FORM - 2
THE PATENTS ACT, 1970
COMPLETE SPECIFICATION
SECTION 10
TITLE : A NOVEL PROCESS FOR EXTENDED RELEASE
METOPROLOL SUCCINATE PHARMACEUTICAL COMPOSITIONS.
APPLICANTS : IPCA LABORATORIES LIMITED.,
48, KANDIVLI INDUSTRIAL ESTATE, MUMBAI - 400 067, MAHARASHTRA, INDIA, AN INDIAN COMPANY.
The following Specification particularly describes the nature of this invention and the manner
in which it is to be performed :

A Novel Process for Extended Release Metoprolol Succinate Pharmaceutical Compositions
Technical Field:
[001] The present invention relates to a novel process for an extended release
oral dosage formulation of metoprolol or a pharmaceutically acceptable succinate salt thereof provided with an extended release polymer base retardant coating.
Background and Prior Art
[002] Metoprolol succinate is a beta-selective (cardioselective) adenoreceptor
blocking agent, for oral administration, available as extended release tablets to treat a heart condition called angina. It reduces the oxygen demand to the heart, slowing the heart rate, reducing cardiac output when at rest and on exercise, reduces systolic blood pressure among other things. There have been many controlled and sustained release metoprolol formulations already known, which comprise of controlled release pellets, where each pellet acts as a separate drug delivery unit. But in order to obtain a desirable release of a drug, a considerable amount of experimentation needs to be done. So, in accordance with the present investigation, an extended release pharmaceutical formulation is devised to release the drug for upto 24 hours in a suitable controlled manner.
[003] U.S. Patent 4792452 to Howard et al., describes a controlled release
pharmaceutical formulation which releases at a controlled rate regardless of the pH of the environment. Its formulation includes up to about 45% by weight of a pH dependent polymer, which is a salt of alginic acid, and a pH independent hydrocarbon gelling agent, such as hydroxypropylmethyl cellulose.
[004] EP 0293347 to Henry A.C. and Christina E.E. describes metoprolol
succinate as a new therapeutically active compound, and pharmaceutical preparations comprising it. This invention discusses a new oral, therapeutically active compound,
2

which is soluble in the pH range 1 to 8, which therefore can be released in the gastrointestinal tract below the upper part of the small intestine. The sustained release excipient is prepared by dry blending the requisite amounts of xanthan gum, dextrose and calcium sulfate.
[005] U.S. Patent 4871549 to Yoshio U. et al, describes a time controlled
explosion system comprising metoprolol, a swelling agent such as a low substituted hydroxypropylcellulose, sodium starch glycolate or carboxymethylcellulose sodium, coated with a water-insoluble coating material so that drug release is caused by the explosion of the membrane after a definite time period.
[006] U.S. Patent 4957745 to Jonsson U.E. et al describes the pharmaceutical
preparation of controlled release preparation containing a number of beads comprising of metoprolol salts, their production and use in cardiovascular disorders.
[007] U.S. Patent 4927640 to Dahlinder L-ED et al also describes controlled
release beads having glass or silicon dioxide core. Metoprolol succinate was sprayed on to the cores of silicon dioxide, glass and sodium chloride from a solution of ethanol 95% and methylene chloride. Then the coated beads were filled into hard gelatin capsules.
[008] U.S. Patent 5081154 to Henry A.C. and Christina E.E. which is a
continuation of EP 0293346 also relates to metoprolol succinate wherein it has been proposed an oral pharmaceutical composition comprising a core containing a therapeutically active compound, which core has been coated with a layer comprising of an anionic polymer and a water insoluble polymer selected from the group of quaternary ammonium substituted acrylic polymers. The investigators suggest that in order to achieve a steady blood plasma level of the therapeutically active compound, a split dose unit of the therapeutically active compound provided with a coating according to the present invention can be administered together with some particles/granules, which are not coated.
3

