Formulation of sumatriptan succinate orodispersible tablets using chitosan and sodium starch glycolate for immediate migraine relief.

Migraine is one of the common neurological disease affecting around 23% of the Pakistani population. Prompt treatment is required to regain the functional ability of patients. The present study was designed to develop sumatriptan succinate orodispersible tablets that would quickly overcome acute migraine episodes using 22 full-factorial design. The chitosan and sodium starch glycolate were taken as independent variables; friability, disintegration, dispersion time and water absorption ratio as response variables. Eight trial formulations were generated by Design Expert® software. The main effect plots were used to check the interaction of formulations with response variables. All trial formulations showed good micromeritic properties in terms of angle of repose (19.59o-24.57°), Carr's index (17.08-24.90%) and Hausner's ratio (1.20-1.33). The tablets wetted quickly (17.1- 39 sec) in dispersion medium, showed higher water absorption ratio (188-341 sec) and disintegrated quickly (13-20 sec) with an excellent dissolution rate (94-99%). The main effect plots show interactions between the independent variables against most of the study responses. A 22 full-factorial model was found to be effective in studying the influence of formulation variables on response parameters. Both chitosan and sodium starch glycolate can be used in combination to fabricate an effective orodispersible formulation of sumatriptan succinate.

Intranasal drug delivery of sumatriptan succinate-loaded polymeric solid lipid nanoparticles for brain targeting.

Migraine is a frequent neurological condition characterized by throbbing headaches, nausea, photophobia, and phonophobia, among other symptoms. Sumatriptan belongs to a BCS class III, which exhibits poor oral bioavailability and several side-effects. The objective of the present study was to develop solid lipid nanoparticles (SLNPs) of sumatriptan succinate for brain targeting by nasal route. Solvent injection method was used to increase the entrapment efficiency of hydrophilic drug. Thus, formulation was optimized by central composite design with minimum particle size, optimized zeta potential, and maximum entrapment efficiency, which was found to be 133.4 nm, -17.7 mV, and 75.5%, respectively. Optimized batch was further evaluated for surface morphology, Fourier-transform infrared spectroscopy, in vitro release, permeation across nasal mucosa, and histopathology. It was seen that most of the particles were spherical in shape as confirmed by scanning electron microscopy and transmission electron microscopy. The release of drug through the lipid showed initial burst release followed by sustained release up to 12 h. The ex vivo diffusion study using goat nasal mucosa at pH 6.8 revealed that SLNPs permeation across nasal mucosa was quick, which was sufficient for brain targeting. Histopathology studies further revealed integrity of nasal mucosa after treatment with SLNPs. The investigation indicated that hydrophilic drug, sumatriptan succinate can be successfully entrapped in SLNPs to target brain via nasal delivery, and thus it could be an effective approach for nose-to-brain delivery.

Simultaneous quantification of sumatriptan succinate and prochlorperazine maleate in orodispersible films using two validated UV-spectroscopic methods.

The study aimed at simultaneous quantification of sumatriptan succinate (SUM) and prochlorperazine maleate (PCP) in an orodispersible film using two validated spectroscopic methods viz. simultaneous equation (Method I) and the Q-absorption ratio (Method II). The Method I involved measurement of absorbances at λmax of both drugs while in Method II, absorbances were measured at isosbestic wavelength and λmax of one of the two components. Method validation were accomplished as per the ICH guidelines. A 1:1 mixture of the drugs and an orodispersible film (ODF) containing these drugs were assayed by both methods. The absorbance data of SUM and PCP in both methods were linear at respective wavelengths with correlation coefficient values >0.995. Both methods were precise as % RSD in repeatability, interday and intraday precision was less than 2. The estimation of SUM and PCP from the film dosage form by method I was104.74% and 98.34% and by method II was 103.45% and 98.85%, respectively, with a standard deviation <2. The study concluded that both the methods were simple, reliable and robust and can be applied successfully for the simultaneous quantification of SUM and PCP in mixture and orodispersible film dosage form.

Formulation of instant disintegrating buccal films without using disintegrant: An in-vitro study.

