CAPSULE DOSAGE FORM OF METOPROLOL SUCCINATE
The present invention provides an extended-release capsule dosage form of metoprolol
succinate in the form of coated discrete units and processes J(Jr their preparation.
Background ofthc lnv~ntion
Metoprolol is a beta-blocker that is prescribed for the treatment of hypertension, angma
pectoris, and stable, symptomatic heart failure. Currently, the marketed extended-release dosage
form of metoprolol succinate is a multiparticulate tablet dosage form comprising silicon dioxide
beads as an inert core (Toprol-XL@ tablet).
U.S. Patent No 5,246,714 discloses a controlled-release preparation containing a number of
insoluble beads coated with one or more pharmaceutically active compounds. It fmiher discloses
examples of insoluble materials such as silicon dioxide, glass, or plastic resin particles.
Compression of multiparticulates into a tablet dosage form is a challenging task. An
additional 30% to 60% oftableting excipients are necessary to avoid any damage to the polymer coat
and to retain the functional properties of the coat during compression. However, even after the
process and excipient optimizations, cracks in the extended-release polymer coat are observed at the
commercial scale. These cracks in the extended-release polymer coat impact the dissolution profile
ofthe dosage form.
A capsule dosage form of coated multi particulates offers an advantage over the tablet dosage
form, as it avoids the compression step. Further, this dosage form is easier to swallow and requires
the addition of fewer excipients than the tablet dosage form.
Therefore, there is a need in the art to prepare an alternate extended-release dosage form of
metoprolol succinate which is bioequivalent to the marketed Toprol-XL C® tablet.
Summary of the Invention
The present invention provides an extended-release capsule dosage form of metoprolol
succinate in the form of coated discrete units, wherein said capsule dosage form is bioequivalent to
the marketed Toprol-XLC® tablet. Moreover, the extended-release capsule dosage form comprising
coated discrete units can be sprinkled onto food to ease administration for patients who have
difficulty swallowing tablets or capsules, e.g., pediatric patients and geriatrics.
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A Jirst aspect of the present invention provides an extended-release capsule dosage form of
metoprolol succinate in the form of coated discrete units, wherein the capsule dosage form comprises
metoprolol succinate in an amount of about 30% to about 70% by total weight of the dosage f(Jrm
and is bioequivalent to the marketed Toprol-XL'"' tablet.
According to one embodiment of this aspect, the extended-release capsule dosage form is in
the form of a sprinkle capsule.
According to another embodiment of this aspect, the sprinkle capsule dosage form may be
sprinkled onto soft food, e.g., applesauce, yogurt, or pudding, at the time of administration.
According to another embodiment of this aspect, the extended-release capsule dosage form
comprises coated discrete units having a particle size fi·om about 0.2 mm to 2.5 mm.
According to another embodiment of this aspect, the extended-release capsule dosage form
in the form of coated discrete units comprising:
a) inert cores;
b) a drug layer over the inert cores comprising metoprolol succinate; and
c) an extended-release layer over the drug layer.
The term "extended-release" includes controlled-release, modified-release, and sustainedrelease.
The capsule dosage form is stable and has a similar release profile as compared to the ToprolXL
®tablet throughout the shelflife of the product. Metoprolol succinate may be present in an amount
of about 30% to about 70% by total weight of the dosage form. In particular, about 40% to about
60% by total weight of the dosage form, wherein the capsule shell weight is not included in the total
weight of the dosage form.
Metoprolol succinate ofthe present invention may be in racemic form or as a pure enantiomer.
Further, metoprolol succinate may be present in the capsule dosage form in a strength of about 25
mg to about 200 mg. Coated discrete unit comprising metoprolol in a strength of 25 mg/50 mg, I 00
mg, and 200 mg may be Jilled in size 4, size 2, and size 0 hard gelatin capsules, respectively.
The term "discrete units," as used herein, refers to coated inert cores in the form of plurality
of pellets, granules, minitablets, or beads.
Bioequivalence is established by comparing pharmacokinetic parameters, for example AUC
and Cmax, of the present invention with Toproi-XL ®tablets in healthy human subjects.
The term "AUC" refers to the area under the time/plasma concentration curve after the
administration of the metoprolol succinate extended-release dosage form to healthy human subjects.
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The term "C,na/' refers to the maximum concentration of metoprolol in the blood following
the administration of the metoprolol succinate extended-release dosage form to healthy human
subjects.
The extended-release capsule dosage f(m11S of metoprolol succinate are stable when subjected
to the stability conditions of 40°C and 75% RH for 6 months. Further, the coated discrete units would
be stable when sprinkled on to the soil food for at least 10 minutes.
Inert cores may be selected fi·om the group comprising of water-soluble or water-swellable
cores.
According to another embodiment of this aspect, water-soluble or water-swellable inert cores
are made up of sugar, microcrystalline cellulose, cellulose, starch, modified starch, or mixtures
thereof.
