Development and evaluation of activity of nano-delivery systems containing low molecular weight heparin for oral administration

The purpose of this thesis was the development and evaluation of nanodelivery systems to increase the oral bioavailability of enoxaparin (low molecular weight heparin). In line with this goal, three nanosystems were prepared such as, three-layered nanofibers (NF), enoxaparin loaded nanoparticles (NP), three-layered nanofibers prepared by loading nanoparticles (NP/NF). In the preparation of nanofibers, the critical parameters (viscosity, conductivity and surface tension of the polymer solution) for the electrospinning process, were measured and the process parameters (flow rate, voltage, etc.) were optimized. Nanoparticles were prepared by ionic gelation method, to determine the formulation content (polymer concentration, polymer: active substance w/w ratio etc.) and process parameters (mixing speed, duration, etc.), studies were carried out. Eudragit S100 was used in the lower and upper layers of the nanofibers which is a pH dependent polymer. As a result of the SEM images of nanofibers, the surfaces of the fibers were found to be smooth and the fiber diameters were between 300-500 nm. The contact angles of nanofibers were found to be higher than 100º and their porosity higher than 50%. The amount of enoxaparin was between 390-400 μg/cm2 in the fibers. As a result of the in vitro release study, nanofibers delayed the drug release compared to the nanoparticles, but similar permeation properties was found as a result of the permeation study through the rabbit intestinal tissue (p> 0,05). As a result of MTT studies, the safest dose that can be used for Caco-2 permeability studies was 75 µg/mL. A a result of Caco-2 studies no significant difference was found between the permeations of the formulations (p> 0,05). In the stability studies, at the end of 12-month period, there was no significant change in fiber diameters in all conditions (4ºC/ambient humidity, 25ºC / 60% relative humidity and 40ºC / 75% relative humidity), while the drug release and the amount of drug did change. As a result of in vivo studies, the highest coagulation times were reached with oral administered NP and NP/NF formulations (52,7 and 42,8 seconds). Promising results have been achieved for oral administration of enoxaparin as an alternative route to parenteral in terms of patient compliance and ease of administration.