The current study was conducted to fabricate Metoclopramide HCL (MCH) and Sumatriptan succinate (SS) instant release buccal films (IRBF) without using any super disintegrant. The solvent casting method was used for the preparation of IRBFs and prepared IRBFs were physicochemically evaluated. Spectrophotometric analysis was done to determine the lambda max followed by the linearity determination of both drugs. Different concentrations such as 100, 125, and 150mg of hydrophilic polymer (HPMC E5) were employed but the concentration of glycerol was variable. Comparatively better results were observed for the formulation with 150mg of HPMC E5 and 30% glycerol. Formulated IRBFs showed good tensile strength with a mean disintegration time of 12.4-28.4 seconds and rapid dissolution with more than 50% drug release within 2 minutes. It was concluded that the chosen combination of polymers was appropriate for the fabrication of MCH and SS buccal strips.

Fabrication of polyvinyl alcohol based fast dissolving oral strips of sumatriptan succinate and metoclopramide HCL.

Migraine is a throbbing condition, usually associated with nausea and vomiting and requires concurrent administration of anti-migraine along with anti-emetic therapy. The current study was undertaken with an aim to fabricate fast dissolving oral strips (FDOSs) containing Sumatriptan succinate (anti-migraine) and Metoclopramide HCl (anti-emetic) in combination without involving any superdisintegrant. Hydrophilic polymer polyvinyl alcohol (PVA) was used alone with three concentrations of 100, 125, and 150 mg using variable concentrations of glycerol. The solvent casting technique was employed to formulate FDOSs and were evaluated for surface morphology, mechanical properties, surface pH, % moisture content, disintegration time (DT), total dissolving time (TDT), drug contents, and dissolution profile. PVA (150 mg) with 5% glycerol concentration gave best formulation results. FDOSs have exhibited good tensile strength with smooth and uniform surface morphology. DT was ranged from 7.7 to 28 s; while TDT was from 26.4 to 77.6 s. Both polymer and plasticizer concentrations were found to be influencing the characteristics of the strips. Dissolution studies were carried out in distilled water for 15 min and all the formulations have shown released more than 50% drug within first 2 min thereby highlighting the usefulness of FDOSs for the delivery of both drugs in combination significantly. Optimized combination of ingredients was found to be suitable for the formulation of FDOSs for simultaneous delivery of Metoclopramide HCl and Sumatriptan succinate.

Combining nuclear magnetic resonance with molecular dynamics simulations to address sumatriptan interaction with model membranes.

The goal of this work is to obtain a complete map on the interactions between sumatriptan, an amphiphilic ionizable anti-migraine drug, with lipid bilayers. To this end, we combined two physico-chemical techniques - nuclear magnetic resonance and molecular dynamics simulations - to obtain a detailed picture at different pH values. Both approaches were used considering the strength and constraints of each one. NMR experiments were performed at pH 7.4 where at least 95% of the drug molecules are in their protonated state. From NMR, sumatriptan shows partition on the interfacial region of model membranes (near the head groups and intercalating between adjacent lipids), inducing changes in chemical environment and affecting lipid dynamics of liposomes, in a dose dependent manner. Due to the experimental instability of lipid bilayers at high pH, we took advantage of the molecular dynamics power to emulate different pH values, to simulate sumatriptan in bilayers including at fully uncharged state. Simulations show that the neutral species have preferential orientation within the bilayer interface while the distribution of protonated drugs is independent on the initial conditions. In summary, several properties depicted the interfacial partition of the anti-migraine drug at the water-lipid interface at different conditions. Both techniques were found complementary to shed light on the structural and dynamics of sumatriptan-lipid bilayer interactions.

Enhanced pharmacological efficacy of sumatriptan due to modification of its physicochemical properties by inclusion in selected cyclodextrins.

The study focused on the pharmacological action of sumatriptan, in particular its antiallodynic and antihyperalgesic properties, as an effect of cyclodextrinic inclusion of sumatriptan, resulting in changes of its physicochemical qualities such as dissolution and permeability through artificial biological membranes, which had previously been examined in vitro in a gastro-intestinal model. The inclusion of sumatriptan into ß-cyclodextrin and 2-hydroxylpropylo-ß-cyclodextrin by kneading was confirmed with the use of spectral (fourier-transform infrared spectroscopy (FT-IR); solid state nuclear magnetic resonance spectroscopy with magic angle spinning condition, 1H and 13C MAS NMR) and thermal (differential scanning calorimetry (DSC)) methods. A precise indication of the domains of sumatriptan responsible for its interaction with cyclodextrin cavities was possible due to a theoretical approach to the analysis of experimental spectra. A high-performance liquid chromatography with a diode-array detector method (HPLC-DAD) was employed to determine changes in the concentration of sumatriptan during dissolution and permeability experiments. The inclusion of sumatriptan in complex with cyclodextrins was found to significantly modify its dissolution profiles by increasing the concentration of sumatriptan in complexed form in an acceptor solution compared to in its free form. Following complexation, sumatriptan manifested an enhanced ability to permeate through artificial biological membranes in a gastro-intestinal model for both cyclodextrins at all pH values. As a consequence of the greater permeability of sumatriptan and its increased dissolution from the complexes, an improved pharmacological response was observed when cyclodextrin complexes were applied.

