Almotriptan Research Articles

Development of Almotriptan Malate Biodegradable Nanoparticles Loaded for Treatment of Migraine

Development of Almotriptan Malate Biodegradable Nanoparticles Loaded for Treatment of Migraine

Design and Characterization of pH Dependent Phase Transition System of Almotriptan Malate for Nasal Drug Delivery System by Employing Factorial Design

Design and Characterization of pH Dependent Phase Transition System of Almotriptan Malate for Nasal Drug Delivery System by Employing Factorial Design

QuEChERS-assisted ion pair chromatography/fluorescence detection method for determination of antimigraine combination therapy in rabbit plasma samples: Application to a pharmacokinetic study

Antimigraine combination therapy has shown significant effectiveness in relieving pain, as well as reducing the frequency, duration, and severity of migraine attacks if compared to a single migraine medication. This work represents the first analytical investigation for emphasizing the synergistic effect of combining ophthalmic beta blockers with triptans in migraine treatment. The presented study was conducted to investigate the pharmacokinetic profile of almotriptan (ALM), a serotonin (5-HT1B/1D) receptor agonist used to treat migraine, when coadministered with timolol (TIM) or verapamil (VER) which are considered as an adjuvant therapy in migraine prevention. Ion pair chromatography (IPC) with online fluorescence detection was applied to simultaneously detect and quantify the binary mixtures of ALM/TIM and ALM/VER in rabbit plasma samples. The separation was achieved using a Platinum C18 analytical column with a mobile phase composed of methanol: 35 mmol L-1 phosphate buffer solution containing 10 mmol L-1 SDS at pH = 6.8 (60:40 v/v). Several parameters were evaluated during the optimization of separation conditions including mobile phase composition, buffer concentration, buffer pH and concentration of ion pair reagent. A thorough investigation of the retention mechanism was performed, and the results showed that Coulomb forces were the main contributors to the overall retention mechanism, which may be hydrophobically assisted. QuEChERS extraction technique was utilized to extract the investigated drugs from plasma samples and a detailed study was carried out to optimize partition/extraction solvents, pH, extraction salts, sample volume and clean-up step. The method had a limit of detection and quantitation of 5.6 and 16.9 ng mL-1 for ALM in ALM/TIM mixture and 2.5 and 7.6 ng mL-1 for ALM in ALM/VER mixture, with an overall recovery not less than 95.22%. This newly proposed method offers a faster alternative to existing chromatographic methods for extraction and determination of ALM in binary mixtures with TIM or VER in rabbit plasma and provides a platform for studying pharmacokinetic parameters. The coadministration of either TIM or VER with ALM resulted in a notable rise in Cmax (maximum plasma concentration) and AUC (area under the plasma concentration-time curve) of ALM, implying possible alterations in the absorption and overall exposure of ALM.

In Vivo Evaluation of Almotriptan malate Formulation through Intranasal Route for the Treatment of Migraine: Systematic Development and Pharmacokinetic Assessment.

Migraine headaches are usually intolerable, and a quick-relief treatment remains an unmet medical need. Almotriptan malate is a serotonin (5-HT1B/1D) receptor agonist approved for the treatment of acute migraine in adults. It is currently available in an oral tablet dosage form and has a Tmax of 1-3h, and therefore, there is a medical need to develop a non-invasive rapidly acting formulation. We have developed an intranasal formulation of almotriptan malate using the quality-by-design (QbD) approach. A 2-factor 3-level full factorial design was selected to build up the experimental setting. The developed formulation was characterized for pH, viscosity, in vitro permeation, ex vivo permeation, and histopathological tolerance. To assess the potential of the developed formulation to produce a rapid onset of action following intranasal delivery, a pharmacokinetic study was performed in the Sprague-Dawley rat model and compared to the currently available marketed oral tablet formulation. For this, the LC-MS/MS bioanalytical method was developed and used for the determination of plasma almotriptan malate concentrations. Results of a pharmacokinetic study revealed that intranasal administration of optimized almotriptan malate formulation enabled an almost five-fold reduction in Tmax and about seven-fold increase in bioavailability in comparison to the currently available oral tablet formulation, suggesting the potential of developed almotriptan malate intranasal formulation in producing a rapid onset of action as well as enhanced bioavailability.

