thicknesses are used, usually three or four, carvedilol will be released at
different
predetermined times to give a delayed release effect, i.e., repeat action. If
a spectrum of
different thicknesses is employed, a more uniform blood level of carvedilol
can be
obtained. The coated particles can be directly compressed into tablet, or
placed in capsules.
Carvedilol in the form of a controlled release or delayed release formulation
can be
used to treat hypertension, angina and congestive heart failure. The
formulations of the
instant invention may also be used in organ protection, for example, in
cardioprotection.
The present invention provides a method of treating hypertension, angina and
congestive heart failure by administering an effective amount of a controlled
release or
delayed release formulation containing carvedilol or a pharmaceutically
acceptable salt
thereof, to a sufferer in need thereof.
The present invention further provides the use of a controlled release or
delayed
release formulation containing carvedilol or a pharmaceutically acceptable
salt thereof in
the manufacture of a medicament, for treating hypertension, angina and
congestive heart
failure.
The present invention also provides a pharmaceutical composition for use in
the
treatment of hypertension, angina and congestive heart failure which comprises
a controlled
release or delayed release formulation, preferably a matrix formulation,
containing
carvedilol or a pharmaceutically acceptable salt thereof.
-6-
CA 02309542 2000-OS-08
WO 99/24017 PCT/US98I24102
No unacceptable toxicological effects are expected when carvedilol is used
according to the present invention.
The examples which follow are not intended to limit the scope of this
invention,
but are provided to illustrate this invention. Many other embodiments will be
readily
apparent to those skilled in the art.
Examples
Manufacturing Process Desc~tion
BLENDING
Step 1. Weigh out the exact amounts of carvedilol, mannitol, hydroxypropyl
methylcellulose, and purified water.
Step 2. Transfer the carvedilol, mannitol, and hydroxypropyl methylcellulose
into
a high shear mixer product bowl.
Step 3. Pre-blend ingredients for 2 minutes with the impeller and chopper at
low
speed setting.
GRANULATION
Step 4. Granulate with purified water at low speed until desired granule
appearance is achieved.
Step 5. Discharge granulation into stainless steel container for the wet-
milling
process.
Step 6. Slowly add the wet granules through the Quadro Comil (with screen)
into
a stainless steel container.
Step 7. Transfer the milled granulation to the pre-heated fluid bed product
bowl.
Step 8. Dry the granules by maintaining the target inlet temperature of
approximately 70°C (65°C - 75°C) until the product
temperature reaches
the target temperature (40 - 47°C) and the loss on drying is within the
target range (0.5 - 1.8%).
Step 9. Set-up the Quadro Comil (variable speed) and attach the screen for
milling.
Step 10. Add the dry granules through the Quadro Comil {with screen) into pre-
tared polyethylene bags.
UNLUBRICATED GRANULATION MIX
Step 11. Screen an excess amount of Carbomer 941 (Carbopol 971P) to de-
aggregate by passing though a #20 mesh stainless steel screen by hand.
_7_
CA 02309542 2000-OS-08
WO 99/24017pCTIUS98/24102
Step 12. Weigh out the exact amount of pre-screened Carbomer
941 (Carbopol
971 P) onto the weigh paper.
Step 13. Weigh out the exact amount of carvedilol internal
granulation into
properly labelled polyethylene bags.
Step 14. Set-up a suitable size V-Blender.
Step 15. Transfer 1/3rd of the carvediloI internal granulation
into the 'V' blender.
Step 16. Add l/3rd of the Carbomer 941 (Carbopol 971P) to
the 'V' blender.
Step 17. Repeat Steps 15 and 16 until all internal granulation
and Carbomer 941
(Carbopol 971P) is in the 'V' blender.
Step 18. Mix for 30 minutes or until homogeneous.
Step 19. Remove samples for in-process testing.
LUBRICATED GRANULATION MIX
Step 20. Screen an excess amount of magnesium stearate (to
de-aggregate) by
passing though a #40 mesh stainless steel screen
by hand.
Step 21. Weigh out the exact amount of pre-screened magnesium
stearate onto
the weigh paper.
Step 22. Load the magnesium stearate into the blender (containing
the
unlubricated granulation) and mix for 3 minutes.
COMPRESSION
Step 23. Transfer the compression mix to the hopper of a
rotary tablet press using
7/16" x 5/8" round standard tooling.
Step 24. Compress tablets to meet the physical properties
targets:
Step 25. Remove samples for in-process testing throughout
the run.
COATING
Step 26. Separately weigh out the exact amount of carvedilol
round active cores,
Opadry~ White and Opadry~ Clear into polyethylene
bags. If
necessary, the round active cores may be bulked
using oval placebo
cores to achieve the batch size necessary to fill
the coating pan.
Step 27. Transfer into a suitable, clean tared container,
the required quantity of
purified water to produce a 12% solids concentration
of Opadry~
White.
Step 28. With a vortex mixing action, slowly add the Opadry~
White to the
purified water. Continue mixing until no solid constituents
are visible.
Use this solution within 24 hours of manufacture.
