FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
COMPLETE SPECIFICATION
(SECTION 10)
"PHARMACEUTICAL COMPOSITION OF PROPAFENONE'


Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957
and having its registered office at
B/2, Mahalaxmi Chambers, 22 Bhulabhai Desai Road,
Mumbai - 400 026

THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED


1. Technical Field
[0001] The present invention relates to an extended release (SR) pharmaceutical
composition comprising a pharmaceutical ly acceptable salt of propafenone, and more particularly propafenone hydrochloride (HC1), having a density less than 1.
BACKGROUND OF THE INVENTION
2. Description of the Related Art
[0002] Propafenone hydrochloride, 2'-[2-Hydroxy-3-(propylamino)-propoxy]-3-
phenylpropiophenone hydrochloride, has structural formula as shown below:

Propafenone is an antiarrhythmic drug, which was first disclosed in the 1970 German patent, DE2001431. Propafenone HCI is commercially available under the trade name Rythmol®, in the form of immediate-release tablets in strengths of 150 mg, 225 mg and 300 mg. Additionally, propafenone is also commercially available as sustained release capsules under the trade name Rythmol SR&, in doses of 225 mg, 325 mg and 425 mg. Each Rythmol SR* capsule encloses several small tablets of propafenone generally called microtabiets. Several patents describe the sustained release compositions of propafenone, especially the sustained release microtabiets of propafenone and propafenone particle size suitable to provide the sustained release.


[0003] Knoll's (BASF) in U.S. Patent No. 4828843 describes the microtablets of
propafenone, wherein the propafenone, was suitably milled so that about 99% of the particles of propafenone were less than 595 microns (0.6 mm) and about 99% of propafenone particles were more than 50 microns. The final microtablets thus produced had about 80% propafenone per microtablet. These microtablets were further coated with HPMC. Knoll's subsequent patents, European Patent Publication EP484331 and Patent Publication WO90/11755, disclose a method of producing monocrystals of propafenone suitable for long acting (sustained release) dosage forms into colorless spherical crystals with a grain size range of 0.4-1.2 mm (400-1200 \im)
|0004] U.S. Patent No. 5,681,588 discloses delayed release microtablets of
propafenone, prepared by using propafenone having density greater than 1 without release-delaying ancillary substances.
|0005] U.S. Patent Publication 2005/0271718, (the '718 patent) describes sustained
release capsules enclosing 25 mg propafenone tablets.
[0006] U.S. Patent Publication 2008/0014257 (the '257 patent) describes controlled
release propafenone capsules comprising non-uniform pellets having non-uniform shape and/ or size.
SUMMARY OF THE INVENTION:
[0007] The present invention provides an extended release (SR) pharmaceutical
composition comprising propafenone or pharmaceutically acceptable salt thereof
[0008] The present invention provides an extended release pharmaceutical
composition comprising propafenone or pharmaceutically acceptable salt thereof, wherein the density of propafenone or a pharmaceutically acceptable salt thereof is less than 1.
[0009] The present invention provides an extended release pharmaceutical
composition comprising propafenone or pharmaceutically acceptable salt thereof, and at least


one release retarding substance, wherein the density of propafenone or a pharmaceutical!;/ acceptable salt thereof is less than 1.
[0010] The present invention provides an extended release pharmaceutical
composition comprising the pellets or granules or minitablets comprising propafenone or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
[0011] The present invention provides an extended release pharmaceutical
composition comprising propafenone HC1, wherein the density of the propafenone HC1 is less than 1.
[0012] The present invention provides an extended release minitablets comprising
Propafenone HC1 and at least one pharmaceutically acceptable carrier, wherein the density of the Propafenone HC1 is less than 1.
[0013] The present invention also provides a process'to prepare extended release
minitablets, and pellets comprising Propafenone HC1 and at least one release retarding substance, wherein the density of the Propafenone HC1 is less than 1.
DETAILED DESCRIPTION OF INVENTION:
[0014] The present invention provides an extended release pharmaceutical
composition of pharmaceutically acceptable salts of propafenone, wherein the density of the propafenone salt is less than 1, preferably less than about 0.75, or more preferably less than about 0.5. Propafenone HC1 is the preferred pharmaceutically acceptable salt.
[0015] The extended release pharmaceutical composition of the present invention
includes tablets, capsules, sachets, pellets, and granules, wherein the preferred solid dosage forms include pellets or minitablets filled into the capsules or pellets or granules compressed into tablet. The amount of propafenone salt in a finished unit dosage form is less than about 90%, preferably less than about 80% and more preferably less than about 75%. The propafenone or its pharmaceutically acceptable salts, may be present in the form of particles, 90% of which are less than about 270 urn, more preferably 90% are less than about 90 u,m.

