Comparative Effect of Physiological Salts upon Micellization of T1304 and T1307.

We present a comprehensive investigation on the interaction of tetronics (T1304 and T1307) with some important physiological salts (NaH2PO4, KH2PO4, Na2CO3, NaCl, and KI). Thermodynamic and microstructural aspects of these interactions were studied as a function of the solution temperature, pH and salt concentration. Characterizations were performed using turbidimetric, calorimetric, and scattering techniques. We show that, at ambient temperature, T1304 molecules aggregated to form spherical core-shell aggregates displaying a unimodal distribution pattern. On the other hand, unimers and large clusters dominated in the case of highly hydrophilic T1307. Its micellization was promoted in the presence of salts as per the following trend: NaCl < KH2PO4 < NaH2PO4 ≪ Na2CO3. Aggregation was found to be endothermic, and hydrophobic interactions (TΔSmic > ΔHmic) prevailed. The enthalpy-entropy compensation plot was found to be linear for both copolymers. Demicellization occurred in the presence of KI as it facilitated the buildup of water structures around the copolymer chains. This could be verified from the increase in the cloud point, critical micelle concentration, and free energy. Overall, the temperature and salts inflicted a stronger hydrophobic effect upon T1304 in comparison to T1307.

Non-ionic Surfactants as a P-Glycoprotein(P-gp) Efflux Inhibitor for Optimal Drug Delivery-A Concise Outlook.

Significant research efforts have been devoted to unraveling the mystery of P-glycoprotein(P-gp) in drug delivery applications. The efflux membrane transporter P-gp is widely distributed in the body and accountable for restricting drug absorption and bioavailability. For these reasons, it is the primary cause of developing multidrug resistance (MDR) in most drug delivery applications. Therefore, P-gp inhibitors must be explored to address MDR and the low bioavailability of therapeutic substrates. Several experimental models in kinetics and dynamic studies identified the sensitivity of drug molecules and excipients as a P-gp inhibitor. In this review, we aimed to emphasize nonionic surface-active agents for effective reversal of P-gp inhibition. As it is inert, non-toxic, noncharged, and quickly reaching the cytosolic lipid membrane (the point of contact with P-gp efflux protein) enables it to be more efficient as P-gp inhibitors. Moreover, nonionic surfactant improves drug absorption and bioavailability through the various mechanism, involving (i) association of drug with surfactant improves solubilization, facilitating its cell penetration and absorption; (ii) weakening the lateral membrane packing density, facilitating the passive drug influx; and (iii) inhibition of the ATP binding cassette of transporter P-glycoprotein. The application of nonionic surfactant as P-gp inhibitors is well established and supported by various experiments. Altogether, herein, we have primarily focused on various nonionic surfactants and their development strategies to conquer the MDR-causing effects of P-gp efflux protein in drug delivery. Graphical Abstract.

Amalgamation of Solid Dispersion and Melt Adsorption Technique: Improved In Vitro and In Vivo Performance of Ticagrelor Tablets.

Ticagrelor (TG) suffers from low peroral bioabsorption (36%) due to P-gp efflux and poor solubility (10 µg/mL). TG solid dispersion adsorbates (TG-SDAs) were formulated using an amalgamation of solid dispersion and melt adsorption techniques which were simple, economic, scalable, and solvent-free. FTIR indicated no incompatibility between drug and excipients. DSC, XRD, and SEM suggested a reduction in TG crystallinity. Q30min from TG-SUSP and TG-conventional tablets was only 2.30% and 6.59% respectively whereas TG-SDA-based tablets exhibited a significantly higher drug release of 86.47%. Caco-2 permeability studies showed 3.83-fold higher permeability of TG from TG-SDAs. TG-SDA-based tablets exhibited relative bioavailability of 748.53% and 153.43% compared to TG-SUSP and TG-conventional tablets respectively in rats. TG-SDA-based tablets were devoid of any cytotoxicity as indicated by MTT assay and exhibited better antiplatelet activity in rats. Enhanced oral bioavailability of TG-SDAs can be attributed to inhibition of P-gp efflux by PEG 4000, increased wettability, and reduced crystallinity of drug leading to improved drug solubility and dissolution. Improved bioabsorption results in a reduction of dose, cost of therapy as well as dose-related side effects. Thus, SDAs can be considered a promising and scalable approach for the improvement of dissolution rate and solubility of TG. TG-SDAs can be translated to an effective and safe dosage form, whereby its rapid onset of action promotes the prevention of heart attack, stroke, and related ill events in individuals with the acute coronary syndrome. However, scale-up, validation, and clinical-studies are necessary for confirmation of the proof-of-concept.

