FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
PHARMACEUTICAL FORMULATION OF RIZATRIPTAN


Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near
Dinesh Hall, Ahmedabad 380 009, Gujarat,
India

The following specification describes the invention


PHARMACEUTICAL FORMULATION OF RIZATRIPTAN
FIELD OF THE INVENTION
The present invention relates to orally disintegrating tablet dosage form of Rizatriptan manufactured by direct compression. It also relates to the process involved therein.
BACKGROUND OF THE INVENTION
Rizatriptan is also known as N, N-dimethyl-5-(lH-l, 2, 4-triazol-l-ylmethyl)-lH-indole-3-ethanamine. Rizatriptan is marketed as rizatriptan benzoate under the brand name of MAXALT® as immediate release tablet and MAXALT® MLT as orally disintegrating tablet.

Rizatriptan has half life of 2 hours and an oral bioavailability of 40%. Rizatriptan is having Tmax of 1 hour, which is considerably less than that of other triptans like sumatriptan (2.5 hrs). Migraine patients suffer from acute attack and require quick medication. Rapidly dissolving formulation is a suitable dosage form for this condition. Rapidly dissolving dosage form of rizatriptan as disclosed or available in the market is prepared by costly and time consuming methods such as freeze drying method.
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Rapidly dissolving dosage forms are also called as fast melt dosage form /mouth dissolving dosage form / orally disintegrating dosage form / fast dispersing dosage form / quick disintegrating dosage form or likewise. These terms are often used interchangeably. These dosage forms are of much help in case of pediatric and geriatric patients who frequently have difficulty swallowing conventional solid-dosage forms. In addition, for many medicaments, the act of swallowing the medicament often requires fluids that increase gastric volume and the likelihood of nausea and vomiting. The patient can quickly take the medicine as soon as the symptoms appear. Orally disintegrating tablets are of great importance, where water is not available for taking the tablet. Orally disintegrating tablets disintegrates rapidly in the mouth and form solution or suspension with the saliva. This may lead to rapid absorption of the drug and rapid onset of the action.
US4642903 assigned to Scherer Corp. discloses a method for the preparation of
freeze dried products including pharmaceuticals, insecticides, nutrients, diagnostics;
fertilizers and insecticides.
US5178878 assigned to Cima Labs Inc. discloses a pharmaceutical dosage form, comprising of immediate release microparticles of an active agent. These microparticles are prepared as a rapidly dissolving tablet dosage form comprising of effervescent disintegrant. These effervescent disintegrant agents cause the dosage form to disintegrate rapidly and also to mask the bitter taste of the active.
US5464632 assigned to Prographarm Lab discloses a rapidly disintegrating multiparticulate tablet dosage form. It uses combination of disintegrating agent and swelling agent to achieve the rapid disintegration of the formulation. The active substances present in the invention are in the form of coated microcrystals or coated
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or uncoated microgranules. It uses high level of disintegrating agent like starch 1500 and crospovidone.
US5807577 assigned to Lab Pharmaceutical Research discloses a fast melt dosage form particularly tablet. It comprises of 30 to 50 weight percent of active, an effervescent couple which contains a base and an acid component, a bulking or disintegrating agent like starch and 3 to 5 percent of tablet lubricant.
US5298520 discloses the compound rizatriptan and also mentions its therapeutic use in the treatment of migraine headache. It also claims pharmaceutical composition of the compound that can be prepared by using conventional techniques.
US2004023948 assigned to Scherer Ltd. discloses a fast dispersing dosage form of 5-HT] agonist. It claims that the pre-systemic metabolism of the drug is reduced by forming a fast dispersing dosage form of the drug. The dosage: form disintegrates, within 1 to 10 seconds of the administration. It uses freeze drying method and contains a network of the active agent. The network of the active ingredient is obtained by subliming a solvent from a composition from the solid state.
US2002001617 assigned to Hanmi Pharma discloses a rapidly disintegrating composition of pharmaceutical actives. The active substance in the invention is present in a particulate form. The particulate form of the active substance is obtained by spray drying a solution of the drug. The described dosage form also contains a sublimable component, poly ethylene glycol and pharmaceutically acceptable additives.
US20040162333 assigned to Biovail Lab. discloses a rapidly disintegrating formulation of selective 5HTi agonist. The rapid disintegration formulation comprises of a spheronisation aid, solubilising agent and other pharmaceutically acceptable
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excipients. Microparticles of the present invention are prepared by two process like the encapsulation process and co-melt process.
US2005232988 assigned to Eurand Pharmaceuticals discloses an orally disintegrating formulation and methods of manufacturing the same. The disclosed formulation comprises of rapidly dispersing microgarnules formed of sugar alcohols or saccharides having particle size less than 30 microns and a disintegrant. The active substance is present in a taste masked microcapsule form. The taste masked microcapsules of active substance comprises of a polymeric material.
WO2007113856 assigned to Rubicon Research Ltd. discloses a rapidly disintegrating
dosage form having optimal mechanical strength. The described dosage form
disintegrates within 60 seconds of its administration. It employs a co-processed
excipient formed by a water soluble and water insoluble excipient. The water
insoluble excipient used in the present process is calcium silicate.
W02007074472 assigned to Jubilant Organosys discloses an orally disintegrating, dosage form. The described dosage form comprises of fillers having particle size more than 100 microns and a high amount of silicone dioxide (5 to 30%). The high concentration of the silicone dioxide gives cushioning effect and improves the mouth fill of the dosage form.
All the methods described above involve complicated process and manufacturing steps to achieve the rapid disintegrability of the dosage form. Manufacturing process, like freeze drying method, is a costly affair and requires special machine and packaging.
Some of the prior art use high level of disintegrating agent, which results in gritty mouth feel. In some prior art, effervescent agent or combination of effervescent
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agents has been used to achieve rapid disintegration. However, tablets which include effervescent pairs are highly sensitive to moisture and require a specific, very costly plant including special handling equipment, controlled-humidity environments and special moisture resistant packaging.
Most of the described techniques have disadvantages like tedious and complex method of manufacturing, special packaging and storage requirements, high cost, limitation on drug load etc. Thus, there continues to be a need for a formulation that eliminates these disadvantages. The desired features of such dosage form include quick disintegrability in an oral cavity, a pleasant mouth feel, simple manufacturing steps and optimal mechanical strength.
The inventors of present invention have surprisingly found that a rapidly disintegrating dosage form can be formed by using direct compression method i.e. without involving any complicated process described above. This invention also
• ■:, ■■ i '!■■■ * ■■■■' \-
provides a dosage form having better stability, good hardness and better mouth feel..