Modelling the in-vitro dissolution and release of sumatriptan succinate from polyvinylpyrrolidone-based microneedles.

A mathematical model was developed to predict the transport of sumatriptan molecules across the skin followed by absorption into the bloodstream. The drug was encapsulated in dissolving polyvinylpyrrolidone-based microneedles shaped in the form of pyramids. Mass balance equations were derived to simulate the dissolution and transport of the pharmaceutical ingredient. The theoretical framework made it possible to assess and predict the effects of key parameters on the release profile. The skin concentration increased with the loading dose and the height of the microneedle. An inverse relationship was noted between the amount of drug released in the dermal layer and the pitch width. These results were validated with in-vitro diffusion studies previously conducted using Göttingen minipig skin. The new mathematical approach successfully explained the in-vitro permeation of three different sumatriptan-containing formulations.

Identification and characterization of stress degradation products of sumatriptan succinate by using LC/Q-TOF-ESI-MS/MS and NMR: Toxicity evaluation of degradation products.

Sumatriptan succinate, a selective 5-HT1B receptor agonist, was subjected to forced degradation studies as per to International Conference on Harmonization-specified conditions. The drug exclusively showed its degradation under basic, photolytic, and oxidative stress conditions, whereas it was found to be stable under acidic, thermal, and neutral conditions. Eight (DP-1 to DP-8) degradation products were identified and characterized by UPLC-ESI/MS/MS experiments combined with accurate mass measurements. The effective chromatographic separation was achieved on Hibar Purospher STAR, C18 (250 × 4.6 mm, 5 µm) column using mobile phase consisting of 0.1% formic acid and methanol at a flow rate of 0.6 mL/minute in gradient elution method. It is noteworthy that 2 major degradation products DP-3 and DP-7 were isolated using preparative HPLC and characterized by advanced NMR experiments. The degradation pathway of the sumatriptan was established, which was duly justified by mechanistic explanation. In vitro cytotoxicity of isolated DPs was tested on normal human cells such as HEK 293 (embryonic kidney cells) and RWPE-1 (normal prostate epithelial cells). This study revealed that they were nontoxic up to 100 µm concentration. Further, in silico toxicity of the drug and its degradation products was determined using ProTox-II prediction tool. This study revealed that DP-4 and DP-8 are predicted for immune toxicity. Amine oxidase A and prostaglandin G/H synthase 1 are predicted as toxicity targets for DP-3, DP-4, and DP-6 whereas DP-1 and DP-2 are predicted for amine oxidase A target.

A sumatriptan coarse-grained model to explore different environments: interplay with experimental techniques.

In this work, we developed a coarse-grained model of sumatriptan suitable for extensive molecular dynamics simulations. First, we confirmed the interfacial distribution of this drug in bilayers through cryogenic transmission electron microscopy and small-angle X-ray scattering techniques, as was predicted by our previous atomistic simulations. Based on these simulations, we developed a coarse-grained model for sumatriptan able to reproduce its overall molecular behavior, captured by atomistic simulations and experiments. We then tested the sumatriptan model in a micellar environment along with experimental characterization of sumatriptan-loaded micelles. The simulation results showed good agreement with photon correlation spectroscopy and electrophoretic mobility experiments performed in this work. The particle size of the obtained micelles was comparable with the simulated ones; meanwhile, zeta-potential results suggest adsorption of the drug on the micellar surface. This model is a step forward in the search for a suitable drug-delivery system for sumatriptan.

Small-Dosing Clinical Study: Pharmacokinetic, Pharmacogenomic (SLCO2B1 and ABCG2), and Interaction (Atorvastatin and Grapefruit Juice) Profiles of 5 Probes for OATP2B1 and BCRP.

