FIELD OF THE INVENTION
The present invention relates to an oral controlled release pharmaceutical composition
comprising a therapeutically effective amount of carvedilol or a pharmaceutically
acceptable salt(s) thereof.
BACKGROUND OF THE INVENTION
U.S. Pat. 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 0-
adrenoceptor antagonist and a vasodilator. The vasodilatory actions of carvedilol
result primarily from ai -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.
A controlled release profile from a drug dosage form is desirable in clinical use to
reduce side effects and improve patient compliance. The technology used to formulate
sustained release dosage forms is well documented. The entrapment of a drug in a
polymer-based matrix is a common approach to formulate sustained release tablets
with a desirable release profiles.
It has been reported that depot drug formulations for controlled release of
pharmaceutical drugs may be prepared using alginates alone (see U.S. Pat. No.
5,132,295), using combinations of alginates and polyacrylates (see U.S. Pat. No.
5,230,901) and using combinations of alginates and a pH independent gelling agent,
such as, for example, hydroxypropyl methylcellulose (see U.S. Pat. No. 4,792,452). It
is also known that the use of alginates alone for this purpose often presents difficulties
in tabletting, film coating and storage.
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It also has been reported that a sustained release dosage form useful in providing
once-a-day medication consists of the admixture of hydroxypropyl methylcellulose
(viscosity of 80 to 120 cps in a 2% aqueous solution) and ethylcelluose with etodolac
(see U.S. Pat. No. 4,966,768).
Matrix drug delivery system has been described in U. S. Patent No. 6,150,410. This
patent discloses extended release pharmaceutical compositions of acidic
pharmacological agents that have reduced dependence of the release rate upon pH and
gastric residence time. The extended release compositions comprise a combination of
water-swellable, hydrophilic polymer and acid soluble polymer, which is swellable
above pH 5. These compositions provide an enhanced rate of release of the acidic
pharmacological agent in the stomach where the pH of the gastric juices is low and
diminished release rate at neutral or slightly alkaline pH of the intestines.
Further, U. S. Patent Nos. 5,695,781 and 6,083,532 disclose a three component,
release rate controlling matrix composition that includes a pH dependent gelling
polymer such as an alginate component, an enteric polymer and a pH independent
gelling polymer.
Additionally, U. S. Patent No. 6,251,430 describes the use of ethyl cellulose or
Eudragit RS or RL in combination with hydroxypropyl methylcellulose and sodium
alginate to provide for a controlled release of the drug.
PCT patent application, WO 2004056336 describes an oral controlled release multiple
unit system, each unit includes at least one core; a first coating layer surrounding a
portion of outer surface of core, the coating layer including carvedilol; a second
coating layer surrounding a portion of the outer surface of first coating layer, the
coating layer including one or more sustained release polymers and one or more
enteric polymers. The multiple unit system may optionally contain a seal coat
between inert core and carvedilol layer, or between carvedilol layer and rate
controlling polymer layer. The units are finally compressed into tablet or filled into
capsule/sachet.
3

PCT patent application, WO 2006044202 describes embodiments of a pharmaceutical
formulation comprising an enteric material. The embodiments release at least a
portion of an active ingredient upon contacting gastric fluid. The remaining portion of
the formulation releases active ingredient upon contacting intestinal fluid. Certain
embodiments of the pharmaceutical composition comprise at least one active
ingredient in a core and a leaky enteric coating, such as an enteric coating comprising
a gastric fluid-channeling agent. Other embodiments of the pharmaceutical
composition comprise at least one active ingredient substantially homogeneously
admixed with at least one enteric material, such as an enteric material comprising a
gastric fluid channeling agent. Disclosed embodiments of the pharmaceutical
composition may comprise a single active ingredient, or may comprise plural active
ingredients.
Despite many efforts, there still remains a need for improved controlled release
pharmaceutical compositions for oral administration, from which a wide range of
drugs can be released, irrespective of pH and gastric residence time.
