Studies on the new drug forms of SERM (Selective estrogen receptor modulators) group drugs raloxifene and tamoxifen

In this study, two active substances (raloxifene hydrochloride and tamoxifene citrate) from the group of SERM were used to prepare and develop orally applicable new dosage forms for the treatment of breast tumors and in vitro and in vivo experiments were performed to enhance their therapeutic effectiveness. Liposome, nanoparticulate and cochleate formulations of raloxifene and tamoxifene were developed containing penetration enhancer (dimethyl- ? -cyclodextrin or sodium taurocholate). Developed formulations were characterized and permeability properties through Caco-2 cell lines were investigated by compared with their solutions and finally permeability coefficients were calculated. Permeability coefficients (as logk) were found to be 4.14, 1.59, 1.22 and 1.22 cm/hour for raloxifen dimethyl- ? -CD liposomes, raloxifen dimethyl- ? -CD cochleates, tamoxifene dimethyl- ? -CD liposomes and tamoxifene dimethyl- ? -CD cochleates respectively. Antitumor activity determinations and MMP-2 enzyme inhibition tests were performed using MCF-7 and MDA-MB 231 cell lines. All formulations were administered to Balb-C healthy female mice and blood concentration profiles were obtained. These profiles were compared with permeability experiment results and in vivo in vitro correlation studies were performed. In general, permeability coefficients were found to be enhanced when dimethyl- ? -CD was present in the formulation (especially for lipid containing formulations). The best formulation selected after in vitro and in vivo studies and then applied orally to the Sprague Dawley female rats whose have breast tumor. Therapeutic effectiveness?s of formulations were evaluated by the tumor mass measurements and pathological observations. Maximum tumor mass reduction was observed after raloxifene dimethyl- ? -CD cochleates (94.8%) reduction p ? 0.001) administration and tamoxifene dimethyl- ? -CD liposomes (92.5% reduction p ? 0.001) administration. Therapeutic effectiveness of raloxifene dimethyl- ? -CD cochleates was found to be the best (60%) where thearepeutical effectiveness of tamoxifene dimethyl- ? -CD liposomes was found to be 50%. Stability studies were also performed for selected formulations and cochleate formulations were found to increase their shelf life.