PHARMACEUTICAL COMPOSITIONS OF METOPROLOL
Field of the Invention
The present invention relates to timed extended-release pharmaceutical compositions
comprising metoprolol and an extended-release polymer. The pharmaceutical compositions of
the present invention exhibit a lag time of at least 2 hours and provide an extended-release of
metoprolol for at least 20 hours.
Background of the Invention
Coordinating biological rhythms (chronobiology) with medical treatment is called
chronotherapy (Narayan et al.; International Journal of Medicine and Pharmaceutical Research,
Vol. l(2):226-234, 2013). Human circadian rhythm is based on the sleep-activity cycle. The
release of a number of hormones depends on this cycle, e.g., estrogen and progesterone are
released by the brain in the morning, while melatonin and Cortisol are released during sleep.
These variations tend to influence the therapeutic efficacy of the drug. Blood pressure and heart
rate are highest from 6:00 a.m. to 12:00 p.m. Hence, there is a need for a composition which
can achieve the desired plasma levels at the time of day when blood pressure and heart rate are
highest.
Beta-blockers are an important class of cardiovascular drugs. Metoprolol is a betablocker
that is typically prescribed for hypertension, angina pectoris, and stable, symptomatic
heart failure. It preferentially acts on betai adrenoreceptors, which predominate in the cardiac
muscles. .
U.S. Publication No. 2012/0070472 discloses a chronotherapeutic composition
comprising metoprolol tartarate and Eudragit® wherein metoprolol is completely released in 12
hours. It discloses a pharmaceutical composition with an in-vivo peak-to-trough ratio of greater
than 4.
The present invention provides timed extended-release pharmaceutical compositions of
metoprolol, wherein the pharmaceutical compositions exhibit a lag time of at least 2 hours.
Further, said pharmaceutical compositions provide an extended-release of metoprolol for at least
20 hours.
2
Summary of the Invention
The pharmaceutical composition of the present invention is administered once daily at
bedtime (approximately 10 p.m.) to a subject. This provides a high plasma concentration of
metoprolol during the early morning hours (approximately 4 a.m. to 10 a.m.), thereby
maintaining therapeutic plasma concentration throughout the day until the next dose is
administered. Hence, the present invention provides synchronization of drug release with the
circadian rhythm of the body. The timed extended-release pharmaceutical compositions of the
present invention exhibit a lag time of at least 2 hours, in particular 4-6 hours, and provide an
extended-release of metoprolol for at least 20 hours.
Detailed Description of the Invention
In one aspect of the present invention, there is provided a timed extended-release
pharmaceutical composition comprising:
a) a core comprising metoprolol;
b) an extended-release coating comprising an extended-release polymer; and
c) an outer coating comprising an enteric polymer;
wherein the pharmaceutical composition exhibits the following in-vitro dissolution profile, when
measured in United States Pharmacopeia (USP) type 2 dissolution apparatus, with a paddle
rotation at 50 rpm, at a temperature of 37°C ± 0.5°C in 500 mL of 0.1N HC1 for 4 hours,
followed by 900 mL of pH 7.5 phosphate buffer: a) not more than about 15% of the total amount
of metoprolol is released in 4 hours; and b) more than 70% of the total amount of metoprolol is
released in 20-24 hours.
The term "timed extended-release" as used herein means that the composition is timed to
release metoprolol after a lag time of at least 2 hours, followed by an extended-release of
metoprolol. The timed extended-release coatings are in particular prepared by applying an inner
coating of an extended-release polymer onto a core, and an outer coating of an enteric polymer
or a blend of an enteric polymer and extended-release polymer. Alternatively, extended-release
cores may be further coated with metoprolol which may then be subsequently coated with an
enteric polymer. Pharmaceutical compositions of the present invention provide an extendedrelease
of metoprolol for at least 20 hours, in particular 20-24 hours.
The term "metoprolol" as used herein includes metoprolol and its pharmaceutically
3
acceptable salts. The pharmaceutically acceptable salts include succinate, fumarate, tartrate,
citrate, pamoate, and mandelate. Metoprolol and its pharmaceutically acceptable salts may be in
their racemic form or as a pure enantiomer.
The term "core" as used herein may be a matrix core or a coated core. It may be in the
form of pellets, granules, spheres or mini-tablets. Coated cores may be prepared by coating
metoprolol, optionally along with other pharmaceutically acceptable excipients, onto an inert
bead. Optionally, a seal coat layer may be present between the inert bead and said coating layer
comprising metoprolol. The inert bead may be water-soluble, water-swellable, or waterinsoluble.
