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Rufinamide (Rufi) is an antiepileptic drug used to manage Lennox-Gastaut Syndrome and partial seizures. The oral bioavailability of Rufi is less due to its poor solubility and low dissolution rate in the gastrointestinal fluids. This results in less amount of drug reaching the brain following the oral administration of drug. Oral formulations of Rufi are prescribed at a high dose and dosing frequency to increase its distribution to the brain. A Rufi loaded thermoresponsive nasal in situ gel which showed significantly high brain concentrations compared to aqueous suspension of Rufi administered through nasal route was developed by our research group and published. In the current work, we have formulated nanocrystals of Rufi and suspended them in a xyloglucan based thermoresponsive gel to improve the nose-to-brain distribution. The particle size, polydispersity index, and yield (%) of the optimized Rufi nanocrystals were 261.2 ± 2.1 nm, 0.28 ± 0.08, and 89.6 ± 2.0 respectively. The narrow PDI indicates that the manufacturing process is reproducible and reliable. Higher % yield suggested that the method of preparation is efficient. The sol-to-gel transition of in situ gel loaded with Rufi nanocrystals was at 32°C which suggested that the formulation transforms into gel at nasal epithelial temperatures. The nasal pharmacokinetic studies showed that Rufi nanocrystals loaded in situ gel produced higher concentration of the drug in brain (higher brain Cmax) and maintained the drug concentrations for longer duration (higher mean residence time) compared to aqueous suspension of Rufi nanocrystals as well aqueous suspension of Rufi and Rufi loaded in situ gel, reported previously. Nanometric size of the Rufi nanocrystals combined with the in situ gelling properties helped the optimized formulation achieve higher brain distribution and also sustain the drug concentrations in brain for longer duration compared to any of the formulations studied by our research group. [ABSTRACT FROM AUTHOR]

In 2004, the US FDA approved Rufinamide, an anti-epileptic drug under the brand name Banzel®. In 2015, Banzel® received approval for its use in pediatric patients (ages 1–4 years). Rufinamide shows low oral bioavailability due to a low dissolution rate resulting in less of the drug reaching the brain. This has led to the high dose and dosing frequency of Rufinamide. In this work, using the principle of design of experiments (DoE), we have formulated Rufinamide-loaded chitosan nanoparticles and suspended them in a solution of a thermoresponsive polymer–tamarind seed xyloglucan to form a nasal in situ gel for direct nose to brain delivery of Rufinamide. The nanoparticles were characterized for particle size, entrapment efficiency, zeta potential, and physical stability. The in situ gel formulations were characterized for rheological properties, stability, and in vivo plasma and brain pharmacokinetics. Pharmacokinetic parameters were computed for aqueous suspension of nanoparticles and in situ gelling formulation for nanoparticles and compared with the pharmacokinetic parameters of an aqueous suspension of plain Rufinamide. The percentage of direct transport efficiency (% DTE) and direct transport percentage (%DTP) values were calculated for all the formulations. The optimized nanoparticle formulation showed a size of 180 ± 1.5 nm, a zeta potential of 38.3 ± 1.5 mV, entrapment efficiency of 75 ± 2.0%, and drug loading of 11 ± 0.3%. The in situ gelling formulation of nanoparticles showed a solution to the gel transition temperature of 32°C. The %DTE values for aqueous suspension of nanoparticles and in situ gelling formulation for nanoparticles were 988.5 and 1177.3 and the %DTP values were 86.06 and 91.5 respectively. [ABSTRACT FROM AUTHOR]

Cilnidipine (CND), an anti-hypertensive drug, possesses low oral bioavailability due to its poor aqueous solubility, low dissolution rate, and high gut wall metabolism. In the present study, an attempt has been made to prepare CND loaded polycaprolactone based nanoparticles (CND-PCL-NPs) by nanoprecipitation method applying the concepts of Design of Experiments. Critical factors affecting particle size and loading efficiency (LE%) were assessed by a hybrid design approach, comprising of Mini Run Resolution IV design followed by Box–Behnken design. Particle size, PDI, zeta potential and LE% of optimized formulations of CND-PCL-NPs were 220.3 ± 2.6 nm, 0.25 ± 0.1, −19.5 ± 0.9 mV, and 46.4 ± 1.8%, respectively. No significant changes were observed in the physical stability of nanoparticles when stored at 25 °C/60% RH over a period of 3 months. Oral pharmacokinetic studies revealed that Fabs of CND-PCL-NPs (0.55) were significantly higher than the CND suspension (0.26). Pharmacodynamic studies have revealed that the mean percent reduction in systolic blood pressure (% ΔSBP) was significantly higher in the case of CND-PCL-NPs (42%) as compared to CND suspension (24%). Optimized CND-PCL-NPs offer great potential in providing higher and sustained antihypertensive effect compared to conventional formulations of CND. Supplemental data for this article is available online at . [ABSTRACT FROM AUTHOR]