Formulation and Evaluation of Mouth Dissolving Tablet of Almotriptan Malate

Mouth dissolving tablet disintegrates and dissolves rapidly in the saliva, within a few seconds without the need of drinking water or chewing. A mouth dissolving tablet usually dissolves in the oral cavity within 15 seconds to 3 minutes. Almotriptan malate is an anti migraine drug with bitter taste and shows hepatic metabolism. In the present work, Mouth dissolving tablets of almotriptan malate were prepared by direct compression method using sodium starch glycolate and croscarmellose sodium as superdisintegrant with a view to enhance patient compliance and to avoid gastric dysmotility which is common with migraine drugs and for fast action of drug. The prepared batches of tablets were evaluated for hardness, friability, drug content uniformity, wetting time, water-absorption ratio and in-vitro dispersion time. Short-term stability studies on the promising formulation indicated that there are no significant changes in drug content and disintegration time. Keywords: Almotriptan malate, Superdisintegrant, Sodium starch glycolate, Crosscarmellose sodium, Taste masking.

SIMPLE RP-HPLC METHOD DEVELOPMENT FOR THE ESTIMATION OF ALMOTRIPTAN MALATE IN NASAL IN-SITU FORMULATION

For the determination of Almotriptan malate in bulk and produced nasal in situ formulation, a new sensitive and quick HPLC technique was developed and validated according to ICH guidelines. The HPLC analysis was carried out using a waters system with a Thermo Scientific C18 (250 cm 4.6 mm) 5 m column and a mobile phase of acetonitrile: 20Mm KH2PO4 in an 80:20 v/v ratio, at a flow rate of 1.0mL/min. The detection was done at a wavelength of 282, and Almotriptan malate had a retention time of 5.658 minutes. The total time spent running was 10.0 minutes. Over the concentration range of 2-10 g/ml, the calibration plot revealed a linear relationship. The LOD and LOQ were 0.12 and 0.35μg, respectively. The accuracy of the proposed method was determined by recovery studies and was found to be near to 100 and % RSD value was found less than 2. The repeatability testing for both standard and sample solutions showed that the method is precise within the acceptable limits. RSD% of the determination of precision was less than 2%. The proposed method showed excellent linearity, accuracy, precision, specificity, LOD, LOQ, and system suitability results within the acceptance criteria. In addition, the main features of the developed method are low run time and retention time around 5 min.

Thermosensitive mucoadhesive in situ gel for intranasal delivery of Almotriptan malate: Formulation, characterization, and evaluation

The present investigation deals with development, characterization, and evaluation of thermosensitive in-situ nasal gel of Almotriptan malate (selective serotonin 5-HT1 receptor agonist), serving as a substitute for drug delivery to the brain. Gels were prepared by cold technique varying the concentration of Pluronics (PF127 and PF68) and carboxymethyl chitosan as thermoreversible and mucoadhesive polymers respectively. Drug content before and after gelation was ranged between 96.42-98.92% and 95.8–98.66% respectively. The pH value was observed in the range of 5.56–6.31. Notably, the results obtained were in agreement with the phase transition and formulations exhibited pseudoplastic rheology. Mucoadhesive strengths of all the formulations increased with the chitosan concentration and were in the range of 3300–5193.65 dyn/cm2. The in-vitro drug diffusion data of the optimized formulation i.e. 17% w/v PF127, 2% w/v PF68, 0.1% w/v carboxymethyl chitosan, revealed 89.36% release at the end of 6 h. Histopathological studies confirmed the non-toxic effect of optimized formulation on the microscopic structure of nasal mucosa during ex-vivo permeation studies. Short term stability study exhibited 4±1 °C as an appropriate storage condition for the formulations. In nutshell, a thermosensitive in-situ gel of Almotriptan malate can be intended as an effective approach of migraine treatment.

