Risk Assessment and QbD-Based Optimization of Sorafenib Tosylate Colon Targeted Bilayer Tablet: In Vitro Characterization, In Vivo Pharmacokinetic, and In Vivo Roentgenography Studies.

The employment of site-specific administration in colon is a promising technique to improve efficacy and reduce systemic side effects of anticancer medications used in colorectal cancer. However, the physiology of the gastrointestinal tract and colonic environment limit the efficient delivery of orally administered anticancer drugs to the colon. These prerequisites can be fulfilled by a release modulated colon targeted drug delivery system (CTDDS) based on pH-dependent chronotherapeutic bilayer tablet of sorafenib tosylate (ST). Quality by design (QbD) was used to examine the risk assessment. The Box-Behnken design was used to optimize the core uncoated bilayer tablet, whereas the 22 factorial design was used to optimize the coating process. The amount of croscarmellose sodium, Eudragit® RLPO, and tablet hardness all had a significant impact on disintegration time and drug release, according to the results of the core uncoated bilayer optimization. The amount of Eudragit® S 100 and PEG 400 in the final coated tablet had a considerable impact on drug release. The optimized formulation demonstrated 5-h lag time, a peculiar feature of CTDDS. The pharmacokinetic studies of coated tablet in rabbits showed lower Cmax (4.45 ± 0.40 µg/mL) and AUC (148.52 ± 3.96 h µg/mL), whereas Tmax was substantially delayed (8.0 ± 0.57 h) compared to core uncoated tablet. The tablet remained intact until it reached the colon (> 4 h), according to the in vivo roentgenography studies. The present study revealed that a QbD approach can be useful to develop a rugged and scalable CTDDS.

QbD-based optimization of raloxifene-loaded cubosomal formulation for transdemal delivery: ex vivo permeability and in vivo pharmacokinetic studies.

Raloxifene (RLX) is a drug that is commonly recommended to postmenopausal women at high risk of invasive breast cancer and to prevent osteoporosis. However, limited water solubility (0.000512 mg/ml) and low oral bioavailability (2%) of RLX limit its therapeutic utility. The objective of the present study was to develop an alternative transdermal delivery of RLX to improve its absorption, bypass first pass metabolism, and subsequently improve bioavailability. RLX-loaded cubosomes were prepared using the ethanol injection method followed by microfluidization technique and optimized using the QbD-based 23 factorial design. The average particle size, entrapment efficiency, and zeta potential of the optimized formulation were found to be 110.6 nm, 98.23%, and 26.2 mV, respectively. In vitro dissolution study indicated that the RLX-loaded cubosomes released 98.26% of the drug compared to pure RLX dispersion (58.6%). Histopathological examination revealed no sign of inflammation, indicating the safety of the developed formulation. Accelerated stability study as per ICH guidelines displayed no significant change in the formulation characteristics and drug-related performance of the developed formulation. Ex vivo permeability studies demonstrated a prolonged release from cubosomal formulation. In vivo pharmacokinetic studies revealed that the relative bioavailability of the optimized transdermal RLX-loaded cubosomes increased by 2.33-fold and 1.22-fold when compared with the oral RLX dispersion and transdermal RLX hydro-ethanolic solution respectively. IVIVC showed level C correlation with linear regression. Thus, the developed RLX-loaded cubosomes may have potential to overcome the problems associated with the existing marketed oral dosage forms of RLX.

Optimization of Diltiazem hydrochloride osmotic formulation using QBD approach

Abstract Diltiazem hydrochloride (DLH) is a calcium channel blocker useful for the treatment of angina pectoris, arrhythmia, and hypertension. DLH having a short half-life needs frequent administration for successful treatment but this poses a problem of poor patient compliance. These requirements are served by elementary osmotic pump tablets (EOP) based controlled-release (CR) systems. Quality by design (QbD) approach assists in screening various factors with subsequent assessment of critical parameters that can have a major impact on the scalability of EOP. Tablets were formulated using wet granulation method followed by osmotic coating. Factorial design based QbD strategy aided in defining the risk assessment of influential variables such as hydrophilic polymers and osmotic coat component on the in-vitro release kinetics of the designed EOP tablets. These formulated EOP systems followed zero-order kinetics, a characteristic feature of EOPs. EOP tablets were formulated applying a systematic QbD statistical approach. The formulated DLH EOP systems with improved concentration-independent behavior helped to address the challenges of IR formulation. Application of QbD strategy in ascertaining the scalability of DLH EOP formulation would help pharmaceutical industries in the translation of EOP based drug delivery systems from R&D to market.