Surface-tailored nanomixed micelles containing quercetin-salicylic acid physical complex for enhanced cellular and in vivo activities: a quality by design perspective.

AIM: The development of surface-tailored quercetin (QCT)-salicylic acid (SA) physical complex for effective treatment of skin carcinoma. MATERIALS & METHODS: QCT-SA nanomixed micelles were prepared by the self-assembly method employing the Quality by Design (QbD) approach and evaluated for various in vitro, ex vivo and in vivo parameters. RESULTS: The optimized formulation showed enhanced percent permeation (Q24), in other words, 78.12 ± 0.47, improved in vitro cellular uptake and annexin-V-apoptosis assay exhibited 60.86% cell death. The 7,12-dimethylbenz(a)anthracene and histopathology protocol revealed the improved antineoplastic action of QCT. The dermatokinetic profile showed the maximum drug concentration (6 h), in other words, 416.02 ± 26 µg/cm2 in epidermis and 103.65 ± 12 µg/cm2 in dermis. CONCLUSION: The overall performance ratified the safety and efficacy of optimized nanomixed micelless of QCT with SA in a synergistic manner.

Natural lipids enriched self-nano-emulsifying systems for effective co-delivery of tamoxifen and naringenin: Systematic approach for improved breast cancer therapeutics.

The nano-miceller drug delivery carriers of tamoxifen (TMX) having natural ingredients like polyunsaturated fatty acid (PUFA) with self-nano-emulsifying properties was developed with naringenin (NG) in a synergistic manner i.e. TMX-NG-SNEDDS. The optimized nano-formulation revealed complete drug release in 30 min and >80% permeation in 45 min. Superior cellular uptake potential (4.6-6.5-fold) of the TMX-NG-SNEDDS using Caco-2 cells while cytotoxicity study on MCF-7 cells indicated significant results (P<0.05) of TMX-NG-SNEDDS. The in vivo pharmacokinetic study also construed remarkable improvement (7.3 and 11.4-fold increase in Cmax and AUC) in rate of drug absorption and 2-fold reduction in Tmax by optimized TMX-NG-SNEDDS. In vivo DMBA model construed superior efficacy of the formulation by reducing tumor size, and improved survival rate of the animals justifies its safety aspect as well.

Novel surface-engineered solid lipid nanoparticles of rosuvastatin calcium for low-density lipoprotein-receptor targeting: a Quality by Design-driven perspective.

AIM: The present studies describe Quality by Design-oriented development and characterization of surface-engineered solid lipid nanoparticles (SLNs) of rosuvastatin calcium for low density lipoprotein-receptor targeting. MATERIALS & METHODS: SLNs were systematically prepared employing Compritol 888 and Tween-80. Surface modification of SLNs was accomplished with Phospholipon 90G and DSPE-mPEG-2000 as the ligands for specific targeting to the low density lipoprotein-receptors. SLNs were evaluated for size, potential, entrapment, drug release performance and gastric stability. Also, the formulations were evaluated for cellular cytotoxicity, uptake and permeability, pharmacokinetic, pharmacodynamic and biochemical studies. RESULTS & CONCLUSION: Overall, the studies ratified enhanced biopharmaceutical performance of the surface-engineered SLNs of rosuvastatin as a novel approach for the management of hyperlipidemia-like conditions.

QbD-Driven Development and Validation of a HPLC Method for Estimation of Tamoxifen Citrate with Improved Performance.

The current studies entail Quality by Design (QbD)-enabled development of a simple, rapid, sensitive and cost-effective high-performance liquid chromatographic method for estimation of tamoxifen citrate (TMx). The factor screening studies were performed using a 7-factor 8-run Taguchi design. Systematic optimization was performed employing Box-Behnken design by selecting the mobile phase ratio, buffer pH and oven temperature as the critical method parameters (CMPs) identified from screening studies, thus evaluating the critical analytical attributes (CAAs), namely, peak area, retention time, theoretical plates and peak tailing as the parameters of method robustness. The optimal chromatographic separation was achieved using acetonitrile and phosphate buffer (pH 3.5) 52:48 v/v as the mobile phase with a flow rate 0.7 mL/min, an oven temperature 40°C and UV detection at 256 nm. The method was validated as per the ICH recommended conditions, which revealed high degree of linearity, accuracy, precision, sensitivity and robustness over the existing liquid chromatographic methods of the drug. Also the method was applied for the estimation of TMx in nanostructured formulations, which indicated no significant change in the retention time. In a nutshell, the studies demonstrated successful development of the HPLC method of TMx with improved understanding of the relationship among the influential variables for enhancing the method performance.

Novel dietary lipid-based self-nanoemulsifying drug delivery systems of paclitaxel with p-gp inhibitor: implications on cytotoxicity and biopharmaceutical performance.