_g_
CA 02309542 2000-OS-08
WO 99/24017PCT/US98/24102
Step 29. Transfer into a suitable, clean tared container,
the required quantity of
purified water to produce a 5 % solids concentration
of Opadry~ Clear.
Step 30. With a vortex mixing action, slowly add the Opadry~
Clear to the
Purified Water. Continue mixing until no solid constituents
are visible.
Use this solution within 24 hours of manufacture.
Step 31. Set-up the Accela Coater coating pan. Set pump to
deliver white and
clear coating solution to spray at a rate of approximately
35 g/minute.
Step 32. Transfer the cores to the coating pan. Pre heat
the cores: Set the inlet
temperature to 55C (40C - 70C) while jogging the
pan periodically.
When product temperature reaches approximately 42C
(37C - 45C)
start spray. Spray the entire quantity of white
coating solution to obtain
approximately a 3% weight gain coat. Follow with
clear coating
solution to obtain approximately a 0.5% weight gain
coat.
Step 33. Remove coated tablets from coating pan into double
polyethylene-lined
drum. If placebo cores were used to bulk up the
coating batch size, a
sortinglinspection process is performed after completion
of the coating
run, to separate the oval placebo cores from the
round active cores.
Example 1
Table 1: Unit Formulae for Controlled Release Carvedilol Formulations
Strength 50 50 mg 50 mg
mg
Formula BC BD BE
Component Compendia Quantity
mgltablet
Carvedilol 50.0 50.0 50.0
Mannitol USP 152.5 366.25 360.0
Hydroxypropyl MethycelluloseUSP 37.5 75.0 75.0
Carbomer 934P NF 7.5 3.75 10.0
Magnesium Stearate NF or Ph. 2.5 S.0 5.0
Eur.
Opadry White (OY-S-9603)NC 7.5 15.0 15.0
Opadry Clear (YS-1-19025A)NC 1.25 2.5 2.5
Purified Water USP or Ph. q.s. q.s, q.s.
Eur.
Totat Tablet Weight 258.75517.5 517.5
-9-
CA 02309542 2000-OS-08
WO 99/24017 PCTIUS98/24102
Example 2
Table 2: Typical Batch Formulae for Controlled Release Carvedilol
Formulations
Strength 50 50 mg 50 mg
mg
Formula BC BD BE
Component Compendia Quantity
kg/batch
Carvedilol NC 1.36 0.68 0.68
Mannitol USP 4.14 4.96 4.87
Hydroxypropyl MethycelluloseUSP 1.01 1.01 1.01
Carbomer 934P NF 0.20 0.05 0.14
Magnesium Stearate NF or Ph. 0.07 0.07 0.07
Eur.
Opadry White (OY-S-9603)NC 0.20 0.20 0.20
Opadry Clear (YS-i-19025A)NC 0.03 0.03 0.03
Purified Water USP or Ph. q.s. q.s. q.s.
Eur.
Total Batch Weight 7.0 7.0 7.0
(kg)
Batch Size (approx. 28,00014,000 14,000
number of
tablets)
Example 3 (pH Sensitive Coat on Immediate Release Core)
Tablet Core %w/w
Carvedilol 11.45
Lactose 64.05
Microcrystalline Cellulose20.0
Sodium Starch Glycollate4.0
Magnesium Stearate 0.5
TOTAL 100.0
Tablet Coating (apply approximately 6-10% of tablet core weight) %w/w
Hydroxypropylmethylcellulose Phthalate 90.0
Triacetin 10.0
- 10-
CA 02309542 2000-OS-08
WO 99/24017 PCTIUS98/24102
Example 4 (pH Sensitive Coat on Immediate Release
Core)
Tablet Core as in Example 3
Tablet Coating (apply approximately 6-10% of %w/w
tablet core weight)
Cellulose Acetate Phthalate 90.0
Diethyl Phthalate 10.0
Example 5 (Controlled Release Coating on Immediate
Release Core)
Tablet Core as in Example 3
Tablet Coating (apply approximately 5-12% of %w/w
tablet core weight)
Eudragit RS 100 86.0
15Dibutyl Phthalate 10.0
Talc 4.0
FD&C Yellow No. 6 ~ 0.01
Example 6 (pH Sensitive Coat on Controlled Release
Core)
Tablet Core as in Example 3
Tablet Coating as in Example 3
25Example 7 (Encapsulated Controlled Release Coated
Beads)
Pellet %w/w (approx)
Non Pareil Seed 30
Carvedilol 40
30Gelatin 8
Lactose 20
Talc 2
Coating kw/w
35Glycerylmonostearate 36.6
Glyceryldistearate 53.4
White Wax 10.0
-11-
CA 02309542 2000-OS-08
WO 99/24017 PCT/US98/24102
The foregoing are illustrative of this invention. This invention, however, is
not
limited to the precise embodiments described herein, but encompasses all
modifications
within the scope of the claims which follow.
The various references to journals, patents, and other publications which are
cited
herein comprise the state of the art and are incorporated herein by reference
as though fully
set forth.
- 22 -
