Enhanced oral bioavailability of paclitaxel by solid dispersion granulation

The main objective of this study was to develop novel orally administrable tablets containing solid dispersion granules (SDG) of amorphous paclitaxel (PTX) prepared by fluid bed technology, and to evaluate its in vitro dissolution and in vivo pharmacokinetics (PK) in beagle dogs. The SDG were prepared using optimized composition by fluid bed technology, and characterized for solid-state properties. The release study of SDG tablet (SDG-T) in simulated gastric fluid showed a rapid release of PTX, reaching maximum dissolution within 20?min. Finally, the PK profile of SDG-T and a reference formulation Oraxol? (oral solution formulation used in Phase I clinical study) at a dose of 60?mg orally with co-administration of P-gp inhibitor HM38101, and Taxol® at a dose of 10?mg intravenously (i.v.) was investigated in beagle dogs. The mean absolute BA% of PTX following SDG-T and Oraxol? solution was 8.23 and 6.22% in comparison to i.v. administration of Taxol®. The relative BA% of PTX from SDG-T in comparison to Oraxol? solution was 132.25% at a dose of 60?mg following oral administration. In conclusion, we have successfully prepared PTX tablets with solid dispersion granules (SDG) of amorphous PTX using fluid bed technology that could provide plasma PTX concentration in the range of 10–150?ng/mL for a period of 24?h following oral administration in dogs with a P-gp inhibitor. Hence, this could be a promising formulation for PTX oral delivery and could be used in our intended clinical studies following pre-clinical efficacy studies.     

N′‐Alkylaminosulfonyl Analogues of 6‐Fluorobenzylideneindolinones with Desirable Physicochemical Profiles and Potent Growth Inhibitory Activities on Hepatocellular Carcinoma

The benzylideneindolinone 6‐chloro‐3‐(3′‐trifluoromethylbenzylidene)‐1,3‐dihydroindol‐2‐one ( 4 ) was reported to exhibit potent and selective growth inhibitory effects on hepatocellular carcinoma (HCC). Corroborative evidence supported multi‐receptor tyrosine kinase (RTK) inhibition as a possible mode of action. However, the poor physicochemical properties of 4 limited its furtherance as a lead compound. In this study, the modification of 4 was investigated with the aim of improving its potency and physicochemical profile. The 6‐fluorobenzylideneindolinone 3‐12 bearing a 3′‐N‐propylaminosulfonyl substituent was found to be a promising substitute. Compound 3‐12 [6‐fluoro‐3‐(3′‐N‐propylaminosulfonylbenzylidene)‐1,3‐dihydroindol‐2‐one] was found to be tenfold more soluble than 4 and to have sub‐micromolar growth inhibitory activities on HCC cells. It is apoptogenic and inhibits the phosphorylation of several RTKs in HuH7, of which the inhibition of FGFR4 and HER3 are prominent. Compound 3‐12 decreased the tumor load in a physiologically relevant orthotopic HCC xenograft murine model. Structure–activity relationships support pivotal roles for the fluoro and N′‐propylaminosulfonyl moieties in enhancing cell‐based activity and moderating the physicochemical profile (solubility, permeability) of 3‐12 .     

Sildenafil vaginal suppositories: preparation,characterization, in vitro and in vivo evaluation

Aim: The main objective was to investigate the in vitro release profile/kinetics, and in vivo plasma pharmacokinetics (PK) and organ biodistribution (BD) of the prepared sildenafil vaginal suppositories (SVS).

Methods: Suppositories containing 25?mg of sildenafil were prepared by the cream melting technique using Witepsol H-15 as a suppository base. The suppositories were characterized for weight variation, content uniformity, hardness, disintegration time and crystallinity change. The in vitro dissolution in pH 4.5, and in vivo plasma PK and organ BD of sildenafil from SVS in female Sprague Dawley rats, were also investigated.

Results: The mean weight variation, content uniformity, hardness and disintegration time of the prepared SVS were 1.127?±?0.020?g, 98.25?±?2.50%, 2.5?±?0.08?kg and 9?±?1.0?min, respectively. The release of sildenafil from the SVS was more than 90% at 30?min, with a release kinetic of Hixson--Crowell model and non-Fickian diffusion (n?=?0.464). The plasma PK study demonstrated a significantly lower C_max (～10 times) and AUC_0–24?h (～13 times) of sildenafil in plasma following intravaginal (IVG) administration of suppositories compared to oral (PO) administration of sildenafil solution. Nevertheless, the organ BD study showed a phenomenally higher C_max (～40 times) and AUC_0–24?h (～20 times) of sildenafil in uterus following IVG administration of suppositories than PO administration of sildenafil solution.

Conclusion: This study demonstrated enhanced sildenafil exposure in the uterus following IVG administration of SVS, which could be used to target the uterus for therapeutic benefits.     

