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.

Nanocosmeceuticals: facets and aspects.

The global cosmetic market prized $532.43 billion USD in 2017 is expected to reach $805.61 billion USD by 2023, with a 7.14% compound annual growth rate. These figures have appealed to the cosmeceutical players for developing new and effective products containing advanced materials. Cosmetics incorporated with pharmaceutical actives, termed as 'cosmeceuticals,' are receiving an overwhelming response from cosmetic industry. Nowadays, the implementation of nanotechnology for enhanced effectiveness of cosmeceuticals is witnessing a huge success. These applications include remedies for hair damage, wrinkles, aging and skin dryness. Currently, there is a need to establish regulations and harmonized guidelines for nanotechnology-based products to assess their efficacy, safety and toxicity profiles. This review summarizes current development, applications, safety and regulations of nanocosmeceuticals.

Global Pediatric Regulations: An Overview.

The purpose of the present review is to summarize the current pediatric regulatory requirements and also the regulatory efforts that need to be taken for the potential benefits of safety and efficacy to the pediatric patients. The importance of pediatric regulations came into existence as adult physiological conditions differ from that of children; therefore, the same dosage regimen cannot be recommended for both. Children deviate from adults with respect to pharmacokinetic and pharmacodynamic characteristics, and hence the effect of the drug has to be reconfirmed for pediatrics. Drugs used in pediatric clinics are often considered as "therapeutic orphans" throughout the world as they are difficult to develop and are not provided with sufficient information. The number of clinical trials performed in children is not sufficient. At present, laws and regulations aimed at drug development in the pediatric field have not been focused significantly. There are different regulatory bodies that administrate the pediatric regulations for a particular region.

Development of Sustained Release Oseltamivir Phosphate Dry Powder Inhaler: In-Vitro Characterization and In-Vivo Toxicological Studies.

BACKGROUND: Oseltamivir Phosphate (OP) is an ethyl ester prodrug prescribed for the treatment of influenza virus infection. Current marketed formulations of OP have been observed to be supplemented with an adverse effect during post-marketing surveillance. These prerequisites are sufficed by developing a sustained release Dry Powder for Inhalation (DPI). OBJECTIVE: The objective of the present study was to develop OP-DPI by an innovative formulation approach comprising of Immediate (IR) and Sustained (SR) Release portions. METHODS: DPI formulation comprising IR and SR portions were prepared by spray drying technique using Hydroxy Propyl Methyl Cellulose (HPMC) as the rate-controlling polymer for SR portion. The spray-dried product was further characterized for various pharmaco-technical, in-vitro and in-vivo parameters. RESULTS: OP-DPI showed a burst release of 49% within 15 min further sustaining the drug release up to 9 hrs. The in-vitro aerodynamic performance of OP-DPI showed maximum deposition at stage 3 and Fine Particle Dose (FPD) of 1.08 mg indicating deposition in the upper respiratory tract. Solid-state characterization by DSC and XRD indicated the partial amorphization of OP due to spray drying. In-vivo toxicological 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 solid-state characterization and drug-related performance of OP-DPI. CONCLUSION: Prepared novel and scalable OP-DPI may have the potential to overcome the problems associated with existing marketed dosage forms of OP. Further, localized drug delivery of the antiviral drug through the pulmonary route might be clinically beneficial in controlling the viral proliferation.

Global Pediatric Regulations: An Overview.

The purpose of the present review is to summarize the current pediatric regulatory requirements and also the regulatory efforts that need to be taken for the potential benefits of safety and efficacy to the pediatric patients. The importance of pediatric regulations came into existence as adult physiological conditions differ from that of children; therefore, the same dosage regimen cannot be recommended for both. Children deviate from adults with respect to pharmacokinetic and pharmacodynamic characteristics, and hence the effect of the drug has to be reconfirmed for pediatrics. Drugs used in pediatric clinics are often considered as "therapeutic orphans" throughout the world as they are difficult to develop and are not provided with sufficient information. The number of clinical trials performed in children is not sufficient. At present, laws and regulations aimed at drug development in the pediatric field have not been focused significantly. There are different regulatory bodies that administrate the pediatric regulations for a particular region.