According to another embodiment of this aspect, the inert core is a sugar core wherein said
sugar is selected from the group consisting of glucose, mannitol, lactose, xylitol, dextrose, and
sucrose.
Coated discrete units may be prepared by coating a drug layer comprising metoprolol
succinate, optionally along with other pharmaceutically acceptable excipients, onto an inert core.
Optionally, a seal coat layer may be present between the inert core and the drug layer. The seal coat
may further comprise film-forming polymers. Further, the drug layer coated cores are coated with
an extended-release layer.
According to one embodiment of this aspect, the extended-release layer comprises watersoluble/
swellable polymers, water-insoluble polymers, or mixtures thereof. The extended-release
layer is present in an amount of 5% to 30% based on the weight of the drug layer coated cores.
Water-soluble/swellable polymers include hydroxypropyl methylcellulose having an
apparent viscosity ranging from 100 cP to 150,000 cP (2% in water at 20°C), e.g., KIOO, K4M,
KI5M, KIOOM, E4M, and ElOM; hydroxypropyl cellulose, e.g., HPC-H, 1-!PC-M, 1-IPC-HF, and
1-!PC-1-!XF; polyethylene glycol (molecular weight of about 3000 or above); poly( ethylene oxide),
e.g., PE0-27, PE0-18, PE0-15, PE0-8, PE0-4, Polyox® WSR-1105, and Polyox® WSR-303;
hydroxyethyl cellulose; carboxymethyl cellulose; xanthan gum; polyvinyl pyrrolidone; starch; and
mixtures thereof.
Water-insoluble polymers include cellulose ethers, e.g., ethyl cellulose; 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 I 00, Eudragit® RL PO, Eudragit''1
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RS PO, and Eudragit"' RS I 00; copolymers of polyvinyl acetate and polyvinyl pyrrolidone, e.g.,
Kollidon''' SR; and mixtures thereof. In particular, the extended-release polymer is a water-insoluble
polymer. More particularly, the water-insoluble polymer is ethyl cellulose.
The extended-release polymer may be present in an amount of 50'Yo to 99% based on the
weight of the extended-release layer.
According to another embodiment of this aspect, the extended-release layer comprises a
water-insoluble polymer.
The extended-release coating comprising a water-insoluble polymer further comprises a poreformer
selected from the group comprising low viscosity grade hydroxypropyl methylcellulose
having an apparent viscosity ofless than 100 cP (2% in water at 20°C), e.g., K3, E5, El5, and E50;
sodium alginate; sugars and sugar alcohols, e.g., sucrose, dextrose, lactose, maltitol, and lactitol; low
molecular weight polyethylene glycol (molecular weight of less than 3000); polyvinyl alcohol;
polyvinylpyrrolidone; hydroxypropyl cellulose; and mixtures thereof. Pore-formers may be present
in an amount of 0% to 60% based on the weight of the extended-release layer.
According to another embodiment of this aspect, the extended-release layer comprises a
mixture of ethyl cellulose and hydroxypropyl methylcellulose.
A second aspect of the present invention provides a process for preparation of an extendedrelease
capsule dosage form of metoprolol succinate in the form of coated discrete units wherein the
process comprises:
a) coating inert cores with a solution or dispersion of metoprolol succinate to obtain drug
layer coated cores;
b) coating the drug layer coated cores of step a) with a solution or dispersion of an
extended-release polymer; and
c) filling the extended-release eo res of step b) into suitable size capsules.
The dosage form may further comprise other pharmaceutically acceptable excipients.
Examples of pharmaceutically acceptable excipients include binders, diluents,
lubricants/glidants, surfactants, and mixtures thereof.
Examples of binders include methyl cellulose, hydroxypropyl cellulose (HPC-L),
carboxymethyl cellulose sodium, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and
mixtures thereof.
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Examples ofdilucnts include lactose, calcium carbonate, calcium phosphate, calcium sulfate,
microcrystalline cellulose, cellulose powdered, fi·uctosc, lactitol, mannitol, sorbitol, starch, sucrose,
and mixtures thereof
Examples oflubricants 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, and mixtures thereof.
Examples of surfactants include sodium Iaury! sulfate, sodium dodecyl sulfate, ammonium
Iaury! sulfate, benzalkonium chloride, alkyl poly( ethylene oxide), copolymers of poly( ethylene
oxide) and poly(propylene oxide) commercially known as poloxamers or poloxamines, polyvinyl
alcohol (PYA), fatty alcohols, polyoxyethylene alkyl ether, polyoxyethylene alkylaryl ether,
polyethylene glycol fatty acid ester, alkylene glycol fatty acid mono ester, sucrose fatty acid ester,
sorbitol monolaurate (e.g., Span® 20 or Span® 80), polyoxyethylene sorbitan fatty acid ester
(polysorbates ), and mixtures thereof.