Examples of water-swellable cores include microcrystalline cellulose spheres such as
Celphere®. Examples of water-soluble cores include sugar spheres made of glucose, mannitol,
lactose, xylitol, dextrose, or sucrose. Examples of water-insoluble cores include glass beads or
silicon dioxide beads. Alternatively, the core may be a matrix core, formulated by mixing
metoprolol, optionally with other pharmaceutically acceptable excipients, followed by
granulation, direct compression, or extrusion-spheronization.
According to one embodiment of this aspect, a) not more than about 15% of the total
amount of metoprolol is released in 4 hours; b) less than about 80% of the total amount of
metoprolol is released in 12 hours; and c) more than 90% of the total amount of metoprolol is
released in 20-24 hours.
According to one embodiment of this aspect, a) not more than about 15% of the total
amount of metoprolol is released in 4 hours; b) less than about 60% of the total amount of
metoprolol is released in 12 hours; and c) more than 70% of the total amount of metoprolol is
released in 20-24 hours.
According to another embodiment of this aspect, the timed extended-release
pharmaceutical composition further comprises a timed immediate-release pharmaceutical
composition.
According to another embodiment of this aspect, timed immediate-release pharmaceutical
composition comprises:
a) a core comprising metoprolol; and
b) an outer coating comprising enteric polymer.
4
According to another embodiment of this aspect, the timed extended-release
pharmaceutical composition further comprises:
a) a first outer coating layer over the extended-release coating layer comprising metoprolol;
and
b) a second outer coating layer over the first outer coating layer comprising an enteric
polymer.
According to another embodiment of this aspect, the core is a matrix core comprising
metoprolol and optionally one or more pharmaceutically acceptable excipients.
According to another embodiment of this aspect, the core is a coated core comprising:
a) an inert bead;
b) a coating layer surrounding said inert bead comprising metoprolol; and
c) optionally, a seal coat layer between the inert bead and the said coating layer comprising
metoprolol.
According to another embodiment of this aspect, the extended-release coating is about
5% to about 15% based on the weight of the core.
According to yet another embodiment of this aspect, the extended-release polymer is a
water-soluble polymer, a water-insoluble polymer, or a mixture thereof. The water-soluble
polymer is selected from the group comprising hydroxypropylmethyl cellulose, hydroxyethyl
cellulose, polyethylene glycol, poly(ethylene oxide), hydroxypropyl cellulose, carboxymethyl
cellulose, xanthan gum, starch, or mixtures thereof. The water-insoluble polymer is selected
from the group comprising cellulose ethers, cellulose esters, polymethacrylic acid esters
copolymers, aminoalkyl methacryiate copolymers, copolymers of polyvinyl acetate and
polyvinyl pyrrolidone, or mixtures thereof. A preferred cellulose ether is ethylcellulose.
According to another embodiment of this aspect, the extended-release coating
comprising a water-insoluble polymer, further comprises a pore-former. The pore-former is
selected from the group comprising low viscosity grade hydroxypropylmethyl cellulose, sodium
alginate, sugars and sugar alcohols, low molecular weight polyethylene glycol, polyvinyl
alcohol, or mixtures thereof.
According to another embodiment of this aspect, the extended-release coating comprises
5
the water-insoluble polymer and the pore-former in a ratio of about 50:50 to 99:1.
According to another embodiment of this aspect, the extended-release coating comprises
the water-insoluble polymer and the pore-former in a ratio of about 75:25 to 95:5.
According to another embodiment of this aspect, the enteric polymer is selected from the
group comprising hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl
cellulose phthalate, cellulose acetate phthalate, methacrylic acid copolymer, or mixtures thereof.
According to another embodiment of this aspect, the enteric polymer is one or more
methacrylic acid copolymer selected from the group comprising Eudragit® L 30 D-55, Eudragit®
L 100-55, Eudragit® L 100, Eudragit® S 100, Eudragit® L 12,5, Eudragit® S 12,5, or Eudragit®
FS 30 D.
According to another embodiment of this aspect, the methacrylic polymer is Eudragit® L 30 D-
55.
According to another embodiment of this aspect, the methacrylic polymer is Eudragit® FS 30 D.
According to another embodiment of this aspect, the methacrylic polymer is Eudragit® S 100.
According to another embodiment of this aspect, the methacrylic polymer is Eudragit® L 100.
According to another embodiment of this aspect, the methacrylic polymer is a
combination of Eudragit® S 100 and Eudragit® L 100.
According to another embodiment of this aspect, Eudragit® S 100 and Eudragit® L 100
are present in a ratio of about 1:1 to about 5:1.
The term "multiparticulates" as used herein means a plurality of discrete pellets, spheres,
granules, or mini-tablets.
