Many Things Can Trigger a Migraine. These Include

a) Brief resume of the intended work: Migraines are recurring attacks of moderate to severe pain. The pain is throbbing or pulsing, and is often on one side of the head. During migraines, people are very sensitive to light and sound. They may also become nauseated and vomit. Migraine is three times more common in women than in men. Some people can tell when they are about to have a migraine because they see flashing lights or zigzag lines or they temporarily lose their vision. Many things can trigger a migraine. These include  Anxiety  Stress  Lack of food or sleep  Exposure to light  Hormonal changes (in women) Doctors used to believe migraines were linked to the opening and narrowing of blood vessels in the head. Now they believe the cause is related to genes that control the activity of some brain cells. Medicines can help prevent migraine attacks or help relieve symptoms of attacks when they happen1. Rizatriptan benzoate tablets contain rizatriptan benzoate, USP, a selective 5-hydroxytryptamine1B/1D (5- HT1B/1D) receptor agonist. Rizatriptan benzoate is described chemically as: N,N-dimethyl-5-(1H-1,2,4- triazol-1-ylmethyl)-1H-indole-3-ethanamine monobenzoate and its structural formula is:

Rizatriptan molecular formula is C15H19N5•C7H6O2, representing a molecular weight of the free base of 269.4. Rizatriptan benzoate is a white to off-white, crystalline solid that is soluble in water at about 42 mg per ml(expressed as free base) at 25°C. Rizatriptan benzoate tablets are available for oral administration in strengths of 5 mg and 10 mg (corresponding to 7.265 mg or 14.53 mg of the benzoate salt, respectively). Each compressed tablet contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch (maize), ferric oxide (red), and magnesium stearate. Each lyophilized orally disintegrating tablet contains the following inactive ingredients: gelatin, mannitol, glycine, aspartame, and peppermint flavor. Mechanism of Action: Rizatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Rizatriptan presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 5- HT1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal system. Pharmacokinetics : Absorption Rizatriptan is completely absorbed following oral administration. The mean oral absolute bioavailability of the rizatriptan benzoate tablet is about 45%, and mean peak plasma concentrations (Cmax) are reached in approximately 1 to 1.5 hours (Tmax). The presence of a migraine headache did not appear to affect the absorption or pharmacokinetics of rizatriptan. Food has no significant effect on the bioavailability of rizatriptan but delays the time to reach peak concentration by an hour. In clinical trials, rizatriptan benzoate was administered without regard to food. AUC of rizatriptan is approximately 30% higher in females than in males. No accumulation occurred on multiple dosing Distribution The mean volume of distribution is approximately 140 liters in male subjects and 110 liters in female subjects. Rizatriptan is minimally bound (14%) to plasma proteins.

Metabolism The primary route of rizatriptan metabolism is via oxidative deamination by monoamine oxidase-A (MAO-A) to the indole acetic acid metabolite, which is not active at the 5-HT1B/1D receptor. N- monodesmethyl-rizatriptan, a metabolite with activity similar to that of parent compound at the 5- HT1B/1D receptor, is formed to a minor degree. Plasma concentrations of N-monodesmethyl-rizatriptan are approximately 14% of those of parent compound, and it is eliminated at a similar rate. Other minor metabolites, the N-oxide, the 6-hydroxy compound, and the sulfate conjugate of the 6-hydroxy metabolite are not active at the 5-HT1B/1D receptor.