OBJECT OF THE INVENTION
It is an object of the present invention to provide orally disintegrating tablet dosage form of Rizatriptan manufactured by direct compression.
One embodiment relates to orally disintegrating tablet dosage form of Rizatriptan manufactured by direct compression, wherein the dosage form comprises of saccharide component, disintegrating agent and other pharmaceutically acceptable excipients.
Another embodiment relates to orally disintegrating tablet dosage form 6f-Rizatriptan manufactured by direct compression, wherein the dosage form comprises of
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saccharide component, disintegrating agent couple and other pharmaceutically acceptable excipients.
Another embodiment relates to orally disintegrating tablet dosage form of Rizatriptan manufactured by direct compression, wherein the dosage form comprises of saccharide component, disintegrating agent and other pharmaceutically acceptable excipients, wherein the saccharide component is sugar alcohol selected from Mannitol and Sorbitol.
Another embodiment relates to orally disintegrating tablet dosage form of Rizatriptan manufactured by direct compression, wherein the dosage form comprises of saccharide component, disintegrating agent couple and other pharmaceutically acceptable excipients, wherein disintegrating agent couple consists of Pregelatinized starch and Crospovidone.
Another embodiment relates to orally disintegrating tablet dosage form of Rizatriptan manufactured by direct compression, wherein dosage form comprises of 50% to 90% Saccharide Component, 8% to 18% of disintegrant couple, 0% to 1.0 % of glidant, 0.1% to 5% of sweetener and flavoring agent and 0.5% to 3% of lubricant based on total weight of dosage form.
Another embodiment relates to orally disintegrating tablet dosage form of Rizatriptan manufactured by direct compression, wherein dosage form comprises of 50% to 90% Spray dried Mannitol, 5% to 15% of Crospovidone, 3% to 10% of Pregelatinized starch, 0% to 1.0 % of Colloidal silicon dioxide, 0.1% to 5% of sweetener and flavoring agent and 0.5% to 3% of lubricant based on total weight of dosage form.
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DETAILED DESCRIPTION OF THE INVENTION
The term "Orally disintegrating tablet" as used herein means physically discrete units to be administered in single or multiple dosages that disintegrate or dissolve in the mouth rapidly without administering extra water. These tablets disintegrate or disperse within 90 seconds as measured by the in vitro disintegration test described in US Pharmacopoeia; in vitro disintegration Test Number 701, without disks. Such a disintegration test result is reasonably related to the actual disintegration time experienced by a mammal when placed in the oral cavity (although placement within such a cavity is not required). The disintegration of the tablet means that the tablet shape / form is destroyed but does not necessarily mean that the entire tablet is dissolved. For example, insoluble fragments can remain. In general no residue remains on the screen, which has 2 mm mesh size, or only a soft mass having no palpably firm core remains.
Preferably, the tablets of the present invention disintegrate in less than 60 seconds,
more preferably less than 50 seconds including less than 40 seconds and even less
than 30 seconds, and most preferably in less than 30 seconds. . .;
The terms "direct compression" refers to a process, wherein the various components of a tablet are blended, optionally milled, sieved and then compressed into tablets. The blending of the compounds may be achieved in one or more steps. For instance, the active ingredient may first be mixed with a saccharide component and this mixture can than be combined with a mixture of other pharmaceutically acceptable excipients. The whole process is preferably performed in the absence of a solvent. The most obvious advantage of direct compression is economy. Savings can occur in a number of areas including reduced processing time and thus reduced labour costs, fewer manufacturing steps and pieces of equipment, less process validation, and a lower consumption of power.
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The term "drug" or "active compound" or "active ingredient" or "rizatriptan" includes here rizatriptan and all the pharmaceutically acceptable and non-toxic salts, solvates as well as its different polymorphic forms and crystalline forms or amorphous form. Preferably rizatriptan benzoate.
The term "saccharide component" as used herein includes sugar alcohol, monosaccharides, oligosaccharides, polysaccharides, derivatives of these or mixtures thereof. It can be exemplified by such as lactose, maltodextrin, starch, modified starch, microcrystalline cellulose, dextrose, mannitol, Sorbitol, lactitol, xylitol, cyclodextrin, sucrose, glucose, galactose, fructose, maltose, maltitol and the like. The above examples are for illustration purpose only, it should not be considered as limiting in nature.
The term "disintegrating agent" as used herein or elsewhere includes agents which aid in the, disintegration of the dosage form. These agents can be exemplified by following examples like natural starch, modified starch or pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc. It is obvious for a person skilled in the art to choose any replacement of the described examples. Preferred disintegrants in the invention include crospovidone and natural, modified or pregelatinized starch. Combination of the disintegrating agent's i.e "disintegrating agent couple" is preferably used in the instant invention. The various disintegrating agent couple may be selected from pregelatinized starch and crospovidone, pregelatinized starch and croscarmellose sodium, pregelatinized starch and sodium starch glycolate and the like.
The pharmaceutical formulations of the present invention may contain additional ingredients selected from a wide variety of pharmaceutically acceptable excipients like lubricants, glidants, sweetening agents, flavoring agents etc.
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Examples of the lubricant include but not limited to magnesium stearate, calcium stearate, stearic acid, talc, and sodium stearyl fumarate etc. The compositions of the invention may also include a glidant selected from colloidal silicon dioxide, colloidal silica, silica gel, precipitated silica, or combinations thereof.
Examples of sweetening agents that can be used in the present invention are aspartame, stevia extract, glycyrrhiza, saccharine, saccharine sodium, acesulfame, sucralose and dipotassium glycyrrhizinate; one or more flavors e.g., mint flavour, orange flavour, peppermint flavor, lemon flavors, strawberry aroma, vanilla flavour, raspberry aroma, cherry flavor. Combinations of these flavors and sweetening agents may be used conveniently.
The composition can also be made without using sweetening or flavouring agent.
The general manufacturing process comprises of following steps:
1. Part quantity of the saccharide component is mixed with rizatriptan followed by. remaining part of saccharide component, disintegrating agent and optionally glidant.
2. Sift mixture obtained from step-1 through suitable screen and mix thoroughly.
3. Sift flavour and sweetener through suitable screen and mix thoroughly with blend obtained in step-2.
4. Sift lubricant through suitable screen and blend thoroughly with mixtures obtained in step-3.
5. Compress the lubricated blend to obtain tablets.
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The invention can be illustrated in a better way by the following example. These examples are for illustration purposes only. In no way they limit the scope of the present invention.
EXAMPLES
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various dosage forms and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever:
Example 1
Table -1