Objective: Design chitosan based nanoparticles for tenofovir disoproxil fumarate (TDF) with the purpose of enhancing its oral absorption. Significance: TDF is a prodrug that has limited intestinal absorption because of its susceptibility to gut wall esterases. Hence, design of chitosan based polymeric novel nanocarrier systems can protect TDF from getting metabolized and also enhance the oral absorption. Methods: The nanoparticles were prepared using the ionic gelation technique. The factors impacting the particle size and entrapment efficiency of the nanoparticles were evaluated using design of experiments approach. The optimized nanoparticles were characterized and evaluated for their ability to protect TDF from esterase metabolism. The nanoparticles were then studied for the involvement of active transport in their uptake during the oral absorption process. Further, in vivo pharmacokinetic studies were carried out for the designed nanoparticles. Results: The application of design of experiments in the optimization process was useful to determine the critical parameters and evaluate their interaction effects. The optimized nanoparticles had a particle size of 156 ± 5 nm with an entrapment efficiency of 48.2 ± 1%. The nanoparticles were well characterized and provided metabolic protection for TDF in the presence of intestinal esterases. The nanoparticles were able to increase the AUC of tenofovir by 380%. The active uptake mechanisms mainly involving clathrin-mediated uptake played a key role in increasing the oral absorption of tenofovir. Conclusions: These results show the ability of the designed chitosan based nanoparticles in enhancing the oral absorption of TDF along the oral route by utilizing the active endocytic uptake pathways. [ABSTRACT FROM AUTHOR]

1. The aim of this study was to evaluate the role of intestinal esterases on the absorption process of tenofovir disoproxil fumarate (TDF). 2. The esterase inhibition capacity of fruit juices (FJs) rich in ester linkages and pharmaceutical excipients (having ester bonds) was performedin vitroby incubating TDF with each FJ and excipient in the intestinal washings. Theex vivoeverted gut sac model was also used to evaluate the absorption enhancement capacity of these FJs and excipients. Single-dose oral pharmacokinetic studies were performed by concomitant administration of TDF with each of the selected FJs and excipients. 3. Thein vitroandex vivostudies showed that cremophor-EL and all FJs prevented the metabolism of TDF with grapefruit juice (GFJ) having the highest level of inhibition. Further, the permeability flux of the monoester form of tenofovir was increased by 113% and 212% by cranberry juice (CBJ) and GFJ, respectively. Thein vivostudies also showed that both CBJ and GFJ enhanced the oral bioavailability of TDF as the AUC was increased by 24% and 97%, respectively. 4. These results indicate that the prevention of the metabolic conversion of TDF to its monoester form is crucial in increasing the oral absorption of TDF. [ABSTRACT FROM PUBLISHER]

In this study, PLGA based nanoparticles of tenofovir disoproxil fumarate (TDF) were designed for enhancing its oral absorption. To develop PLGA based TDF nanoparticles with the goal of minimum particle size and maximum entrapment efficiency statistical optimization techniques (factorial design and response surface methodology) were employed. The optimized nanoparticles were characterized for size, shape, charge and physical state. Further, the stability, cytotoxicity and metabolic protective effect of the nanoparticles were evaluated. Single dose pharmacokinetic study in rats was conducted to evaluate the oral absorption of the designed nanoparticles. Ex vivo everted gut sac studies were performed to evaluate the role of active uptake mechanisms in the absorption of the designed nanoparticles. The results showed that the statistical models employed could determine the interaction effects of the critical factors which were used in the optimization of the nanoparticles. The optimized nanoparticles with a particle size of 218 ± 3.85 nm and an entrapment efficiency of 57.3 ± 1.6%. The nanoparticles were able to increase the AUC of tenofovir by 5.8 fold. It was observed that active uptake mechanisms predominantly via clathrin-mediated uptake played a key role in increasing the oral absorption of TDF. [ABSTRACT FROM AUTHOR]