OBJECT OF THE INVENTION
The object of the invention is to provide oral controlled release pharmaceutical
compositions of carvedilol or a pharmaceutically acceptable salt(s) thereof.
SUMMARY OF THE INVENTION
According to one aspect of the present invention there is provided an oral controlled
release pharmaceutical composition comprising a) a core comprising a therapeutically
effective amount of carvedilol or a pharmaceutically acceptable salt(s) thereof and/or
other pharmaceutically acceptable excipient(s) thereof;
b) a functional coating comprising one or more pH dependent polymer(s), water
soluble pore forming agent and/or other pharmaceutically acceptable excipient(s)
thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an oral controlled release pharmaceutical composition
comprising a) a core comprising a therapeutically effective amount of carvedilol or a
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pharmaceutically acceptable salt(s) thereof and/or other pharmaceutically acceptable
excipient(s) thereof;
b) a functional coating comprising one or more pH dependent polymer(s), water
soluble pore forming agent and/or other pharmaceutically acceptable excipient(s)
thereof.
Carvedilol or pharmaceutically acceptable salts thereof can be used in the present
invention, the preferred salt being carvedilol phosphate. Carvedilol or a
pharmaceutically acceptable salt thereof used in the present invention may be in
crystalline or amorphous or anhydrous or hydrate form thereof. These forms include
but are not limited to carvedilol phosphate hemihydrate (Form I) or Form A or Form
B or anhydrous form or amorphous form.
By controlled release it is meant as any formulation that achieves slow release of drug
over an extended period of time. It is taken to encompass sustained release, prolonged
release, timed release, modified release, retarded release and extended release. The
formulations of the present invention allow for once-a-day dosing containing 10, 20,
40, or 80 mg of carvedilol phosphate.
According to the instant invention, core comprises active ingredient, carvedilol or a
pharmaceutically acceptable salt thereof and also includes an inert substance with or
without other pharmaceutical excipients. Inert substances, which do not interfere with
the biological activity of the active ingredient, include but not limited to beads, such
as sugar beads, particles, spheres, granules etc. The active ingredient may be present
in the core or layered over an inert substance. The active ingredient present in the core
may range from about 60 to 100 % by total weight of the active ingredient in the
dosage form.
Functional coating comprises pH dependent polymers selected from the group but not
limited to cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate
(HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose
acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl
methylcellulose succinate, cellulose acetate succinate, cellulose acetate
hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate,
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cellulose acetate butyrate, cellulose acetate propionate, copolymer of
methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate,
methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic
anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-
chlorotrimethylammonium ethyl acrylate copolymer, polyvinyl acetate phthalate,
natural resins such as zein, shellac and copal collophorium and combinations thereof.
Functional coating also comprises water-soluble pore-forming agent selected from the
group but not limited to salts such as sodium chloride and potassium chloride; sugars,
such as lactose, sucrose, sorbitol, and mannitol; hydroxylated compounds, including
polyvinyl alcohols and glycols, such as polyethylene glycol and propylene glycol;
cellulose derived materials, such as hydroxypropyl cellulose, hydroxypropyl
methycellulose, polyvinyl pyrrolidone, or mixtures thereof.
Pharmaceutically acceptable excipients used in the oral controlled release
formulations of carvedilol include those known to a person ordinarily skilled in the art
such as diluents, binders, and lubricants. Diluents may include but not limited to
lactose, microcrystalline cellulose, dibasic calcium phosphate, mannitol, cellulose and
the like. Binders may include but not limited to starches, alginates, gums, celluloses,
vinyl polymers, sugars and the like. Lubricants may include but not limited to
stearates such as magnesium stearate, talc, colloidal silicon dioxide and the like.
Oral controlled release pharmaceutical composition of carvedilol or a
pharmaceutically acceptable salt thereof of the present invention may further
comprise an immediate release portion of carvedilol or a pharmaceutically acceptable
salt(s) thereof coated over the functional coating. Immediate release portion over
functional coating comprises about 0 to 40% of carvedilol or a pharmaceutically
acceptable salt thereof by total weight of the active present in the dosage form.