S.No Ingredients Mg/ Tablet

01 02 03 04 05
1. Rizatriptan Benzoate 14.53 14.53 14.53 14.53 14.53
2. Mannitol (Pearlitol SD 200) 107.72 108.77 104.27 109.52 108.02
3. Crospovidone 12.00 12.00 16.50 12.00 12.00
4. Pregelatinized Starch (Starch 1500) 7.50 7.50 7.50 7.50 7.50
5. Colloidal Silicon Dioxide 0,75 1.20 1.20 1.20 1.20
6. Peppermint flavour 1.50 1.50 1.50 1.50 1.50
7. Aspartame 4.50 3.00 3.00 3.00 3.00
8. Magnesium Stearate 1.50 1.50 1.50 0.75 2.25
Total 150.00 150.00 150.00 150.00 150.00
Disintegration Time Less than 20 seconds
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Manufacturing process:
1. Half of the mannitol was mixed with rizatriptan followed by adding the remaining half of mannitol, pregelatinized starch, and crospovidone and silicone dioxide to it.
2. Mixtures obtained from step-1 were sifted through sieve of 60 mesh size and mixed thoroughly.
3. Peppermint flavour and aspartame are sifted through sieve no 40 and mixed thoroughly with that of blend obtained in step-2.
4. Magnesium stearate was sifted through sieve no-60 and blended thoroughly with that of mixtures obtained in step-3.
5. Blend obtained from step -4 was compressed to get tablets.
Dated this 18th day of June, 2008
For Torrent Pharmaceuticals Ltd, Praveeh Chand Gandhi