Elimination The total radioactivity of the administered dose recovered over 120 hours in urine and feces was 82% and 12%, respectively, following a single 10 mg oral administration of 14C-rizatriptan. Following oral administration of 14C-rizatriptan, rizatriptan accounted for about 17% of circulating plasma radioactivity. Approximately 14% of an oral dose is excreted in urine as unchanged Rizatriptan while 51% is excreted as in dole acetic acid metabolite, indicating substantial first pass metabolism. The plasma half-life of Rizatriptan in males and females averages 2 to 3 hours. Cytochrome P450 Is forms Rizatriptan is not an inhibitor of the activities of human liver cytochrome P450 is forms 3A4/5, 1A2, 2C9, 2C19, or 2E1; rizatriptan is a competitive inhibitor (Ki=1400 nM) of cytochrome P450 2D6, but only at high, clinically irrelevant concentrations2. Oral tablets are the most widely used dosage form because of its advantage in terms of self-administration, compactness, low cost and ease in manufacturing. The major demerits of conventional tablets include poor patient compliance, low bioavailability and delayed on set of action. Because of these problems, scientists developed innovative drug delivery systems known as ‘Oro dispersible tablets’. United States Food and Drug Administration (FDA) defined Oro dispersible tables as “A solid dosage form containing medicinal substance or active ingredient which disintegrates rapidly within a matter of seconds when placed upon the tongue advantages of Oro dispersible tablets include administration without water, rapid on set of action and increased bioavailability”. The characteristic recent advances in novel drug delivery system (NDDS) aims to enhance safety and by the formulating a convenient dosage form for administration to achieve the better patient compliance. One such approach is formulation of orally disintegrating tablets, these are useful for pediatric, geriatric and also dysphasic patients, leading to improved patient compliance. These dosage forms dissolve or disintegrate rapidly in the oral cavity within a matter of seconds without the need of water. Tablet disintegration has been considered as the rate limiting step in faster drug release. 1-4 Natural gums and mucilage have been widely explored as pharmaceutical excipients. These are widely used in the pharmaceutical industry as thickener, emulsifier, stabilizer, gelling agent, granulating agent, suspending agent, binder, film former, disintegrant and as sustained release matrix. Demand for these natural sources is increasing and new sources are being developed. Natural gums and mucilages are preferred over semisynthetic and synthetic excipients in the field of drug delivery because they are cheap and easily available, have soothing action and nonirritant nature. Further, they are eco-friendly, capable of multitude of chemical modifications, potentially degradable and compatible due to their natural origin3.

ENCLOSURE-II

REVIEW OF LITERATURE : 1. Keny R et al., have developed mouth disintegrating tablets of rizatriptan benzoate to produce the intended benefits. Mouth disintegrating tablets of rizatriptan benzoate had been prepared using superdisintegrants crospovidone, carboxymethylcellulose calcium, Indion 414 and Indion 234 using the direct compression method. The prepared tablets had been evaluated for thickness, uniformity of weight, content uniformity, hardness, friability, wetting time, in vitro and in vivo disintegration time, mouth feel, in vitro drug release and assay by high performance liquid chromatography. The tablets had disintegrated in vitro and in vivo within 4 to 7 s and 6 to 19 s, respectively. Almost 90% of drug had been released from all formulations within 20 min. The drug releasd from the formulations followed first order kinetics. Stability studies of the tablets at 40±2°/75%±5% RH for 1 mo had showed non significant drug loss. Conclusion; The formulation containing combination of crospovidone and Indion 234 had been found to give the best results. Apart from fulfilling all official and other specifications, the tablets had exhibited higher rate of release4.

2 Chang R et al., developed fast dissolving tablet of cinnarizine. A combination of superdisintegrants, i.e., sodium starch glycolate (SSG) and crosscarmellose sodium (CCS) wereused along with camphor as a subliming material. An optimized concentration of camphorwas added to aid the porosity of the tablet. A 32 full factorial design was applied to investigate the combined effect of two formulation variables: Amount of SSG and CCS. Infrared (IR)spectroscopy was performed to identify the physicochemical interaction between drug and polymer. IR spectroscopy had showed that there is no interaction of drug with polymer. In that study, direct compression was used to prepare the tablets. The powder mixtures were compressed into tablet using flat face multi punch tablet machine. Camphor was sublimed from the tablet by exposing the tablet to vacuum drier at 60°C for 12 hours. All the formulations were evaluated for their characteristics such as average weight, hardness, wetting time, friability, content uniformity, and dispersion time (DT), and dissolution rate. Conclusion ; An optimized tablet formulation (F 9) was found to have good hardness of 3.30 ± 0.10 kg/cm2, wetting time of 42.33 ± 4.04 seconds, DT of 34.67 ± 1.53 seconds, and cumulative drug release of not less than 99% in 16 minutes5. 3. Mothilal M et al., formulated and evaluated orally disintegrating tablets of rizatriptan benzoate. Formulation research was oriented towards safety, efficacy and quick onset of action of existing drug molecule through novel concepts of drug delivery. Orally disintegrating tablets of Rizatriptan benzoate were prepared by direct compression method to provide faster relief from pain to migraine sufferers. About twelve formulations for the present study were carried out based on 2 level 2 factor full factorial design for each set of superdisintegrants. Croscarmellose sodium, Crospovidone and Sodium starch glycolate (SSG) were used as superdisintegrants, while microcrystalline cellulose was used as diluent. The prepared batches of tablets were evaluated for weight variation, hardness, friability, wetting time, invitro dispersion time, drug content and invitro dissolution studies. Conclusion: The formulation containing combination of Croscarmellose sodium and Sodium starch glycolate showed rapid invitro dispersion time as compared to other formulations. The optimized formulation dispersed in 8 seconds. It also showed a higher water absorption ratio and 99.58% of drug is released within 2 minutes6.

