Freeze dried solid dispersion of exemestane: A way to negate an aqueous solubility and oral bioavailability problems.

This study was envisaged to demonstrate the potential of exemestane loaded phospholipid/sodium deoxycholate solid dispersions (EXE-PL/SDC-SDs) on the solubility and oral bioavailability of EXE. Initial studies were performed to screen the best suitable phospholipid among lysophosphatidylcholine, Phospholipon® P80H and Lipoid® E80S for solid dispersion preparation. Further studies were carried out to optimize the molar concentration of phospholipid and sodium deoxycholate (SDC) for EXE-PL/SDC-SDs preparation. Optimized EXE-PL/SDC-SDs was prepared using Lipoid® E80S and SDC in 1:4M concentration, respectively and lyophilized using 10% w/w 2-hydroxypropyl-ß-cyclodextrin (2-HPCD). The physical state of EXE in lyophilized formulation was confirmed by DSC and PXRD. Lyophilized formulation exhibits a significant increase in solubility and dissolution rate as compared to free drug EXE. Apparent permeability study was performed on Caco-2 cell line for 2h. The lyophilized EXE-PL/SDC-SDs exhibits 4.6-fold increase in absorptive transport as compared to EXE. Pharmacokinetic study in fasted female Sprague-Dawley rats revealed a 2.3-fold increase in AUC0-72h. Thus, the results suggest that PL/SDC-SDs is a promising carrier for EXE delivery.

Potential of amphiphilic graft copolymer α-tocopherol succinate-g-carboxymethyl chitosan in modulating the permeability and anticancer efficacy of tamoxifen.

Recent studies showed an enhanced oral bioavailability of tamoxifen (TMX) by hydrophobically modified α-tocopherol succinate-g-carboxymethyl chitosan (Cmc-TS) micelles. As a continued effort, here we evaluated TMX-loaded polymeric micelles (TMX-PMs) for its enhanced permeability with increased anticancer efficacy and decreased hepatotoxicity. We employed co-solvent evaporation technique to encapsulate TMX into Cmc-TS. Apparent permeability assay of TMX-PMs was performed on Caco-2 cell line. The absorptive transport of TMX increased significantly about 3.8-fold when incorporated into Cmc-TS PMs. Cytotoxicity of Cmc-TS PMs was studied on MCF-7 cell line by MTT and; confocal microscopy was used for cellular uptake. Confocal microscopy revealed that Cmc-TS PMs could effectively accumulate in the cytosol of MCF-7 cell lines. In vitro data was further validated using N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis model in Sprague-Dawley rats. Hepatotoxicity profiles of TMX-PMs at three different doses were also evaluated against the free drug TMX. TMX-PMs were more effective in suppressing breast tumor in MNU-induced mammary carcinoma model than free TMX with better safety profile. In addition, histological data shows that tumors are "benign" in TMX-PMs treated group compared with "malignant" tumors in free TMX treated and control groups. Overall, the results implicate that our Cmc-TS PMs may serve as a promising carrier for the intracellular delivery of anticancer drug molecules via oral route.

Alpha-lipoic acid-stearylamine conjugate-based solid lipid nanoparticles for tamoxifen delivery: formulation, optimization, in-vivo pharmacokinetic and hepatotoxicity study.

OBJECTIVES: This study was designed to demonstrate the potential of novel α-lipoic acid-stearylamine (ALA-SA) conjugate-based solid lipid nanoparticles in modulating the pharmacokinetics and hepatotoxicity of tamoxifen (TMX). METHODS: α-lipoic acid-stearylamine bioconjugate was synthesized via carbodiimide chemistry and used as a lipid moiety for the generation of TMX-loaded solid lipid nanoparticles (TMX-SLNs). TMX-SLNs were prepared by solvent emulsification-diffusion method and optimized for maximum drug loading using rotatable central composite design. The optimized TMX-SLNs were stabilized using 10% w/w trehalose as cryoprotectant. In addition, pharmacokinetics and hepatotoxicity of freeze-dried TMX-SLNs were also evaluated in Sprague Dawley rats. KEY FINDINGS: Initial characterization with transmission electron microscopy revealed spherical morphology with smooth surface having an average particle size of 261.08 ± 2.13 nm. The observed entrapment efficiency was 40.73 ± 2.83%. In-vitro release study showed TMX release was slow and pH dependent. Pharmacokinetic study revealed a 1.59-fold increase in relative bioavailability as compared to TMX suspension. A decrease in hepatotoxicity of TMX is evidenced by the histopathological evaluation of liver tissues. CONCLUSIONS: α-lipoic acid-stearylamine conjugate-based SLNs have a great potential in enhancing the oral bioavailability of poorly soluble drugs like TMX. Moreover, this ALA-SA nanoparticulate system could be of significant value in long-term anticancer therapy with least side effects.

Polymeric micelles of amphiphilic graft copolymer of α-tocopherol succinate-g-carboxymethyl chitosan for tamoxifen delivery: Synthesis, characterization and in vivo pharmacokinetic study.