Objective Drug-induced hepatotoxicity is a major cause of concern in patients receiving HIV/ TB co-treatment. Lopinavir ( LPV), an anti- HIV drug, shows poor plasma exposure due to hepatic first-pass metabolism. In this study, we investigated the effect of hepatotoxicity on pharmacokinetics of free LPV and LPV-loaded solid lipid nanoparticles ( LPV SLNs) in male Wistar rats. Methods Hepatic impairment model in rats was developed by injecting CCl4 (i.p., 2 ml/kg). Comparative pharmacokinetic ( n = 5) and tissue distribution studies ( n = 3) were conducted following oral administration (20 mg/kg) of free LPV and LPV SLNs in normal and hepatic impaired rats. Isolated perfused liver ( IPL) model ( n = 3) and cycloheximide intervened lymphatic uptake studies ( n = 3) were conducted to appreciate disposition pattern of LPV. Key findings In contrary to free LPV, pharmacokinetic results demonstrated no significant ( P > 0.05) difference in drug plasma profile of LPV SLNs in normal and impaired rats. IPL model demonstrated trivial role of liver in disposition of LPV SLNs. Tissue distribution studies of SLNs showed higher ( P < 0.05) LPV accumulation in lymphoidal organs. Pretreatment of cycloheximide significantly ( P < 0.05) reduced AUC and Cmax of LPV SLNs. Conclusion From the results, we conclude that unlike conventional formulations of LPV, disposition characteristics of LPV SLNs were similar both in normal and hepatic impaired rats. [ABSTRACT FROM AUTHOR]

Lopinavir (LPV)-loaded poly-&varepsilon;-caprolactone (PCL) nanoparticles (NPs) were prepared by emulsion solvent evaporation technique. Effects of various critical factors in preparation of loaded NPs were investigated. Box-Behnken design (BBD) was employed to optimize particle size and entrapment efficiency (EE) of loaded NPs. Optimized LPV NPs exhibited nanometeric size (195.3 nm) with high EE (93.9%). In vitro drug release study showed bi-phasic sustained release behavior of LPV from NPs. Pharmacokinetic study results in male Wistar rats indicated an increase in oral bioavailability of LPV by 4-folds after incorporation into PCL NPs. From tissue distribution studies, significant accumulation of loaded NPs in tissues like liver and spleen indicated possible involvement of lymphatic route in absorption of NPs. Mechanistic studies using rat everted gut sac model revealed endocytosis as a principal mechanism of NPs uptake. In vitro rat microsomal metabolism studies demonstrated noticeable advantage of LPV NPs by affording metabolic protection to LPV. These studies indicate usefulness of PCL NPs in enhancing oral bioavailability and improving pharmacokinetic profile of LPV. [ABSTRACT FROM AUTHOR]

Highlights: [•] Pullulan was successfully modified to formulate lopinavir loaded nanoparticles. [•] Nanoparticles had high entrapment efficiency and suitable particle size. [•] Nanoparticles provided metabolic protection to lopinavir against microsomal enzymes. [•] Bioavailability of nanoparticles was two-fold higher compared to free drug. [•] Distribution to viral reservoirs was higher for nanoparticles compared to free drug. [Copyright &y& Elsevier]

Objectives To prepare stearic acid-based lopinavir ( LPV) loaded solid lipid nanoparticles ( SLNs) using a hybrid design and compare in-vivo performance of optimized formulation with marketed LPV/ritonavir (RTV) coformulation. Methods LPV SLNs were prepared by hot melt emulsion technique and optimized using Plackett- Burman design and Box- Behnken design. Physical characterization studies were conducted for the optimized SLNs. Comparative oral pharmacokinetic studies and tissue distribution studies of optimized SLNs and LPV/ RTV coformulation were done in Wistar rats. In-vitro metabolic stability and intestinal permeability studies for LPV SLNs were undertaken to elucidate the mechanism involved in the pharmacokinetic improvement of LPV. Key findings Optimized SLNs exhibited nanometeric size (223 nm) with high entrapment efficiency (83%). In-vitro drug release study of SLNs showed biphasic sustained release behaviour. Significant increase in oral bioavailability of LPV from LPV SLNs (5 folds) and LPV/ RTV coformulation (3.7 folds) was observed as compared with free LPV. LPV SLNs showed better tissue distribution of LPV in HIV reservoirs than LPV/ RTV coformulation. In-vitro studies demonstrated that SLNs provided metabolic protection of LPV and were endocytosized during absorption. Conclusions SLNs enhanced oral bioavailability and improved distribution profile of LPV to HIV reservoirs and hence could be better alternative to LPV/ RTV coformulation. [ABSTRACT FROM AUTHOR]

