Brain-Targeted Intranasal Delivery of Zotepine Microemulsion: Pharmacokinetics and Pharmacodynamics.

The purpose of our study was to improve the solubility, bioavailability, and efficacy of zotepine (ZTP) by brain-targeted intranasal delivery of microemulsion (ME) and its physicochemical properties, the pharmacokinetic and pharmacodynamic parameters were evaluated. The optimized ME formulations contain 10% w/w of oil (Capmul MCM C8, monoglycerides, and diglycerides of caprylic acid), 50% w/w of Smix (Labrasol and Transcutol HP, and 40% w/w of water resulting in a globule size of 124.6 ± 3.52 nm with low polydispersity index (PDI) (0.212 ± 0.013) and 2.8-fold higher permeation coefficient through porcine nasal mucosa compared to pure drug). In vitro cell line studies on RPMI 2650, Beas-2B, and Neuro-2A revealed ZTP-ME as safe. ZTP-ME administered intranasally showed higher AUC0-t24 (18.63 ± 1.33 h × µg/g) in the brain by approximately 4.3-fold than oral ME (4.30 ± 0.92 h × µg/g) and 7.7-fold than intravenous drug solutions (2.40 ± 0.36 h × µg/g). In vivo anti-schizophrenic activity was conducted using catalepsy test scores, the formulation showed better efficacy via the intranasal route; furthermore, there was no inflammation or hemorrhage in the nasal cavity. The results concluded that the ZTP microemulsion as a safe and effective strategy could greatly enhance brain distribution by intranasal administration.

QbD aided development of ibrutinib-loaded nanostructured lipid carriers aimed for lymphatic targeting: evaluation using chylomicron flow blocking approach.

Ibrutinib (IBR) is the choice of drug for the treatment of chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL). IBR has low oral bioavailability of 2.9% owing to its high first pass metabolism. Present study was aimed to develop the nanostructured lipid carriers (NLC) using glyceryl monostearate (GMS) as solid lipid and Capryol™ PGMC as liquid lipid. Plackett-Burman design (PBD) was applied to screen the significant factors; furthermore, these significant factors were subjected to optimisation using Central Composite design (CCD). The size, poly dispersity index (PDI) and entrapment efficiency (E.E.) of the developed NLC were 106.4 ± 8.66 nm, 0.272 ± 0.005 and 70.54 ± 5.52% respectively. Morphological evaluation using transmission electron microscope (TEM) and field emission scanning electron microscope (FESEM) revealed spherical particles. Furthermore, differential scanning calorimetry (DSC) indicates the formation of molecular dispersion of drug in the melted lipid matrix while Powder X-Ray Diffraction (PXRD) studies reveal the absence of crystalline drug peaks in the formulation diffractogram. In-vivo pharmacokinetics of NLC displayed an increase in Cmax (2.89-fold), AUC0-t (5.32-fold) and mean residence time (MRT) (1.82-fold) compared with free drug. Furthermore, lymphatic uptake was evaluated by chylomicron flow blocking approach using cycloheximide (CXI). The pharmacokinetic parameters Cmax, AUC0-t and MRT of NLC without CXI were 2.75, 3.57 and 1.30 folds higher compared with NLC with CXI. The difference in PK parameters without CXI indicates significant lymphatic uptake of the formulation. Hence, NLC can be a promising approach to enhance the oral bioavailability of drugs with high first-pass metabolism. Graphical abstract.

Fabrication of Ibrutinib Nanosuspension by Quality by Design Approach: Intended for Enhanced Oral Bioavailability and Diminished Fast Fed Variability.

