Development, optimization, and in vitro characterization of dasatinib-loaded PEG functionalized chitosan capped gold nanoparticles using Box-Behnken experimental design.

OBJECTIVE: The purpose of this research study was to develop, optimize, and characterize dasatinib loaded polyethylene glycol (PEG) stabilized chitosan capped gold nanoparticles (DSB-PEG-Ch-GNPs). METHODS: Gold (III) chloride hydrate was reduced with chitosan and the resulting nanoparticles were coated with thiol-terminated PEG and loaded with dasatinib (DSB). Plackett-Burman design (PBD) followed by Box-Behnken experimental design (BBD) were employed to optimize the process parameters. Polynomial equations, contour, and 3D response surface plots were generated to relate the factors and responses. The optimized DSB-PEG-Ch-GNPs were characterized by FTIR, XRD, HR-SEM, EDX, TEM, SAED, AFM, DLS, and ZP. RESULTS: The results of the optimized DSB-PEG-Ch-GNPs showed particle size (PS) of 24.39 ± 1.82 nm, apparent drug content (ADC) of 72.06 ± 0.86%, and zeta potential (ZP) of -13.91 ± 1.21 mV. The responses observed and the predicted values of the optimized process were found to be close. The shape and surface morphology studies showed that the resulting DSB-PEG-Ch-GNPs were spherical and smooth. The stability and in vitro drug release studies confirmed that the optimized formulation was stable at different conditions of storage and exhibited a sustained drug release of the drug of up to 76% in 48 h and followed Korsmeyer-Peppas release kinetic model. CONCLUSIONS: A process for preparing gold nanoparticles using chitosan, anchoring PEG to the particle surface, and entrapping dasatinib in the chitosan-PEG surface corona was optimized.

Development and optimization of locust bean gum and sodium alginate interpenetrating polymeric network of capecitabine.

OBJECTIVE: The objective of the study was to develop interpenetrating polymeric network (IPN) of capecitabine (CAP) using natural polymers locust bean gum (LBG) and sodium alginate (NaAlg). SIGNIFICANCE: The IPN microbeads were optimized by Box-Behnken Design (BBD) to provide anticipated particle size with good drug entrapment efficiency. The comparative dissolution profile of IPN microbeads of CAP with the marketed preparation proved an excellent sustained drug delivery vehicle. METHODS: Ionotropic gelation method utilizing metal ion calcium (Ca2+) as a cross-linker was used to prepare IPN microbeads. The optimization study was done by response surface methodology based Box-Behnken Design. The effect of the factors on the responses of optimized batch was exhibited through response surface and contour plots. The optimized batch was analyzed for particle size, % drug entrapment, pharmacokinetic study, in vitro drug release study and further characterized by FTIR, XRD, and SEM. To study the water uptake capacity and hydrodynamic activity of the polymers, swelling studies and viscosity measurement were performed, respectively. RESULTS: The particle size and % drug entrapment of the optimized batch was 494.37 ± 1.4 µm and 81.39 ± 2.9%, respectively, closer to the value predicted by Minitab 17 software. The in vitro drug release study showed sustained release of 92% for 12 h and followed anomalous drug release pattern. The derived pharmacokinetic parameters of optimized batch showed improved results than pure CAP. CONCLUSION: Thus, the formed IPN microbeads of CAP proved to be an effective extended drug delivery vehicle for the water soluble antineoplastic drug.

Quality by Design Methodology Applied to Process Optimization and Scale up of Curcumin Nanoemulsions Produced by Catastrophic Phase Inversion.

In the presented study, we report development of a stable, scalable, and high-quality curcumin-loaded oil/water (o/w) nanoemulsion manufactured by concentration-mediated catastrophic phase inversion as a low energy nanoemulsification strategy. A design of experiments (DoE) was constructed to determine the effects of process parameters on the mechanical input required to facilitate the transition from the gel phase to the final o/w nanoemulsion and the long-term effects of the process parameters on product quality. A multiple linear regression (MLR) model was constructed to predict nanoemulsion diameter as a function of nanoemulsion processing parameters. The DoE and subsequent MLR model results showed that the manufacturing process with the lowest temperature (25 °C), highest titration rate (9 g/minute), and lowest stir rate (100 rpm) produced the highest quality nanoemulsion. Both scales of CUR-loaded nanoemulsions (100 g and 500 g) were comparable to the drug-free optimal formulation with 148.7 nm and 155.1 nm diameter, 0.22 and 0.25 PDI, and 96.29 ± 0.76% and 95.60 ± 0.88% drug loading for the 100 g and 500 g scales, respectively. Photostability assessments indicated modest loss of drug (<10%) upon UV exposure of 24 h, which is appropriate for intended transdermal applications, with expected reapplication of every 6-8 h.

Gold nanoparticles for sustained antileukemia drug release: development, optimization and evaluation by quality-by-design approach.

AIM: To design, develop, optimize and evaluate sustained-release dasatinib-loaded gold nanoparticles (DSB-GNPs) to treat chronic myeloid leukemia (CML) by using quality by design. MATERIALS & METHODS: In this study, we performed risk assessment, optimization, in vitro characterizations, stability study, drug release studies, cytotoxicity study and in vivo pharmacokinetic evaluation. RESULTS: DSB-GNPs of desired size, entrapment, smooth, spherical, stable and sustained drug release for 48 h were achieved. DSB-GNPs exhibited significantly more percentage growth inhibition and enhanced systemic bioavailability compared with pure DSB. CONCLUSION: The in vitro and in vivo evaluation exhibited that the DSB-GNPs have a potential cytotoxic effect, systemic bioavailability and sustained release making them a promising system of DSB delivery in the treatment of chronic myeloid leukemia.