The term "timed immediate-release" as used herein means that the composition is timed
to release metoprolol after a lag time of at least 2 hours when administered to a subject, followed
by an immediate-release of metoprolol. The timed immediate-release pharmaceutical
6
composition comprises multiparticulates produced by applying an enteric polymer coating onto
the immediate-release core comprising metoprolol.
The compositions of the present invention exhibit the following in-vivo profile following
administration to a subject:
a) Lag time may vary from 2-10 hours, in particularly, 4-6 hours. "Lag time" refers to the
time between drug administration to a subject and the first quantifiable plasma
concentration of drug in the plasma concentration versus time curve. The percentage
drug release of not more than 15% in 0.1 N HC1 under in-vitro conditions is an indication
of lag time under in-vivo conditions. The current commercially available metoprolol
extended-release Toprol-XL® composition does not exhibit such a lag time. This lag
time is crucial for chronotherapeutic release profile.
b) Tmax at about 10-14 hours. The term "Tmax" refers to the time at which the peak level of
drug plasma level is attained in a subject following administration of the drug.
c) Peak-to-trough ratio is preferably less than 4 hours in order to achieve less fluctuation in
a drug plasma concentration at steady state. The term "peak-to-trough ratio" refers to the
ratio of the maximum plasma concentration to the minimum plasma concentration in a
dosing interval at steady-state.
Extended-release polymers used herein include water-soluble polymers, water-insoluble
polymers, or mixtures thereof.
Water-soluble polymers include hydroxypropylmethyl cellulose having an apparent
viscosity ranging from 100 - 1, 50,000 cP (2% in water at 20°C), e.g., KlOO, K4M, K15M,
K100M, E4M, and E10M; hydroxypropyl cellulose, e.g., HPC-H, HPC-M, HPC-HF, HPC-HXF;
polyethylene glycol (Mw of about 3000 or above); poly(ethylene oxide), e.g., PEO-27, PEO-18,
PEO-15, PEO-8, PEO-4, Polyox® WSR 1105, and Polyox® WSR-303; hydroxyethyl cellulose;
carboxymethyl cellulose; xanthan gum; starch; or mixtures thereof.
Water-insoluble polymers include cellulose ethers, e.g., ethylcellulose; cellulose esters,
e.g., cellulose acetate; polymethacrylic acid esters copolymers, e.g., Eudragit® NE 30 D, and
Eudragit® NE 40 D; aminoalkyl methacrylate copolymers, e.g., Eudragit® RL 100, Eudragit® RL
PO, Eudragit® RS PO, and Eudragit® RS 100; copolymers of polyvinyl acetate and polyvinyl
pyrrolidone, e.g., Kollidon® SR; or mixtures thereof. In particular, the extended-release polymer
is a water-insoluble polymer. More particularly the extended-release polymer is ethyl cellulose.
7
The extended-release coating comprising a water-insoluble polymer further comprises a poreformer
selected from the group comprising low viscosity grade hydroxypropylmethyl cellulose
having an apparent viscosity of less than 100 cP (2% in water at 20°C), e.g., K3, E5, E15, and
E50; sodium alginate; sugars and sugar alcohols, e.g., sucrose, dextrose, lactose, maltitol, and
lactitol; low molecular weight polyethylene glycol (Mw of less than 3000); polyvinyl alcohol; or
mixtures thereof. The extended release water-insoluble polymer and pore former are present in
a ratio of about 50:50 to about 99:1, in particular, from about 75:25 to 95:5.
Enteric polymers used herein include hydroxylpropylmethyl cellulose acetate succinate;
hydroxypropylmethyl cellulose phthalate, e.g., hypromellose phthalate-55; cellulose acetate
phthalate; methacrylic acid copolymer, e.g., Eudragit® L 30 D-55, Eudragit® L 100-55,
Eudragit® L 100, Eudragit® S 100, Eudragit® L 12,5, Eudragit® S 12,5 or Eudragit® FS 30 D; or
mixtures thereof. The amount of an enteric polymer may vary from 1% to 70% by weight of the
total composition. In particular, the enteric polymer is Eudragit® L 30 D-55, Eudragit® FS 30 D,
Eudragit® L 100, Eudragit® S 100, or a combination of Eudragit® S 100 and Eudragit® L 100 in
a ratio of about 1:1 to about 5:1.
Pharmaceutical compositions used herein may be in the form of capsules or tablets.
Coated multiparticulates may be filled directly into a capsule shell, or compressed into a tablet.
Further, capsules may be filled with a single type of coated multiparticulates comprising timed
extended-release multiparticulates. Alternately, capsules may be filled with two types of coated
multiparticulates comprising timed extended-release multiparticulates and timed immediaterelease
multiparticulates. The ratio of timed extended-release multiparticulates to timed
immediate-release multiparticulates may vary from 1:100 to 100:1. In particular, the ratio is
from 50:50 to 100:1.