A New Spectrophotometric Method for the Estimation of Almotriptan Malate in Tablets Using Metol - Cr (VI) Reagent

A New Spectrophotometric Method for the Estimation of Almotriptan Malate in Tablets Using Metol - Cr (VI) Reagent

Development, Characterization & Statistical Optimization of Matrix Type Transdermal Patches of Almotriptan Malate for The Treatment of Migraine

Development, Characterization & Statistical Optimization of Matrix Type Transdermal Patches of Almotriptan Malate for The Treatment of Migraine

Estimation of Almotriptan malate in tablets by sensitive Visible Spectrophotometric method

Estimation of Almotriptan malate in tablets by sensitive Visible Spectrophotometric method

Design and Characterization of Biodegradable Chitosan Nanoparticles Loaded With Almotriptan Malate For Migraine Therapy

Design and Characterization of Biodegradable Chitosan Nanoparticles Loaded With Almotriptan Malate For Migraine Therapy

A novel nasal almotriptan loaded solid lipid nanoparticles in mucoadhesive in situ gel formulation for brain targeting: Preparation, characterization and in vivo evaluation

This work aimed at designing efficient safe delivery system for intranasal (IN) brain targeting of the water soluble anti- migraine drug Almotriptan malate (ALM). Solid lipid nanoparticles (SLNs) were prepared by w/o/w double emulsion-solvent evaporation method. Selection of the optimized SLNs formula was based on evaluating particle size (PS), poly dispersity index (PDI) and entrapment efficiency (%EE). Optimized formula exhibited acceptable ranges; PS of 207.9 nm, PDI of 0.41 and %EE of 50.81%. Poloxamer 407 (Plx) at different concentrations (16%, 18%, 20% w/v), with different mucoadhesive polymers (Carbopol-974P, Na alginate, Na-CMC) were evaluated for gelling time and temperature, pH and mucoadhesion. The chosen mucoadhesive in-situ gel formula; 18% Plx 407 based-0.75%w/v Na-CMC, showed acceptable results, so that the optimized SLNs formula was further dispersed in it and evaluated for in vitro release, stability, in vivo and pharmacokinetics studies. Biomarkers’ evaluation and histopathological examination were also investigated. Results revealed rapid ALM brain delivery of the optimized formula; Brain/blood ratios at 10 min. for NF (SLNs based IN in-situ gel), ND (Free ALM IN in situ gel) and ALM i.v. (ALM IV solution) were 0.89, 0.19 and 0.31, respectively. Toxicological results confirmed the safety of NF for nasal administration. The achieved out comings are encouraging for further clinical trials of the developed system in humans in future research.

Microneedle-assisted delivery of anti-migraine drugs across porcine skin: almotriptan malate and naratriptan hydrochloride

Microneedle-assisted delivery of anti-migraine drugs across porcine skin: almotriptan malate and naratriptan hydrochloride

Spectrophotometric Determination of Certain Antimigraine Drugs in Pharmaceutical Formulations Using p-Chloranil Reagent; Application to Content Uniformity Testing

A sensitive, simple and reliable spectrophotometric method has been developed for determination of definite anti-migraine drugs namely; Almotriptan malate, Rizatriptan benzoate, Sumatriptan succinate and Zolmitriptan in their pharmaceutical preparations. The suggested procedure is based on charge transfer complexation of the cited antimigraine drugs with tetrachloro-1, 4-benzoquinone (p-chloranil). The formed charge transfer complex was measured spectrophotometrically at 558 nm. Beer’s law was obeyed in concentration ranges of 80-850, 70-650, 50-450 and 50-400 μg ml-1, for Almotriptan malate, Rizatriptan benzoate, Sumatriptan succinate and Zolmitriptan, respectively. The detection limits were 16.54, 12.43, 11.28 and 11.06 ug ml-1 while quantitation limits were 50.12, 37.68, 34.19 and 33.53 μg ml-1 for Almotriptan malate, Rizatriptan benzoate, Sumatriptan succinate and Zolmitriptan, respectively. The suggested assay has been validated according to ICH and USP guidelines and favorably has been applied to determination of cited drugs in their dosage forms and content uniformity testing.

