FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule!3)

1. TITLE OF THE INVENTION:
ORALLY DISINTEGRATING COMPOSITION OF ZOLMITRIPTAN
2. APPLICANT (S):
(a) NAME: AJANTA PHARMA LIMITED.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Ajanta House, Charkop, Kandivali (West), Mumbai - 400 067.
The following specification particularly describes the invention and the manner in which it is to be performed.


Field of the Invention:
The present invention discloses a composition containing Zolmitriptan in the form of oral disintegrating tablet for the acute treatment of migraines.
Background of the Invention:
Migraine headaches are a major public health problem. The impact of these headaches on patients and their families is tremendous, with many patients reporting frequent and significant disability.
The US patent No.5,466,699 discloses Zolmitriptan as a serotonin (selective 5-HT1B/1D) receptor agonist of the IB and ID subtype, used in the acute treatment of migraine attacks with or without aura and cluster headaches. During migraine excessive cerebrovascular dilation and neutrogena inflammatory processes are considered to contribute to pain. The 5-HTIB/ID-receptors mediate cerebrovascular vasoconstriction and inhibit neurogenic inflammation. 5-HT1B/1D receptor agonists are beneficial in the treatment (including prophylaxis) of disease conditions wherein vasoconstriction and neurogenic inflammation in the cerebrovascular bed is indicated, for example migraine, cluster headache and headache associated with vascular disorders, hereinafter referred to collectively as migraine. Zolmitriptan has been developed for the acute treatment of migraine in the form of a 2.5 mg and 5 mg tablet intended to be taken up to a maximum of 15 mg per day.

Formula I
Chemically, Zolmitriptan is (4S)-4-{[3-(2-dimethylaminoethyl)-lH-indol-5-yl] methyl}-1, 3-oxazolidin-2-one (CAS No. 139264-17-8). The chemical structure of Zolmitriptan can be represented as Formula I

Zolmitriptan is a synthetic tryptamine derivative and appears as a white powder that is readily soluble in water.
Zolmitriptan was developed by Burroughs Wellcome Co, as a new chemical compound useful for the prophylaxis and treatment of migraine and is currently marketed by Astra Zenica as ZOMIG-ZMT™ Orally Disintegrating Tablets.
ZOMIG-ZMT™ Orally Disintegrating Tablets are available as 2.5mg white uncoated tablets for oral administration. The orally disintegrating tablets contain mannitol USP, microcrystalline cellulose NF, crospovidone NF, aspartame NF, sodium bicarbonate USP, citric acid unhydrous USP, colloidal silicon dioxide NF, magnesium stearate NF, and orange flavor SN 027512.
Orally disintegrating dosage forms are becoming an increasingly important issue in the area of better patient compliance comparative to the conventional solid dosage forms such as capsules and tablets for oral administration, which are the most commonly used. In particular paediatric and geriatric patients often experience difficulties in swallowing solid dosage forms. Besides, conventional solid dosage forms are not suitable for bedridden or busy and travelling patients, who may not have access to water. Thus orally dispersible tablets represent an alternative for those patients and provide for a better patient compliance with recommended pharmaceutical therapies.
Orally disintegrating tablets containing olanzapine are known and sold under the trade name Zyprexa® Zydis . They are prepared by a freeze-drying technique, as is for example described in EP435684AL Freeze drying on a large scale has not been found to be very effective. Moreover, it is a time consuming technique. The Zydis tablets prepared by this technique are so fragile that the formation of the matrix material has to take place in a specific container. Tablets manufactured by this technology require a special type of packaging and careful handling during dispensing and administration to the patients, since they are prone to breakage.
Orally disintegrating tablets were described in the various patent applications such as WO 03/103629, EP1323417AI, WO 03/086361, EP1120109A2, EP1260215AI and WO 06/074951.

