Development of stabilized tenofovir disoproxil tablet: degradation profile, stabilization, and bioequivalence in beagle dogs.

The purpose of this study was to develop a hydrolysis-resistant optimized oral formulation of tenofovir disoproxil (TD) using a stabilizer. To develop a stabilized TD tablet bioequivalent to the commercial TD fumarate (TDF, Viread®) tablet, TD free base was prepared and its degradation profile and stability were investigated. The TD tablet showed antiviral activity, but its absorption was limited in the intestinal tract because of premature degradation. The drug subjected to severe conditions for the stress test was catalyzed under neutral, basic, oxidative, and thermolytic conditions, whereas it was comparatively stable under acidic, photolytic, and humid states. The compatibility study showed that sodium bisulfite (SB) stabilized TD by preventing its degradation in aqueous and 3% peroxide solutions compared with the unstabilized TD. According to the stability analysis and degradation profile, four TD tablet formulations were prepared. The selected TD tablets were composed of non-hygroscopic excipients (lipophilic-fumed silica, anhydrous lactose, and microcrystalline cellulose [MCC]), SB, croscarmellose sodium (CCS), and hydrogenated castor oil (HCO), and were manufactured using a dry granulation method because of their hydrolytic properties. The stabilized TD tablet showed similar dissolution properties as the TDF (Viread®) reference tablet in pH 1.2, 4.0, and 6.8 and water. Moreover, the lower degradation rate of the tablet in simulated gastrointestinal fluid demonstrated that its intestinal absorption might have improved owing to prevention of its enzymatic hydrolysis and the pH effect. Finally, the formulated TD tablet was bioequivalent to the TDF (Viread®) reference tablet in beagle dogs.

Quality-by-design approach for the development of telmisartan potassium tablets.

A quality-by-design approach was adopted to develop telmisartan potassium (TP) tablets, which were bioequivalent with the commercially available Micardis® (telmisartan free base) tablets. The dissolution pattern and impurity profile of TP tablets differed from those of Micardis® tablets because telmisartan free base is poorly soluble in water. After identifying the quality target product profile and critical quality attributes (CQAs), drug dissolution, and impurities were predicted to be risky CQAs. To determine the exact range and cause of risks, we used the risk assessment (RA) tools, preliminary hazard analysis and failure mode and effect analysis to determine the parameters affecting drug dissolution, impurities, and formulation. The range of the design space was optimized using the face-centered central composite design among the design of experiment (DOE) methods. The binder, disintegrant, and kneading time in the wet granulation were identified as X values affecting Y values (disintegration, hardness, friability, dissolution, and impurities). After determining the design space with the desired Y values, the TP tablets were formulated and their dissolution pattern was compared with that of the reference tablet. The selected TP tablet formulated using design space showed a similar dissolution to that of Micardis® tablets at pH 7.5. The QbD approach TP tablet was bioequivalent to Micardis® tablets in beagle dogs.

Fucosterol inhibits adipogenesis through the activation of AMPK and Wnt/ß-catenin signaling pathways.

Fucosterol is a sterol constituent primarily derived from brown algae. Recently, the antiadipogenic effect of fucosterol has been reported; however, its molecular mechanism remains to be studied. Fucosterol effectively upregulated the phosphorylations of both adenosine monophosphate (AMP)-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), and downregulated the expression levels of lipogenesis-related factors. Moreover, fucosterol activated the major components of the Wnt/ß-catenin signaling pathway, including ß-catenin, disheveled 2 (DVL2), and cyclin D1 (CCND1), whereas it inactivated glycogen synthase kinase 3ß (p-GSK3ß) by stimulating its phosphorylation. In the presence or absence of fucosterol, the adipogenic transcriptional factors [peroxisome proliferator activated-receptor γ (PPARγ), CCAAT/enhancer binding protein α (C/EBPα), and sterol regulatory element binding protein-1c (SREBP-1c)] were upregulated by the inhibition of AMPK by compound C or the knockdown of ß-catenin by siRNA. Overall, these data demonstrate that fucosterol prevents adipogenesis by mediating both AMPK- and Wnt/ß-catenin-signaling pathways.

Fucosterol inhibits matrix metalloproteinase expression and promotes type-1 procollagen production in UVB-induced HaCaT cells.

Ultraviolet (UV) radiation damages human skin and causes skin diseases such as epidermal hyperplasia, sunburn, inflammatory responses and photoaging. Photoaging is associated with upregulated matrix metalloproteinase (MMP) expression and downregulated collagen synthesis. Fucosterol, which is isolated from marine brown algae, has been reported to possess antioxidant and anticancer activities; however, its effects on photoaging are unknown. This study assessed the effects of fucosterol on photoaging and investigated its mechanisms of action in UV-irradiated immortalized human keratinocytes (HaCaT) by enzyme-linked immunosorbent assay, semi-quantitative reverse transcription-polymerase chain reaction, Western blot analysis and 2',7'-dichlorofluorescein diacetate assay. Our results showed that fucosterol attenuated UV-induced MMP and inflammatory cytokine expression by deactivating mitogen-activated protein kinases (MAPKs) induced by reactive oxygen species. Fucosterol also increased type-I procollagen and antioxidant enzyme expression. Taken together, fucosterol regulates the expression of MMPs and type-I procollagen in UV-irradiated HaCaT by modulating MAPK, suggesting it as a potential candidate for prevention and treatment of skin aging.