Title of Invention	"A THERAPEUTIC COMPOSITION FOR TREATMENT OF MIGRAINE AND PROCESS FOR PREPARATION THEREOF"
Abstract	A therapeutic composition for the treatment of migraine and process for preparing such composition is provided. The composition comprises a 5HTiD receptor agonist as herein described from 0.05 to 85% w/w and nimesulide and salts thereof from 0.05 to 85% w/w of the composition along with other conventional ingredients.

Full Text

Migraine is an important and fascinating disorder. It's importance is due to the high prevalence and disabling severity. The total sum of suffering caused by migraine is probably higher than that with any other kind of headache. Nearly 15% of the population suffer from this recurrent debilitating attacks of headache associated with anorexia, nausea, vomiting and photo/ or phonophobia (Dechant, K.L. et al. ; Drugs 43(5) 776 - 798, 1992). Migraine had not been clearly defined or classified until 1988, and its subforms had not been studied individually until very recently. Migraine could be two types namely, migraine without aura (common migraine) and migraine with aura (classic migraine), respectively. First, migraine without aura is characterised by headache attacks lasting 4 to 72 hours. This headache is usually severe, unilateral pulsating aggravated by physical activity and accompanied by nausea, vomiting, photophobia and phonophobia. In the second type, the attacks are initiated by neurological symptoms called aura (visual, sensory, speech or motor symptoms). 5 HT (serotonin) has long been implicated in its pathophysiology. Probably 5-HT is released from platelets at the onset of attack, this release is associated with increase in free 5-HT in the plasma. Later stage of the attack is characterized by lower levels of 5-HT. Because 5-HT acts on many different receptors (mainly 5-HT1D/5-HT2 receptors), it may induce vasodilation or vasoconstriction, depending on the type of receptor dominated in a particular blood vessels. Two subtypes of 5 HT receptors namely 5-HT1Dand 5-HT2 have particular importance in migraine therapy. 5-HT1D receptors located on cerebral blood vessels which are dilated and distended during migraine headache ((Dechant, K.L. et al. ; Drugs 43(5) 776 - 798, 1992). 5-HT1D agonists are potent cerebral vasoconstrictors able to close arteriovenous anastomoses (AVAs) and also inhibit release of neurotransmitter acting on presynaptic 5-HT1D receptors. 5-HT1D receptors mediate vasconstriction and platelet aggregation but also depolarize serotonergic neurons of brain stem. Sumatriptan is a novel 5-HT1D receptor agonist which is effective in the acute treatment of migraine headache. The antimigraine activity has been attributed to the selective vasoconstriction of cranial blood vessels which are dilated and distended during migraine headache and/or from inhibition of neurogenically mediated inflammation in dura mater. Beside this, Sumatriptan is also reported to have affinity for 5-HT1A and 5-HT1B receptors ((Dechant, K.L. et al. ; Drugs 43(5) 776 - 798, 1992, Ghelardini et al., J, Pharmacol. Exp. Ther 279: 884 -890, 1996). The discovery of Sumatriptan is very interesting. In 1972, migraine project was initiated by Humphrey et al. in 1972 at Glaxo Laboratories, U.K. Although it was synthesized in 1984, first scientific report on Sumatriptan was published by Humphrey et al. in 1987. Later, its clinical profile and receptor profile was investigated. New Drug Application (NDA) for this wonderful compound (GR 43175) was submitted to US-FDA. Later in 1993, it was approved by US-FDA and opened for clinical use. Peak plasma concentration of Sumatriptan reached at a median of 10 min (range 5 to 20 min) after 6 mg subcutaneous dose and median of 1.5 hour (range 0.5 to 4.5 hours) after a 100 mg oral dose. The mean bioavailability of Sumatriptan was 96% after subcutaneous administration but only 14% after