The aims of this study were (1) to investigate the effects of atorvastatin (10 mg, therapeutic dose) and grapefruit juice (GFJ), inhibitors of OATP2B1, on the pharmacokinetics of substrates for OATP2B1 and BCRP under oral small-dosing conditions (300 µg sulfasalazine, 250 µg rosuvastatin, 300 µg glibenclamide, 1200 µg celiprolol, and 600 µg sumatriptan), and (2) to evaluate the contribution of SLCO2B1*3 and ABCG2 c.421C>A polymorphisms to the pharmacokinetics of the 5 test drugs in 23 healthy volunteers. In the 3 phases, the test drugs were administered to volunteers with either water (control phase), atorvastatin, or GFJ. GFJ but not atorvastatin reduced the exposure of the test drugs significantly more than the control phase, suggesting that all 5 test drugs are substrates for OATP2B1. The SLCO2B1*3 genotype had no effect on the pharmacokinetics of the test drugs. In contrast, the exposure of sulfasalazine and rosuvastatin was significantly higher in ABCG2 421C/A than in ABCG2 421C/C individuals at all 3 phases, even under small-dosing conditions.

Comparative Study Between Different Ready-Made Orally Disintegrating Platforms for the Formulation of Sumatriptan Succinate Sublingual Tablets.

Sumatriptan succinate (SS) is a selective serotonin receptor agonist used for the treatment of migraine attacks, suffering from extensive first-pass metabolism and low oral bioavailability (∼14%). The aim of this work is to compare the performance of different ready-made co-processed platforms (Pharmaburst®, Prosolv ODT®, Starlac®, Pearlitol Flash®, or Ludiflash®) in the formulation of SS sublingual orodispersible tablets (ODTs) using direct compression technique. The prepared SS ODT formulae were evaluated regarding hardness, friability, simulated wetting time, and in vitro disintegration and dissolution tests. Different mucoadhesive polymers-HPMC K4M, Carbopol®, chitosan, or Polyox®-were tested aiming to increase the residence time in the sublingual area. A pharmacokinetic study on healthy human volunteers was performed, using LC/MS/MS assay, to compare the optimum sublingual formula (Ph25/HPMC) with the conventional oral tablet Imitrex®. Results showed that tablets prepared using Pharmaburst® had significantly (p < 0.05) the lowest simulated wetting and in vitro disintegration times of 17.17 and 23.50 s, respectively, with Q 5 min of 83.62%. HPMC showed a significant (p < 0.05) increase in the residence time from 48.44 to 183.76 s. The relative bioavailability was found to be equal to 132.34% relative to the oral tablet Imitrex®. In conclusion, Pharmaburst® was chosen as the optimum ready-made co-processed platform that can be successfully used in the preparation of SS sublingual tablets for the rapid relief of migraine attacks.

A Comparative Study of Orally Delivered PBCA and ApoE Coupled BSA Nanoparticles for Brain Targeting of Sumatriptan Succinate in Therapeutic Management of Migraine.

PURPOSE: The present investigation aimed at brain targeting of sumatriptan succinate (SS) for its optimal therapeutic effect in migraine through nanoparticulate drug delivery system using poly (butyl cyanoacrylate) (PBCA) and bovine serum albumin linked with apolipoprotein E3 (BSA-ApoE). METHOD: The study involved formulation optimization of PBCA nanoparticles (NPs) using central composite design for achieving minimum particle size, maximum entrapment efficiency along with sustained drug release. SS incorporated in BSA-ApoE NPs (S-AA-NP) were prepared by desolvation technique and compared with SS loaded polysorbate 80 coated optimized PBCA NPs (FPopt) in terms of their brain uptake potential, upon oral administration in male Wistar rats. The NPs were characterized by FTIR, thermal, powder XRD and TEM analysis. RESULTS: The in vivo studies of FPopt and S-AA-NP on male Wistar rats demonstrated a fairly high brain/plasma drug ratio of 9.45 and 12.67 respectively 2 h post oral drug administration. The behavioural studies on male Swiss albino mice affirmed the enhanced anti-migraine potential of S-AA-NP than FPopt (P < 0.001). CONCLUSION: The results of this work, therefore, indicate that BSA-ApoE NPs are significantly better than polysorbate 80 coated PBCA NPs for brain targeting of SS (P < 0.05) and also offer an improved therapeutic strategy for migraine management.

Amorphous Protic Ionic Systems as Promising Active Pharmaceutical Ingredients: The Case of the Sumatriptan Succinate Drug.

