Preparation and evaluation of polymeric microparticulates for improving cellular uptake of gemcitabine

Ji-Ho Lim1,*, Sung-Kyun You1,*, Jong-Suep Baek1, Chan-Ju Hwang1, Young-Guk Na1, Sang-Chul Shin2, Cheong-Weon Cho11College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Gungdong, Yuseonggu, Daejeon, South Korea, 2College of Pharmacy, Chonnam National University, Buggu, Gwangju, South Korea *These authors contributed equally to this workBackground: Gemcitabine must be administered at high doses to elicit the required therapeutic response because of its very short plasma half-life due to rapid metabolism. These high doses can have severe adverse effects.Methods: In this study, polymeric microparticulate systems of gemcitabine were prepared using chitosan as a mucoadhesive polymer and Eudragit L100-55 as an enteric copolymer. The physicochemical and biopharmaceutical properties of the resulting systems were then evaluated.Results: There was no endothermic peak for gemcitabine in any of the polymeric gemcitabine microparticulate systems, suggesting that gemcitabine was bound to chitosan and Eudragit L100-55 and its crystallinity was changed into an amorphous form. The polymeric gemcitabine microparticulate system showed more than 80% release of gemcitabine in 30 minutes in simulated intestinal fluid. When mucin particles were incubated with gemcitabine polymeric microparticulates, the zeta potential of the mucin particles was increased to 1.57 mV, indicating that the polymeric gemcitabine microparticulates were attached to the mucin particles. Furthermore, the F53 polymeric gemcitabine microparticulates having 150 mg of chitosan showed a 3.8-fold increased uptake of gemcitabine into Caco-2 cells over 72 hours compared with gemcitabine solution alone.Conclusion: Overall, these results suggest that polymeric gemcitabine microparticulate systems could be used as carriers to help oral absorption of gemcitabine.Keywords: gemcitabine, polymeric microparticulates, mucoadhesive, enteric coating, cellular uptake, oral absorptio

Sustained Cytotoxicity of Wogonin on Breast Cancer Cells by Encapsulation in Solid Lipid Nanoparticles

While wogonin has been known to have cytotoxicity against various cancer cells, its bioavailability and cytotoxicity are low due to its low water solubility. Therefore, wogonin-loaded solid lipid nanoparticles were fabricated using a hot-melted evaporation technique. The highest solubility of wogonin was observed in stearic acid. Hence, wogonin-loaded solid lipid nanoparticles were composed of stearic acid as the lipid matrix. The physicochemical properties of the wogonin-loaded solid lipid nanoparticles were evaluated by dynamic laser scattering and scanning electron microscopy. The wogonin-loaded solid lipid nanoparticles exhibited sustained and controlled release up to 72 h. In addition, it was observed that the wogonin-loaded solid lipid nanoparticles exhibited enhanced cytotoxicity and inhibited poly (ADP-ribose) polymerase in MCF-7 breast cancer cells. Overall, the results indicate that wogonin-loaded solid lipid nanoparticles could be an efficient delivery system for the treatment of breast cancer

Enhanced Controlled Transdermal Delivery of Torasemide Using Ethylene-vinyl Acetate

Purpose: To develop an ethylene-vinyl acetate (EVA) matrix system containing a permeation enhancer for enhanced transdermal delivery of torasemide. Methods: The solubility of torasemide was studied at various volume fraction of polyethylene glycol (PEG) 400. The effect of drug concentration was tested at 1.0, 2.0 and 3.0 %, respectively while the effect of temperature on drug release from drug-EVA matrix was evaluated at 27, 32, 37 and 42 oC. To increase pore size and flexibility of the EVA matrix, plasticizers with citrate and phthalate groups were added to the matrix containing torasemide. To improve the penetration of torasemide from the EVA matrix across the skin, enhancers (propylene glycol derivatives, fatty acids, glycerides, pyrrolidones and non-ionic surfactants) were incorporated into the torasemide-EVA matrix. The effects of the enhancers on the skin penetration were evaluated using Franz diffusion cell fitted with the intact excised rat skin. Results: Solubility and permeation of torasemide was highest at 40 %v/v PEG 400. The release rate of drug from drug-EVA matrix increased with increased loading dose and temperature. Release rate was proportional to the square root of loading dose. The activation energy (Ea), which was derived from the slope of log P versus 1000/T, was 14.95 kcal/mol for 2.0% loading dose. Among the plasticizers used, diethyl phthalate showed the highest release rate of torasemide. Among the enhancers used, polyoxyethylene 2-oleyl ether showed the greatest enhancing effect. Conclusion: For the enhanced controlled transdermal delivery of torasemide, the application of the EVA matrix containing plasticizer and penetration enhancer could be useful in the development of a transdermal drug delivery system

