Technical Field of Invention
The present invention relates to fixed dose compositions comprising sumatriptan and a nonsteroidal anti-inflammatory drug (NSAID), like naproxen, and the process of preparation
thereof.
Background of the Invention
Sumatriptan, a selective vascular 5-hydroxytryptaminei (5-HTT) receptor subtype agonist, is
chemically designated as 3-[2-(dimethylamino) ethyl]-N-methyl-indole-5-
methanesulfonamide. It mediates vasoconstriction of the human basilar artery and vasculature of human dura mater, which correlates with the relief of migraine headache. Sumatriptan is marketed as tablets in strengths of 25 mg, 50mg or 100mg under the proprietary name IMITREX® from GlaxoSmithKline, USA. The tablet dosage form contains sumatriptan in the form of its succinate (1:1) salt, and is indicated for the acute treatment of migraine attacks with or without aura in adults. The US Patents 4,816,470 and 5,037,845 discloses sumatriptan and salts thereof and also its use in treatment of migraine attacks.
It is well documented in the art that, when a triptan, like sumatriptan is used in combination with an anti-inflammatory drug, there is a two fold action - the dosage form targets the nerves and blood vessels believed to trigger a migraine and also relieves inflammation that can cause migraine pain, and thus acts in a superior way in comparison to the individual drug formulations. Naproxen, in particular has been effective in such fixed dose combination dosage formulations. It is a member of the acrylacetic acid group of nonsteroidal antiinflammatory drugs (NSAID), with analgesic and antipyretic properties. The sodium salt of naproxen has been developed as a more rapidly absorbed formulation of naproxen for use as an analgesic. It is chemically designated as (S)-6-methyoxy-a-methyl-1-2-naphthaleneacetic acid, sodium salt. The US Patents US 3,904,682; 3,998,966; 4,001,301 and 4.009,197 disclose naproxen, and its use in treating inflammatory conditions.
Recently, the fixed dose combination tablet of sumatriptan succinate and naproxen sodium containing 85 mg of sumatriptan and 500 mg of naproxen has been commercialized by GlaxoSmithKline under the trade name TREXIMET® in the United States of America. The US Patent Numbers 5,872,145; US 6,060,499 and 6,586,458 discloses unit dosage forms comprising a triptan and a long-acting NSAID, and their efficacy in treating a migraine headache.

There are prior art documents which teach fixed dose formulations comprising a triptan and an NSAID. The PCT Publication WO 2008/124081 exemplifies such tablets, which comprise of sumatriptan and naproxen granules, prepared separately - mixed along with other excipients and finally subjected to compression into monolayer tablets. The US Patent No. 7,332,183 in contrast suggests that, in the stomach, NSAIDs like naproxen forms a gel-like matrix that retards the dissolution of triptans (or other drugs) unless the two agents are maintained in distinct, side by side layers. Consequently, it discloses multilayer pharmaceutical tablets comprising an NSAID and a triptan wherein: substantially all of said triptan is in a first layer of said tablet and substantially all of said naproxen is in a second, separate layer; and said first layer and said second layer are in a side by side arrangement such that the dissolution of said naproxen occurs independently of said triptan, in a way that said dissolution rates are approximately same to that, if the drugs are given separately. It further defines the term "substantially all" as that, at least 90%, and preferably greater than 95%, of the total therapeutic agent (i.e. sumatriptan, or naproxen) present in the tablet is included within one distinct layer. Further, the US Publication No. 2007/0184109 reinforces the theory of US Patent No. 7,332,183 and teaches a pharmaceutical composition comprising a triptan in combination with a NSAID, preferably naproxen, in a way that each of the said drugs is located in discrete zones with respect to each other. It further, exemplifies and suggests that having sumatriptan and naproxen in the same zone, hinders the dissolution rate of the individual drugs, especially sumatriptan.
However, in the present case, the inventors have prepared bilayer tablets wherein unlike the teachings of the prior art, the drugs sumatriptan and an NSAID are present admixed in the each of the layers, in a way that at least about 90% of sumatriptan is released in 15 minutes when subjected to in vitro dissolution conditions in USP I Dissolution Apparatus, at 75rpm, at 37±0.5°C, in 900mL of pH 6.8-phosphate buffer medium.
Summary of the Invention
In one general aspect, it relates to a bilayer tablet which comprises
(a) sumatriptan or a composition comprising sumatriptan; and
(b) an NSAID or a composition comprising an NSAID;
characterized in that the first layer of the said tablet comprises at least about 15% of (a) and not more than about 85% of (b), and the second layer of the said tablet comprises the remaining amounts of (a) and (b).
In another general aspect, it relates to a bilayer tablet which comprises