FORMULATION DEVELOPMENT AND EVALUATION OF FAST DISSOLVING TABLET OF TRIPTAN DRUG

Almotriptan malate is a triptan class anti-migraine drug with rapid action, highest bioavailability and low side effects. Fast dissolving tablets of almotriptan malate were prepared by wet granulation technique using sodium starch glycolate, Crosscarmellose sodium and Crosspovidone (2%, 4%, and 6%), respectively, FT-IR spectroscopy and differential scanning calorimetry were used to investigate the physical characteristics of the drug. The granules were examined for angle of repose, bulk density, tapped density, index and Hausner’s ratio. Developed tablets were evaluated for hardness, drug content, friability, wetting time, wetting absorption ratio, in vitro drug release and disintegration time. Formulation with 4% crosspovidone showed disintegration time of 21.5 sec. In vitro dissolution studies showed drug release of 94.66% after 12 minutes. The drug release from the formulation followed zero order kinetics. The optimized formulation was found to be promising and can be considered for further study.

Development and validation of a liquid chromatography-tandem mass spectrometric assay for quantitative analyses of triptans in hair.

Triptans are specific drugs widely used for acute treatment of migraine, being selective 5HT1B/1D receptor agonists. A proper assumption of triptans is very important for an effective treatment; nevertheless patients often underuse, misuse, overuse or use triptans inconsistently, i.e., not following the prescribed therapy. Drug analysis in hair can represent a powerful tool for monitoring the compliance of the patient to the therapy, since it can greatly increase the time-window of detection compared to analyses in biological fluids, such as plasma or urine. In the present study, a liquid chromatography-tandem mass spectrometric (LC-MS/MS) method has been developed and validated for the quantitative analysis in human hair of five triptans commonly prescribed in Italy: almotriptan (AL), eletriptan (EP), rizatriptan (RIZ), sumatriptan (SUM) and zolmitriptan (ZP). Hair samples were decontaminated and incubated overnight in diluted hydrochloric acid; the extracts were purified by mixed-mode SPE cartridges and analyzed by LC-MS/MS under gradient elution in positive multiple reaction monitoring (MRM) mode. The procedure was fully validated in terms of selectivity, linearity, limit of detection (LOD) and lower limit of quantitation (LLOQ), accuracy, precision, carry-over, recovery, matrix effect and dilution integrity. The method was linear in the range 10-1000pg/mg hair, with R(2) values of at least 0.990; the validated LLOQ values were in the range 5-7pg/mg hair. The method offered satisfactory precision (RSD <10%), accuracy (90-110%) and recovery (>85%) values. The validated procedure was applied on 147 authentic hair samples from subjects being treated in the Headache Centre of Modena University Hospital in order to verify the possibility of monitoring the corresponding hair levels for the taken triptans.

Validation of Rapid and Sensitive Spectrofluorimetric Assay for Determination of Four Triptans in Pure and Dosage Forms; Application to Human Plasma and Content Uniformity Testing

A sensitive, simple, rapid and reliable spectrofluorimetric assay was developed for the assay of definite antimigraine drugs namely; Almotriptan malate, Rizatriptan benzoate, Sumatriptan succinate and Zolmitriptan in their pharmaceutical preparations and biological fluid. The suggested procedure was established on determination of the quenching process resulting from the action of the studied drugs on the native fluorescence of Eosin Y via developing of a binary complex reaction between the cited antimigraine preparations and Eosin Y in 0.2 M acetate buffer (pH.3.5). Under the optimized experimental conditions, the relative fluorescence capacity was determined at λex=301.3 nm and λem=542.8 nm. The calibration graphs were linear through extent from 0.07-1.0, 0.20-1.0, 0.2-1.0 and 0.1-1.0 μg/mL, for Almotriptan malate, Rizatriptan benzoate, Sumatriptan succinate and Zolmitriptan, respectively. The detection limits were 0.019, 0.041, 0.055 and 0.032 μg/mL while quantitation limits were 0.059, 0.125, 0.168 and 0.096 μg/mL for Almotriptan malate, Rizatriptan benzoate, Sumatriptan succinate and Zolmitriptan, respectively. The suggested assay has been validated according to ICH and USP guidelines and favorably has been applied to assay of cited drugs in their dosage forms and content uniformity testing. The high sensitivity of the developed assay allowed quantification of the studied antimigraine drugs in human plasma.