Objectives The objective of this study was to explore potential drug-drug/food interactions of ciprofloxacin and grapefruit juice, known hepatic cytochrome P450 ( CYP) 1 A2 inhibitors, on single-dose oral pharmacokinetics of riluzole, a substrate of CYP 1 A2 enzymes. Methods Pharmacokinetic parameters of riluzole were determined in Wistar rats after single-dose co-administration with ciprofloxacin and grapefruit juice. In-vitro metabolic inhibition studies using rat and human liver microsomes and intestinal absorption studies of riluzole in a rat everted gut-sac model were conducted to elucidate the mechanism of interaction. A validated HPLC method was employed to quantify riluzole in the samples obtained in various studies. Key findings Co-administration of ciprofloxacin with riluzole caused significant increase in systemic exposure of riluzole (area under the curve, maximum plasma concentration and mean residence time were found to increase). Co-administration of grapefruit juice with riluzole did not cause any significant difference in the pharmacokinetic parameters of riluzole. In-vitro metabolism studies demonstrated significant inhibition of riluzole metabolism when it was co-incubated with ciprofloxacin or grapefruit juice. No significant change was observed in apparent permeability of riluzole. Conclusions Co-administration of ciprofloxacin with riluzole increases the systemic levels of riluzole and thereby the oral pharmacokinetic properties of riluzole while co-administration of grapefruit juice with riluzole has no significant effect. [ABSTRACT FROM AUTHOR]

[Display omitted] • Piribedil is an anti-Parkinson's drug with unique pharmacological advantages. • Its clinical use is limited due to high dosing frequency of the oral tablets. • SLNs were developed for intranasal delivery of PBD to improve direct brain uptake. • In situ gel loaded SLNs were found to be superior over plain piribedil suspension. • Direct nose to brain transport with in situ gel loaded SLNs of Piribedil was 27%. Piribedil (PBD) is an anti-Parkinson's drug that gained interest recently due to its unique pharmacological profile. But its clinical use is severely limited by drug delivery issues like high dosing frequency (up to 5 tablets/day), low oral bioavailability (<10%), severe GI side-effects, etc. In this work, we have developed solid lipid nanoparticles (PBD-SLNs) to access the nose to brain pathways for direct uptake of PBD. PBD-SLNs were optimized using design of experiments approach to a mean particle size of 358 nm, and drug loading of 15%. The optimized PBD-SLNs were found to be nearly spherical in shape and showed good stability. Further, the SLNs were loaded in thermoresponsive Methyl Cellulose in situ gel (PBD-SLN-ISG) to delay mucociliary clearance upon intranasal administration in rats. Intranasal administration at the olfactory region was achieved with a cannula-microtip setup. In vivo pharmacokinetic studies showed that PBD-SLN-ISG increased the PBD (AUC) brain by about 4-folds and reduced the (C max) plasma by 2.3-folds when compared to plain intranasal suspension of PBD (PBD-Susp). Further, PBD-Susp showed limited direct nose to brain uptake with direct transport percentage (DTP) values less than 0, while the optimized PBD-SLN-ISG showed DTP value of 27% indicating efficient direct nose to brain uptake. [ABSTRACT FROM AUTHOR]