Present study was aimed to increase the oral bioavailability and reduce the fast fed variability of Ibrutinib by developing nanosuspension by simple precipitation-ultrasonication method. A three factor, three level, box-behnken design was used for formulation optimization using pluronic F-127 as stabilizer. Size and polydispersity index of the developed formulations were in the range of 278.6 to 453.2 nm and 0.055 to 0.198, respectively. Field emission scanning electron microscope (FESEM) revealed discrete units of nanoparticles. Further, differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies confirmed the transformation of crystal drug to amorphous. The amorphous nature was retained after 6-month storage at room temperature. Size reduction to nano range and polymorphic transformation (crystalline to amorphous) increased the solubility of nanosuspension (21.44-fold higher as compared to plain drug). In vivo studies of plain drug suspension displayed a significant pharmacokinetic variation between fasting and fed conditions. The formulation had shown increased Cmax (3.21- and 3.53-fold), AUC0-t (5.21- and 5.83-fold) in fasting and fed states compared to that of values obtained for plain drug in fasting state (Cmax 48.59 ± 3.30 ng/mL and AUC0-t 137.20 ± 35.47 ng.h/mL). Significant difference was not observed in the pharmacokinetics of nanosuspension in fasting and fed states. The formulation had improved solubility in the intestinal pH, which might be the driving force behind the decreased precipitation and increased absorption at intestinal region. Optimistic results demonstrated nanosuspension as a promising approach for increasing the solubility, extent of absorption and diminishing the fast fed variability.

Quality by Design Approach for the Development of Self-Emulsifying Systems for Oral Delivery of Febuxostat: Pharmacokinetic and Pharmacodynamic Evaluation.

The goal of the present investigation is to formulate febuxostat (FXT) self-nanoemulsifying delivery systems (liquid SNEDDS, solid SNEDDS, and pellet) to ameliorate the solubility and bioavailability. To determine the self-nanoemulsifying region, ternary plot was constructed utilizing Capmul MCM C8 NF® as an oil phase, Labrasol® as principal surfactant, and Transcutol HP® being the co-surfactant. Liquid SNEDDS (L-SNEDDS) were characterized by evaluating droplet size, zeta potential, % transmission, and for thermodynamic stability. In vitro dissolution study of FXT loaded L-SNEDDS (batch F7) showed increased dissolution (about 48.54 ± 0.43% in 0.1 N HCl while 86.44 ± 0.16% in phosphate buffer pH 7.4 within 30 min) compared to plain drug (19.65 ± 2.95% in 0.1 N HCl while about 17.61 ± 2.63% in phosphate buffer pH 7.4 within 30 min). Single pass intestinal permeability studies revealed fourfold increase in the intestinal permeability of F7 compared to plain drug. So, for commercial aspects, F7 was further transformed into solid SNEDDS (S-SNEDDS) as readily nanoemulsifying powder form (SNEP) as well as pellets prepared by application of extruder spheronizer. The developed formulation was found superior to pure FXT with enhanced oral bioavailability and anti-gout activity (with reduced uric acid levels), signifying a lipidic system being an efficacious substitute for gout treatment.

Intranasal Zotepine Nanosuspension: intended for improved brain distribution in rats.

BACKGROUND: Zotepine (ZTP), an antipsychotic drug is well tolerated and particularly effective for treating negative symptoms of psychosis. But is limited by low oral bioavailability caused by substantial first pass metabolism and thereby less amount of drug reaches the brain due to blood brain barrier (BBB). OBJECTIVES: Since ZTP displays dose dependent side effects, purpose of the contemporary study is to develop zotepine loaded nanosuspension (ZTP-NS) for increased brain targeting in rats at lower doses. METHODS: ZTP-NS is prepared by two techniques viz., sonoprecipitation (SP) and combination technique (high pressure homogenization preceded by precipitation) by employing various stabilizers. Optimized ZTP-NS was characterized for particle size, solid state, morphology and solubility. In vitro drug release of ZTP and formulations was conducted using Franz diffusion cell. Stability study was performed at different temperature conditions. Pharmacokinetic study was performed in Wistar rats to determine the bioavailability and brain distribution of ZTP after intra-nasal (IN) and intravenous (IV) administration. Histopathology of brain was done after repeated administration of IN ZTP dispersion and NS up to 14 days. RESULTS: The optimized ZTP-NS formulated with Pluronic F-127 (0.3%w/v), Hydroxypropyl methyl cellulose E15 (0.3%w/v) and soya lecithin (0.4%w/v) showed particle size of 519.26 ± 10.44 nm & 330.2 ± 12.90 nm and zeta potential of -21.7 ± 1.39 mV and - 18.26 ± 1.64 mV with sonoprecipitation and combination technique respectively. In vitro drug release was high (81.79 ± 3.23%) for ZTP-NS prepared by combination technique. Intranasal NS resulted in high brain concentrations of 8.6 fold (sonoprecipitation) and 10.79-fold hike in AUC0-24h in contrast to intravenous ZTP solution. Histopathology results reveal no significant changes in brain microscopic images. CONCLUSION: ZTP-NS was successfully developed, characterized and found that nanosuspension is a favorable approach for intranasal delivery of zotepine. Graphical abstract Graphical abstract representing zotepine drawbacks, nanosuspension preparation, characterization and pharmacokinetic study in rats.