4. Ravi kumar et al., isolated and evaluated the disintegrating properties of fenugreek seed mucilage. Mucilage extracted from fenugreek seeds were subjected to toxicity studies, it showed that extracted mucilage is devoid of toxicity. Fast disintegrating tablet (FDT) of metformin HCl was formulated using different concentrations(2, 4,6, 8 and 10% w/w) of natural disintegrant viz; isolated mucilage of fenugreek seed and synthetic superdisintegrants like croscarmellose sodium and were compared. Disintegration time and drug relese were taken as the basis to optimize the rapidly disintegrating tablet. Prepared tablets were evaluated for thickness, hardness, friability, uniformity, of weight, disintegration time, wetting time, and dissolution study. The formulated tablet had good appearance and better drug relese properties as compared to the marketed conventional tablets. Fenugreek mucilage in the concentration of 4% gives shorter disintegration in 15 sec. and shows 100% drug release within 18 min. is selected as the optimized formulation (f2). Hence, the present study revealed that this natural disintegrant (fenugreek mucilage) showed better disintegrating property than the most widely used synthetic superdisintegrants like ac-di-sol in the formulation of FDTs. Studies indicated that the extracted mucilage is a good pharmaceutical adjuvant, specifically a disintegrating agent. Optimized formulation was subjected to stability studies as per ICH guidelines at 25 C and 65%RH, 4O and 75% RH showed insignificant change in hardness, disintegration time and in vitro drug release at the end of three months7.

6. Nitin Bansal et al., formulated and evaluated the orally disintegrating tablets of ondansetron HCl using natural Superdisintegrants. Tablets containing the drug were prepared by dry granulation method using different concentrations of superdisintegrants such as modified gum karaya, modified natural agar, crosscarmellose sodium and sodium starch glycollate. The formulations were evaluated for weight variation, hardness, friability, drug content, wetting time, in vitro disintegration time and in vitro dissolution study. The results showed that modified gum karaya and modified natural agar produce rapid disintegration of tablets.The optimized formulation showed acceptable physical characteristics. The optimized batch produced complete drug release within 6 minutes. The incorporation of clove oil provided additional properties such as symptomatic relief from nausea and vomiting, good mouth feel and taste masking. Kinetic analysis showed that drug release from optimized formulation was adequately described by first order release kinetics. Conclusion: Modified gum karaya and modified natural agar can be used as an alternative superdisintegrants to commonly available synthetic and semisynthetic superdisintegrants due to their low cost, biocompatibility as well as easily availability.8

7.Jani Girish K et al., studied about new superdisintegrants (agar gum and modified agar gum) for dispersible tablets. A 3 2 Factorial design was used to optimize process variable i.e. amount of distilled water and its temperature on swelling characterstics of A and GK respectively. Selected forms of MA and MGK were characterized for their intrinsic properties in comparision with A and GK respectively. Formulations contains MA(7.5%) and MGK (7.5%) showed faster disintegration time 14 sec and 18 sec compared with A and GK. The study revealed that both modified forms of agar and karanya gum could be used as super disintegrating agents at 7.5% w/w concentration9. 8. K.P.R. Chowdary et al., studied natural superdisintegrants changed scenario and there latest advances in pharmacy field. They were studied about modified traganth as a super disintegrating in tablet formulations. Modified traganth exhibited swelling index of 1,011% in water. Tablets formulated employing modified traganth as disintegrants fulfilled all official requirements and disintegrated rapidly in 2 min. Modified traganth was found to be an excellent super disintegrants in tablets and also suitable for wet addition10.

9. Snehalatha et al., formulated and evaluated the Piroxicam dispersible tablets using natural disintegrants (cross linked trigacanth). Six batches of Piroxicam dispersible tablets were prepared by using various natural disintegrating agents in order to get required theoretical release profilies. The influence of the disintegrant concentration and granulation technique on the release of Piroxicam was studied. The formulated batches were characterized by different physical parameters. The study reveals that the formulation prepared by direct compression F5 exhibits better dissolution, disintegration at low concentration of natural disintegrants. Physical parameters of all the formulated tablets were within the acceptable limits.