The pharmaceutical composition may further comprise other pharmaceutically
acceptable excipients. Examples of pharmaceutically acceptable excipients include binders,
diluents, lubricants/glidants, surfactants, or mixtures thereof.
Examples of binders include methyl cellulose, hydroxypropyl cellulose (HPC-L), methyl
cellulose, carboxymethyl cellulose sodium, hydroxypropylmethyl cellulose,
polyvinylpyrrolidone, or mixtures thereof.
Examples of diluents include lactose, calcium carbonate, calcium phosphate, calcium
8
sulfate, microcrystalline cellulose, cellulose powdered, fructose, lactitol, mannitol, sorbitol,
starch, sucrose, or mixtures thereof.
Examples of lubricants or glidants include colloidal silicon dioxide, stearic acid,
magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid,
microcrystalline wax, yellow beeswax, white beeswax, or mixtures thereof. They may be added
intragranularly as well as extragranularly.
Examples of surfactants include sodium lauryl sulfate, sodium dodecyl sulfate,
ammonium lauryl sulfate, benzalkonium chloride, alkyl poly(ethylene oxide), copolymers of
poly(ethylene oxide) and poly(propylene oxide) commercially known as poloxamers or
poloxamines, polyvinyl alcohol (PVA), fatty alcohols, polyoxyethylene alkyl ether,
polyoxyethylene alkylaryl ether, polyethylene glycol fatty acid ester, alkylene glycol fatty acid
mono ester, sucrose fatty acid ester, and sorbitan fatty acid mono ester, sorbitol monolaurate
(Span 20 or Span 80), polyoxyethylene sorbitan fatty acid ester (polysorbates), or mixtures
thereof.
The coatings of the present invention comprise excipients selected from the group
comprising plasticizers, binders, opacifiers, anti-tacking agents, anti-foaming agents, filmforming
polymers, colors, or mixtures thereof. Organic or aqueous solvents may be used during
the coating process. Solvents may be selected from the group comprising water, acetone,
isopropyl alcohol, ethanol, isopropyl acetate, methylene chloride, or mixtures thereof.
Examples of plasticizers include propylene glycol, triethyl citrate, tributyl citrate, dibutyl
sebacate, acetyl tributyl citrate, glyceryl monostearate, triacetin, polyethylene glycol, diethyl
phthalate, acetylated monoglycerides, diacetylated monoglyceride, cetyl alcohol, or mixtures
thereof.
Examples of opacifiers include titanium dioxide, silicon dioxide, talc, calcium carbonate,
behenic acid, or mixtures thereof.
Examples of anti-tacking agents include talc, colloidal silicon dioxide or mixtures
thereof.
Examples of anti-foaming agents include silicon based surfactants, e.g., simethicone;
9
0
vegetable oils; waxes; hydrophobic silica; polyethylene glycol or mixtures thereof.
Coloring agents may be selected from FDA approved colorants such as iron oxide, lake
of tartrazine, allura red, titanium dioxide, or mixtures thereof.
Examples of film-forming polymers include hydroxypropylmethyl cellulose, methyl
cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, polyethylene glycol, polyvinyl
alcohol, or mixtures thereof. Alternatively, commercially available coating compositions
comprising film-forming polymers marketed under various trade names, such as Opadry®, may
also be used for coating.
Coating may be carried out by using any conventional coating techniques known in the
art, such as spray coating in a conventional coating pan or fluidized bed processor, or dip
coating.
The term "about" as used herein, refers to any value which lies within the range defined
by a variation of up to ±10% of the value.
The following examples illustrate the invention but are not to be construed as limiting
the scope of the invention.
EXAMPLES
Example 1
Timed extended-release multiparticulates:
Ingredients
Metoprolol succinate
Opadry®
Sugar spheres
Isopropyl alcohol
Purified water
Extended-release coating
Ethocel®20cps
Opadry®
Isopropyl alcohol
Purified water
Enteric coating on extended-release
multiparticulates
mg/capsule
190.00
19.00
150.00
q.s.
q.s.
18.10
4.50
q.s.
q.s.
10
Eudragit®S100
Eudragit®L100
Triethyl citrate
Talc
Acetone
Isopropyl alcohol
Purified water
82.20
27.40
32.90
11.00
q.s.
q.s.
q.s.
Timed immediate-release multiparticulates:
Enteric coating on immediate-release drugcoated
cores
Eudragit®S100
Eudragit® L 100
Triethyl citrate
Talc
Acetone
Isopropyl alcohol
Purified water
29.40
9.80
11.80
3.90
q.s.
q.s.
q.s.