[0016] The shape and size of each individual unit filled in the capsule is almost
uniform. The size of pellets as well as minitablets is between about 1.5 mm to about 3 mm. preferably about 2.0 mm to about 2.8 mm, wherein the height and the diameter of a minitablet are independent of each other.
[0017] The amount of propafenone in each minitablet should be less than about 85%,
preferably less than about 80%. The average weight of minitablets is in range of about 3mg to about 20 mg, preferably about 6 mg to about 15 mg, wherein propafenone or its pharmaceutically acceptable salt is in range of about 2mg to about 18 mg preferably about 4.5 mg to about 12 mg.
[0018] The present invention provides an extended release (SR) pharmaceutical
composition of pharmaceutically acceptable salts of propafenone, wherein, the propafenone salt is in the form of particles, 90% of which are less than about 270 pirn, more preferably less than about 90 urn.
[0019] In a preferred embodiment, the present invention provides minitablets or
pellets including pharmaceutically acceptable excipients, suitable to carry out the conventional pharmaceutical techniques of making pellets and minitablets, using the commonly available machineries available for aforesaid purpose, as known in the art.
[0020] The term "finished unit dosage form", as intended herein, include solid dosage
forms such as tablets, capsules, pellets, and granules. Preferable dosage forms include pellets or minitablets filled inside capsules and pellets, and granules compressed into tablets.
[0021] For the purpose of the present invention, the term microtablet or minitablet
carries the same meaning and are interchangeable.
[0022] The pharmaceutical composition of the present invention comprises,
propafenone, pharmaceutically acceptable salts thereof and carriers or diluents, release retarding ancillary substances, lubricants, and optionally binders and disintegrants.


[0023] The pharmaceutical composition of the present invention comprises excipients
from about 0%- to about 30%, more specifically from about 5%- to about 25% of the total weight of the pharmaceutical composition.
[0024] The present invention provides carriers or diluents, which are selected from
starch, saccharides, microcrystalline cellulose, other cellulose derivatives, calcium phosphate, sodium calcium phosphate (NaCaP04). sugar alcohol (sorbitol, mannitol, xylitol), lactose and mixtures thereof.
[0025] The release retarding ancillary substances of the present invention can be
selected from the group comprising of, but not limited to, "water swellable and/or water gellable, water insoluble, water permeable polymers. The release retarding substance can be present in matrix or be coated on the surface of matrix. Preferably the release retarding ancillary substances of the present invention are selected from cellulosic ethers like hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethylcellulose (Ethocel), hydroxyethyl cellulose, most preferably hydroxypropyl methylcellulose (HPMC) of viscosity more than 6 cps.
[0026] The binders can be selected from cellulose derivatives (hydroxypropyl
methylcellulose or hydroxypropyl cellulose), sugars, gums, gelatin, povidone, pregelatinized starch, sugar solution, and polyvinyl alcohol.
[0027] Disintegrating agents are the substances or mixtures of substances added to a
pellet to facilitate its breakup or disintegration after administration. The typical examples of disintegrants are modified or unmodified starches, clays, cross-linked PVP, modified or unmodified celluloses.
[0028] It is also preferred, that the dosage form of present invention comprises a
lubricant such as magnesium stearate, zinc stearate, stearic acid etc. The propafenone minitablets of the present invention comprises a lubricant from about 1% to about 6%, preferably from about 3% to about 6%.