PLGA Nanoparticles for Nose to Brain Delivery of Clonazepam: Formulation, Optimization by 32 Factorial Design, In Vitro and In Vivo Evaluation.

BACKGROUND: Intranasal administration of biodegradable nanoparticles has been extensively studied for targeting the drug directly to CNS through the olfactory or trigeminal route bypassing the blood brain barrier. OBJECTIVE: The objective of the present study was to optimize Clonazepam loaded PLGA nanoparticles (CLO-PNPs) by investigating the effect of process variables on the responses using 32 full factorial design. METHODS: Effect of two independent factors-amount of PLGA and concentration of Poloxamer 188, were studied at low, medium, and high levels on three dependent responses-%Entrapment efficiency, Particle size (nm), and % cumulative drug release at 24hr. RESULTS: %EE, Particle size, and %CDR at 24hr of the optimized batch was 63.7%, 165.1 nm, and 86.96%, respectively. Nanoparticles were radiolabeled with 99mTc and biodistribution was investigated in BALB/c mice after intranasal and intravenous administrations. Significantly higher brain/blood uptake ratios and AUC values in the brain following intranasal administration of CLO-PNPs indicated more effective brain targeting of CLO. Higher brain uptake of intranasal CLO-PNPs was confirmed by rabbit brain scintigraphy imaging. A histopathological study performed on goat nasal mucosa revealed no adverse response of nanoparticles. TEM image exhibited spherical shaped particles in the nano range. DSC and XRD studies suggested Clonazepam encapsulation within the PLGA matrix. The onset of occurrence of PTZ-induced seizures in rats was significantly delayed by intranasal nanoparticles as compared to intranasal and intravenous CLO-SOL. CONCLUSION: This investigation exhibits rapid rate and higher extent of CLO transport in the brain with intranasal CLO-PNPs suggesting a better option as compared to oral and parenteral route in the management of acute status epilepticus.

Synthesis, Colloidal Characterization and Targetability of Phenylboronic Acid Functionalized α-Tocopheryl Polyethylene Glycol Succinate in Cancer Cells.

This study reports targetable micelles developed after covalent functionalization of α-tocopheryl polyethylene glycol succinate (TPGS) with amino phenylboronic acid (APBA). Nuclear magnetic resonance (NMR) and infrared (IR) spectroscopic results showed successful attachment of APBA to the hydrophilic segment of TPGS. Dynamic light scattering and small-angle neutron scattering studies revealed that the conjugate self-assembled in water to produce spherical core-shell micelles (14-20 nm) which remained stable against temperature (ca. 25-45 °C) and pH changes. The micelles could solubilize a high payload of paclitaxel (PLX) without exhibiting changes in the average size. However, at the saturation solubility, drug molecules migrated from the core to the shell region and engaged with APBA groups via π-π stacking interaction. Confocal microscopy and cell sorting analyses verified the effective translocation ability of TPGS-APBA micelles in sialic acid (SA) expressing MDA-MB-453 cells. At equivalent PLX dose, TPGS-APBA micelles showed about a twofold improvement in apoptotic death among the cells exposed for 2 h. Our findings indicate that the attachment of APBA can be a potential strategy for improving the intra-cellular localization of carriers among cancer cells expressing SA residues.