Quality by Design Approach for Developing Lipid-Based Nanoformulations of Gliclazide to Improve Oral Bioavailability and Anti-Diabetic Activity.

The aim of the current investigation was to generate a self-nanoemulsifying drug delivery system (SNEDDS) of gliclazide (GCZ) to address the poor solubility and bioavailability. Ternary phase diagram was created with Capmul MCM C8 NF (oil), Cremophor RH 40 (surfactant), and Transcutol HP (co-surfactant) to distinguish the self-emulsifying region. A D-optimal design was employed with three variables, such as oil, surfactant, and co-surfactant, for further optimization of liquid (L)-SNEDDS. GCZ-loaded L-SNEDDs were analyzed for globule size, polydispersity index (PDI), and solubility. In vitro dissolution of optimized L-SNEDDS exhibited (F5) faster drug release (97.84%) within 30 min as compared to plain drug (15.99%). The optimized L-SNEDDS was converted to solid (S)-SNEDDS as a self-nanoemulsifying powder (SNEP) and pellets by extrusion-spheronization. Optimized S-SNEDDS were characterized using Fourier-transform infrared spectroscopy (FTIR), X-ray diffractometry (XRD), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). In vitro dissolution of SNEP (S3) and pellet were 90.54 and 73.76%, respectively, at 30 min. In vivo studies showed a twofold rise in bioavailability through SNEDDS with a significant decline in blood glucose levels compared to plain drug suspension suggesting a lipid-based system as an alternative approach for treating diabetes.

A multi-institution prospective observational study of small bowel obstruction: Clinical and computerized tomography predictors of which patients may require early surgery.

BACKGROUND: For patients with adhesive small bowel obstruction (ASBO), early surgery after a failed trial of nonoperative treatment can improve outcome. However, deciding which patients require early surgery is difficult, given the lack of specific clinical or radiographic signs. The study goals were to identify clinical and computed tomography (CT) predictors of which patients may need early surgery and to evaluate the utility of the common CT findings. METHODS: This was a multi-institution prospective observational study for patients who were admitted with ASBO. Patients were excluded if their SBO were not managed conservative initially; were within 30 days postoperatively; were caused by external hernias, small bowel tumor, or intussusception; and were related to Crohn's disease. Clinical and laboratory variables were collected prospectively. CT findings were interpreted by a blinded designated radiologist. To identify significant predictors, we performed a multivariable regression analysis. RESULTS: During 22 months, we enrolled 200 patients with ASBO. Patients' mean (SD) age was 60 (18) years; 50% were male. Fifty-two patients (26%) underwent surgery. Of those who underwent surgery, the median duration of nonoperative treatment was 1.5 days (interquartile range, 1-2.5 days). In the regression model, we identified no flatus (odds ratio [OR], 3.28; 95% confidence interval [CI], 1.51-7.12; p = 0.003), presence of free fluid on CT (OR, 2.59; 95% CI, 1.13-5.90; p = 0.023), and high-grade obstruction by CT (OR, 2.44; 95% CI, 1.10-5.43; p = 0.028) to be significant predictors for ASBO patients who may need early surgery. CONCLUSION: In this study, we prospectively derived one clinical and two CT predictors which ASBO patients may benefit from an early surgical intervention. However, a future study to validate these predictors is needed. LEVEL OF EVIDENCE: Therapeutic study, level III; prognostic study, level II.