[009] U.S. Patent 5399358 to Stanoforth George N and Baichwal Anand R is
directed to sustained release formulations for 24 hour release of metoprolol using a combination of xanthan gum with locust bean gum as the preferred gum combination.
[010] EP Application 110542 by Mccall Troy W and Baichwal Anand R
describes once-a-day oral dosage form of metoprolol to be released over a period of 24 hours in the gastrointestinal tract. The sustained release matrix comprised of heterosaccharide derivatives of xanthan gum.
[011] A number of patents in the prior art deal with sustained or controlled
release formulations of metoprolol. These include water insoluble glass, silicon dioxide or plastic resin beads, which are sprayed with metoprolol salt and then coated with controlled release polymeric membrane. Another sustained release excipient commonly used is a heteropolysaccharide e.g., xanthan gum or a gum combination of xanthan and locust bean gum for delaying the drug release. In other cases there is the use of a heteropolysaccharide gum along with a homopolysaccharicle gum, which can cross-link with the heteropolysaccharide gum in the gastro-intestinal fluid. Thus the need for a simple and economical process of formulation of metoprolol succinate extended release drug was felt and the present invention for the first time deals with the use of wet granulation method with carbomers and a water insoluble hydrophobic polymer retarding coating of ethyl cellulose to provide up to 24 hours of extended release.
Summary
[012] The present invention relates to a process for a sustained release oral
dosage form of metoprolol or a succinate salt thereof, comprising metoprolol or a pharmaceutically acceptable succinate salt thereof in an amount necessary to render a therapeutic effect.
[013] The present invention further provides a process for oral solid extended
release pharmaceutical formulations, which release metoprolol succinate over a time period of up to 24 hours.
4

Detailed Description
[014] The present invention describes a process for pharmaceutical extended-
release preparations of metoprolol succinate. The object of this invention is to obtain a solid preparation with a high extent of bioavailability of the drug in combination with an extended absorption from the gastrointestinal tract thus achieving an even effect of up to 24 hours after once (or twice in case of 12.5mg) daily administration.
[015] In the embodiments of the invention, the carbomer is included in an
amount from about 4.54% to about 11.5%, by weight of the final product. The drug to carbomer ratio may be, e.g., from about 10:1 to about 1:12. More appropriately, the drug to carbomer ratio is from about 10:1.25 to about 1:12 by weight of formulation.
[016] Preferred embodiment of the invention comprises of ingredients in the
ranges are metoprolol succinate 27 to 30 %, microcrystalline cellulose 17 to 30 %, carbomer 1 to 6 %, hydroxypropyl methyl cellulose (K100M)14 to 56 %, hydroxypropyl methyl cellulose (K4M) 4 to 10 %, povidone 8 to 12 %, magnesium stearate 1 to 1.5 %, isopropyl alcohol q.s. and the coating solution comprises of opadry 04-C-7000 A (colorcon) 4 to 5%, ethyl Cellulose 1 to 2%, isopropyl alcohol q.s., methylene chloride q.s.
[017] The preparation of the said tablet is by compression and mixing of
polymers. Carbomers are used both in granulation as well as mixing stages.
[018] By "extended release" it is meant for purposes of the present invention that
the therapeutically active medicament is released from the formulation at an extended rate such that therapeutically beneficial blood levels (but below toxic levels) of the medicament are maintained over an extended period of time, e.g., providing a 24 hour dosage form.
5

[019] The term "environment" is meant for purposes of the present invention to
encompass, e.g., the gastro-intestinal area, such as that used for in-vitro dissolution testing.
[020] By a careful choice of fillers and binders as well as gel forming material
the preparation is manufactured into a commercially acceptable form, e.g. a tablet that shows unexpectedly good absorption of both active compounds as well as a prolonged duration of action.
The following examples illustrate various aspects of the present invention:
[021] EXAMPLE 1
Wet Granulation Method for Compression
The active, MCC, carbopol and HPMC are blended together, and then the blend may be milled through a screen with appropriate size mesh. The blended material is granulated with a solution of polymer in non-aqueous/ hydroalcoholic solvent. The granules are dried at a suitable temperature and screened through a mesh of appropriate size. The blend is lubricated with a soluble or insoluble lubricant. The tablets are then formed by compression.
The pharmaceutical composition of the tablets containing 100mg metoprolol succinate without carbomer has the following composition:
6