OBJECTIVES: This work describes the development and characterization of novel self-nanoemulsifying drug delivery systems (SNEDDS) employing polyunsaturated fatty acids for enhancing the oral bioavailability and anticancer activity of paclitaxel (PTX) by coadministration with curcumin (Cu). METHODS: Preformulation studies endorsed sesame oil, labrasol, and sodium deoxycholate as lipid surfactants and cosurfactants based on their solubility for the drugs and spontaneity of emulsification to produce nanoemulsions. Further, phase titration studies were performed to identify a suitable nanoemulsion region for preparing the SNEDDS formulation. RESULTS: The prepared formulations were characterized through in vitro, in situ, and in vivo studies to evaluate the biopharmaceutical performance. In vitro drug release studies showed 2.8- to 3.4-fold enhancement in the dissolution rate of both drugs from SNEDDS as compared with the pure drug suspension. Cell line studies revealed 1.5- to 2.7-fold reduction in the cytotoxicity on MCF-7 cells by plain PTX-SNEDDS and PTX-Cu-SNEDDS vis-à-vis the PTX-suspension. In situ intestinal perfusion studies revealed significant augmentation in permeability and absorption parameters of drug from PTX-Cu-SNEDDS over the plain PTX-SNEDDS and PTX-suspension (p < 0.001). In vivo pharmacokinetic studies also showed a remarkable improvement (i.e., 5.8- to 6.3-fold) in the oral bioavailability (Cmax and AUC) of the drug from PTX-SNEDDS and PTX-Cu-SNEDDS vis-à-vis the PTX-suspension. CONCLUSIONS: Overall, the studies corroborated superior biopharmaceutical performance of PTX-Cu-SNEDDS.

QbD-based systematic development of novel optimized solid self-nanoemulsifying drug delivery systems (SNEDDS) of lovastatin with enhanced biopharmaceutical performance.

Of late, solid self-nanoemulsifying drug delivery systems (S-SNEDDS) have been extensively sought-after owing to their superior portability, drug loading, stability and patient compliance. The current studies, therefore, entail systematic development, optimization and evaluation (in vitro, in situ and in vivo) of the solid formulations of (SNEDDS) lovastatin employing rational quality by design (QbD)-based approach of formulation by design (FbD). The patient-centric quality target product profile (QTPP) and critical quality attributes (CQAs) were earmarked. Preformulation studies along with initial risk assessment facilitated the selection of lipid (i.e. Capmul MCM), surfactant (i.e. Nikkol HCO-50) and co-surfactant (i.e. Lutrol F127) as CMAs for formulation of S-SNEDDS. A face-centered cubic design (FCCD) was employed for optimization using Nikkol-HCO50 (X1) and Lutrol-F127 (X2), evaluating CQAs like globule size, liquefaction time, emulsification time, MDT, dissolution efficiency and permeation parameter. The design space was generated using apt mathematical models, and the optimum formulation was located, followed by validation of the FbD methodology. In situ SPIP and in vivo pharmacodynamic studies on the optimized formulation carried out in unisex Wistar rats, corroborated superior drug absorption and enhanced pharmacodynamic potential in regulating serum lipid levels. In a nutshell, the present studies report successful QbD-oriented development of novel oral S-SNEDDS of lovastatin with distinctly improved biopharmaceutical performance.

Recent advances in self-emulsifying drug delivery systems (SEDDS).

One of the biggest challenges confronting the contemporary drug delivery science today is to improve on the oral bioavailability of a vast number of drugs exhibiting poor and inconsistent gastrointestinal absorption. Self-emulsifying drug delivery systems (SEDDS) have been proved as highly useful technological innovations to surmount such bioavailability hiccups by virtue of their diminutive globule size, higher solubilization tendency for hydro-phobic drugs, robust formulation advantages, and easier scalability in the industrial milieu. Besides, these systems are also known to inhibit the P-glycoprotein (P-gp) efflux, reduce metabolism by gut Cytochrome P-450 enzymes, and circumnavigate the hepatic first-pass effect, facilitating absorption of drugs via intestinal lymphatic pathways. In the last two decades, the phenomenal success of SEDDS as a potential tool for oral delivery of drugs has extrapolated their applications to non-oral delivery also. Various innovative approaches and patented techniques have been reported on formulation of diverse oral and non-oral self-emulsifying (SE) systems not only of various synthetic and semisynthetic drugs, but also of several phytopharmaceuticals, nutraceuticals, and biological macromolecules. Of late, an escalating number of reports have been pouring in on special types of SE systems, mostly nanosized, employing functional excipients such as polar lipids, phospholipids, cellulosic polymer, diblock polymers, etc. This review paper provides an updated bird's-eye view account on the publications and patents of such novel SE approaches for use in both oral and non-oral therapeutics. Providing a relatively pithy overview, this paper thus endeavors to act as a repertoire of knowledge and know-how to guide the product development scientist in formulating variegated SE systems.