Evaluation of in vitro mucoadhesiveness and texture profile analysis of doxycycline in situ hydrogels

Acknowledgements: This work was supported by a research grant from the University of Iceland (Rannsóknarsjóður Háskóla Íslands). Publisher Copyright: © 2020 Govi-Verlag Pharmazeutischer Verlag GmbH. All rights reserved.Delivery of active ingredients to the oral mucosa from topically applied formulations reduces side effects from systemic administration and enhances the treatment efficiency. The challenge however, is to maintain the formulation at the administration site due to rapid salivary flow and mechanical movements of the mouth. Therefore, addition of mucoadhesive polymers could aid in enhancing the formulation residence time by increasing the mucoadhesion capacity but this effect is negligible especially if low ratio of mucoadhesive polymers are added to the formulation. Different mucoadhesive polymers at 0.5% w/w (either single or combination of two polymers) were added to the hydrogels and tested for mucoadhesion capacity, tensile strengths, adhesiveness, cohesiveness, compressibility and hardness. 0.5% povidone showed significantly highest work of mucoadhesion, 0.5% Carbopol formulation showed least cohesiveness and 0.5% HPMC showed highest adhesiveness, but a formulation containing a combination of 0.25% HPMC and 0.25% povidone showed the ideal parameters among all the mucoadhesive polymers tested. The effect of increase in concentration of HPMC (0.5, 1, 1.5, 2%) showed linear relationship for work of mucoadhesion and tensile strengths whereas for TPA the values were non-linear. The drug release from the optimized polymer matrices was found to follow zero-order release profile and the mechanism was found to be super case-II transport relaxation release. The results of this study indicate the mucoadhesive polymers do not impact the tensile strengths (p=0.05), but the texture properties and work of mucoadhesion of the formulations can be significantly (p<0.05) altered by the choice of mucoadhesive component at 0.5%w/w, though not for all the polymers tested. The study provides scope to predict in vivo performance and helps optimize for localized delivery.Peer reviewe

Chemopreventive Effects of the p53-Modulating Agents CP-31398 and Prima-1 in Tobacco Carcinogen-Induced Lung Tumorigenesis in A/J Mice

AbstractLung cancer is the leading cause of cancer deaths worldwide. Expression of the p53 tumor suppressor protein is frequently altered in tobacco-associated lung cancers. We studied chemopreventive effects of p53-modulating agents, namely, CP-31398 and Prima-1, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung adenoma and adenocarcinoma formation in female A/J mice. Seven-week-old mice were treated with a single dose of NNK (10 µmol/mouse) by intraperitoneal injection and, 3 weeks later, were randomized to mice fed a control diet or experimental diets containing 50 or 100 ppm CP-31398 or 150 or 300 ppm Prima-1 for either 17 weeks (10 mice/group) or 34 weeks (15 mice/group) to assess the efficacy against lung adenoma and adenocarcinoma. Dietary feeding of 50 or 100 ppm CP-31398 significantly suppressed (P < .0001) lung adenocarcinoma by 64% and 73%, respectively, after 17 weeks and by 47% and 56%, respectively, after 34 weeks. Similarly, 150 or 300 ppm Prima-1 significantly suppressed (P < .0001) lung adenocarcinoma formation by 56% and 62%, respectively, after 17 weeks and 39% and 56%, respectively, after 34 weeks. Importantly, these results suggest that both p53 modulators cause a delay in the progression of adenoma to adenocarcinoma. Immunohistochemical analysis of lung tumors from mice exposed to p53-modulating agents showed a significantly reduced tumor cell proliferation and increased accumulation of wild-type p53 in the nucleus. An increase in p21- and apoptotic-positive cells was also observed in lung tumors of mice exposed to p53-modulating agents. These results support a chemopreventive role of p53-modulating agents in tobacco carcinogen-induced lung adenocarcinoma formation

Osteoinduction of Human Mesenchymal Stem Cells by Bioactive Composite Scaffolds without Supplemental Osteogenic Growth Factors

The development of a new family of implantable bioinspired materials is a focal point of bone tissue engineering. Implant surfaces that better mimic the natural bone extracellular matrix, a naturally nano-composite tissue, can stimulate stem cell differentiation towards osteogenic lineages in the absence of specific chemical treatments. Herein we describe a bioactive composite nanofibrous scaffold, composed of poly-caprolactone (PCL) and nano-sized hydroxyapatite (HA) or beta-tricalcium phosphate (TCP), which was able to support the growth of human bone marrow mesenchymal stem cells (hMSCs) and guide their osteogenic differentiation at the same time. Morphological and physical/chemical investigations were carried out by scanning, transmission electron microscopy, Fourier-transform infrared (FTIR) spectroscopy, mechanical and wettability analysis. Upon culturing hMSCs on composite nanofibers, we found that the incorporation of either HA or TCP into the PCL nanofibers did not affect cell viability, meanwhile the presence of the mineral phase increases the activity of alkaline phosphatase (ALP), an early marker of bone formation, and mRNA expression levels of osteoblast-related genes, such as the Runt-related transcription factor 2 (Runx-2) and bone sialoprotein (BSP), in total absence of osteogenic supplements. These results suggest that both the nanofibrous structure and the chemical composition of the scaffolds play a role in regulating the osteogenic differentiation of hMSCs