Zolmitriptan being a drug of choice in acute treatment of migraine attack, it is expected to
be formulated in a convenient dosage form capable of delivering the drug immediately
after administration for immediate relief from the painful attack of the migraine.
The present invention relates to an orally disintegrating composition, in particular in form
of tablets, which contains Zolmitriptan, and a process for manufacture of such a
composition.
Detailed Description of the Invention:
An orally disintegrating pharmaceutical composition comprising (a) Zolmitriptan, a salt or solvate or polymorph thereof as active ingredient, (b) mannitol, and (c) calcium silicate and (d) optionally, one or more polysaccharides along with one or more pharmaceutically acceptable excipients.
The term "orally disintegrating" means that the composition disintegrates or disperses within 90 s as measured by the in vitro disintegration test.
The composition according to the invention preferably disintegrates in less than 60 s, and more preferably in less than 30 s.
Preferably, the composition takes the form of a tablet. Such a tablet has preferably a mass of less than 250 mg.
ft is also preferred that a single dosage form of the composition according to the invention, such as a tablet or capsule, comprises 1 to 10 mg of Zolmitriptan or salt or solvate thereof, calculated as Zolmitriptan.
The calcium silicate used in the composition can be in crystalline or amorphous form or a mixture therof. The particle size of the calcium silicate is preferably in the range from 1 to 500 μm. The average particle size is preferably 1 to 100 μm.

The composition comprises usually 5 to 50, preferably 10 to 30 % by weight of calcium silicate.
The said composition optionally contains polysaccharide such as starch, pregelatinized starch, cellulose and mixtures thereof.
The composition usually comprises at least one further excipient, other than mannitol and calcium silicate, selected from the group of disintegrants, binders, fillers, flavouring agents, sweetening agents, glidants, colouring agents and lubricants.
The disintegrant is preferably selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate low-substituted hydroxypropyl cellulose or pregelatinized starch. Preferably the disintegrant is crospovidone or low substituted hydroxypropyl cellulose or a combination of both is used.
The binders used in the composition of the invention are preferably selected from gelatin, pregelatinized starch, starch DC, acacia, tragacanth, guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methylcellulose, glucose, sucrose, sorbitol, polyvinyl pyrrolidone and the like. The preferred binder is low-substituted hydroxypropyl cellulose.
Suitable fillers are preferably selected from at least one of starch derivatives, such as corn starch, potato starch or rice starch; polysaccharides such as dextrins, maltodextrins, dextrates, microcrystalline cellulose, powdered cellulose, mixtures of microcrystalline cellulose and guar gum, coprocessed blends of microcrystalline cellulose; and polyhydric alcohols, such as xylitol and sorbitol. The preferred filler is corn (maize) starch and microcrystalline cellulose.
Suitable sweeteners include sugars, such as sucrose, lactose and glucose; cyclamate and salts thereof; saccharin and salts thereof; and aspartame. The preferred sweetener is aspartame.

Flavouring agents can be natural or synthetic flavours such as strawberry flavour, wild cherry flavour, green apple flavour, spearmint flavour, and peppermint flavour. Glidants such as aerosil (fumed silicon dioxide), starch, talc, and magnesium stearate. The proffered glidants is aerosil. Lubricants are magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulphate, polyethylene glycol, and glyceryl behenate. The preferred lubricant is magnesium stearate.
In one embodiment, the active ingredient, mannitol and the calcium silicate are blended together and the blend is then mixed with other ingredients and the resulting mixture then finally subjected to direct compression to form a tablet dosage form.
It is a very advantageous aspect of the invention that the compositions of the thermo-labile and moisture sensitive compounds such as Zolmitriptan are prepared without subjecting the active ingredient to the moisture by a wet granulation step and the elevated temperatures used in the drying procedure usually concluding the wet granulation. Moreover, as the active ingredient do not need to be subjected to wet granulation their polymorphic form remains unchanged which is a further very strong benefit of the composition according to the invention.
Moreover, the composition according to the invention has sufficient strength and only a low friability of preferably less than I allowing for example tablets to be packed into regular containers, such as bottles, blisters, strip packs or sachets, and to be stored in bulk in drums.