Immediate release portion of the active may be present in the dosage form as separate
pellets together with controlled release pellets filled into hard gelatin capsules or
compressed into a bi-layered dosage form.
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Oral controlled release pharmaceutical compositions of carvedilol or a
pharmaceutically acceptable salt thereof of the present invention may be prepared by
processes like direct compression, wet granulation and dry granulation methods.
Preferably oral controlled release pharmaceutical composition of the present invention
is prepared by the process comprising: providing a core having an inert substance
layered with carvedilol or a pharmaceutically acceptable salt(s) thereof and coating
the core with a functional coating comprising one or more pH dependent polymer(s)
and a water soluble pore forming agent. Further, this may be optionally coated with an
immediate release coating comprising carvedilol or a pharmaceutically acceptable salt
thereof.
The binder is dispersed in a suitable solvent and the active is added to get a clear
solution. Load the inert substance with the solution of active to get spherical drug
loaded particles of uniform size. Coat the drug loaded particles by spraying the
solution containing pH dependent polymer and water-soluble pore forming agent.
These pellets may be further optionally coated with an immediate release portion of
the active and/or a film coating over the immediate release portion. These are further
filled into hard gelatin capsules.
The following examples are illustrative of the present invention, and the examples
should not be considered as limiting the scope of this invention in any way, as these
examples and other equivalents thereof will become apparent to those versed in the
art, in the light of the present disclosure, and the accompanying claims.
EXAMPLES
Examples 1:

Ingredients Quantity per unit
dose of 80 mg (% w/w)
Drug Loading
Sugar Spheres 71
Carvedilol Phosphate
Amorphous 25
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Hydroxypropyl
methylcellulose (HPMC) 4
Methanol QS
Dichloromethane QS
Coating of Drug Loaded Pellets
Hydroxypropyl
methylcellulose phthalate
(HPMCP) 75
Hydroxypropyl
methylcellulose 25
Triethyl citrate QS
Methanol QS
Dichloromethane QS
Brief Manufacturing Procedure:
1. Disperse HPMC in small quantity of methanol. To it add dichloromethane to
dissolve it completely under stirring.
2. Add remaining methanol to the above solution under stirring and dissolve
Carvedilol Phosphate to get clear solution.
3. Load the weighed quantity of sugar spheres in Fluidized Bed Processor.
4. Adjust the spray rate and air pressure and spray the solution of Carvedilol Phosphate
of step -2 on the sugar spheres to get spherical drug loaded particles of uniform size.
5. Disperse HPMC & HPMCP in methanol by stirring. Add dichloromethane to dissolve
the polymer.
6. Add triethyl citrate to above solution and stir to get clear solution.
7. Coat the drug-loaded pellets by spraying the solution under proper fluidization and at
temperature to the target build.
8. These pelletes are then are then filled into pharmaceutically acceptable hard gelatin
capsules.
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Example 2:

Ingredients Quantity per unit
dose of 80 mg (%w/w)
Drug Loading
Sugar Spheres 71
Carvedilol Phosphate
Amorphous 20
Polyvinyl pyrrolidone
(PVP) 4
Methanol QS
Dichloromethane QS
Coating of Drug Loaded Pellets
Hydroxypropyl
methylcellulose phthalate
(HPMCP) 75
Poly ethylene glycol (PEG) 25
Triethyl citrate QS
Methanol QS
Dichloromethane QS
Immediate Release Coating
Carvedilol Phosphate 5
Methanol QS
Film Coa ting QS
Manufacturing Procedure: Same as examples 1
Example 3:
Ingredients Quantity per unit
dose of 80 mg (mg% w/w)
Drug Loading
Sugar Spheres 71
Carvedilol Phosphate
Hemihydrate (Form I) 25
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Hydroxypropyl
methylcellulose (HPMC) 4
Methanol QS
Dichloromethane QS
Coating of Drug Loaded Pellets
Hydroxypropyl
methylcellulose phthalate
(HPMCP) 75
Polvinyl pyrollidone 25
Triethyl citrate QS
Methanol QS
Dichloromethane QS
Manufacturing Procedure: Same as examples 1
DISSOLUTION
The formulations exemplified above were studied for dissolution release using USP I
apparatus, 100 rpm and using 900 ml 0.1N hydrochloric acid for 2 hours followed by
pH 6.8 phosphate buffer. Results of the dissolution profile of Example 1 are
summarized in Table I.