Locust bean gum and sodium alginate based interpenetrating polymeric network microbeads encapsulating Capecitabine: Improved pharmacokinetics, cytotoxicity &in vivo antitumor activity.

A combination of biopolymers sodium alginate and locust bean gum has been used to prepare an interpenetrating polymeric network of an anticancer drug Capecitabine by ionotropic gelation method. For the optimization 32 levels, a full factorial design was employed to examine the influence of independent factors, i.e. polymer ratio and cross-linker concentration on responses particle size and drug entrapment. The obtained optimized formulation was examined for solid-state characterization, swelling study, in vitro drug release, SRB study, oral toxicity study, in vivo pharmacokinetic and in vivo antitumor study. The results of all the studies performed were found suitable in extending the release of a short elimination half-life drug with improved bioavailability and suggesting it to be safe and effective for oral drug delivery in treating colon cancer.

Development of biopolymers based interpenetrating polymeric network of capecitabine: A drug delivery vehicle to extend the release of the model drug.

The research aims the development and optimization of capecitabine loaded interpenetrating polymeric network by ionotropic gelation method using polymers locust bean gum and sodium alginate by QbD approach. FMEA was performed to recognize the risks influencing CQAs. BBD was applied to study the effect of factors (polymer ratio, amount of cross-linker and curing time) on responses (particle size, % drug entrapment and % drug release). Polynomial equations and 3-D graphs were plotted to relate between factors and responses. The results of the optimized batch viz. particle size (457.92 ±â€¯1.6 µm), % drug entrapment (74.11 ±â€¯3.1%) and % drug release (90.23 ±â€¯2.1%) were close to the predicted values generated by Minitab® 17. Characterization techniques SEM, EDX, FTIR, DSC and XRD were also performed for the optimized batch. To study the water transport inside IPN microbeads, swelling study was done. In vitro drug release of optimized batch showed controlled drug release for 12 h. Pharmacokinetic study carried out following oral administration in Albino Wistar rats exhibited that optimized microbeads had better PK parameters than free drug. In vitro cytotoxicity against HT-29 cells revealed significant reduction of the cell growth when treated with optimized formulation indicating IPN microbeads as effective dosage form for treating colon cancer.

Process optimization and in vivo performance of docetaxel loaded PHBV-TPGS therapeutic vesicles: A synergistic approach.

This research was motivated due to substantial requirement of improved treatment for breast cancer which accounts for over 0.52 million deaths annually worldwide. Utilizing nanoparticles carrying active medicaments as targeted delivery carrier is emerging as a promising approach. For a drug to be clinically effective, it needs to be suitably protected in the biological fluid till it is delivered to the targeted site. Keeping above in mind, we prepared and optimized polymeric nanoparticles by polyhydroxybutyrate-co-hydroxyvalerate (PHBV) a biodegradable polymer utilizing modified emulsification solvent evaporation method. The optimized formulation had particle size of 349±3.51nm with entrapment efficiency of 69±1.28%. Nanoparticle formation and its surface morphology were confirmed by various electron microscopes. The in vitro and pharmacokinetic studies demonstrated a sustained release of drug in a non-biological system and into rat's bloodstream respectively. Also, the in vitro cytotoxicity and in vivo toxicological evaluation at the therapeutic dose demonstrated the safety and antitumor efficacy of the formulation. Due to formulation characteristic properties, it was found to be effective in enveloping and chaperoning the drug to the suitable site of action. The PHBV-TPGS combination causes the drug to be released in controlled and sustained modes, thereby reducing drug dose and toxicity.

Long-circulating polyhydroxybutyrate-co-hydroxyvalerate nanoparticles for tumor targeted docetaxel delivery: Formulation, optimization and in vitro characterization.

In the present research an attempt was made to develop and optimize docetaxel-loaded polyhydroxybutyrate-co-hydroxyvalerate (PHBV) nanoparticles, using modified emulsification solvent evaporation technique and design of experiment (DOE) methodology. Formulation of docetaxel-loaded PHBV nanoparticles was conducted by factor screening studies with Plackett-Burman design (PBD) followed by Box-Behnken experimental design (BBD) to evaluate the effect of independent variables on responses. Five most important independent variables were screened out, which were obtained from failure mode effect analysis (FMEA) and factor screening studies. The effect of formulation parameters on selected responses was depicted by 2-D and 3-D response surface methodology (RSM). The final optimized batch was evaluated by various in vitro characterizations. The observed particle size, zeta potential and entrapment efficiency of optimized formulation was found to be 283±2.79nm, -17±2.64mV and 44±0.59% respectively. Morphological studies demonstrated the smooth and spherical shape of nanoparticles. In vitro drug release follows the Peppas-Korsmeyer model of drug release kinetics. Cytotoxicity study was assessed using MCF-7 for percentage inhibition of human breast cancer cell line. These results indicate that the PHBV Nanoparticles could be a promising drug delivery system for efficient prolong drug release.