oral, due to extensive presystemic metabolism (metabolized predominantly by the 'A' isoenzyme of monoamine oxidase). Protein binding is approximately 14 to 21%. The terminal elimination half life is 2 hours. Like Sumatriptan, newer congeners zolmitriptan, avitriptan and naratriptan have affinity for both 5-HT1B and 5-HT1D receptors. Zolmitriptan showed similar pharmacology as compared to Sumatriptan with better potency, oral bioavailability and increased lipophilicity with central as well as peripheral synapses. The rational for the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the prophylaxis of migraine is based on the possible involvement of prostaglandins in the pathophysiology of the migraine process. Naproxen and tolfenamic acid are non-selective COX-inhibitors used as first line migraine prophylactics but their chronic use is associated with wide variety of side effects like dyspepsia, erosive gastritis, peptic ulceration, diarrhoea (specially with tolfenamic and mefenamic acids), hematological complication and hypersensitivity reactions. Nimesulide is a sulfonanilide non-steroidal anti-inflammatory drug (selective COX-2 inhibitor) whose anti-inflammatory, analgesic and antipyretic activities have been demonstrated in several widely used animal experimental models. It acts rather as an inhibitor of oxygen free radicals and hypochlorous acid production and release of neutrophils without affecting their function, and as a potent and specific inhibitor of cyclo-oxygenase-2, the inducible form of the enzyme present in inflammatory cells. By respecting the activity of cyclo-oxygenase-1, Nimesulide has a much lower risk of gastroduodenal lesions in comparison with most NSAIDs (Rabasseda, X. Drugs of Today; 32 (Suppl. D) 1 - 23, 1996). In the present invention, a suitable combination of NSAIDs with Sumatriptan is described which will have a better therapeutic compliance. The inventors have undertaken a detailed experimentation to study a combined treatment of Nimesulide in varying doses with Sumatriptan (10 mg) and was evaluated against acetic acid induced chemonociception in mice and this combination treatment was compared with the cases when Nimesulide and Sumatriptan were administered alone. It was surprisingly found that Nimesulide (2 mg) potentiated the Sumatriptan (10 mg) induced antinociception. In accordance with the present invention there is provided a synergistic pharmaceutical composition comprising Nimesulide and Sumatriptan. A controlled release composition of Sumatriptan and Nimesulide is also envisaged within the scope of the invention. Mentioned herewith our particulars of experiment indicated by the inventors for studying modification by Nimesulide of Sumatriptan-induced antinociception in acetic acid induced writhing in mice. Naproxen exerted dose dependent (1,2,5,10 mg/kg) antinociceptive effect against acetic acid induced writhing in mice (Table 1). When Sumatriptan (10 mg/kg) was administered along with varying doses of naproxen it did not potentiate the antinociceptive action of naproxen. When Nimesulide was administered with Surnatriptan (10 mg/kg), it showed a potentiating effect (Table 1). The effect was significant when Surnatriptan (10 mg/kg) was combined with Nimesulide (2 mg/kg). The combined effect was significantly more than individual Surnatriptan (10 mg/kg) or Nimesulide (2 mg/kg) effect per se (p The combination effect of this was highly significant than their individual effect per se. This potentiating effect was not blocked by naloxone indicating thereby non-involvement of opioid system. L-NAME (L-nitroarginine methyl ester) significantly enhanced the antinociceptive effect of Nimesulide (2 mg) and Surnatriptan (10 mg) combination. Previously it has been observed that L-NAME potentiated the cholinergic antinociception. Hence it is speculated that potentiation of Sumatriptan-Nimesulide antinociception by L-NAME