In this study, we report the development and evaluation of soy lecithin-chitosan hybrid nanoparticles to improve the oral bioavailability of raloxifene hydrochloride. The nanoparticles were formed by interaction of negatively charged soy lecithin with positively charged chitosan. The ratio of soy lecithin to chitosan was critical for the charge, and hence the size of the nanoparticles. The optimal soy lecithin to chitosan ratio was 20:1 to obtain nanoparticles with particle size of 208 ± 3 nm, a ζ-potential of 36 ± 2 mV and an entrapment efficiency of 73 ± 3%. The nanoparticles were also characterized by differential scanning calorimetry and FT-IR spectrophotometer. In-vitro drug release was assessed using dialysis bag method in pH 7.4 buffer. The drug loaded nanoparticles did not cause significant reduction in the cell viability at low doses. Pharmacokinetic studies in female Wistar rats showed significant improvement (~4.2 folds) in the oral bioavailability of the drug when loaded into nanoparticles. Further, the modified everted gut sac study showed that these nanoparticles are taken up by active endocytic processes in the intestine. The ex-vivo mucoadhesion studies proved that the nanoparticles get bound to the mucus layer of the intestine, which in turn correlates with reduced excretion of the drug in faeces. In conclusion, the proposed nanoparticles appear promising for effective oral delivery of poorly bioavailable drugs like raloxifene hydrochloride. [ABSTRACT FROM AUTHOR]

• Cilnidipine loaded solid lipid nanoparticles were prepared and optimized using DoE. • Optimized SLNs were characterized for physical properties, in-vitro release and stability. • PK and PD properties of optimized SLNs and free drug were compared in Wistar rats. • Optimized SLNs provided better anti-hypertensive therapy compared to free drug. Cilnidipine (CND), an anti-hypertensive drug, is known to have low oral bioavailability due to its poor aqueous solubility, low dissolution rate and high gut wall metabolism. In the present study, CND loaded compritol based nanoparticles (CND-CMP-NPs) were prepared by emulsification-solvent evaporation method applying the concepts of design of experiments. Critical factors affecting particle size and loading efficiency (LE%) were assessed by hybrid design approach, comprising of Mini Run Resolution IV design followed by Box–Behnken design. Particle size, PDI, zeta potential and LE% of optimized formulations of CND-CMP-NPs were 207.1 ± 2.9 nm, 0.27 ± 0.1, −22.2 ± 1.9 mV and 15.9 ± 1.3% respectively. No significant changes were observed in physical stability of NPs when stored at 25 °C/60% RH over a period of three months. Pharmacokinetic studies revealed that F abs of CND-CMP-NPs (0.66) was significantly higher than the free CND (0.27). The C max and AUC 0–∞ of CND-CMP-NPs (572.4 ± 25.3 ng/mL and 5588.6 ± 229.5 ng/mL × h) were significantly higher (P cal < 0.0001) as compared to free CND (363.6 ± 23.5 ng/mL and 2316.1 ± 163.6 ng/mL × h). MRT of CND-CMP-NPs (9.8 ± 0.9 h) was significantly higher (P cal < 0.0001) as compared to free CND (5.7 ± 0.5 h). Pharmacodynamic studies showed a maximum of 38% decrease in systolic blood pressure with more than 20% drop in systolic blood pressure sustained for a total duration of 64 h in the case of CND-CMP-NPs as compared to free CND. CND-CMP-NPs not only provide higher and sustained plasma levels of CND but also higher and sustained antihypertensive therapy as compared to free CND. [ABSTRACT FROM AUTHOR]

