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.

No published experience exists with almotriptan during breastfeeding. If almotriptan is required by the mother, it is not a reason to discontinue breastfeeding; however, alternate drugs may be preferred, especially while nursing a newborn or preterm infant.

A practical palladium-mediated cascade Tsuji-Trost reaction/Heck coupling of N-Ts o-bromoanilines with 4-acetoxy-2-butenonic acid derivatives using a Pd(OAc)2/P(o-tol)3/DIPEA system is described for a straightforward synthesis of indole-3-acetic acid derivatives. This methodology was successfully applied to synthesize various substituted indole/azaindole-3-acetic acid derivatives and Almotriptan, which is a drug for the acute treatment of migraines. Moreover, a plausible cyclization mechanism has been proposed.

Almotriptan maleate (ALMT), a highly selective 5-hydroxy tryptamine 1B/1D (5-HT1B/1D) receptor agonist used in the treatment of migraine headache was subjected to various ICH (Q1A (R2)) specified guidelines. The drug underwent significant degradation under hydrolytic (acid, base and neutral), oxidative and photolytic stress conditions, while it was stable under thermal stress condition. A total of seven significant degradation products (DPs) were obtained. A simple, selective and reliable UPLC method has been developed for the separation of ALMT and its DPs using Acquity UPLC HSS Cyano (100 × 2.1 mm, 1.8 μm) column with mobile phase consisting of ammonium acetate (10 mM, pH 4.4) buffer and acetonitrile in gradient elution mode. Chromatographic analysis was performed at a flow rate of 0.3 mL/min using a PDA detector at a wavelength of 230 nm. All the DPs (DP-1 to DP-7) were characterized using UHPLC-ESI-QTOF based on mass fragmentation pattern and accurate m/z values. The developed UPLC method was validated in terms of specificity, linearity, precision and accuracy. The developed stability-indicating method helps in quantification of drug in the presence of DPs.

Migraine is a common neurovascular disorder, affecting millions of people worldwide. Current guidelines recommend triptans as first-line treatment for moderate-to-severe migraine attacks. Frovatriptan is a second-generation triptan with a longer terminal elimination half-life in blood than other triptans (~26 hours). Three double-blind, randomized crossover preference studies have been recently conducted, assessing efficacy and safety of frovatriptan versus rizatriptan, zolmitriptan, and almotriptan, respectively. Frovatriptan showed favorable tolerability and sustained effect, with a significantly lower rate of relapse over 48 hours versus the other triptans. These findings were confirmed in a series of analyses of patient subsets from the three studies, including patients with menstrually related and oral contraceptive-induced migraine, hypertension, obesity, weekend migraine, as well as patients with migraine with aura. In all patient subsets analyzed, lower headache recurrence rates were observed versus the comparator triptans, indicating a more sustained pain-relieving effect on migraine symptoms. A further randomized, double-blind study demonstrated that frovatriptan given in combination with the fast-acting cyclooxygenase inhibitor dexketoprofen provided improved migraine pain-free activity at 2 hours, and gave more sustained pain-free activity at 24 hours, versus frovatriptan alone. These benefits were observed both when the combination was administered early (<1 hour after symptom onset) or late (>1 hour after onset). Different pharmacokinetic, but synergistic, properties between frovatriptan and dexketoprofen may make the combination of these agents particularly effective in migraine treatment, with rapid onset of action and sustained effect over 48 hours. These benefits, together with potential cost-effectiveness advantages versus other triptans could drive selection of the most appropriate treatment for acute migraine attacks.