ENCLOSURE-III

6.3) Objective of the study: The present study is planned with the following objectives: Pre formulation:  To develop discriminative dissolution medium for rizatriptin benzoate.  To study the effect of pH. on solubility of rizatriptin benzoate.  To extract and purify natural polymers from their biological source.  To study the effect of particle size on solubility of rizatriptin benzoate  To perform the compatibility studies of drug with excipients. Formulation: To formulate oral dispersible tablets of rizatriptan benzoate. More rapid drug absorption from the pre-gastric area i.e. mouth, pharynx and oesophagus which may produce rapid onset of action. Convenience of administration and accurate dosing as compared to liquid formulations. Evaluation of pre-compression parameters consists of:  Bulk Density  Tapped density  Carr’s index  Hausner ratio  Angle of repose  FT-IR Spectroscopy Evaluation of Post-Formulation consists of:  Tablet dimensions  Drug content uniformity  Weight variation  Tablet hardness  Friability testing  Wetting time and water absorption ratio  In vitro dispersion time  Disintegration time  In vitro drug release studies  The prepared tablets compared with marketed product  Stability studies b) Materials and methods: Active Drug (rizatriptam), superdisintegrants (Agar gum, fenugreek seeds mucilage, Traganth gum) Excipients : The excipients aspartame, mannitol, colloidal anhydrous silica and lactose monohydrate will be used for its sweeteners, diluents and flow properties. The trusil lemon limeASV, peppermint powder used as flavors and quinoline yellows, ferric oxide red used for its colouring property, magnesium stearate will be used for lubricant, micro crystalline cellulose will be used as a bulking agent. Equipment UV Visible Spectrophotometer (HACH, model-DR/4000u); Dissolution Tester (PHARMA TEST, model-DT 70); Disintegration Tester (PHARMA TEST, D-63512); Hardness Tester (PHARMA TEST, Germany); Friability Tester (PHARMA TEST, Germany); Electric Balance (Denver Instrument, model-M-310); Digital pH Meter (LIDA Instrument, model-PHS-25); Single Punch Tablet Press (Cadmach, India). Methodology: Direct compression process will be selected for these formulations, because porous nature will be more in direct compression blend than wet granulation blend. So, it will give faster disintegration. After

compression the tablets will be subjected to sublimation at 60⁰ C for 6 hrs in vacuum oven.

Extraction of mucilage from fenugreek seeds The seeds will be powdered using pestle and mortar and 100 g of the powder will be extracted with hexane to remove lipophilic compounds using a soxhelet apparatus. To remove pigments and to deactivate enzyme, the defatted powder will be boiled in ethanol for 20 min. This treated powder will be then soaked in 10 liters water and the pH is adjusted to 3.5 using 0.5 M Hydrochloric acid. The mixture will be stirred by a mechanical stirrer for 12 h and then filtered through filtration paper. The filtrate will be centrifuged (5000 RPM) and the supernatant will be concentrated in vacuum to 50% of its initial volume. The resulting solution will be mixed with the same volume of 96% ethanol and stored in a refrigerator for 4 h. The precipitated mucilage will be separated by centrifugation (5000 RPM). The collected mucilage will be re-suspended in distilled water, agitated for 20 min and re-precipitated one more time to eliminate chloride ions and other impurities. Finally the residue will be washed with diethyl ether and acetone and dried overnight at 45°C, resulting in an off-white powder. PREPARATION OF TREATED AGAR: Agar suitable quantity of agar powder(5-10)g weighed and added in distilled water(100ml). agitation is done continuously by a stirrer for one day to swell. The swollen contents are dried on a tray for 3 days at room temperature. The dried powders are grinded by mortar and pestle. Then grinded powder is passed through sieve no .1oo. . 3.PREPARATION OF MODIFIED TRAGACANTH :

Tragacanth(5g), tween80(0.05)g and hydrogen peroxide (30%w/v) solution (1ml) were taken in 100 ml of purified water and boiled for 15 min. The mixture was allowed to cool and settle. The clear supernatant fluid was decanted and the sediment was washed repeatedly with water. Finally the sediment was collected by centrifuging at 2500RPM and dried at 80 c for 4 hrs. The dried product was ground to fine powder and passed through mesh no.200

7.1) Source of data:

Data is collected from:

 RGUHS Library.  Science direct & other internet facilities.  National and international research and review publications.  Poster presentations.  Textbooks and reference books.