In this article, we highlight the benefits coming from the application of amorphous protic ionic systems as active pharmaceutical ingredients (APIs). Using the case of the sumatriptan (STR) drug, we show that the conversion of nonionic API to partially ionized amorphous protic succinate salt (STR SUCC) brings a substantial improvement in apparent solubility. Since in general the disordered systems reveal a tendency to self-arrangement during storage, the dominant part of this article is dedicated to the physical stability issue of sumatriptan and its ionic counterpart. To recognize the crystallization tendency of the studied systems, the calorimetric measurements were performed. Additionally, the role of ion dynamics in spontaneous nucleation of amorphous sumatriptan succinate is discussed. The differential scanning calorimetry analysis of ionic and nonionic sumatriptan reveals many similarities in thermal properties of these APIs as well as distinct differences in their resistance against crystallization in the supercooled liquid state. To determine the long-term physical stability of STR SUCC at room temperature conditions, the time scale of structural relaxation below their glass transition temperatures is estimated. We show that in contrast to nonionic materials, τα predictions of STR SUCC are much more complex and require aging experiments.

Sumatriptan succinate sublingual fast dissolving thin films: formulation and in vitro/in vivo evaluation.

Sumatriptan succinate (SS) is a 5-HT1 receptor agonist used in the treatment of migraine having poor bioavailability (15%) due to its extensive first-pass effect. The aim of this work was to prepare SS sublingual fast dissolving thin films (SFDTFs) allowing the drug to directly enter the systemic circulation and bypassing the first-pass metabolism. Plain thin films were prepared using solvent casting technique adopting 2(3) × 3 factorial design to study the effect of polymer and plasticizer type and concentration on mechanical properties and in vitro disintegration time of the plain prepared films using Design-Expert®. Medicated films were prepared after addition of 35 mg SS to each of the two selected plain formulae (F6 and F7) having desirability values above 0.9 showing the values of: 0.038, 0.039 kgf/mm(2) and 156.24, 164.16% and 0.0248, 0.0240 kgf/mm(2) as tensile strength, percent elongation and elastic modulus, respectively. PVP K30 was efficient as crystallization inhibitor in retarding SS crystallization. Pharmacokinetic study of the optimum formula F7 (PVP K30:SS (1:1 w/w)) in healthy human volunteers using LC/MS/MS revealed a shorter tmax (0.25 h) compared to Imitrex® tablet 25 mg (2 h) which is considered promising especially for the rapid relief of acute migraine attacks.

Non-ionic surfactants as novel intranasal absorption enhancers: in vitro and in vivo characterization.

OBJECTIVE: To explore the potential of non-ionic surfactants as novel intranasal absorption enhancers. METHODS: Taking sumatriptan succinate (SMS) as a model drug, influence of different non-ionic surfactants, including laurate sucrose ester (SE), cremophor EL and poloxamer 188, on the intranasal absorption of SMS was investigated using an in situ nasal perfusion technique in rats. Ciliotoxicity of the non-ionic surfactants was evaluated using an in situ toad palate model. In vivo behavior of the selected formulations was studied in rats. RESULTS: All the non-ionic surfactants investigated increased the intranasal absorption of SMS remarkably but with varied extent and trend. Moreover, it was revealed that at the same concentration, laurate SE had better permeation-enhancing effect than that of cremophor EL and poloxamer 188. The ciliotoxicity results showed that all the non-ionic surfactants were regarded as safe at selected concentrations. Based on the in situ absorption data and ciliotoxicity results, the following three samples, 0.5% laurate SE, 0.1% cremophor EL and 0.5% poloxamer 188 were selected for in vivo absorption studies in rats. Among them, 0.5% laurate SE group presented the highest enhancing effect, followed by 0.1% cremophor EL and 0.5% poloxamer 188 group, with absolute bioavailability 29.99%, 22.64% and 20.90%, respectively. CONCLUSIONS: Laurate SE is a promising intranasal absorption enhancer.

Sumatriptan succinate loaded chitosan solid lipid nanoparticles for enhanced anti-migraine potential.

