FIELD OF THE INVENTION

The present invention relates to the stabilized pharmaceutical formulations of Zolmitriptan orally disintegrating tablets and the process for preparing the same.

BACKGROUND OF THE INVENTION

Zolmitriptan is chemically known as (S)-N, N-dimethyl-2-[5-(2-oxo-l, 3-oxazolidm- 4-ylmethyl)-1H-indole-3yl] ethylamine and is represented by the following structural formula Zolmitriptan is a selective 5-hydroxytryptamine IB/ID receptor agonist. This receptor mediates vasoconstriction and thus modifies blood flow to the carotid vascular bed. Agonists of the 5-HT IB/ ID receptor are therefore beneficial in the treatment (including prophylaxis) of disease conditions include migraine, cluster headache and headache associated with vascular disorders referred to collectively as "migraine". Due to its agonist effect at the 5-HT receptor, Zolmitriptan has been developed for the acute treatment of migraine.

Zolmitriptan is sold under the brand name ZOMIG-ZMT which is marketed by ASTRAZENECA Pharmaceuticals. ZOMIG-ZMT is available as an orally disintegrating tablet for oral administration in 2.5 and 5 mg strength. The inactive ingredients of the ZOMIG-ZMT are reported to be mannitol, microcrystalline cellulose, Crospovidone, Aspartame, Sodium bicarbonate, citric acid anhydrous, colloidal silicon dioxide, magnesium stearate and orange flavor.

US patent 6,024,981 discloses a rapidly dissolvable dosage form comprising an active ingredient and a matrix including non-direct compression filler and a lubricant. The usage of the non-direct compression filler decreases the compressibility and the friability of the tablet

US patent 6,759,029 discloses that the degradants of the Zolmitriptan are formed as a result of a thermally or photo chemically induced reaction. Such reaction include without limitation to oxidation (e.g. N-oxide formation) and elimination (e.g. E1 and E2 elimination pathways).

There is a problem in formulating the satisfactory composition of the orally disintegrating tablets comprising the Zolmitriptan as Zolmitriptan is relatively unstable in presence of many common excipients (i.e. the inactive ingredients) used to make the orally disintegrating tablets. So there is a need to develop a stable formulation of orally disintegrating tablets of Zolmitriptan to overcome the difficulties disclosed in the prior art.

SUMMARY OF THE INVENTION

The present invention relates to the stable orally disintegrating tablets of Zolmitriptan comprising the Zolmitriptan as an active ingredient and a stabilizer.

In one embodiment of the invention the stabilizer is an acidic substance selected from the group consisting of citric acid, tartaric acid, malic acid and phosphoric acid.

The present invention also relates to the stable Zolmitriptan orally disintegrating tablets comprising the Zolmitriptan as an active ingredient, atleast one stabilizer, atleast one directly compressible water soluble carbohydrate, atleast one directly compressible water insoluble filler, atleast one disintegrant and atleast one lubricant.

DETAILED DESCRIPTION OF THE INVENTION

The orally disintegraiing tablets of Zolmitriptan as per the present invention comprise the Zolmitriptan as an active ingredient and a stabilizer.

The stabilizer is an acidic substance selected from the group consisting of citric acid, tartaric acid, malic acid and phosphoric acid. The stabilizer preferably used is citric acid.

The active ingredient is provided in an amoimt of between greater than zero and about 80% by weight of the finished tablet and, more preferably, in a range of between greater than zero and about 60% by weight thereof. Put in other terms, the active ingredient can be included in an amount of between about 1 microgram to about 2 grams, and luore preferably between about 0.01 and about 1000 milligrams per dosage form, i.e., per tablet.

The stabilizer in the composition will be preferably from about 0.1% to about 10% of tablet by weight; more preferably from about 0.5% to about 5% of tablet by weight; and most preferably from about 0.5% to about 3% of tablet by weight.

The present invention also relates to the stable Zolmitriptan orally disintegrating tablets comprising the Zolmitriptan as an active ingredient, stabilizer, a directly compressible water soluble carbohydrate, directly compressible water insoluble filler, a disintegrant and a lubricant.

Directly compressible excipients are well known in the art, and have been characterized by their ability to bond to other materials to form a strong compact. Any suitable directly compressible, water soluble carbohydrate can be used in the tablet of the present invention. Suitable directly compressible, water soluble carbohydrates can include, for example, directly compressible, water soluble sugars and directly compressible, water soluble sugar alcohols.