TABLE 1
Ingredients Parts by weight of tablet
Metoprolol succinate 27.14 %
Micro Crystalline Cellulose 25.71 %
Hydroxy propyl methyl cellulose (K4M) 4.28 %
Hydroxy propyl methyl cellulose (Kl 00M) 14.29 %
Povidone 8.57 %
Isopropyl alcohol Qs
Hydroxy propyl methyl cellulose (K4M) 4.28 %
Hydroxy propyl methyl cellulose (Kl00M) 14.29 %
Magnesium stearate 1.43
Tablets containing 12.5mg, 25 mg, 50 mg, 100 mg and 200 mg metoprolol succinate are
similarly prepared.
[021] EXAMPLE 2
The coating solution to be coated on the tablets has the following composition:
TABLE 2
Ingredients Parts by weight of tablet
Hydroxy propyl methyl cellulose 15cps 5 %
Poly ethyene glycol 400 0.5 %
Talc 0.7 %
Titanium dioxide 3.8%
Isopropyl alcohol Qs
Methylene chloride Qs
There is a 3% weight gain by coating.
7

[022] EXAMPLE 3
Tablets containing 100 mg dose of metoprolol with carbomer have the following
composition:
TABLE 3
Ingredients Parts by weight of tablet
Metoprolol succinate 28.35 %
Micro Crystalline Cellulose 17.91 %
Carbomer 1.49%
Hydroxy propyl methyl cellulose (Kl00M) 28.35 %
Povidone 10.45 %
Iso propyl alcohol Qs
Carbomer 4.47 %
Hydroxy propyl methyl cellulose (K100M) 28.35 %
Magnesium stearate 1.49 %
Tablets containing 12.5mg, 25 mg, 50 mg, and 200 mg are similarly prepared.
[023] EXAMPLE 4
Retarding Coating Solution
A retarding coating solution with the following composition is used to further coat the
tablets from Examples 1 and 3.
TABLE 4
Ingredients Parts by weight of Tablet
Opadry OY-C-7000A (M/S colorcon) 4.5 %
Ethyl cellulose 1.0%
Iso propyl alcohol Qs
Methylene chloride Qs
8

In this case 6-7% weight gain after coating was noted.
[024] EXAMPLE 5
Dissolution tests were then carried out for the tablets of Examples 1-4. The dissolution
tests are conducted in an automated USP dissolution apparatus (Paddle type II, pH 6.8
buffer, 50 rpm). The results are given in Table 5 & 6.
TABLE 5: Carbomers with matrix control only
Time in Example 1 (core) Example 2 (coated) USP Limits
hours
1 15.19% 13.90% NMT 25%
4 35.32% 34.46% 20-40%
8 52.43% 51.70% 40-60%
20 101.92% 103.19% NLT 80%
TABLE 6: Polymers with retardant coating.
Time in Example 3 (core) Example 4 (coated) USP Limits
hours
1 21.28% 17.51% ' NMT 25%
4 37.45% 39.24% 20-40%
8 59.05% 58.88% 40-60%
20 96.38% 103.11% NLT 80%
[025] From the dissolution results in Table 5 & 6, it can be inferred that formulations made with carbomer had slower drug release rates compared to formulations made without carbomer. Further it was also noticed that formulations with the retarding coating had slower drug release rates when compared to those not coated with retarding coating. Similar dissolution results were seen with 12.5, 25, 50 and 200mg formulations.
9

[026] Although this invention has been described with reference to specific embodiments thereof, it is understood that other embodiments and variations of the invention as described and exemplified may be made by those skilled in the art without departing from the true spirit of the invention. It is intended that the appended claims be construed to include all such embodiments and variations.
10

References
Beta-blockers in chronic heart failure: considerations for selecting an agent. Mayo Clin
Proc 2002 Nov;77( 11): 1199-206.
Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure: analysis
of the experience in metoprolol CR/XL randomized intervention trial in chronic heart
failure. J Am Coll Cardiol 2002 Aug 7;40(3):491-8.
Successful blood pressure control in the African American Study of Kidney Disease and
Hypertension. Arch Intern Med 2002 Jul 22;162(14):1636-43.
Metoprolol CR/XL in female patients with heart failure: analysis of the experience in
Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure.
Circulation 2002 Apr 2;105(13):1585-91.
Tolerability of beta-blocker initiation and titration in the Metoprolol CR/XL Randomized
Intervention Trial in Congestive Heart Failure.Circulation 2002 Mar 12;105(10):1182-8.
Effects of metoprolol CR/XL on mortality and hospitalizations in patients with heart
failure and history of hypertension. J Card Fail 2002 Feb;8(l):8-14.
Effect of controlled release/extended release metoprolol on carotid intima-media
thickness in patients with hypercholesterolemia: a 3-year randomized study. Stroke 2002
Feb;33(2):572-7.
Longitudinal myocardial contraction improves early during titration with metoprolol
CR/XL in patients with heart failure. Heart 2002 Jan;87(l):23-8.
11