Example 1

Sr, No. Ingredient mg/tablet
1 Zolmitriptan 5.00
2 Mannitol 137.15
3 Calcium Silicate 31.25
4 Crospovidone 20
5 Aspartame 3.00
6 Silicon Dioxide (Aerosil) 1.60
7 Magnesium Stearate 2.00
Total weight 200
The ingredients 1 to 3 were weighed, sifted, and mixed in blender. Ingredients 4 to 6 are weighed, sifted and mixed in above blend. The resulting blend is then lubricated with magnesium stearate and silicon dioxide in blender. The lubricated blend is then compressed in to tablets using Cadmach Compression Machine.
Example 2

Sr. No. Ingredient mg/tablet
1 Zolmitriptan 5.00
2 Mannitol 86.25
3 Calcium Silicate 28.75
4 Maize starch 36.4
5 Crospovidone 15.00
6 Micro crystal line Cellulose 22.00
7 Aspartame 3.00
8 Silicon Dioxide (Aerosil) 1.60
9 Magnesium Stearate 2.00
Total weight 200

The ingredients 1 to 7 were weighed, sifted, and mixed in V-blender. The above blend was lubricated with Silicon Dioxide and Magnesium Stearate in octagonal blender. The lubricated blend is then compressed in to tablets using Cadmach Compression Machine.
Example 3

Sr. No. Ingredient mg/tablet
1 Zolmitriptan 2.5
2 Mannitol 68.575
3 Calcium Silicate 15.625
4 Crospovidone 10
5 Aspartame 1.5
6 Silicon Dioxide (Aerosil) 0.8
7 Magnesium Stearate 1
Total weight 100
The ingredients 1 to 3 were weighed, sifted, and mixed in blender. Ingredients 4 to 6 are weighed, sifted and mixed in above blend. The resulting blend is then lubricated with magnesium stearate and silicon dioxide in blender. The lubricated blend is then compressed in to tablets using Cadmach Compression Machine.

Example 4

Sr. No. Ingredient mg/tablet
1 Zolmitriptan 2.5
2 Mann i to 1 43.125
3 Calcium Silicate 14.375
4 Maize starch 18.2
5 Crospovidone 7.5
6 Microcrystalline Cellulose 11
7 Aspartame 1.5
8 Silicon Dioxide (Aerosil) 0.8
9 Magnesium Stearate 1
Total weight 100
The ingredients 1 to 7 were weighed, sifted, and mixed in V-blender. The above blend was lubricated with Silicon Dioxide and Magnesium Stearate in octagonal blender. The lubricated blend is then compressed in to tablets using Cadmach Compression Machine.

We claim:
1. An orally disintegrating pharmaceutical composition which comprises (a)
Zolmitriptan, a salt or solvate or polymorph thereof as active ingredient, (b) mannitol,
and (c) calcium silicate, and (d) optionally, one or more polysaccharides along with one
or more pharmaceutically acceptable excipients.
2. Composition according to claim 1 wherein mannitol is selected from pearlitol 160, pearlitol 200 SD.
3. Composition according to claim I which comprises 30 to 90 % by weight of mannitol.
4. Composition according to claim 1 which comprises 5 to 40 % by weight of calcium silicate.
5. Composition according to claim 1 which comprises 5 to 40% by weight of one or more polysaccharides

6. Composition according to claim 1 wherein the one or more polysaccharide is selected from starch, pregelatinized starch, cellulose and mixtures thereof.
7. A process for preparing an orally disintegrating composition comprising (a) Zolmitriptan, a salt or solvate or polymorph thereof as active ingredient, (b) mannitol, and (c) calcium silicate and (d) optionally one or more polysaccharides along with one or more pharmaceutically acceptable excipients by direct compression.
8. The process according to claim 7, wherein direct compression method comprises
(a) mixing of weighed and sifted active ingredient with mannitol, calcium silicate and optionally other pharmaceutically acceptable excipients,
(b) lubricating the blend of (a), and
(c) compressing the lubricated blend in to tablets.

9. Composition according to claim /, which disintegrates in less than 60 seconds in the oral cavity.