Preferred directly compressible, water soluble carbohydrates include, for example, directly compressible mannitol, directly compressible sorbitol, directly compressible maltitol, directly compressible lactose, directly compressible sucrose, directly compressible xylose, directly compressible trehalose, directly compressible dextrose, and the like, and combinations thereof. Preferred directly compressible, water soluble carbohydrates include directly compressible maniutol, which is preferably a directly compressible spray dried mannitol.

When a directly compressible mannitol is used in the tablet of the present invention, the directly compressible mannitol preferably comprises crystalline particles having a substantially rounded shape. It is further preferred that, when a directly compressible spray dried mannitol is used, the directly compressible spray dried mannitol comprises particles having a diameter of from about 150 ^m to about 500 m and more preferably from about 100 ^m to about 400 ^m and most preferably from about 75|im to about 325 ^m. In a preferred embodiment, the directly compressible mannitol comprises crystalline mannitol particles having a substantially rounded shape, wherein about 40% to about 80% of the mannitol particles have a diameter of from about 300 ^im to about 500 jim. In a particularly preferred embodiment, the directly compressible mannitol comprises crystalline mannitol particles having a substantially rounded shape, wherein about 60% of the particles of the spray dried mannitol have a diameter of from about 150 m to about 325 nm.

The directly compressible, water soluble carbohydrate can be present in the tablet of the present invention in any suitable amount, e.g., in an amount of from about 1% by weight to about 99% by weight based on the total weight of the tablet. Preferably, the directly compressible, water soluble carbohydrate is present in an amount of from about 30% by weight to about 95% by weight based on the total weight of the tablet, and more preferably from about 50% by weight to about 85% by weight based on the total weight of the tablet.

Any suitable directly compressible, water insoluble filler can be used in accordance with the present invention. Suitable directly compressible, water insoluble fillers can include, for example, directly compressible water insoluble celluloses (e.g., microcrystalline cellulose), directly compressible water insoluble cellulose derivatives (e.g., ethyl cellulose), and the like. Preferably, the directly compressible, water insoluble filler is directly compressible, water insoluble cellulose, which is most preferably microcrystalline cellulose. The mean particle size of the directly compressible microcrystalline cellulose used in accordance with the present invention preferably is from about 75 |j,m to about 250^m.

The directly compressible, water insoluble filler can be present in the tablet of the present invention in any suitable amount, e.g., in an amount of from about 20% by weight to about 40% by weight based on the total weight of the tablet. Preferably, the directly compressible, water insoluble filler is present in an amount of from about 20% by weight to about 30% by weight based on the total weight of the tablet, and is more preferably present in an amount of from about 20% by weight to about 25% by weight based on the total weight of the tablet.

Suitable disintegrants can include, for example, microcrystailine cellulose, sodium carboxy methyl cellulose, calcium carboxymethyl cellulose, modified cellulose gum, crospovidone, alginic acid and alginates, pregelatinized starch, sodium starch glycolate, modified com starch, starch (e.g. potato/maize starch), Polacrilin potassium and the like, and combinations thereof.

Suitable lubricants can include, for example, stearates (e.g. stearic acid, magnesium stearate, zinc stearate, calcium stearate, and the like), talc, polyethylene glycol, liquid paraffin, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silicon dioxide, pahnitostearate, vegetable oil, hydrogenated vegetable oil, and the like, and combinations thereof.

The friability of the tablet of the present invention preferably is at most about 1.5%, but is more preferably at most about 1%, and is most preferably at most about 0.5% (e.g., about 0.3% or about 0.4%).

The Tablet of the present invention more preferably disintegrates from within about 2 seconds to within about 30 seconds, and still more preferably from within about 2 seconds to within about 20 seconds, and most preferably from within about 2 seconds to within about 15 seconds (e.g., from within about 5 seconds to within about 15 seconds, or from within about 5 seconds to within about 12 seconds), as measured by the Standard US? Disintegration Test for orally disintegrating tablets.

The tablet of the present invention optionally can include surface active agents, taste masking agents, flavorants, sweeteners, colorants, and the like, and combinations thereof.