(a) sumatriptan or a composition comprising sumatriptan; and
(b) an NSAID or a composition comprising an NSAID;
characterized in that the first layer of the said tablet comprises at least about 15% of (a) and not more than about 85% of (b), and the second layer of the said tablet comprises the remaining amounts of (a) and (b), wherein the said NSAID is naproxen.
In another general aspect, it relates to a bilayer tablet which comprises
(a) sumatriptan or a composition comprising sumatriptan; and
(b) an NSAID or a composition comprising an NSAID;
characterized in that the first layer of the said tablet comprises at least about 15% of (a) and not more than about 85% of (b), and the second layer of the said tablet comprises the remaining amounts of (a) and (b), wherein the said tablet releases at least about 90% of sumatriptan in 15 minutes when subjected to in vitro dissolution in a USP I apparatus, at 75rpm, at a temperature of 37°C±0.5°C in 900ml_ of pH 6.8 phosphate buffer.
In another general aspect, it relates to a bilayer tablet which comprises
(a) sumatriptan or a composition comprising sumatriptan; and
(b) an NSAID or a composition comprising an NSAID;
characterized in that the first layer of the said tablet comprises at least about 15% of (a) and not more than about 85% of (b), and the second layer of the said tablet comprises the remaining amounts of (a) and (b), wherein the said tablet further comprises at least one component of an effervescent couple.
In another general aspect, it relates to a process for the preparation of a bilayer tablet which comprises
(a) sumatriptan or a composition comprising sumatriptan; and
(b) an NSAID or a composition comprising an NSAID;
characterized in that the first layer of the said tablet comprises at least about 15% of (a) and
not more than about 85% of (b), and the second layer of the said tablet comprises the
remaining amounts of (a) and (b), wherein the process comprises of the following steps
(i) at least about 15% of sumatriptan or a composition comprising sumatriptan is
admixed with not more than about 85% of an NSAID or a composition comprising an
NSAID, optionally along with pharmaceutically acceptable excipient(s) to form the
first composition;
(ii) the remaining amount of sumatriptan or a composition comprising sumatriptan is.
admixed with the remaining amount of an NSAID or a composition comprising an
NSAID, optionally along with pharmaceutically acceptable excipient(s) to form the

second composition; (iii) the first and second compositions of (i) and (ii) are compressed into bilayer tablets.
Detailed Description of the Invention
A "bilayer tablet" as referred to herein, is a tablet which is made up of two distinct layers or discrete zones. The bilayer tablets as described herein may further comprise of additional layers which may or may not comprise of any active ingredient.
The term "layer" or "zone" as used herein refers to a distinct region or part in the said bilayer tablet of the invention which comprise of - at least about 15% and not more than about 85% each of (a) sumatriptan/ composition comprising sumatriptan and (b) an NSAID/composition comprising an NSAID, of the total amounts of the respective active ingredients/ compositions comprising the active ingredients; and (c) optionally, one or more of pharmaceutically acceptable excipients. The layer may comprise of granules, dispersion, a non-intimate or intimate blend, pellets, or beads. The layer may comprise of a sumatriptan composition and an NSAID composition. The layer may, alternately comprise of sumatriptan and an NSAID homogeneously dispersed in a pharmaceutical carrier. In one embodiment, the first layer of a bilayer tablet comprises (a) at least about 15% of sumatriptan or a composition comprising sumatriptan; and (b) not more than about 85% of an NSAID or a composition comprising an NSAID; and the second layer of the said tablet comprises the remaining amounts of (a) and (b).
The term "pharmaceutical carrier" encompasses pharmaceutically acceptable excipients and combinations thereof.
The active ingredients, sumatriptan and an NSAID include without limitation, free base/acid and the pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, and polymorphs thereof In one embodiment, sumatriptan is in the succinate salt form.
NSAIDs that may be used includes without limitation, naproxen, etoricoxib, valdecoxib, rofecoxib, parecoxib, lumiracoxib, meloxicam, piroxicam, diclofenac, ibuprofen, ketorolac, etodolac, oxaprozin, indomethacin, and the like. In one embodiment, the NSAID is naproxen
in its sodium salt form.
Sumatriptan and an NSAID present in the said bilayer tablet are in "therapeutically effective amount(s)" i.e., sumatriptan and the NSAID are in amounts that result in the alleviation