ENCLOSURE-V 7.2) Method of collection of data:

Standardization, selection, process development, stabilization of polymer and preparation of

RizatriptanOD tablets.

Evaluation of precompression and post compression parameters for developed formulations is as follows:

Pre compression parameters:  Angle of repose

 Bulk density

 Tapped density

 FT-IR Spectroscopy

 Compressibility index

Post compression parameters:

 Tablet dimensions  Drug content uniformity  Weight variation  Tablet hardness  Friability testing  Wetting time and water absorption ratio  In vitro dispersion time  Disintegration time  In vitro drug release studies  The prepared tablets compared with marketed product  Stability studies

7.3 Does the study require any investigation or interventions to be conducted on patients of humans or animals? If so, please describe briefly.

------NO------

7.4 Has ethical clearance been obtained from your institution in case of 7.3?

------NOT APPLICABLE------

c) List of references:

List of References :

1. Nlm.nih.gov. Migraine: MedlinePlus. [Online] Available from: http://www.nlm.nih.gov/medlineplus/migraine.html [Accessed 29 Dec 2013].

2. Dailymed.nlm.nih.gov. DailyMed. [Online] Available from: http://dailymed.nlm.nih.gov [Accessed 29 Dec 2013].

3. Prakash P, Chaudhry S, Porwal M, Vishwakarma DK. Natural Superdistegrant: Recent Investigation and Current Approaches. Pharm Sci Monitor 2011:2014-2026.

4. Keny R, Desouza C, Lourenco C. Formulation and evaluation of rizatriptan Benzoate mouth disintegrating tablets. Indian journal of pharmaceutical sciences. 2010; 72 (1): 79

5. Chang R, Guo X, Burnside B, Couch R. A review of fast dissolving tablets. Pharm Tech North Am. 2000;12:52–8. 6. Mothilal. M*, Srikanth Kota, Sivagirish babu G, Gnanendra Kumar, Manimaran. V and Damodharan. N “Formulation and evaluation of Rizatriptan Benzoate Orally Disintegrating Tablets”, Int. J. Drug Dev. & Res., April-June 2012, 4(2): 117-123

7. Ravi Kumar, Swati Patil, Patil M.B, Sachin Patil R , Mahesh Paschapur S. Isolation and Evaluation of Disintegrant Properties of Fenugreek Seed Muciliage. International Journal of PharmaTech Research. 1(4);2009:982-996.

8. Nitin Bansal, Govind Sharma. Formulation and Evaluation of orally disintegrating tablets of Ondansetron Hydrochloride using Natural Superdisintegrants. International Journal of PharmTech Research. Vol.3,No.3,pp 1616-1621, July-Sept 2011

9. Jani girish K, G. Jitendra, P. Vipul kumar. Studies on formulation and evaluation of new super disintegrants for dispersible tablets. International journal of pharmaceutical excepients. 2005; April- June issue:37-43

10. Chowdary K.P.R, Murali Krishna M.N, Tripura Sundari P. Evaluation of modified tragacanth as superdisintegrant in tablets. International Journal of Pharmaceutical Excepients. Vol:5(2);April-June 2006:49-52

11. Snehalatha.,Lakshmi Radhika.,Yogananda R. Formulation and Evaluation of Piroxicam dispersible tablets using Natural disintegrants.J.Pharm. Sci.& Res. Vol.1(4),2009,146-150

12. B.Dhandapani, N.Anjaneyulu, Y.Venkateshwarlu and Shaik Harun Rasheed. HPTLC Method Development and Validation for the Simultaneous Estimation of Amlodepine Besylate and Nebivolol Hydrochloride in tablet dosage form. Journal of Pharmacy Reserch.2010;3(2):332-334

13. V.C.Chandini, K.R. Gupta, C.T.Chopde. Simultaneous Uv-Spectrophotometric Determination Of Amlodepine Besylate And Nebivolol Hydrochloride In Tablet Dosage Form.Int.J.Chemtech Res.2010;2(1):69-73

14. www.fda.gov.

15. Sanders-Bush E, Mayer SE. 5-hydroxytryptamine (Serotonin): Receptor agonists & antagonists. In: Brunton LL, Lazo JS, Parker KL, editors. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw Hill; 2006. p. 305–9.