Comparing the performance of UASB and GRABBR treating low strength wastewaters

Anaerobic technologies have proved successful in the treatment of various high strength wastewaters with perceptible advantages over aerobic systems. The applicability of anaerobic processes to treat low strength wastewaters has been increasing with the evolution of high-rate reactors capable of achieving high sludge retention time (SRT) when operating at low HRT. However, the performance of these systems can be affected by high variations in flow and wastewater composition. This paper reports on the comparative study carried out with two such high rate reactors systems to evaluate their performances when used for the treatment of low strength wastewaters at high hydraulic rates. One of the two systems is the most commonly used upflow anaerobic sludge blanket (UASB) reactor in which all reactions occur within a single vessel. The other is the granular bed baffled reactor (GRABBR) that encourages different stages of anaerobic digestion in separate vessels longitudinally across the reactor. The reactors, with equal capacity of 10 litres, were subjected to increasing organic loading rates (OLRs) and hydraulic retention times (HRTs) of up to 60 kg COD m(-3) d(-1) and 1 h respectively. Results show that the GRABBR has greater processes stability at relatively low HRTs, whilst the UASB seems to be better equipped to cope with organic overloads or shockloads. The study also shows that the GRABBR enables the harvesting of biogas with greater energetic value and hence greater re-use potential than the UASB. Biogas of up to 86% methane content is obtainable with GRABBR treating low strength wastewaters.     

On estimating the mean time to failure with unknown censoring

Sometimes, in reliability studies, neither the life of all failed units nor the number of units still functioning is known at any specific time due to problems such as administrative delays. Consequently, one might consider an estimate of the mean time to failure (MTTF) based only on known failure times of part of the units. An investigation is conducted into the bias and efficiency of such an estimator for either an exponential or a Weibull distribution. In the exponential case, exact expressions are obtained, and, for the Weibull case, a Monte Carlo simulation was used. The estimate of MTTF based on known lifetimes of failed units alone underestimates with smaller variance and higher mean squared error than does the estimate based on the total accumulated lifetime of both failed and surviving units     

Geographic Information System for Coordination of Fast-Track Projects

To meet the increasing demands to deliver projects within a short period of time, many projects are being executed on a fast-track basis. On fast-track projects, the construction begins when the design is between 35% and 65% complete. This poses numerous challenges. One of the key challenges is to ensure that the flow of information and deliverables between the engineering, procurement, and construction is synchronized. This work initially studied the information flow on process plant projects, the disruptions to information flow, and the problems faced due to the disruptions. It was identified that an information system that has the capability to (1) capture the relationships between different deliverables, (2) record the status of deliverables, and (3) process queries from any of the teams regarding status and impact of disruptions will support the decision-making required for rapid development of pragmatic plans. Further, as the information requirements require the representation and querying of both spatial and nonspatial data, the design and implementation of the system using the concepts and features of a geographic information system was explored. The paper discusses the design of the geographic information system and its implementation within the AutoCAD Map environment. The use of the system to retrieve information required for project coordination is illustrated through sample queries.     

Height gain measurements for DTV reception in Singapore

Very few height-gain measurements have been made especially in built-up areas. Measurements made in Singapore confirm that the height-gain is different in different locations and depends on the local clutter, ground reflection and the radiation pattern of the transmitting antenna. In high rise HDB (Housing Development Board) estates, height loss is observed instead of gain.     

Statistical optimization of conditions for minimum H2 consumption in mixed anaerobic cultures: Effect on homoacetogenesis and methanogenesis

Hydrogen (H₂) production using mixed anaerobic cultures often suffers severe yield reduction due to the syntrophic association between H₂ consumers (methanogens and homoacetogens) and H₂ producers (acidogens). The objective of this study was to uncouple the syntrophic association between H₂ producers and consumers by optimizing conditions for minimum H₂ consumption using a Box–Behnken design approach. The factors investigated in this study include temperature, pH and linoleic acid (LA) concentration. A quadratic response surface model was developed to predict the H₂ consumed by mixed anaerobic cultures and the optimum conditions for minimum H₂ consumption were 38 °C, pH 5.5 and 2 g L⁻¹ LA. Methanogenesis was inhibited in cultures fed 2 g L⁻¹ LA and maintained at pH 6.0 and 53 °C. In comparison, both methanogenesis and homoacetogenesis were inhibited in cultures fed 1–2 g L⁻¹ LA and maintained at a pH of 4.5 (Fig. 2B and 2E and Table 2 Expt. # 1, 2 and 11). Microbial diversity analysis revealed that LA fed cultures was dominated by spore forming Clostridium sp. in addition to Syntrophus aciditrophus. In comparison, control cultures were dominated by Eubacterium sp., Methanocalculus halotolerans and Methanococcoides alaskense. This study described an approach for regulating H₂ consumption in mixed cultures by optimizing process and environmental factors. Understanding the effects of these individual factors and their interaction is important in the full-scale operation of H₂ production facilities.