and/or prophylaxis of the symptoms of the disease or condition being treated by the drugs. The amount of sumatriptan present may be in the range of 1mg to 250mg. When the NSAID is naproxen, it may be present in an amount of 100 mg to 1100 mg. The recommended dose of TREXIMET® may be considered as standard dose.
Other triptans, viz., zolmitriptan, rizatriptan, naratriptan, eletriptan, donitriptan, frovatriptan, almotriptan, avitriptan, and the like, may be suitably used as an alternative of sumatriptan to
prepare similar formulations.
The term "pharmaceutically acceptable excipients" as recited herein includes conventional pharmaceutical additives known in the art, such as diluent(s), binder(s), disintegrant(s), superdisintegrant(s), lubricants(s), granulating solvent(s), glidants(s) or combinations
thereof.
Diluents may be selected from saccharides like lactose, dextrose, sucrose, fructose, maltose; sugars like mannitol, erythritol, sorbitol, xylitol and lactitol; cellulose derivatives like powdered cellulose, microcrystalline cellulose; starch and pregelatinized starch; dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium carbonate, kaolin
and the like.
Binders that may be used include, but are not limited to, starch derivatives like corn starch and pregelatinized starch; cellulose ethers such as carboxymethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose; carboxy vinyl polymers like carbomers; acrylates such as Eudragits; polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer; xanthan gum, guar gum and other such materials routinely used in the art of pharmaceutical manufacturing.
Disintegrants and superdisintegrants may be selected from the group consisting of alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide croscarmellose sodium, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, guar gum magnesium aluminium silicate, sodium starch glycolate, , corn starch, potato starch, pregelatinized starch, low-substituted hydroxypropylcellulose, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, and methacrylic acid divinylbenzene copolymer salts.
Lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, powdered stearic acid, magnesium oleate, calcium palmitate, potassium laureate,

sodium suberate, vegetable oil, mineral oil and the like. Glidants may be selected from talc, colloidal silicon dioxide, corn starch and the like.
Suitable granulating solvents may be used include without limitation, water, ethanol, methanol, isopropyl alcohol, methylene chloride, acetone and the like.
The bilayer tablets, as referred to herein may further comprise of at least one component of an effervescent couple to facilitate faster dissolution. The effervescent couple comprises of a basic and an acid component, which reacts with each other to liberate carbon dioxide in the presence of water. The acid component of the effervescent couple may comprise the sumatriptan itself, or the NSAID or an aliphatic carboxylic acid and salts thereof, such as citric acid or tartaric acid. The basic component may comprise the likes of alkali metal or alkaline earth metal carbonates and bicarbonates, such as sodium bicarbonate, potassium bicarbonate, and magnesium carbonate.
The bilayer tablets, as disclosed herein may optionally be coated using conventional coating compositions, which are available under the trade name of Opadry, Opaspray, from Colocron Limited, UK.
Each layer of the bilayer tablets which comprise of granules, dispersion, a non-intimate or intimate blend, pellets, or beads, may be processed using conventional techniques known in the art, viz. dry, aqueous or non-aqueous wet granulation, pelltization, melt granulation, roller compaction, drug layering, etc.
The following embodiments have been explained considering naproxen as the representative example of NSAIDs.
In one embodiment, a bilayer tablet comprises
(a) sumatriptan; and
(b) naproxen
characterized in that the first layer of the said tablet comprises about 15% of (a) and about 85% of (b), and the second layer of the said tablet comprises the remaining amounts of (a) and (b)
In one embodiment, a bilayer tablet comprises
(a) a composition comprising sumatriptan, diluent(s), binder(s), disintegrant(s), superdisintegrant(s), glidant(s) and lubricant(s); and