• LC-MS/MS method for analysis of both the analytes in rabbit aqueous humor & plasma. • The method was rapid, sensitive, selective and thus suitable for routine analysis. • Validation & stability studies were carried out for both analytes in both matrices. • Application of the method was proved by ocular PK study in rabbits. Beta blockers is the class of choice of drugs in treatment of open angle Glaucoma. However, many of these drugs suffer from systemic side effects due to their absorption into systemic circulation via nasolachrymal duct. To evaluate the safety and efficacy of nebivolol and labetalol for the treatment of open angle glaucoma, it is important to have a bioanalytical method for measuring the drug concentrations both in aqueous humor and plasma. A simple, sensitive and high throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with protein precipitation technique was developed for simultaneous quantification of nebivolol and labetalol using nebivolol-d4 and metoprolol, respectively, as internal standards in aqueous humor and plasma. Nebivolol and labetalol were monitored in electrospray positive ionization (ESI) mode at transition 406.2/151.1 and 329.2/162.0, respectively. Mobile phase comprised of mixture of aqueous buffer (solvent A) and organic phase (solvent B) (mixture of A:B in the ratio of 30:70, v/v). The aqueous buffer was 5 mM ammonium acetate buffer adjusted to pH 3.5 ± 0.05 with formic acid while the organic phase was a mixture of methanol and acetonitrile in the ratio of 25:75, v/v. Chromatographic separation was achieved using reverse phase Zorbax SB-C18 column (4.6 × 100 mm, 3.5 µm). Method was linear in both the matrices in the concentration range of 0.43–750 ng/mL for nebivolol and 0.39–668 ng/mL for labetalol with r2 > 0.99. Accuracy values, expressed in terms of bias (%), for nebivolol in aqueous humor and plasma were ≤9.6% and ≤11.4% and for labetalol were ≤8.6% and ≤5.9%, respectively. Inter-day and intra-day precision values, expressed in terms of RSD (%), for both the drugs were within 11.4%. No interference was obtained due to matrix components. Mean recovery (%) values in aqueous humor and plasma were 72.4% and 73.0% for nebivolol and 56.7% and 54.4% for labetalol, respectively. No significant degradation was observed in both the drugs in both the matrices when stored at −20 °C for 1 month. Aqueous humor and plasma samples of nebivolol and labetalol on bench top were stable for 18 h and 8 h, respectively. The developed method was applied for determining pharmacokinetic parameters of both drugs in aqueous humor following single dose ocular administration in rabbits. [ABSTRACT FROM AUTHOR]

Lopinavir is a new specific and potent HIV-1 protease inhibitor. A simple and rapid Reverse Phase High-Performance Liquid Chromatographic method using UV detection was developed and validated for the analysis of lopinavir in rat plasma under isocratic conditions. The method involves a single step protein precipitation technique. The detector response was linear over the concentration range of 250 to 4000 ng mL-1. High recovery ranging from 97.5 to 101.2 percent was obtained which precludes the use of internal standard. The developed method was validated as per standard guidelines. Validation of the developed method demonstrated accuracy, precision and selectivity of the proposed method. The drug was found to be stable under various processing and storage conditions. This rapid and cost-effective method was successfully applied in the estimation of lopinavir and determination of various pharmacokinetic parameters during post intravenous bolus administration of the drug in rats. The developed method can be suitably employed in preclinical pharmacokinetic evaluation of new formulations designed to improve the bioavailability of lopinavir. [ABSTRACT FROM AUTHOR]

Abstract This study reports a fully validated HPLC-UV (High Performance Liquid Chromatography- Ultra Violet) method for quantitative estimation of Rufinamide (RUFI), an antiepileptic drug, in rat plasma and brain matrices. A response surface methodology based Box Behnken experimental design, using the principles of Design of Experiments (DoE), was employed to optimize critical chromatographic conditions viz. pH and proportion of the buffer and wavelength of detection, for achieving good sensitivity (peak area) and specificity (number of theoretical plates). A desirability function was employed to identify the optimized conditions, which gave a highest value of 0.971. The optimized chromatographic conditions were: pH of the buffer: 4.7, wavelength of detection: 215 nm and proportion of buffer in mobile phase: 84.7% v/v for responses: 124839.6 mV ∗ min as the peak area (1 μg/mL) and 20,000 as the theoretical plate number for the same. A simple protein precipitation method, using methanol, was employed to extract RUFI from the biological matrices. Piribedil was used as the internal standard (IS). At the optimized conditions, the LOQ values of RUFI in plasma and brain were found to be 13.84 ng/mL and 105.24 ng/g respectively. The developed method was validated as per ICH guidelines and its applicability in analysing RUFI in rat plasma and brain matrices was demonstrated by i.v. administration in rats. The AUC 0-t in plasma was found to be 91.9% of AUC 0−∞ indicating that the method is very sensitive and can capture almost the entire plasma time course of RUFI, at a dose of 0.5 mg/kg. Highlights • HPLC/UV method was developed for analysis of Rufinamide, in rat plasma and brain. • Chromatographic conditions were optimized using Box Behnken design. • The method was rapid, sensitive, inexpensive and thus suitable for routine analysis. • Validation and stability studies were carried out for Rufinamide in both matrices. • Application of the method was proved by i.v PK study (plasma and brain) in rats. [ABSTRACT FROM AUTHOR]