Process:
1) Metoprolol succinate and Opadry® were dispersed in purified water and isopropyl
alcohol.
2) The dispersion of step 1) was sprayed onto sugar spheres to form drug-coated cores.
3) Eudragit® S 100, Eudragit® L 100, triethyl citrate and talc were dispersed in a mixture of
acetone, isopropyl alcohol and purified water to obtain an enteric coating dispersion.
4) Approximately 30% of the drug-coated cores of step 2) were coated with the dispersion
of step 3) to obtain timed immediate-release multiparticulates.
5) Ethocel® 20cps and Opadry® were dispersed in isopropyl alcohol and purified water.
6) The remaining part of the drug-coated cores of step 2) were coated with the dispersion of
step 5) to obtain extended-release multiparticulates.
7) The extended-release multiparticulates of step 6) were coated with the enteric coating
dispersion of step 3) to obtain timed extended-release multiparticulates.
8) The timed immediate-release multiparticulates of step 4) and the timed extended-release
multiparticulates of step 7) were filled into suitable size capsule shells.
11
Example 2
Timed extended-release multiparticulates:
Ingredients
Metoprolol succinate
Hydroxypropylmethyl cellulose
Sodium lauryl sulphate
Sugar spheres
Isopropyl alcohol
Purified water
Extended-release coating
Ethocel®20cps
Hydroxypropylmethyl cellulose
Triethyl citrate
Talc
Purified water
Isopropyl alcohol
Enteric coating on extended-release
multiparticulates
Eudragit®S100
Triethyl citrate
Talc
Purified water
Acetone
Isopropyl alcohol
mg/capsule
190.00
40.00
30.00
65.00
q.s.
q.s.
18.28
2.43
2.43
1.22
q.s.
q.s.
39.24
8.41
8.41
q.s.
q.s.
q.s.
Timed immediate-release multiparticulates:
Enteric coating on immediate-release drugcoated
cores
Eudragit® S 100
Triethyl citrate
Talc
Purified water
Acetone
Isopropyl alcohol
39.24
8.41
8.41
q.s.
q.s.
q.s.
Process:
1) Disperse metoprolol succinate, hydroxypropylmethyl cellulose, and sodium lauryl
sulphate in a mixture of isopropyl alcohol and purified water.
2) Spray the dispersion of step 1) onto sugar spheres to form drug-coated cores.
3) Disperse Eudragit® S 100, triethyl citrate, and talc into a mixture of acetone, isopropyl
alcohol, and purified water to obtain an enteric coating dispersion.
4) Coat 50% of the drug-coated cores of step 2) with the enteric coating dispersion of step
3) to form timed immediate-release multiparticulates.
12
5) Disperse Ethocel® 20cps, hydroxypropylmethyl cellulose, triethyl citrate, and talc in a
mixture of isopropyl alcohol and purified water.
6) Coat the remaining part of the drug-coated cores of step 2) with the dispersion of step 5)
to obtain extended-release multiparticulates.
7) Coat the extended-release pellets of step 6) with the enteric coating dispersion of step 3)
to obtain timed extended-release multiparticulates.
8) Fill the timed immediate-release multiparticulates of step 4) and the timed extendedrelease
multiparticulates of step 7) into suitable size capsule shells.
Example 3
Ingredients
Drug coating-1
Metoprolol succinate
Hydroxypropylmethyl cellulose
Sodium lauryl sulphate
Sugar spheres
Isopropyl alcohol
Purified water
Extended-release coating
Ethocel® 20cps
Hydroxypropylmethyl cellulose
Triethyl citrate
Talc
Purified water
Isopropyl alcohol
Drug coating-2
Metoprolol succinate
Hydroxypropylmethyl cellulose
Sodium lauryl sulphate
Purified water
Isopropyl alcohol
Enteric coating
Eudragit®S100
Eudragit® L 100
Triethyl citrate
Talc
Acetone
Isopropyl alcohol
Purified water
mg/capsule
133.00
40.00
30.00
65.00
q.s.
q.s.
22.78
1.34
1.34
1.34
q.s.
q.s.
57.00
17.10
12.90
q.s.
q.s.
57.27
57.27
38.18
38.18
q.s.
q.s.
q.s.
Process:
1) Disperse metoprolol succinate, hydroxypropylmethyl cellulose, and sodium lauryl
13
sulphate in a mixture of isopropyl alcohol and purified water.
2) Spray the dispersion of step 1 onto sugar spheres to obtain drug-coated cores.
3) Disperse Ethocel® 20cps, hydroxypropylmethyl cellulose, triethyl citrate, and talc in
isopropyl alcohol and purified water.