The coating of the present invention may further comprise excipients selected from the group
comprising plasticizers, binders, opacitiers, anti-tacking agents, anti-foaming agents, colors, filmforming
polymers, and 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, and 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, diaeetylated monoglyceride, cetyl alcohol, and mixtures
thereof.
Examples of opacifiers include titanium dioxide, silicon dioxide, talc, calcium carbonate,
behenic acid, and mixtures thereof.
Examples of anti-tacking agents include talc, colloidal silicon dioxide, and mixtures thereof.
Examples of anti-foaming agents include silicon based surfactants, e.g., simethicone;
vegetable oils; waxes; hydrophobic silica; polyethylene glycol; and mixtures thereof.
Coloring agents may be selected from FDA approved colorants such as iron oxide, lake of
tartrazine, allura red, titanium dioxide, and mixtures thereof.
Examples of film-forming polymers include hydroxypropyl methylcellulose, methyl
cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, polyethylene glycol, polyvinyl alcohol,
and mixtures thereof. Alternatively, commercially available coating compositions comprising film-
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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, fluidized bed processor, or dry powder coating.
The following example illustrates the invention but is not to be construed as limiting the scope
of the invention.
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Example I
",--~~···-·------···- ---··-··----·-----
·------.. ·-·-·--~------~---··--
··--- ~_rug La_xer
Mctoprolol succinate
=:::--··--·---~- --~··· --;;---~-· -----···----~~
USP equivalent to 25 mg of
Metoprolol Ta1~trate, U
Opadrl" clear -
--1'.l1gar S[>heres
Purified water
·-·-·
SP --+-~--=2:::3_. 750
2.375 ·-----·· ··~-·-~-~~:---- -~-j
18.750
~--t~~---~···--------
q.s.
Extended-Release La yer
----·······-·······-~~---~~--·~ ~---~~-----
Ethyl cellulose ·-······-·· 3.269 -~--=:=c:.--··~---
_1-l:)'drOX:)'[>rop:)'l meth
_T~ieth:)'l citrate .
Isopropyl alcohol
ylcellulose ------1--···--·-0.~}.'-'7.,..----~--1
----~· -~--t~~-......::.0·:.::0"9-'6 --~--1
-~~-·-··---~~·-----
q.s.
Talc
Purified water
0.096 -----1-~-·-~:.::C:.----·~-
q.s . •.
Lubrication q.s.
Talc 0.489
Manufacturing Process:
I) Metoprolol succinate and Opadry® clear were added to purified water to form a dispersion.
2) The dispersion of step I) was sprayed onto sugar spheres to form drug coated cores.
3) Ethyl cellulose was dispersed in isopropyl alcohol and purified water.
4) Hydroxypropylmethylcellulose, talc, and triethyl citrate were added into the dispersion of
step 3).
5) The dispersion of step 4) was sprayed onto the drug coated cores of step 2) to form extendedrelease
discrete units.
6) The extended-release discrete units of step 5) were lubricated with talc.
7) The lubricated extended-release discrete units of step 6) were filled into size 4 capsule shells.
Dissolution studies:
Dissolution tests were carried out using capsules prepared in Example I and Toprol-XL ®
tablet.
Dissolution was carried out in a USP type II apparatus, paddle rotating at 50 rpm, at a
temperature of37°C ±0.5°C, in 500 mL of pH 7.5 phosphate buffer.
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Table I: Dissolution prolllc of Example I and Toprol-XLJ'' tablet.
--=:---
Time 'Yo Drug released (mctoprolol succinate)
(hrs)
in 500 mL of phosphate buffer
~-----~----
Toproi-XL@ Example I
---
-,--I- -- II -- 3 ---···~~· ~---
2 19 16 - ·--··-· ... - ---·····-
4 31 30 -----'---- --···-·--- -- ----
8 53 57 ·--···-···
12 71 76
16 ---··--- .. ·--····· ---
84 87 - ··-·- .. --
20 91 92 - -·····
The results of the dissolution tests are shown in Table I. It is evident that Example I provides
a release profile which is comparable to Toprol-XL@tablet.
Simulation studies:
The pharmacokinetic profile (Cmax and AUC) of Example I was predicted using software
Phoenix WinNonlin@ 6.4 and Phoenix IVIVC Toolkit 2.2. The predicted pharmacokinetic values of
Example I was compared with pharmacokinetic values of Toproi-XL@ tablet under fed and fasted
conditions. Table 2 shows the simulated bioequivalence data of Example I.
Table 2: Simulated T/R ratio for Example I w.r.t Toprol-XL@tablet
Parameters
Fed Fasted
T/R Ratio T/R Ratio -
AUC!ast 1.03 0.95
Cmax 1.03 1.09
From the above data it is evident that metoprolol extended release capsules of Example I
would be bioequivalent to Toproi-XL@tablet under fed and fasted conditions.