Suitable surface active agents can include, for example, sodium dodecyl sulfate, sodiimi lauryl sulfate, polyoxyethylene sorbitan fatty acid esters (Tweens), polyoxyethylene stearates, sorbitan fatty acid esters (Spans), and the like, and combinations thereol.
Suitable flavorants can include, for example, flavors, which are known to those of skill in the art, such as, for example, natural flavors, artificial flavors, and combinations thereof. Flavorants may be chosen, e.g., from synthetic flavor oils and flavoring aromatics and/or oils, oleoresins, extracts derived fi-om plants, leaves, flowers, fmits, and the like, and combinations thereof. Non-limiting examples of flavor oils include spearmint oil, cinnamon oil, oil of wintergreen (methyl salicylate), peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, oil of nutmeg, allspice, oil of sage, mace, oil of bitter almonds, and cassia oil. Suitable flavoring agents also include, for example, artificial, natural and synthetic finit flavors such as vanilla, citrus oils (e.g., lemon, orange, lime, and grapefiiiit), and fhiit essences (e.g., apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, and apricot), and the like, and combinations thereof. The flavoring agents may be used in liquid or solid form and, as indicated above, may be used individually or in admixture. Other flavorants can include, for example, certain aldehydes and esters, e.g., cinnamyl acetate, cinnamaldehyde, citral diethylacetal, dihydrocarvyl acetate, eugenyl formate, p-methylamisol, and the like, and combinations thereof.
Suitable sweeteners can include, for example, solid natural or synthetic sweeteners, e.g., amino acid and dipeptide based sweeteners, e.g., glycerrhizin, saccharin and its salts, aspartame, Acesulfame potassium and the like, and combinations thereof
Suitable colorants can include, for example, red, black and yellow iron oxides; FD & C dyes (e.g., FD & C blue No. 2, FD & C red No. 40); and the like, and combinations thereof.
The present invention further relates to the process of the direct compression for the preparation of the stable Zolmitriptan orally disintegrating tablets.
The further examples illustrate the invention but, of course, should not be construed as any way limiting its scope.
Example-1:
The Zolmitriptan orally disintegrating tablets are prepared by the direct compression process with the composition as described in the Table-1.
Composition Mg/Tab
Zobnitriptan 5.0
Directly Compressible 102.0 Mannitol
Microcrystailine cellulose 10.0
Anhydrous lactose 45.5
Crospovidone 6.0
Colloidal silcondioxide 2.0
Acesulfame potassium 2.0
Aspartame 2.0
Orange flavor 2.0
Magnesium Stearate 3.5
Total weight of the tablet 180.0
Example-2;
The Zolmitriptan orally disintegrating tablets are prepared by the direct compression process with the composition as described in the Table-2.
Composition Mg/Tab
Zolmitriptan 5.0
Directly compressible 101.5 Mannitol
Microcrystalline cellulose 10.0
Anhydrous lactose 45.0
Citric acid 1.0
Crospovidone 6.0
Colloidal silcondioxide 2.0
Acesulfame potassiimi 2.0
Aspartame 2.0
Orange flavor 2.0
Magnesium Stearate 3.5
Total weight of the tablet 180.0
(
Example 3:
The stability of the Zolmitriptan orally disintegrating tablets described in the Example-1 and Example-2 are described in Table-3.
The Zolmitriptan orally disintegrating tablets in the Example-2 are said to be stable when compared with the composition described in the Example-1.
Table-3
Im Im Maximum ^^^^
Impurities Imp-01 methyl Imp-A N-oxide Unknown urities
Imp impurity e
Example-1
Initial 0.012 ND ND ND ND 0.2691 0.0167 0.3227
3M 0.1514 ND ND ND ND 0,9593 0.3251 1.4563
Example-2
Initial 0.003 ND ND ND 0.0095 0.0372 0.0301 0.1769
3M 0.0118 ND ND ND 0.0025 0.1461 0.0664 0,4803
ND-Not detected

We Claim

1. An orally disintegrating tablet comprising the Zolmitriptan as the active ingredient and atleast one stabilizer.

2. An orally disintegrating tablet of claim 1 wherein the stabilizer is an acid substance.

3. An orally disintegrating tablet of claim 2 wherein the acid substance is selected from the group consisting of citric acid, tartaric acid, malic acid and phosphoric acid.

4. An orally disintegrating tablet to any of the preceding claims wherein the stabilizer is citric acid.

5. An orally disintegrating tablet comprising

i. Zolmitriptan as the active ingredient
ii. Atleast one stabilizer
iii. Atleast one directly compressible water soluble carbohydrate
iv. Atleast one directly compressible water insoluble filler
v. Atleast one disintegrant
vi. Atleast one lubricant
vii. And optionally comprises surface active agents, taste masking agents, flavorants, sweeteners and colorants etc.

6. An orally disintegrating tablet of claim 5 wherein the stabilizer is citric acid.

7. An orally disintegrating tablet of claim 5 wherein the directly compressible water soluble carbohydrate is mannitol.

8. An orally disintegrating tablet of claim 5 wherein the directly compressible water insoluble filler is microcrystalline cellulose.

9. An orally disintegrating tablet of claim 5 wherein the disintegrant is cross linked povidone.