4) Coat the drug-coated cores of step 2) with the dispersion of step 3) to obtain extendedrelease
pellets.
5) Disperse metoprolol succinate, hydroxypropylmethyl cellulose and sodium lauryl
sulphate in a mixture of isopropyl alcohol and purified water.
6) Coat the extended-release pellets of step 4) with the dispersion of step 5).
7) Disperse Eudragit® S 100, Eudragit® L 100, triethyl citrate, and talc in a mixture of
acetone, isopropyl alcohol and purified water to obtain an enteric coating dispersion.
8)" Coat the coated pellets of step 6) with the enteric coating dispersion of step 7) to obtain
timed extended-release multiparticulates.
9) Fill the timed extended-release multiparticulates of step 8) into suitable size capsule
shells.
Example 4
Timed extended-release multiparticulates:
Ingredients
Seal coating
Sugar spheres
Ethocel® 20cps
Isopropyl alcohol
Drug coating
Metoprolol succinate
Hydroxypropylmethyl cellulose
Purified water
Extended-release coating
Ethocel® 20cps
Hydroxypropylmethyl cellulose
Triethyl citrate
Talc
Isopropyl alcohol
Purified water
Enteric coating on extended-release
multiparticulates
Eudragit® FS 30 D (on dried basis)
Talc
Simethicone
Purified water
mg/Capsule
65.00
6.50
q.s.
200.00
40.00
q.s.
35.04
7.01
2.34
2.34
q.s.
q.s.
112.84
11.28
1.25
q.s.
14
Timed immediate-release multiparticulates:
Enteric coating on immediaterelease
drug-coated cores
Eudragit® FS 30 D
Talc
Simethicone
Purified water
112.84
11.28
1.25
q.s.
Process:
1) Coat sugar spheres with a dispersion of Ethocel® in isopropyl alcohol.
2) Dissolve metoprolol succinate and hydroxypropylmethyl cellulose in purified water.
3) Spray the solution of step 2) onto the coated sugar spheres of step 1) to obtain drugcoated
cores.
4) Disperse Eudragit® FS 30 D, talc, and simethicone in purified water to obtain an enteric
coating dispersion.
5) Coat approximately 40% of the drag-coated cores of step 3) with the enteric coating
dispersion of step 4) to obtain timed immediate-release multiparticulates.
6) Disperse Ethocel® 20cps, hydroxypropylmethyl cellulose, triethyl citrate, and talc in
isopropyl alcohol and purified water.
7) Coat the remaining part of the drag-coated cores of step 3) with the dispersion of step 6)
to obtain extended-release multiparticulates.
8) Coat the extended-release pellets of step 7) with the enteric coating dispersion of step 4)
to obtain timed extended-release multiparticulates.
9) Fill the timed extended-release multiparticulates of step 8) and timed immediate-release
multiparticulates of step 5) into suitable size capsule shells.
Example 5
Timed extended-release multiparticulates:
Ingredients
Metoprolol succinate eq. to 100 mg metoprolol
tartarate
Opadry®
Sugar spheres
Purified water
Extended-release coating
Ethocel® 20cps
Hydroxypropylmethyl cellulose
mg/capsule
95.00
9.50
75.00
q.s.
10.17
1.79
15
•
Triethyl citrate
Talc
Isopropyl alcohol
Purified water
Enteric coating on extended-release
multiparticulates
Eudragit®S100
Eudragit®L100
Triethyl citrate
Talc
Acetone
Isopropyl alcohol
Purified water
Lubrication
Talc
0.29
0.29
q.s.
q.s.
40.72
13.57
16.29
5.42
q.s.
q.s.
q.s.
2.14
Timed immediate-release multiparticulates:
Enteric coating on immediate-release drugcoated
cores
Eudragit®S100
Eudragit® L 100
Triethyl citrate
Talc
Acetone
Isopropyl alcohol
Purified water
Lubrication
Talc
15.86
5.29
6.34
2.11
q.s.
q.s.
q.s.
0.84
Process:
Metoprolol succinate and Opadry® were dispersed in purified water.
The dispersion of step 1) was sprayed onto sugar spheres to form drug-coated cores.
Eudragit® S 100, Eudragit® L 100, triethyl citrate, and talc were dispersed in a mixture of
acetone, isopropyl alcohol, and purified water to obtain an enteric coating dispersion.
Approximately 30% of the drug-coated cores of step 2) were coated with the dispersion
of step 3) to obtain timed immediate-release multiparticulates.
Ethocel® 20cps, hydroxypropylmethyl cellulose, triethyl citrate, and talc were dispersed
in isopropyl alcohol and purified water.
The remaining part of the drug-coated cores of step 2) were coated with the dispersion of
step 5) to obtain extended-release multiparticulates.