WE CLAIM:
1. An extended-release capsule dosage f(mn of metoprolol succinate in the form of coated
discrete units, wherein the capsule dosage form comprises metoprolol succinate in an amount
of about 30% to about 70% by the total weight of the dosage form and is bioequivalent to the
marketed extended release tablet ofmctoprolol succinate.
2. The extended-release capsule dosage form according to claim 1, wherein the capsule is in the
form of a sprinkle capsule.
3. The extended-release capsule dosage form according to claim 1, wherein the coated discrete
units have a particle size from about 0.2 mm to 2.5 mm.
4. The extended-release capsule dosage form according to claim 1, wherein the coated discrete
units are coated inert core in the form of plurality of pellets, granules, minitablets, or beads.
5. The extended-release capsule dosage form according to claim 1, wherein the coated discrete
units comprise
a) inert cores;
b) a drug layer over the inert cores comprising metoprolol succinate; and
c) an extended release layer over the drug layer coated cores.
6. The extended-release capsule dosage form according to claim 5, wherein the inert cores are
water-soluble or water-swellable.
7. The extended-release capsule dosage form according to claim 6, wherein the water-soluble
or water-swellable inert cores are made up of sugar, microcrystalline cellulose, cellulose,
starch, modified starch, or mixtures thereof.
8. The extended-release capsule dosage form according to claim 7, wherein the sugar is selected
from the group consisting of glucose, mannitol, lactose, xylitol, dextrose, and sucrose.
9. The extended-release capsule dosage form according to claimS, wherein the extended-release
layer comprises an extended-release polymer in an amount of about 5% to about 20% based
on the weight of drug layer coated cores.
I 0. The extended-release capsule dosage form according to claim 9, wherein the extended-release
polymer is selected from the group consisting of water-soluble/swellable polymers, waterinsoluble
polymers, and mixtures thereof.
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II. The extended-release capsule dosage form according to claim 10, wherein the water-soluble
polymer is selected 11·om the group consisting of hydroxypropyl methyl cellulose,
hydroxyethyl cellulose, polyethylene glycol, poly( ethylene oxide), hydroxypropyl cellulose,
carboxymethyl cellulose, xanthan gum, starch, and mixtures thereof.
I 2. The extended-release capsule dosage form according to claim I 0, wherein the water-insoluble
polymer is selected fi·om the group consisting of cellulose ethers, cellulose esters,
polymethacrylic acid esters copolymers, aminoalkyl methacrylate copolymers, copolymers
of polyvinyl acetate and polyvinylpyrrolidone, and mixtures thereof.
13. The extended-release capsule dosage form according to claim 12, wherein the cellulose ether
is ethyl cellulose.
14. The extended-release capsule dosage form according to claim 12, wherein the water-insoluble
polymer further comprises a pore-former.
15. The extended-release capsule dosage form according to claim 14, wherein the pore-former is
selected from the group consisting of low viscosity grade hydroxypropyl methylcellulose,
sodium alginate, sugars and sugar alcohols, low molecular weight polyethylene glycol,
polyvinyl alcohol, and mixtures thereof.
16. An extended-release sprinkle capsule dosage form of metoprolol succinate comprising coated
discrete units, having a particle size from about 0.2 mm to 2.5 mm, wherein the capsule
dosage form releases not less than 15% ofmetoprolol succinate after 4 hours, when measured
in a United States Pharmacopeia (USP) type 2 dissolution apparatus, paddle at 50 rpm, at a
temperature of37°C ±0.5°C in 500 mL of pH 7.5 phosphate buffer.
17. The extended-release sprinkle capsule dosage form according to claim 16, wherein the
capsule dosage form releases about 15% to about 45% of metoprolol succinate after 4 hours,
when measured in a United States Pharmacopeia (USP) type 2 dissolution apparatus, paddle
at 50 rpm, at a temperature of37°C ±0.5°C in 500 mL of pH 7.5 phosphate buffer.
18. An extended-release sprinkle capsule dosage form of metoprolol succinate comprising coated
discrete units, having a particle size from about 0.2 mm to 2.5 mm, wherein the capsule
dosage form exhibits the following in-vitro dissolution profile, when measured in a United
States Pharmacopeia (USP) type 2 dissolution apparatus, paddle at 50 rpm, at a temperature
of37°C ±0.5°C in 500 mL of pH 7.5 phosphate buffer: a) not less than 15% ofmetoprolol
succinate is released after4 hours; and b) not less than 60% ofmetoprolol succinate is released
afler 12 hours.
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19. The extended-release sprinkle capsule dosage J(mn according lo claim 16 wherein the capsule
dosage form comprises meloprolol succinate in an amount of about 30% to about 70% by the
lola! weight oflhe dosage Jrm11.