Time (hr.) Cumulative % Drug
Release
1.0 28.5
2.0 40.3
3.0 43.0
4.0 45.1
5.0 49.0
6.0 53.3
7.0 56.8
8.0 60.6
9.0 64.1
10.0 66.8
11.0 70.8
12.0 75.4
14.0 82.7
16.0 90.6
18.0 97.8
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We claim:
1. An oral controlled release pharmaceutical composition comprising:
a) a core comprising a therapeutically effective amount of carvedilol or a
pharmaceutically acceptable salt(s) thereof and/or other pharmaceutically
acceptable excipient thereof;
b) a functional coating comprising one or more pH dependent polymer(s), water
soluble pore forming agent and/or other pharmaceutically acceptable
excipient(s) thereof.

2. An oral controlled release pharmaceutical composition of claim 1, wherein the pH
dependent polymer is selected from the group comprising cellulose acetate
phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate,
hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate,
hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose
acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate
maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of
methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate,
methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and
maleic anhydride, ethyl methyacrylate-methylmethacrylate-
chlorotrimethylammonium ethyl acrylate copolymer, polyvinyl acetate phthalate,
natural resins such as zein, shellac and copal collophorium and combinations
thereof.
3. An oral controlled release pharmaceutical composition of claim 1, wherein the
water-soluble pore-forming agent is selected from the group comprising salts such
as sodium chloride and potassium chloride; sugars, such as lactose, sucrose,
sorbitol, and mannitol; hydroxylated compounds, including polyvinyl alcohols and
glycols, such as polyethylene glycol and propylene glycol; cellulose derived
materials, such as hydroxypropyl cellulose, hydroxypropyl methycellulose,
polyvinyl pyrrolidone, or mixtures thereof.
4. An oral controlled release pharmaceutical composition of claim 1, wherein the
pharmaceutically acceptable excipients comprise diluents, binders, and lubricants.
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5. An oral controlled release pharmaceutical composition of claim 4, wherein the
diluent comprises lactose, microcrystalline cellulose, dibasic calcium phosphate,
mannitol, cellulose and mixtures thereof.
6. An oral controlled release pharmaceutical composition of claim 4, wherein the
binder comprises starches, alginates, gums, celluloses, vinyl polymers, sugars and
mixtures thereof.
7. An oral controlled release pharmaceutical composition of claim 4, wherein the
lubricant comprises magnesium stearate, talc, colloidal silicon dioxide and
mixtures thereof.
8. An oral controlled release pharmaceutical composition of claim 1, wherein
carvedilol or pharmaceutically acceptable salt thereof may be in crystalline or
amorphous or anhydrous or hydrate form thereof.
9. An oral controlled release pharmaceutical composition of claim 1, wherein
carvedilol or pharmaceutically acceptable salt thereof is carvedilol phosphate
hemihydrate (Form I) or Form A or Form B thereof.
10. An oral controlled release pharmaceutical composition of claim 1, further
comprises an immediate release portion comprising carvedilol or a
pharmaceutically acceptable salt thereof coated over the functional coating.
Dated this 9th day of October 2007

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An oral controlled release pharmaceutical composition comprising a carvedilol or a
pharmaceutically acceptable salt(s) thereof. The oral controlled release pharmaceutical
composition comprises a core comprising a therapeutically effective amount of carvedilol
or a pharmaceutically acceptable salt(s) thereof and/or other pharmaceutically acceptable
excipient thereof; and a functional coating comprising one or more pH dependent
polymer(s), water soluble pore forming agent and/or other pharmaceutically acceptable
excipient(s) thereof.