Potential herb-drug interaction risk of thymoquinone and phenytoin.

Thymoquinone is a main bioactive compound of Nigella sativa L. (N.sativa), which has been used for clinical studies in the treatment of seizures due to its beneficial neuroprotective activity and antiepileptic effects. It has been evidenced that thymoquinone may inhibit the activity of cytochrome P450 2C9 (CYP2C9). However, little is known about the effect of thymoquinone or N.sativa on the pharmacokinetic behavior of phenytoin, a second-line drug widely used in the management of status epilepticus. In this study, we systematically investigated the risk of the potential pharmacokinetic drug interaction between thymoquinone and phenytoin. The inhibitory effect of thymoquinone on phenytoin hydroxylation activity by CYP2C9 was determined using UPLC-MS/MS by measuring the formation rates for p-hydroxyphenytoin (p-HPPH). The potential for drug-interaction between thymoquinone and phenytoin was quantitatively predicted by using in vitro-in vivo extrapolation (IVIVE). Our data demonstrated that thymoquinone displayed effective inhibition against phenytoin hydroxylation activity. Enzyme kinetic studies showed that thymoquinone exerted a competitive inhibition against phenytoin hydroxylation with a Ki value of 4.45 ± 0.51 µM. The quantitative prediction from IVIVE suggested that the co-administration of thymoquinone (>18 mg/day) or thymoquinone-containing herbs (N.sativa > 1 g/day or N.sativa oil >1 g/day) might result in a clinically significant herb-drug interactions. Additional caution should be taken when thymoquinone or thymoquinone-containing herbs are co-administered with phenytoin, which may induce unexpected potential herb-drug interactions via the inhibition of CYP2C9.

Three-ply biocompatible pH-responsive nanocarriers based on HNT sandwiched by chitosan/pectin layers for controlled release of phenytoin sodium.

Today, efficient straightforward biocompatible drug carriers have revoluted advanced drug delivery systems. The study aims to investigate the modification of halloysite nanotubes by chitosan (CTS) and pectin (PCN) for forming a new pH-sensitive bionanocomposites via Layer-by-Layer method. The main objective of this study is to improve loading efficiency and control release of phenytoin sodium (PHT) prepared in various pH. The formation of nanocomposite was confirmed through using FTIR, zeta-potential, TG, SEM, XRD, and UV spectroscopy analyses. Based on the obtained results, HNT/CTS/PCN nanocomposite prepared with the molar ratio of 2:1:2 had the best loading capacity (34.6 mg/g) compared with pure HNT (18.3 mg/g). In-vitro studies showed that prepared bionanocomposites had a low release of PHT in the simulated gastric fluid while having a more controlled release in the simulated intestinal fluid. Because of the loading efficiency and controlled release profile, the composites exhibited great potential for the controlled drug delivery of PHT.

Protein-based fluorescent metal nanoclusters for small molecular drug screening.

A facile drug screening method based on synthesis of fluorescent gold nanoclusters inside albumin proteins loaded with small molecular drugs and comparing the relative fluorescence intensities of the resultant gold nanoclusters has been developed and successfully applied for the quantitative measurement of drug-protein binding constants.

Preliminary anticonvulsant and toxicity screening of substituted benzylidenehydrazinyl-N-(6-substituted benzo[d]thiazol-2-yl)propanamides.

Keeping in view the structural requirements suggested in the pharmacophore model for anticonvulsant activity, a new series of 3-(2-(substitutedbenzylidene)hydrazinyl)-N-(substituted benzo[d]thiazol-2-yl)-propanamides were synthesized with aromatic hydrophobic aryl ring (A), NH-C=O as hydrogen bonding domain (HBD), nitrogen atom as electron donor (D), and phenyl as distal aryl ring (C). Synthesized compounds were characterized by FTIR, (1)H NMR, (13)C NMR, mass spectroscopy, and elemental analysis. Preliminary in vivo anticonvulsant screening (phase I) was performed by two most adopted seizure models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ). Based on anticonvulsant screening results, two compounds, 5h and 5p, were found to be most active; they exhibited activity comparable to standard drugs phenytoin (PHY) and carbamazepine (CBZ). These active compounds were subjected to phase II and phase III screening, where they displayed much higher protective index (PI) in comparison to the standard drugs. In phase IV screening, the bioavailability of active compounds was assessed on oral administration. Further, preliminary safety profiles of 5h and 5p were evaluated by the neurotoxicity testing and liver enzyme estimation.

Universal wet-milling technique to prepare oral nanosuspension focused on discovery and preclinical animal studies - Development of particle design method.