may be cholinergic in nature. The composition can be administered by oral, parenteral, ocular, intranasal, inhalation, sublingual, buccal, transdermal, rectal, vaginal routes. The composition of the invention can be in any form commonly employed for administration e.g. tablet, drink solution, suspension, soft gelatin capsules, hard gelatin capsules, granules, elixirs, powders, wafers, lozenges, freeze dried powder, injectable solutions, powder for reconstitution, etc. The formulations may be fast release, modified release, sustained release, controlled release or timed release. Statement of the Invention: Accordingly the present invention describes a therapeutic composition for the treatment of migraine comprising a 5HT1D receptor agonist as herein described from 0.05 to 85% w/w and nimesulide and salts thereof from 0.05 to 85% w/w of the composition along with other conventional ingredients. Accordingly the present invention describes a process for the preparation of therapeutic composition for the treatment of migraine as claimed in claim 1, comprising mixing together a 5HT1D receptor agonist from 0.05 to 85% w/w and nimesulide and salts thereof from 0.05 to 85% w/w of the composition along with other conventional ingredients. The invention will now be described with reference to the foregoing examples: Example 1 Conventional film coated tablets Composition Sumatriptan(as Sumatriptan Succinate) 50.0 mg Nimesulide 100.0 mg Microcrystalline Cellulose 23.0 mg Starch 66.0 mg Purified Talc 2.5 mg Magnesium Stearate 2.5 mg Sodium Starch glycollate 1.5 mg Sodium Lauryl sulphate 1.5 mg Povidone 3.0 mg Film coating formula Hydroxy Propyl Methyl Cellulose 0.800 Kg PEG 400 0.08 Kg Isopropyl Alcohol 7.5 Itr. Methylene Chloride 15.0 Itr. Purified Talc 0.14 Kg Titanium Dioxide 0.14 Kg All the ingredients are weighed and sifted through a sieve of mesh 40 (linear inch) and blend. Compress into tablets. A film coating dispersion is prepared and passed through colloid mill and the core tablets are coated with it. Example 2. Fast Mouth Dissolving tablet Composition % w/w Sumatriptan 15.7 (as Sumatriptan Succinate) Nimesulide 32.0 Mannitol 41.3 Sodium starch glycollate 4.0 Croscarmellose sodium 3.0 Aspartame 2.0 Flavour 1.0 Magnesium stearate 1.0 Sumatriptan, Nimesulide, Mannitol, Sodium starch glycollate, Croscarmellose Sodium, Aspartame, Flavour and Magnesium Stearate were screened through 750 µm sieve and thoroughly blended. The mixed powders were compressed into tablets using conventional tabletting machine at a hardness of 1.0 to 2.5 Kg. Example 3 Controlled release matrix tablet Composition Sumatriptan 100.0 mg (as Sumatriptan Succinate) Nimesulide 200.0 mg Lactose 73.0 mg Hydroxypropyl Methylellulose 70.0 mg Magnesium Stearate 3.5 mg Purified Talc 3.5 mg Sumatriptan, Nimesulide, Lactose, Hydroxypropyl MethylCellulose, Magnesium Stearate and Purified Talc were screened through 750 (µm sieve and thoroughly blended. The mixed powders were compressed into tablets using conventional tabletting machine at a hardness of 3.0 to 6.0 Kg. Example 4 Inhalation Aerosol Composition Sumatriptan 0.1 % (as Sumatriptan Succinate) Nimesulide 0.1 % Lactose 2.0 % Propellant114 40.0% Propellant12 57.8% Example 5. Transdermal patch Composition Sumatriptan Succinate 10.0 % Nimesulide 10.0 % Silicone Adhesive Matrix 80.0 % (BIO-PSA X7-3045, Dow Corning) Polyester film laminate Release Liner Disperse Sumatriptan and Nimesulide in the Silicone Adhesive Matrix and apply as a thin layer on the Polyester film laminate and cover with the release liner. Example 6. Parenteral Preparation Composition Sumatriptan 6.0 mg (as Sumatriptan Succinate) Nimesulide Choline Salt equivalent to nimesulide 50.0 mg Water for Injection q.s. to 2 ml Example 7. Nasal Solution Composition Sumatriptan 6.0 mg (as Sumatriptan Succinate) Nimesulide Choline Salt 2.000 g Timol 0.010 g Propylene glycol 30..000 g Polyethylene