Topical Semisolid Drug Product Critical Quality Attributes with Relevance to Cutaneous Bioavailability and Pharmacokinetics: Part I-Bioequivalence of Acyclovir Topical Creams.

PURPOSE: To develop a toolkit of test methods for characterizing potentially critical quality attributes (CQAs) of topical semisolid products and to evaluate how CQAs influence the rate and extent of active ingredient bioavailability (BA) by monitoring cutaneous pharmacokinetics (PK) using an In Vitro Permeation Test (IVPT). METHODS: Product attributes representing the physicochemical and structural (Q3) arrangement of matter, such as attributes of particles and globules, were assessed for a set of test acyclovir creams (Aciclostad® and Acyclovir 1A Pharma) and compared to a set of reference acyclovir creams (Zovirax® US, Zovirax® UK and Zovirax® Australia). IVPT studies were performed with all these creams using heat-separated human epidermis, evaluated with both, static Franz-type diffusion cells and a flow through diffusion cell system. RESULTS: A toolkit developed to characterize quality and performance attributes of these acyclovir topical cream products identified certain differences in the Q3 attributes and the cutaneous PK of acyclovir between the test and reference sets of products. The cutaneous BA of acyclovir from the set of reference creams was substantially higher than from the set of test creams. CONCLUSIONS: This research elucidates how differences in the composition or manufacturing of product formulations can alter Q3 attributes that modulate myriad aspects of topical product performance. The results demonstrate the importance of understanding the Q3 attributes of topical semisolid drug products, and of developing appropriate product characterization tests. The toolkit developed here can be utilized to guide topical product development, and to mitigate the risk of differences in product performance, thereby supporting a demonstration of bioequivalence (BE) for prospective topical generic products and reducing the reliance on comparative clinical endpoint BE studies.

Radical scavenging and anti-inflammatory activities of (hetero)arylethenesulfonyl fluorides: Synthesis and structure-activity relationship (SAR) and QSAR studies.

A series of (hetero)arylethenesulfonyl fluorides (1-58) were synthesized and screened for their in vitro antioxidant (DPPH, ABTS and DMPD methods) and anti-inflammatory activities. The results revealed that compounds 4, 15, 16, 24, 25, 26, 38, 39, 40, and 54 exhibited excellent antioxidant activity using all the three performed antioxidant methods, which were superior to the standard antioxidants ascorbic acid and gallic acid. Compounds 6-9, 11, 18, 19, 21, 22, 30, 39, 40, 44, 45, 48-50, 54, 55 and 57 displayed promising anti-inflammatory activity, which were better than the reference drug indomethacin. Preliminary structure-activity relationship (SAR) revealed that compounds containing electron donating (OH and OCH3) groups on the phenyl ring possessed excellent antioxidant properties while compounds containing electron-withdrawing (Cl, NO2, F and Br) groups on the phenyl ring were found to be most potent anti-inflammatory agents. The presence of SO2F group played a crucial role in increases both antioxidant and anti-inflammatory activities.

Xanthone Conjugated Amino Acids as Potential Anticancer and DNA Binding Agents: Molecular Docking, Cytotoxicity and SAR Studies.

BACKGROUND: Amino acids conjugated with heterocyclic molecules are well known for their effective bioactive properties. In search of effective anticancer agents, a series of xanthone linked amino acids 2-23 were synthesized and tested for in vitro anticancer activity. METHODS: In vitro anticancer activity of the synthesized xanthone linked amino acids 2-23 are tested against three different cancer cell lines MCF-7, MDA-MB-435 and A549 by MTT assay and validated by DNA binding and molecular docking approaches. Doxorubicin and ethidium bromide used as standard and positive control respectively. RESULTS: Compounds 7, 8 and 9 exhibited potent anticancer activity against tested cancer cell lines and DNA binding study using methyl green. In the molecular docking study, binding interactions of the most active compounds 7, 8 and 9 were confirmed to molecular surface of DNA. CONCLUSION: Structure-Activity Relationship (SAR) showed that the aromatic and hydrophobic amino acids (phenylalanine, tyrosine, and tryptophan) favoured the DNA binding studies and anticancer activity whereas, aliphatic amino acids showed least anticancer activity.

Human skin penetration and local effects of topical nano zinc oxide after occlusion and barrier impairment.

Public health concerns continue to exist over the safety of zinc oxide nanoparticles that are commonly used in sunscreen formulations. In this work, we assessed the effects of two conditions which may be encountered in everyday sunscreen use, occlusion and a compromised skin barrier, on the penetration and local toxicity of two topically applied zinc oxide nanoparticle products. Caprylic/capric triglyceride (CCT) suspensions of commercially used zinc oxide nanoparticles, either uncoated or with a silane coating, were applied to intact and barrier impaired skin of volunteers, without and with occlusion for a period of six hours. The exposure time was chosen to simulate normal in-use conditions. Multiphoton tomography with fluorescence lifetime imaging was used to noninvasively assess zinc oxide penetration and cellular metabolic changes that could be indicative of toxicity. We found that zinc oxide nanoparticles did not penetrate into the viable epidermis of intact or barrier impaired skin of volunteers, without or with occlusion. We also observed no apparent toxicity in the viable epidermis below the application sites. These findings were validated by ex vivo human skin studies in which zinc penetration was assessed by multiphoton tomography with fluorescence lifetime imaging as well as Zinpyr-1 staining and toxicity was assessed by MTS assays in zinc oxide treated skin cryosections. In conclusion, applications of zinc oxide nanoparticles under occlusive in-use conditions to volunteers are not associated with any measurable zinc oxide penetration into, or local toxicity in the viable epidermis below the application site.

Effect of caffeine and alcohol on the toxicity and metabolism of methacrylonitrile in male Sprague-Dawley rats.

This study reports the toxicity and metabolism of methacrylonitrile (MeAN) in normal male Sprague-Dawley rats and those pre-treated with caffeine, alcohol or both. Rats were divided into groups often. One group received an oral dose by gavage of 6 % MeAN solution in corn oil (equivalent to 0.5 LD50). Other three groups of rats were pre-treated with alcohol (2 ml of 50% solution in water), caffeine (1 ml of 2% solution in water) or both alcohol and caffeine 12 hr before receiving MeAN dose by gavage. The rats were observed for mortality, cholinomimetic and central nervous system (CNS) effects and urinary dysfunction for 6 hr. The concentrations of cyanide, thiocyanate and glutathione (GSH) were determined in blood, liver, kidney and brain. Alcohol and alcohol + caffeine pre-treatment caused significant increase in cholinomimetic, CNS and urinary dysfunction effects of MeAN and mortality. However, caffeine alone pre-treatment protected rats from these effects. In the rats treated with MeAN alone and those pre-treated with alcohol and alcohol + caffeine the GSH concentrations significantly decreased in liver, brain and kidney. In the rats pre-treated with caffeine alone the concentrations of GSH were not significantly different from controls. In the rats treated with MeAN alone and those pretreated with alcohol and alcohol + caffeine the cyanide and thiocyanate concentrations increased in the blood and other organs up to 2-4 folds whereas in rats pre-treated with caffeine alone the concentrations of cyanide and thiocyanate were not significantly different from controls. Western Blot experiment showed CYP2E1 induction in rats pretreated with alcohol and MeAN. These results suggest that caffeine inhibited and alcohol enhanced toxicity and metabolism of MeAN.