We claim,
1) A process for the manufacture of an extended release preparation containing
metoprolol succinate by wet granulation process comprising of active
pharmaceutical ingredient, metoprolol succinate 27 to 30% and pharmaceutical
excipients such as microcrystalline cellulose 17 to 30%, carbomer 1 to 6%,
hydroxypropyl methyl cellulose (K100M) 14- to 56%, hydroxypropyl methyl
cellulose (K4M) 4 to 10%, povidone 8 to 12%, magnesium stearate 1 to 1.5%,
isopropyl alcohol (q.s.) and the coating solution comprises of opadry 04-C-7000
A (colorcon) 4 to 5%, ethyl Cellulose 1 to 2%, isopropyl alcohol (q.s.) and
methylene chloride (q.s.)
characterized in that the said process comprises
a) introduction of metoprolol succinate, carbomer and hydroxy polymethyl cellulose by blending, milling and sieving prior to granulation;
b) introduction of a solution of polymer in non-aqueous / hydroalcoholic solvent during granulation of the blended material as in 1(a);
c) compressing the said granules as in 1(b) into tablets;
d) spray coating of the said compressed tablets as in 1(c), with a water-insoluble polymeric membrane containing derivatives of cellulose without protylasable groups; and
e) thereby incorporating the tablet and the coating into a matrix forming a swelling gel in contact with water.

2) A process as claimed in claim 1, wherein the amount of the said metoprolol succinate is in concentrations of 12.5 mg to 200 mg.
3) A process as claimed in claim 1 and 2, wherein the amount of said metoprolol
succinate is in the concentrations of 12.5mg, 25 mg, 50 mg, 100 mg and 200 mg respectively.
4) A process as claimed in claim 1, wherein the ratio of metoprolol succinate to
carbomer is in the range of 10:1 to 1:12 by weight of formulation.
5) A process as claimed in claim 1 to 4, wherein the carbomers are introduced into the
preparation both during granulation and blending.
6) A process as claimed in claim 1, wherein the said microcrystalline cellulose is in
the range of 1:1 to l.5:1 with respect to metoprolol succinate.
7) A process as claimed in claims 1 to 6, wherein the tablet is prepared by mixing and
compression of polymers.
8) A process as claimed in claim 1 to 7, where in the gel forming matrix contains
hydroxypropyl methyl cellulose.
12

9) A process as claimed in claim 1, wherein the binder is a povidone
10) A process as claimed in claim 1, wherein the said process includes the polymer coating as ethyl cellulose.
11) A process as claimed in claim 1, wherein the said granulation process is nonaqueous/ hydroalcoholic.
12) A process as claimed in claims 1 to 11, wherein the gain in weight by 3% to 7%.
13) A process as claimed in claims 1 to 12, wherein the said tablet is oval, circular or oblong depending on the strength of metoprolol succinate.
14) A process as claimed in claim 1 to 13, wherein the hardness of the said tablet varies from 35 Nortons to 160 Nortons for different strength.
Dated this 3™ Day of February 2003

Dr. GOPAKUMAR G. NAIR
Agent for the Applicant GOPAKUMAR NAIR ASSOCIATES
Nair Baug, Akurli Road
Kandivli (East), Mumbai - 400 101
To
The Controller of Patents
The Patent Office,
At Mumbai.
13

Abstract
A novel process for an extended release oral solid dosage formulation of metoprolol succinate is provided which includes an extended release polymer base retardant coating. In the present invention metoprolol succinate tablets comprising of strengths varying from 12.5 to 200mg are prepared via a wet granulation method and the formulation for release of metoprolol for upto 24 hours is provided.