The extended-release pellets of step 6) were coated with the enteric coating dispersion of
16
1)
2)
3)
4)
5)
6)
7)
step 3) to obtain timed extended-release multiparticulates.
8) The timed immediate-release multiparticulates of step 4) and the timed extended-release
multiparticulates of step 7) were lubricated with talc and filled into suitable size capsule
shells.
Example 6
Ingredients
Metoprolol succinate eq. to 100 mg metoprolol
tartarate
Opadry®
Sugar spheres
Purified water
Extended-release coating
Ethocel®20cps
Hydroxypropylmethyl cellulose
Triethyl citrate
Talc
Isopropyl alcohol
Purified water
Enteric coating on extended-release
multiparticulates
Eudragit®L30D55
Triethyl citrate
Talc
Purified water
Lubrication
Talc
A
mg/capsule
95.00
9.50
75.00
q.s.
14.20
2.51
0.42
0.42
q.s.
q.s.
85.91
8.59
12.89
q.s.
3.04
B
mg/capsule
95.00
9.50
75.00
q.s.
11.29
1.99
0.33
0.33
q.s.
q.s.
84.34
8.43
12.65
q.s.
2.99
Process:
1) Metoprolol succinate and Opadry® were dispersed in purified water.
2) The dispersion of step 1) was sprayed onto sugar spheres to form drug-coated cores.
3) Eudragit® L 30 D 55, triethyl citrate, and talc were dispersed in purified water to obtain
an enteric coating dispersion.
4) Ethocel® 20cps, hydroxypropylmethyl cellulose, triethyl citrate, and talc were dispersed
in isopropyl alcohol and purified water.
5) The drug-coated cores of step 2) were coated with the dispersion of step 4) to obtain
extended-release multiparticulates.
6) The extended-release pellets of step 5) were coated with the enteric coating dispersion of
step 3) to obtain timed extended-release multiparticulates.
17
7) The timed extended-release multiparticulates of step 6) were lubricated with talc and
filled into suitable size capsule shells.
Example 7
Example 7 is same as Example 6, but comprises an additional seal coat layer on the inert beads.
Seal coated inert beads
Sugar spheres
Ethocel® 20cps
IPA
Purified water
Seal coated total
Example 7
68.18
6.82
q.s.
q.s.
75.00
Dissolution studies:
Dissolution tests were carried out using capsules prepared according to Examples 5, 6 (A
and B), and 7. The dissolution studies were carried out in a USP type II apparatus, with a paddle
rotation of 50 rpm, at a temperature of 37°C ± 0.5°C, in 500 mL of 0.1N HCl for 4 hours,
followed by changing the dissolution media to 900 mL of pH 7.5 phosphate buffer. The
percentage of drug released was calculated from the concentration of metoprolol succinate in the
sample solutions collected at different time points and analyzed by an HPLC method using
column inertfil ODS3 and a mobile phase comprising sodium dihydrogen orthophosphate
monohydrate. The results of dissolution studies are provided in table 1.
Table 1: Percentage release of Metoprolol in 500 mL of 0.1N HCl for 4 hours followed by 900
mL of pH 7.5 phosphate buffer
Time (Hours)
Acid stage (0.1N HCl)
0
2
4
0
2
4
Buffer stage (pH 7.5 Phosphate buffer)
1
2
4
8
12
16
20
24
5
6
8
12
16
20
24
28
Comparative Example
Toprol-XL®
0
-
34
44
49
59
75
88
95
99
100
Examples
5
0
0
2
32
41
55
75
84
90
93
100
6(A)
0
-
3
12
19
32
52
65
74
80
84
6(B)
0
-
4
16
27
45
68
81
89
93
97
7
0
-
6
20
32
49
72
87
96
100
103
The results of the dissolution studies with respect to the compositions of Example 5,
18
Example 6 (A and B), and Example 7 show that compositions of the present invention release
not more than 15% of the total amount of drug in O.IN HCl in 4 hours, and thereafter provide an
extended-release of metoprolol for at least 20 hours in pH 7.5 phosphate buffer, wherein more
than 70% of the drug is released in 20-24 hours. The currently available metoprolol extendedrelease
Toprol-XL® composition does not exhibit a lag time; and around 34% of drug is released
in 4 hours.