(b) a composition comprising naproxen, diluent(s), binder(s), disintegrant(s), superdisintegrant(s), glidant(s) and lubricant(s); and characterized in that the first layer of the said tablet comprises about 15% of (a) and about 85% of (b), and the second layer of the said tablet comprises the remaining amounts of (a)
and (b).
In one embodiment, a bilayer tablet comprises
(a) sumatriptan; and
(b) naproxen
characterized in that the first layer of the said tablet comprises about 20% of (a) and about 80% of (b), and the second layer of the said tablet comprises the remaining amounts of (a) and (b).
In one embodiment, a bilayer tablet comprises
(a) a composition comprising sumatriptan, diluent(s), binder(s), disintegrant(s), superdisintegrant(s), glidant(s) and lubricant(s); and
(b) a composition comprising naproxen, diluent(s), binder(s), disintegrant(s), superdisintegrant(s), glidant(s) and lubricant(s); and
characterized in that the first layer of the said tablet comprises about 20% of (a) and about 80% of (b), and the second layer of the said tablet comprises the remaining amounts of (a) and (b)
In one embodiment, a process of preparation of a bilayer tablet comprises of the following steps
(i) about 15% of sumatriptan is admixed with about 85% of naproxen, along with
pharmaceuticaly acceptable excipient(s) to form the first composition; (ii) the remaining amount of sumatriptan is admixed with the remaining amount of naproxen, along with pharmaceutically acceptable excipient(s) to form the second composition; (iii) the first and the second compositions of (i) and (ii) are compressed into bilayer tablets.
In one embodiment, a process of preparation of a bilayer tablet comprises of the following steps
(i) about 20% of sumatriptan is admixed with about 80% of naproxen, along with pharmaceutically acceptable excipient(s) to form the first composition;

(ii) the remaining amount of sumatriptan is admixed with the remaining amount of naproxen, along with pharmaceuticaly acceptable excipient(s) to form the second composition;
(lii) the first and the second compositions of (i) and (ii) are compressed into bilayer
tablets.
In one embodiment, a process of preparation of a bilayer tablet comprises of the following steps
(i) about 15% of a composition comprising sumatriptan is admixed with about 85% of a
composition comprising naproxen to form the first composition; (ii) the remaining amount of the composition comprising sumatriptan is admixed with the remaining amount of the composition comprising naproxen to form the second composition; (iii) the first and the second compositions of (i) and (ii) are compressed into bilayer tablets.
In one embodiment, a process of preparation of a bilayer tablet comprises of the following steps
(i) about 20% of a composition comprising sumatriptan is admixed with about 80% of a
composition comprising naproxen to form the first composition; (II) the remaining amount of the composition comprising sumatriptan is admixed with the remaining amount of the composition comprising naproxen to form the second composition; (iii) the first and the second compositions of (i) and (ii) are compressed into bilayer tablets.
In one embodiment, the bilayer tablet of the above embodiments comprises of at least one component of an effervescent couple.
From the above it is apparent that various modifications and combinations of the formulations detailed in the text may be made without departing from the spirit and scope of the invention. The invention as described herein may be illustrated by the following examples but is not to be construed to be limiting by them.
Example 1:

(Table Removed)
Procedure
Part I- Sumatriptan granules:
Sumatriptan succinate and lactose were blended and granulated using an aqueous solution in a Rapid Mixer Granulator. The granules were dried, sized and blended with lactose (anhydrous), microcrystalline cellulose, croscarmellose sodium, talc, and colloidal silicon dioxide The blend so formed was further blended with magnesium stearate to obtain the final blend.
Part ll-Naproxen granules
Naproxen sodium was blended with croscarmellose sodium and microcrystalline cellulose and granulated using an aqueous solution of polyvinylpyrrolidone in a Rapid Mixer Granulator. The granules were dried, sized and blended with microcrystalline cellulose, croscarmellose sodium, talc, and colloidal silicon dioxide. The blend so formed was further blended with magnesium stearate to obtain the final blend.
Preparation of First Layer Composition
Eighty-five percent of the final blend in Part II was blended with fifteen percent of the final
blend of Part I to obtain the first layer composition.
Preparation of Second Layer Composition
Eighty-five percent of the final blend in Part I was blended with fifteen percent of the final
blend of Part II to obtain second layer composition.
The first and the second layer compositions so obtained were compressed using a bilayer tablet compression machine.
Example 2:

(Table Removed)

Second Layer Composition
(A) Intragranuiar:
Procedure
First Layer Composition:
Eighty percent of the total amount of naproxen sodium, and twenty percent of the total amount of sumatriptan, were blended with dibasic calcium phosphate and microcrystalline cellulose and granulated using an aqueous solution of polyvinylpyrrolidone in a Rapid Mixer Granulator. The granules were dried and sized and blended with microcrystalline cellulose, sodium starch glycolate, sodium bicarbonate, talc and colloidal silicon dioxide. The blend so obtained was further blended with magnesium stearate to obtain the first layer composition.
Second Layer Composition:
Eighty percent of the total amount of sumatriptan, and twenty percent of the total amount of naproxen sodium, were blended with dibasic calcium phosphate and microcrystalline cellulose and granulated using an aqueous solution of polyvinylpyrrolidone in a Rapid Mixer Granulator. The granules were dried and sized and blended with microcrystalline cellulose, sodium starch glycolate, sodium bicarbonate, talc and colloidal silicon dioxide. The blend so obtained was further blended with magnesium stearate to obtain the second layer composition.
The first and the second layer compositions so obtained were compressed using a biiayer tablet compression machine.
Tablets in Example 1 were subjected to in vitro dissolution studies in a USP type I apparatus, at 75rpm, at a temperature of 37°C±0.5°C in 900ml_ of pH 6.8 phosphate buffer medium. Aliquot of sample was withdrawn at predetermined time intervals and replaced with an equal amount of fresh media. Samples were processed and analysed suitably. Dissolution profiles of these tablets are provided in Table 1.
Table 1: In vitro release pattern of sumatriptan and naproxen from tablets prepared as per composition in Examples 1 in USP I apparatus in 900mL of pH 6.8 phosphate buffer medium at 75 rpm at a temperature of 37°C±0.5°C.

WE CLAIM:
1. A bilayer tablet which comprises
(a) sumatriptan or a composition comprising sumatriptan; and
(b) an NSAID or a composition comprising an NSAID;
characterized in that the first layer of the said tablet comprises at least about 15% of (a) and not more than about 85% of (b), and the second layer of the said tablet comprises the remaining amounts of (a) and (b).
2. The bilayer tablet according to claim 1, wherein the NSAID is naproxen.
3. The bilayer tablet according to claim 1, wherein the said composition comprising of sumatriptan, further comprises of pharmaceutical^ acceptable excipients.

4 The bilayer tablet according to claim 1, wherein the said composition comprising of an NSAID, further comprises of pharmaceutical^ acceptable excipients.
5 The bilayer tablet according to claims 3 and 4, wherein the pharmaceuticalY acceptable excipients are selected from the group comprising of diluent(s), binder(s), disintegrant(s), superdisintegrant(s), glidant(s), lubricant(s), effervescent couple(s) and combinations thereof.
6 The bilayer tablet according to claim 1, wherein the said tablet further comprises of at least one component of an effervescent couple.
7. The bilayer tablet according to claim 1, wherein the said tablet releases at least about 90% of sumatriptan in 15 minutes when subjected to in vitro dissolution in a USP type I apparatus, at 75rpm, at a temperature of 37°C±0.5°C in 900ml_ of pH 6.8 phosphate
buffer.
8 A process of preparation of the bilayer tablet according to claim 1, wherein the process comprises of the following steps
(i) at least about 15% of sumatriptan or a composition comprising sumatriptan
is admixed with not more than about 85% of an NSAID or a composition
comprising an NSAID to form the first composition;
(ii) the remaining amount of the composition comprising sumatriptan or a
composition comprising sumatriptan is admixed with the remaining amount

of the NSAID or the composition comprising the NSAID to form the second composition; (iii) the first and the second compositions of (i) and (ii) are compressed into bilayer tablets.
9 A bilayer tablet which comprises
(a) sumatriptan or a composition comprising sumatriptan; and
(b) an NSAID or a composition comprising an NSAID;
characterized in that the first layer of the said tablet comprises at least about 15% of (a) and not more than about 85% of (b) and the second layer comprises the remaining amounts of (a) and (b), and the process of preparation thereof, substantially as described and illustrated by examples herein.