[0029] The minitablets of the present inventions may be coated with aqueous or non-
aqueous solution or dispersion of hydrophilic or hydrophobic materials. In one of preferred aspect, hydroxypropylmethylcellulose of 3 cps is coated to an extent that it constitutes from about 4% to about 6% of the coated propafenone HC1 minitablets. In another aspect the coating composition comprises Ethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, and triethyl citrate in alcoholic solvent.
[0030] The choice of excipients is not limited to the example disclosed herewith; it
may include any suitable excipients mentioned in the Handbook of Pharmaceutical Excipients (edited by Raymond Rowe, Paul Sheskey and Sian Owen; 5lhed.: Pharmaceutical Press and the American Pharmacists Association; 2006).
[0031] The dosage form of the present invention can be prepared by tablet press,
roller compactor, extrusion spheronization, or any other machine or machine aid used to prepare solid dosage forms, known in the art.
[0032] The prior art discloses that pellets having different sizes and surface areas
result to different release rates. The number and size of non-uniform pellets filled in a capsule will affect the drug content in a unit dose, further resulting to variant release profiles of capsules prepared from the same batch. Thus, non-uniform pellets require more controlled and number specific filling in a capsule. And further to fill said capsules optimally requires a definite number of pellets of one size.
[0033] According to the compositions described herein, the drug release rate can be
modified by using a delayed release substance in a compressed powder or by coating the pellets with a release delaying substance.
|0034] The examples, which follow, are not intended to be limiting of the scope of
the present invention but read in conjunction with the detailed and general description above, provide further understanding of the present invention and an outline of a process for preparing the compositions of the invention.


EXAMPLES:
[0035] PART A: PREPARATION OF SR CAPSULES
[0036] EXAMPLE I: Minitablets for propafenone SR capsules, 425 mg:

Ingredients Quantity
Propafenone HC1 425
Microcrystalline cellulose (Avicel PH 101) 115.2
Hydroxypropyl methylcellulose 25
Purified water qs
Magnesium Stearate 6
[0037] Process for minitablets of propafenone SR capsules, 425 mg:
[0038] A mixture of pre-sifted propafenone and microcrystalline cellulose was
granulated in rapid mixture granulator by using granulating solution of hydroxypropyl methylcellulose in water. Wet granules were dried in a fluid bed dryer and screened through #30 mesh. The screened granules were lubricated with magnesium stearate and compressed into minitablets, with an average weight of 4.8 mg by using suitable punches. The compressed minitablets with propafenone content of about 74% per minitablet were filled into capsules.
[0039] EXAMPLE II: Minitablets for propafenone SR capsules, 425 mg:

Ingredients Quantity
Propafenone HCI 425
Microcrystalline cellulose (Avicel PH 101) 96
Hydroxypropyl methylcellulose 17
Purified water qs
Magnesium Stearate 5.4


[0040] Process for minitablets of propafenone SR capsules, 425 mg:
[0041] Minitablets were prepared as per EXAMPLE I. The minitablets were
compressed, with an average weight of 8.0 mg by using suitable punches. The compressed minitablets with propafenone content of about 78% per minitablet were filled into capsules.
[0042] EXAMPLE III: Minitablets for propafenone SR capsules, 425 mg:

Ingredients Quantity
Propafenone HC1 425
Lactose Monohydrate (Pharmatose 200M) 89.54
Microcrystalline cellulose (Avicel PH 101) 15
Hydroxypropyl methylcellulose (Methocel El5 Premium - 15cps) 17
Magnesium Stearate 31.8
[0043] Process for minitablets of propafenone SR capsules, 425 mg:
[0044] Propafenone HC1, Lactose Monohydrate (Pharmatose 200M). microcrystalline
cellulose (Avicel PH 101) were sifted through sieve 60 # ASTM and the sifted mass was transferred into a rapid mixer granulator and the blend was mixed for 10 minutes. Hydroxypropyl methylcellulose (HPMC 15cps) was dissolved in purified water and the solution thus prepared was used to granulate the above dry blend. The granulated wet mass was dried in a fluid bed dryer until the LOD (105°C, 5 minutes) of NMT 2.5 % w/w is achieved. The dried granules were sifted through mesh # 30 and further lubricated with Magnesium Stearate. The lubricated blend was compressed into minitablets using 2.5 mm multitip punches. The minitable thus obtained was filled into capsules.
[0045] EXAMPLE IV: Pellets for propafenone SR capsules, 425 mg:

Ingredients Quantity
Propafenone HC1 425
Microcrystalline cellulose (Avicel PH 105) 36
Hydroxypropyl methylcellulose (HPMC 6CPS) 32 qs
Purified water

(0046] Extrusion process for pellets of propafenone SR capsules, 425 mg:
[0047] Propafenone hydrochloride, microcrystalline cellulose and hydroxypropyl
methyicellulose were mixed and granulated in a rapid mixer granulator by using water as granulation liquid, these wet granulates were extruded through 2 mm mesh size at 30 rpm speed, by using Fuji Paudal (MG55) extruder. The extrudates were spheronized and dried. The dried spheroids or pellets were filled into hard gelatin capsules.
[0048] EXAMPLE V: Minitablets for propafenone SR capsules, 425 mg:

Ingredients Qty/ (in mg)
Dry Mix
Propafenone HC1 425.0
Microcrystalline cellulose (Avicel PHI01) 47.0
Binder
Hydroxy Propyl Methyl Cellulose (HPMC 15cps) 10.0
Purified Water q.s.
Lubrication
Magnesium Stearate 28.00
Coating
Ethyl cellulose 4 cps (Ethocel 4 cps) 15.0
Polyvinyl pyrrolidone (Povidone k-30) 25.0
Polyethylene Glycol (PEG 4000) 4.5
Triethyl Citrate 6.5
Ethanol (95%) q.s.
[0049] Process for minitablets of propafenone SR capsules, 425 mg:
[0050] Propafenone HC1 and microcrystalline cellulose (Avicel PH 101) was sifted
through sieve 60 # ASTM and the sifted mass was transferred into a rapid mixer granulator and the blend was mixed for 10 minutes. Hydroxypropyl methyicellulose (HPMC 15cps) was
9


dissolved in purified water and the solution thus prepared was used to granulate the above dry blend. The granulated wet mass was dried in a fluid bed dryer until the LOD (105°C, 5 minutes) of NMT 2.5 % w/w is achieved. The dried granules were sifted through mesh # 30 and further lubricated with Magnesium Stearate. The lubricated blend was compressed into minitablets using 2.0 mm multitip punches. The minitablets thus obtained were coated with coating solution (Ethocel 4 cps, Povidone k-30, PEG-4000 & Triethyl citrate dissolved in Ethanol (95%)), and filled into capsules.
(00511 PART B: COMPARATIVE DISSOLUTION STUDIES
[0052] A comparison of the dissolution profile of Propafenone SR, prepared as in
EXAMPLES I-I1-IV, and the commercially available Rythmol SR®, were ran. The dissolution studies were carried out in USP dissolution apparatus II, at 50 rpm by using 900 ml dissolution media (0.08N HCI as dissolution media for first two hours and then phosphate buffer of pH 6.8).
[0053] Tablet I: Release profiles of preferred embodiments:

Time in hours % of Propafenone released

Rythmol SR® Example I Example II Example IV
0.5 5 9 8 5
1 10 15 12 9
2 18 26 24 21
3 67 70 69 81
4 89 83 86 93
6 97 92 93 96
[0054] The release profiles of compositions of propafenone SR prepared as in
EXAMPLES I-II-IV, having propafenone HCI of density less than 1; were found to be comparable to that of marketed composition Rythmol SR®.


Claims:
1. An extended release pharmaceutical composition comprising propafenone or pharmaceutically acceptable salt thereof, and at least one release retarding substance, wherein the density of propafenone is less than 1.
2. The extended release pharmaceutical composition according to claim 1 wherein the release retarding substances selected from cellulosic derivatives like Hydroxypropyl Methylcellulose, Hydroxypropylcellulose, Hydroxyethyl cellulose, ethyl cellulose and combinations thereof.
3. The extended release pharmaceutical composition according to claim 2 wherein the release retarding substance is Hydroxypropyl Methylcellulose of viscosity greater than 6 cps.
4. The extended release pharmaceutical composition according to claim 1 further comprising at least one additive ingredient.
5. The extended release pharmaceutical composition according to claim 4 wherein said additive ingredient is selected from the group comprising of binders, diluents, and lubricants.
6. The extended release pharmaceutical composition according to claim 5 wherein the binder is selected from the group consisting of HPMC, HPC, HC, PVP, PVA.
7. The extended release pharmaceutical composition according to claim 5 wherein the diluent is selected from the group consisting of microcrystalline cellulose, lactose, and starch.
8. An extended release pharmaceutical composition comprising propafenone or pharmaceutically acceptable salt thereof, hydroxypropyl methylcellulose, microcrystalline cellulose, lactose, and magnesium stearate, wherein the density of propafenone is less than 1.
9. The extended release pharmaceutical composition according to claim 1 or 8 is in the tablet, minitablet, pellets or granular form.
10. The extended release pharmaceutical composition of claim 8, prepared by wet granulation method, comprising of
1) blending Propafenone and diluent, and optionally release retarding substance

2) Wet granulating the blend of step 1) with solvent/ binder solution, optionally consisting release retarding substance
3) Drying and screening the granules of step 2)
4) Lubricating and compressing the granules of step 3) into minitablet.
5) Optionally coating the compressed minitablets.
6) Filling the minitablets of step 4) into the capsules