Enhanced Controlled Transdermal Delivery of Torasemide Using Ethylene-vinyl Acetate

Purpose: To develop an ethylene-vinyl acetate (EVA) matrix system containing a permeation enhancer for enhanced transdermal delivery of torasemide. Methods: The solubility of torasemide was studied at various volume fraction of polyethylene glycol (PEG) 400. The effect of drug concentration was tested at 1.0, 2.0 and 3.0 %, respectively while the effect of temperature on drug release from drug-EVA matrix was evaluated at 27, 32, 37 and 42 oC. To increase pore size and flexibility of the EVA matrix, plasticizers with citrate and phthalate groups were added to the matrix containing torasemide. To improve the penetration of torasemide from the EVA matrix across the skin, enhancers (propylene glycol derivatives, fatty acids, glycerides, pyrrolidones and non-ionic surfactants) were incorporated into the torasemide-EVA matrix. The effects of the enhancers on the skin penetration were evaluated using Franz diffusion cell fitted with the intact excised rat skin. Results: Solubility and permeation of torasemide was highest at 40 %v/v PEG 400. The release rate of drug from drug-EVA matrix increased with increased loading dose and temperature. Release rate was proportional to the square root of loading dose. The activation energy (Ea), which was derived from the slope of log P versus 1000/T, was 14.95 kcal/mol for 2.0% loading dose. Among the plasticizers used, diethyl phthalate showed the highest release rate of torasemide. Among the enhancers used, polyoxyethylene 2-oleyl ether showed the greatest enhancing effect. Conclusion: For the enhanced controlled transdermal delivery of torasemide, the application of the EVA matrix containing plasticizer and penetration enhancer could be useful in the development of a transdermal drug delivery system

Enhanced Supersaturation and Oral Absorption of Sirolimus Using an Amorphous Solid Dispersion Based on Eudragit® E

The present study aimed to investigate the effect of Eudragit® E/HCl (E-SD) on the degradation of sirolimus in simulated gastric fluid (pH 1.2) and to develop a new oral formulation of sirolimus using E-SD solid dispersions to enhance oral bioavailability. Sirolimus-loaded solid dispersions were fabricated by a spray drying process. A kinetic solubility test demonstrated that the sirolimus/E-SD/TPGS (1/8/1) solid dispersion had a maximum solubility of 196.7 μg/mL within 0.5 h that gradually decreased to 173.4 μg/mL after 12 h. According to the dissolution study, the most suitable formulation was the sirolimus/E-SD/TPGS (1/8/1) solid dispersion in simulated gastric fluid (pH 1.2), owing to enhanced stability and degree of supersaturation of E-SD and TPGS. Furthermore, pharmacokinetic studies in rats indicated that compared to the physical mixture and sirolimus/HPMC/TPGS (1/8/1) solid dispersion, the sirolimus/E-SD/TPGS (1/8/1) solid dispersion significantly improved oral absorption of sirolimus. E-SD significantly inhibited the degradation of sirolimus in a dose-dependent manner. E-SD also significantly inhibited the precipitation of sirolimus compared to hydroxypropylmethyl cellulose (HPMC). Therefore, the results from the present study suggest that the sirolimus-loaded E-SD/TPGS solid dispersion has great potential in clinical applications