WE CLAIM:
Claim 1. A timed extended-release pharmaceutical composition comprising:
a) a core comprising metoprolol;
b) an extended-release coating comprising an extended-release polymer; and
c) at least one outer coating layer comprising an enteric polymer;
wherein the pharmaceutical composition exhibits the following in-vitro dissolution profile,
when measured in United States Pharmacopeia (USP) type 2 dissolution apparatus, with a
paddle rotation of 50 rpm, at a temperature of 37°C ± 0.5°C in 500 mL of O.IN HCl for 4
hours, followed by 900 mL of pH 7.5 phosphate buffer: a) not more than about 15% of the
total amount of metoprolol is released in 4 hours; and b) more than 70% of the total amount
of metoprolol is released in 20 hours.
Claim 2. The pharmaceutical composition according to claim 1, further comprising a timed
immediate-release pharmaceutical composition.
Claim 3. The pharmaceutical composition according to claim 2, wherein the timed immediaterelease
pharmaceutical composition comprises:
i) a core comprising metoprolol; and
ii) an outer coating comprising an enteric polymer.
Claim 4. The pharmaceutical composition according to claim 1, further comprising:
a) a first outer coating layer over the extended-release coating layer comprising metoprolol;
and
b) a second outer coating layer over the first outer coating layer comprising an enteric
polymer.
Claim 5. The pharmaceutical composition according to claim 1, wherein the core is a matrix
core comprising metoprolol and optionally one or more pharmaceutically acceptable excipients.
Claim 6. The pharmaceutical composition according to claim 1, wherein the core is a coated
core comprising:
a) an inert bead;
b) a coating layer surrounding said inert bead comprising metoprolol; and
c) optionally, a seal coat layer between the inert bead and said coating layer.
Claim 7. The pharmaceutical composition according to claim 1, wherein the extended-release
coating is about 5% to 15% based on the weight of the core.
Claim 8. The pharmaceutical composition according to claim 1, wherein the extended-release
polymer is a water-soluble polymer, a water-insoluble polymer, or a mixture thereof
Claim 9. The pharmaceutical composition according to claim 8, wherein the water-soluble
polymer is selected from the group comprising hydroxypropylmethyl cellulose, hydroxyethyl
cellulose, polyethylene glycol, poly(ethylene oxide), hydroxypropyl cellulose, carboxymethyl
cellulose, xanthan gum, starch, or mixtures thereof.
Claim 10. The pharmaceutical composition according to claim 8, wherein the water-insoluble
polymer is selected from the group comprising cellulose ethers, cellulose esters, polymethacrylic
acid esters copolymers, aminoalkyl methacrylate copolymers, copolymers of polyvinyl acetate
and polyvinyl pyrrolidone, or mixtures thereof.
Claim 11. The pharmaceutical composition according to claim 10, wherein the cellulose ether is
ethyl cellulose.
Claim 12. The pharmaceutical composition according to claim 8, wherein the extended-release
coating comprising a water-insoluble polymer further comprises a pore-former.
Claim 13. The pharmaceutical composition according to claim 12, wherein the pore-former is
selected from the group comprising low viscosity grade hydroxypropylmethyl cellulose, sodium
alginate, sugars and sugar alcohols, low molecular weight polyethylene glycol, polyvinyl
alcohol, or mixtures thereof.
Claim 14. The pharmaceutical composition according to claim 12, wherein the water-insoluble
polymer and the pore-former are present in a ratio of about 50:50 to 99:1.
Claim 15. The pharmaceutical composition according to claim 14, wherein the water-insoluble
polymer and the pore-former are present in a ratio of about 75:25 to 95:5.
Claim 16. The pharmaceutical composition according to claim 1, wherein the enteric polymer
is selected from the group comprising hydroxypropylmethyl cellulose acetate succinate,
hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, methacrylic acid
copolymer, or mixtures thereof.
Claim 17. The pharmaceutical composition according to claim 16, wherein the enteric polymer
is one or more methacrylic acid copolymer selected from the group comprising Eudragit® L 30
D-55, Eudragit® L 100-55, Eudragit® L 100, Eudragit® S 100, Eudragit® L 12,5, Eudragit® S
12,5, or Eudragit® FS SOD.
Claim 18. The pharmaceutical composition according to claim 17, wherein the methacrylic
polymer is Eudragit® L 30 D-55.
Claim 19. The pharmaceutical composition according to claim 17, wherein the methacrylic
polymer is Eudragit® FS 30 D.
Claim 20. The pharmaceutical composition according to claim 17, wherein the methacrylic
polymer is Eudragit® S 100.
Claim 21. The pharmaceutical composition according to claim 17, wherein the methacrylic
polymer is Eudragit® L 100.
Claim 22. The pharmaceutical composition according to claim 17, wherein the methacrylic
polymer is a combination of Eudragit® S 100 and Eudragit® L 100.
Claim 23. The pharmaceutical composition according to claim 22, wherein Eudragit® S 100 and
Eudragit® L 100 are present in a ratio of about 1:1 to about 5:1.