The objective of the present investigation was to prepare chitosan solid lipid nanoparticles (SLN), containing sumatriptan succinate using solvent injection method and to optimize the formulations for brain targeting potential. The formulation optimization was performed using three factor two level full factorial design so as to minimize the particle size and zeta potential, maximize the entrapment efficiency as well as maximize the concentration of drug in brain with maximized brain/plasma ratio of the drug. The particle size, zeta potential and entrapment efficiency for all the batches were in the range of 192-301.4nm, 30.2-51.4mV and 76.3-91.1% respectively. The optimized formulation showed a 4.54-fold increase in brain/blood ratio of drug after 2h of drug administration in male Wistar rats. The optimized nanoparticles were characterized by FT-IR spectroscopy, DSC, TGA, powder X-ray diffraction study and TEM analysis. It could be elucidated from the experimental in vivo and behavioral studies that the formulations successfully crossed the blood brain barrier and significantly exhibited its anti-migraine activity. Present investigation indicated that the hydrophilic drug sumatriptan succinate, loaded in chitosan SLN, can be successfully targeted to brain via oral delivery and thus present an effective approach for the therapeutic management of migraine.

Application of design of experiment for polyox and xanthan gum coated floating pulsatile delivery of sumatriptan succinate in migraine treatment.

Migraine follows circadian rhythm in which headache is more painful at the awakening time. This needs administration of dosage form at night time to release drug after lag period when pain gets worse. Sumatriptan succinate is a drug of choice for migraine. Sumatriptan succinate has bitter taste, low oral bioavailability, and shorter half-life. Present work deals with application of design of experiment for polyox and xanthan gum in development of press coated floating pulsatile tablet. Floating pulsatile concept was applied to increase gastric residence of the dosage form. Burst release was achieved through immediate release tablet using crospovidone as superdisintegrant (10%). Pulse lag time was achieved using swellable polymer polyox WSR 205 and xanthan gum. 3(2) experimental design was applied. Optimized formulation was evaluated for physical characteristics and in-vitro and in-vivo study. From results, it can be concluded that optimized batch F8 containing polyox WSR205 (72.72%) and xanthan gum (27.27%) of total weight of polymer has shown floating lag time of 55 ± 2 sec, drug content of 100.35 ± 0.4%, hardness of 6 ± 0.1 Kg/cm(2), and 98.69 ± 2% drug release in pulse manner with lag time of 7 ± 0.1 h. Optimized batch showed prolong gastric residence which was confirmed by in-vivo X-ray study.

Triptan partition in model membranes.

In this work, we report a molecular dynamics simulations study of protonated triptans, sumatriptan and naratriptan, in a fully hydrated bilayer of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidyl-choline (POPC). The simulations were carried out at two concentrations for each drug. Our results show partition between the lipid head-water interphase and water phase for both triptans, with increasing access to the water phase with increasing concentrations. The triptans were stabilized at the interphase through different specific interactions with the POPC bilayer such as hydrogen bonds, salt bridges, and cation-π. Besides, sumatriptan and naratriptan protonated molecules have no access to the hydrophobic region of the bilayer at the studied conditions. Similar results were found for both drugs, however protonated naratriptan shows slightly higher affinity for the water phase. This behavior was attributed to the bulky lateral amino group in its structure under the studied conditions (drugs were originally placed at the water phase). This work represents a first insight to the comprehensive understanding of triptan partition in model membranes.

Development and optimization of press coated floating pulsatile drug delivery of sumatriptan succinate.

Floating pulsatile is combined approach designed according to circadian rhythm to deliver the drug at right time, in right quantity and at right site as per pathophysiological need of disease with prolong gastric residence and lag phase followed by burst release. As the migraine follows circadian rhythm in which headache is more painful at the awakening time, the dosage form should be given during night time to release drug when pain get worsen. Present work deals with formulation and optimization of floating pulsatile tablet of sumatriptan succinate. Core tablet containing crospovidone as superdisintegrant (10%) showed burst release. Lag time was maintained using swellable polymer as polyoxN12K and xanthum gum. 3(2) experimental design was carried out. Developed formulations were evaluated for physical characteristics, in vitro and in vivo study. Optimized batch F2 with concentration of polyox N12K (73.43%) and xanthum gum (26.56%) of total polymer weight showed floating lag time 15±2 sec, drug content 99.58±0.2 %, hardness 6±0.2 Kg/cm(2) and drug release 99.54±2% with pulsatile manner followed lag period of 7±0.1h. In vivo x-ray study confirms prolong gastric residence of system. Programmable pulsatile release has been achieved by formulation F2 which meet demand of chronotherapeutic objective of migraine.