Novel amphiphilic graft copolymers were prepared from low molecular weight carboxymethyl chitosan (LMW Cmc) and α-tocopherol succinate (TS) via an amidation reaction and confirmed by (1)H NMR and IR spectroscopy. These graft copolymers are self-assembled to nanosized core-shell-structural micelles in an aqueous milieu. The critical micelle concentration (CMC) decreased with an increasing substitution of TS on LMW Cmc, which ranged from 7.94×10(-8) to 1.58×10(-6)g/mL. Cmc-TS4.5 (Cmc-TS with a charged molar ratio of TS to glucosamine units of Cmc∼4.5) was shown maximum TMX loading up to 8.08±0.98%. Both blank and TMX-loaded PM's of Cmc-TS4.5 exhibit spherical shape with particle size below 200nm. An in vitro release study in simulated gastric and intestinal fluid demonstrated that TMX release from TMX-PM4.5 (TMX-PMs prepared with amphiphilic polymer Cmc-TS4.5, and the weight ratio of Cmc-TS4.5 to TMX was 8:1) was slow and pH dependent. In vivo oral absorption study revealed Cmc-TS4.5 based PM's permeated the epithelial barrier via the paracellular route without causing any intestinal damage. In vivo toxicity study demonstrated the safety of PM's after oral administration. Compared to tamoxifen control, TMX-PM4.5 dosed to fasted female Sprague Dawley rats showed a 1.9 fold increase in AUC0-72h. Thus, the results suggested that Cmc-TS micelles are a promising carrier for TMX delivery.

Modulation of tamoxifen-induced hepatotoxicity by tamoxifen-phospholipid complex.

OBJECTIVES: Tamoxifen (TMX), a non-steroidal antiestrogen is a first-line drug in the treatment and prevention of all stages of estrogen-receptor-positive breast cancer. However, oxidative liver damage and hepatocarcinoma are the major problems associated with its long-term clinical use. The aim of this study was to investigate the ameliorative effect of phospholipid against TMX-induced hepatotoxicity. METHODS: Fifteen female Sprague-Dawley rats were divided into three groups with five rats in each group. Group I received only standard diet and distilled water for 28 days and served as normal. Group II received TMX per day p.o., for 28 days and served as control, and group III received TMX-phospholipid complex (TMX-PLC) per day p.o., for 28 days. Rats were examined for the effect of phospholipid on TMX-induced depletion of antioxidant enzymes, serum biochemical parameters and induction of lipid peroxidation. KEY FINDINGS: Treatment with TMX-PLC significantly ameliorates the TMX-induced hepatotoxicity by diminishing the toxicity markers such lipid peroxidation, aspartate transaminase and alanine transaminase, accompanied by an increase in antioxidant enzyme activity in TMX-treated rats. Histological findings further confirmed the hepatoprotective effect of phospholipid. CONCLUSIONS: Data of the present study suggests that phospholipid may prove as a useful component of combination therapy in cancer patients under the TMX treatment regimen.

Preparation, in-vitro and in-vivo evaluation of spray-dried ternary solid dispersion of biopharmaceutics classification system class II model drug.

OBJECTIVES: The objective of this study was to investigate the impact of a novel spray-dried ternary solid dispersion (TSD) on the dissolution rate and bioavailability of a biopharmaceutics classification system (BCS) class II model drug, atorvastatin calcium trihydrate (ATC), and evaluate its in-vitro and in-vivo performance. METHODS: TSD of ATC was prepared by spray-drying method employing ethanol/water solvent systems. The TSD formulations, composed of hydroxypropyl methylcellulose (HPMC E5) and nicotinamide, were optimized by rotatable central composite design. Physicochemical characterization along with dissolution, stability and pharmacokinetic study of optimized TSD was evaluated. KEY FINDINGS: The optimized TSD was found to be amorphous with spherical shape morphology. It exhibited a fourfold increase in dissolution rate in comparison to ATC, with a considerable enhancement in oral bioavailability (relative bioavailability of 134.11%). Physicochemical characterization and dissolution study of optimized TSD at the end of stability studies clearly indicated that the stability of optimized TSD was due to hydrogen bonding between drug and HPMC E5 and nicotinamide. This bonding remained unaffected even under stressful conditions of high temperature and humidity. CONCLUSION: The TSD exhibits a significant increase in dissolution rate, and for this reason should be useful as an efficacious tool to enhance the bioavailability of BCS class II drug molecule, ATC.

Formulation, optimization and in vitro-in vivo evaluation of febuxostat nanosuspension.

The purpose of the present study was to develop febuxostat nanosuspension and investigate its effect on febuxostat solubility, dissolution rate and oral bioavailability. The wet media milling technique was adopted with a combination of hydroxypropyl methylcellulose (HPMC E3) and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) as surface stabilizers for the generation of nanocrystals. Rotatable central composite design (CCD) was selected for nanosuspension optimization. The critical parameters were bead volume, milling time, polymer and surfactant concentrations; whereas particle size, polydispersity index (PDI) and zeta potential were taken as responses. The presence of crystallinity was confirmed by differential scanning calorimetry and powder X-ray diffraction. Scanning electron microscopy and transmission electron microscopy revealed small and uniform plate like morphology. A significant increase was observed in saturation solubility and dissolution rate of the optimized nanosuspension in all the pH conditions tested. Oral bioavailability of FXT and optimized FNC was evaluated in SD rats. The nanosuspension exhibited enhanced Cmax (26.48±2.71 vs. 19.85±2.96µg/mL) and AUC0-∞ (222.29±9.81 vs. 100.32±9.36µgh/mL) with a 221.6% increase in relative bioavailability. Thus, FNC is a viable approach to enhance the bioavailability of FXT, a BCS Class II drug.