Simple and easy methods to prepare oral nanosuspension of a poorly water-soluble pharmaceutical candidate compound, called a candidate, have been developed to support the discovery and preclinical studies using animals. The different wet-milling processes in miniature, middle and large preparation scales have been established in order to cover the various types of studies with wide scale. The powder of phenytoin, a poorly water-soluble model drug candidate, was suspended in the aqueous medium, in which the appropriate dispersing agents were dissolved, and milled by agitating together with small hard beads made of zirconia. Three general-purpose equipments with stirring, oscillating and turbulent motions were applied instead of the specific milling machine with high power to avoid much investment at such early development stage. The operational condition and dispersing agents were optimized to obtain finer particles using the middle-scaled oscillating beads-milling apparatus in particular. It was found that the nanosuspension, which whole particle distribution was in the submicron range, was successfully produced within the running time around 10min. By applying the newly developed dispersing medium, the nanoparticles with identical size distribution were also prepared using the stirring and turbulent methods on miniature and large scales, respectively; indicating only 50mg to 30g or more amount of candidate could be milled to nanosuspension using three equipments. The crystalline analysis indicated that the both crystal form and crystallinity of the original bulk drug completely remained after wet-milling process. The results demonstrated that the wet-milling methods developed in this research would be a fundamental technique to produce nanosuspension for poorly water-soluble and oral absorbable drug candidates.

Semisolid matrix filled capsules: an approach to improve dissolution stability of phenytoin sodium formulation.

Seven semisolid fill bases were selected for the formulation of 24 capsule formulations, each containing 100 mg of phenytoin sodium. The fill materials were selected based on the water absorption capacity of their mixtures with phenytoin sodium. The fill matrices included lipophilic bases (castor oil, soya oil, and Gelucire (G) 33/01), amphiphilic bases (G 44/14 and Suppocire BP), and water-soluble bases (PEG 4000 and PEG 6000). The drug:base ratio was 1:2. Excipients such as lecithin, docusate sodium, and poloxamer 188 were added to some formulations. The dissolution rate study indicated that formulations containing lipophilic and amphiphilic bases showed the best release profiles. These are F4 (castor oil-1% docusate sodium); F10 (castor oil-3% poloxamer 188); F14 (G33/01-10% lecithin); F17 (G33/01-1% docusate sodium), and F20 (Suppocire BP). Further, the dissolution stability of the five formulations above was assessed by an accelerated stability study at 30 degrees C and 75% RH using standard Epanutin capsules for comparison. The study included the test and standard capsules either packed in the container of marketed Epanutin capsules (packed) or removed from their outer pack (unpacked). Release data indicated superior release rates of castor oil based formulations (F4 and F10) relative to standard capsules in both the unpacked and packed forms. For instance, the extent of drug release at 30 min after 1 month was 91% for F4 and F10 and 20% for standard capsules. Drug release from packed capsules after 6 months storage was 88% for both formulations F4 and F10 and 35% for standard capsules. In conclusion, the pharmaceutical quality of phenytoin sodium capsules can be improved by using a semisolid lipophilic matrix filled in hard gelatin capsules.

Compatibility and pH variability of four injectable phenytoin sodium products.

The interlot variability in apparent pH of injectable phenytoin sodium products and the compatibility and stability of phenytoin sodium in admixtures of these products in 0.9% sodium chloride injection were studied. Dilantin (Parke-Davis) and three generic products (Elkins-Sinn, Lyphomed, Solopak) were used. Six lots of each product were diluted to 9.2 and 18.4 mg/mL concentrations. The apparent pH values of undiluted lots and diluted product admixtures were measured. Phenytoin concentrations in the admixtures were measured by turbidimetric immunoassay. Concentration and pH were measured immediately after admixture and at 0.5, 1, and 2 hours; samples were examined for crystallization at each time, and portions were filtered to determine differences in drug concentration between the filtered and unfiltered samples. The Dilantin lots had the lowest interlot variability and significantly higher mean +/- S.D. apparent pH (12.00 +/- 0.06) than the Solopak (11.38 +/- 0.33), Elkins-Sinn (11.39 +/- 0.21), and Lyphomed (11.68 +/- 0.36) products. The apparent admixture pH was significantly higher for Dilantin than for the other products. No crystallization occurred in the Dilantin admixtures; crystallization varied in the other products. Filtration did not significantly alter phenytoin concentrations. No significant differences were detected in phenytoin concentrations between products or sampling times. Interlot variability in pH was lowest for Dilantin, and apparent pH values of the undiluted products and in the admixtures at both drug concentrations were significantly higher for Dilantin than for the other products. Microscopic evidence of physical incompatibility was noted in some generic product lots with lower apparent pH values. Stability of phenytoin in the admixtures over two hours was demonstrated for all four phenytoin sodium injectable products studied.