An integrated quality by design and mixture-process variable approach in the development of a capillary electrophoresis method for the analysis of almotriptan and its impurities

The development of a capillary electrophoresis (CE) method for the assay of almotriptan (ALM) and its main impurities using an integrated Quality by Design and mixture-process variable (MPV) approach is described. A scouting phase was initially carried out by evaluating different CE operative modes, including the addition of pseudostationary phases and additives to the background electrolyte, in order to approach the analytical target profile. This step made it possible to select normal polarity microemulsion electrokinetic chromatography (MEEKC) as operative mode, which allowed a good selectivity to be achieved in a low analysis time. On the basis of a general Ishikawa diagram for MEEKC methods, a screening asymmetric matrix was applied in order to screen the effects of the process variables (PVs) voltage, temperature, buffer concentration and buffer pH, on critical quality attributes (CQAs), represented by critical separation values and analysis time. A response surface study was then carried out considering all the critical process parameters, including both the PVs and the mixture components (MCs) of the microemulsion (borate buffer, n-heptane as oil, sodium dodecyl sulphate/n-butanol as surfactant/cosurfactant). The values of PVs and MCs were simultaneously changed in a MPV study, making it possible to find significant interaction effects. The design space (DS) was defined as the multidimensional combination of PVs and MCs where the probability for the different considered CQAs to be acceptable was higher than a quality level π=90%. DS was identified by risk of failure maps, which were drawn on the basis of Monte-Carlo simulations, and verification points spanning the design space were tested. Robustness testing of the method, performed by a D-optimal design, and system suitability criteria allowed a control strategy to be designed. The optimized method was validated following ICH Guideline Q2(R1) and was applied to a real sample of ALM coated tablets.

Gellan gum-based mucoadhesive microspheres of almotriptan for nasal administration: Formulation optimization using factorial design, characterization, and in vitro evaluation.

Background:Almotriptan malate (ALM), indicated for the treatment of migraine in adults is not a drug candidate feasible to be administered through the oral route during the attack due to its associated symptoms such as nausea and vomiting. This obviates an alternative dosage form and nasal drug delivery is a good substitute to oral and parenteral administration.Materials and Methods:Gellan gum (GG) microspheres of ALM, for intranasal administration were prepared by water-in-oil emulsification cross-linking technique employing a 23 factorial design. Drug to polymer ratio, calcium chloride concentration and cross-linking time were selected as independent variables, while particle size and in vitro mucoadhesion of the microspheres were investigated as dependent variables. Regression analysis was performed to identify the best formulation conditions. The microspheres were evaluated for characteristics such as practical percentage yield, particle size, percentage incorporation efficiency, swellability, zeta potential, in vitro mucoadhesion, thermal analysis, X-ray diffraction study, and in vitro drug diffusion studies.Results:The shape and surface characteristics of the microspheres were determined by scanning electron microscopy, which revealed spherical nature and nearly smooth surface with drug incorporation efficiency in the range of 71.65 ± 1.09% – 91.65 ± 1.13%. In vitro mucoadhesion was observed the range of 79.45 ± 1.69% – 95.48 ± 1.27%. Differential scanning calorimetry and X-ray diffraction results indicated a molecular level dispersion of drug in the microspheres. In vitro drug diffusion was Higuchi matrix controlled and the release mechanism was found to be non-Fickian. Stability studies indicated that there were no significant deviations in the drug content, in vitro mucoadhesion and in vitro drug diffusion characteristics.Conclusion:The investigation revealed promising potential of GG microspheres for delivering ALM intranasally for the treatment of migraine.

Highly sensitive spectrofluorimetric method for the determination of two antimigraine drugs in their tablets and in biological fluids. Application to content uniformity testing

A highly sensitive and simple spectrofluorimetric method has been developed for the determination of almotriptan malate (ALM) and zolmitriptan (ZOL) in their pharmaceutical preparations. The proposed method is based on the investigation of the fluorescence spectral behavior of the two drugs in aqueous acidic systems. The fluorescence intensity was measured at 360 and 350 nm after excitation at 270 nm for ALM and ZOL, respectively. The fluorescence–concentration plots were rectilinear over the range 0.1–1.2 μg mL−1 and 5–40 ng mL−1, with lower detection limits of 0.03 μg mL−1 and 0.70 ng mL−1 for ALM and ZOL, respectively. The proposed method was successfully applied for the assay of commercial tablets as well as for content uniformity testing. The application of the proposed method was extended to the assay of ZOL in biological fluids. The results were statistically compared to those obtained by comparison methods and were found to be in good agreement.