glycol stearate 1.000 g Povidone 0.500 g Depurated Water q.s. to 100.0 ml Dissolve Polyethylene glycol stearate and Povidone in a portion of water followed by dissolution of Sumatriptan and Nimesulide Choline Salt. Separately dissolve Timol in Propylene glycol and add to the drug solution. Mix uniformly. Filter through 0.45 micron nylon filter, fill and seal in vials. Example 8. Oral suspension Composition Sumatriptan (as Sumatriptan Succinate) 1.00% Nimesulide 1.00 % Polysorbate - 80 0.05 % Xanthan Gum 2.00 % Glycerin 10.00 % Sodium Benzoate 0.20 % Methyl Paraben 0.10% Flavour 0.50 % Sucrose 40.00 % Water q.s. to 100.00 % Step 1. Wet Nimesulide in a portion of water containing polysorbate - 80. Step 2. Dissolve Sucrose in a portion of water by heating to 80° C. Add Glycerin, Sodium Benzoate, Methyl Paraben and Xanthan Gum. Step 3. Dissolve Sumatriptan in a portion of water and mix with bulk of step 2 followed by addition or wetted Nimesulide of step 1. Step 4. Add flavour and mix and make up the volume with water. Example 9. Dry powder for inhalation Composition Sumatriptan (as Sumatriptan Succinate) 1.00 % Nimesulide 1.00 % Lactose q.s. to 100.00 % Sumatriptan, Nimesulide and Lactose are blended and micronized to produce powder having mean particle size 20 microns. The powder is filled in dry powder inhalers. Example 10. Suppository Composition Sumatriptan (as Sumatriptan Succinate) 50.00 mg Nimesulide 100.00 mg Suppository base q.s. to 2000.00 mg (Suppocire, Gattefosse, France) Melt the suppository base at 60 to 70°C. Mix Sumatriptan and Nimesulide in the molten base. Fill in the suppository molds and cool. Pack when the suppositories have solidified. Table 1: Effect of Sumatriptan, Nimesulide and their combinations on acetic acid induced writhing in mice (Table Removed) * p WE CLAIM: 1. A therapeutic composition for the treatment of migraine comprising a 5HT1D receptor agonist as herein described from 0.05 to 85% w/w and nimesulide and salts thereof from 0.05 to 85% w/w of the composition along with other conventional ingredients. 2. A composition as claimed in claim1, wherein the said 5HT1D receptor agonist is selected from the group comprising Sumatriptan, Zolmitriptan, Avitriptan, and Naratriptan and salts thereof. 3. A composition as claimed in claim 2, wherein the 5HT1D receptor agonist in the composition is Sumatriptan or Sumatriptan Succinate. 4. A composition as claimed in claims 1 to 3, wherein the composition can be administered by oral, parenteral, ocular, intranasal, inhalation, sublingual, buccal, transdermal, rectal or vaginal route. 5. A composition as claimed in claims 1 to 5, wherein the composition may be in the form of tablet, drink solution, suspension, soft gelatin capsule, hard gelatin capsule, granules, elixir, powder, wafer, lozenge, freeze dried powder, injectable solution or powder for reconstitution. 6. A process for the preparation of therapeutic composition for the treatment of migraine as claimed in claim 1, comprising mixing together a 5HT-1D receptor agonist from 0.05 to 85% w/w and nimesulide and salts thereof from 0.05 to 85% w/w of the composition along with other conventional ingredients. 7. A therapeutic composition for the treatment of migraine substantially as herein described with reference to the foregoing description and the accompanying examples. 8. A process for the preparation of a therapeutic composition for the treatment of migraine as herein described with reference to the foregoing description and the accompanying examples.

Documents:

1358-del-1999-abstract.pdf

1358-del-1999-claims.pdf

1358-del-1999-correspondence-others.pdf

1358-del-1999-correspondence-po.pdf

1358-del-1999-description (complete).pdf

1358-del-1999-form-1.pdf

1358-del-1999-form-13.pdf

1358-del-1999-form-19.pdf

1358-del-1999-form-2.pdf

1358-del-1999-form-3.pdf

1358-del-1999-form-5.pdf

1358-del-1999-petition-138.pdf