Date of Award
Ph.D. in Pharmaceutical Sciences
Pharmaceutics and Drug Delivery
Retinoblastoma (RB) is a rare type of cancer that develops quickly from immature retinal cells. Enucleation, external beam radiotherapy, episcleral plaque radiotherapy, and cryotherapy have been the treatment options for the RB.
Paclitaxel (PTX) is an effective antineoplastic medication with a wide range of applications in the treatment of malignant tumors., systemic toxicity, quick elimination, and resistance limit its clinical use. Due to its limited solubility, PTX formulations have proven difficult to develop, necessitating the use of Cremophor® EL and organic solvents. Furthermore, the blood-retinal barrier prevents PTX from penetrating into the ocular tissues. The goal of this work was to develop non-PEGylated and PEGylated PTX-loaded α-tocopherol succinate (TS) based nanostructured lipid carrier (NLCs; αTS-PTX-NLC) that could bypass ocular barriers and transport the PTX to the back of the eye exhibit stability on storage after sterilization with controlled release of drug on administration. The formulations were characterized for particle size distribution, zeta potential, drug content, drug release behavior and were imaged using TEM technology to evaluate the morphological characteristics of the nano formulations such as particle shape and size.
The therapy for the RB often gets complicated and invasive due to the development of multidrug resistance (MDR) by the tumor leading to use of higher doses of the chemotherapeutic agents. P-glycoprotein mediated(P-gp) mediated drug resistance is one of the most common types of MDR responsible for failure the chemotherapy and leads to need to increase the doses or seek out alternate options. One of the ways to bypass the MDR is to inhibit the efflux proteins and prevent the flushing of the drug out of the cells. Tariquidar (TQ) is a 3rd generation P-gp inhibitor that was developed to specifically target P-gp and avoid the unpredictable pharmacokinetics of the previous generation P-gp inhibitors.
The goal of this work was to develop a PTX and TQ α-TS based nanostructured lipid carrier (PTX-TQ-NLC) to over the MDR due P-gp overexpression in RB cells. The formulated NLCs did not show any significant change in physiochemical characteristics on sterilization by autoclaving and were stable for up to 60days (last time point checked) under refrigerated conditions. PTX-TQ-NLC formulations were successfully developed with desirable particle size, narrow PDI and stable ZP. The transcorneal studies exhibited an equivalent permeation of the drug when compared to the drug solution. PTX-NLC could be considered as an alternative delivery system in the treatment and management of RB.
Traditionally f2 value has been used for the comparison of the release profile of the drug from the dosage form. This method suffers the primary drawback of being a model independent methodology as well as applicable for comparison of just 2 profiles. Also, the f2 value cannot be used to determine the statistical difference between the release profiles. The use of linear mixed models can help to over come this drawback as well as understanding the effect of the independent variables employed in the study to investigate the effect on the release of the drug from the formulation. In this study, indomethacin was used as a model compound and its amorphous solid dispersions were prepared to evaluate the release behaviors from the polymer matrices.
Marathe, Sushrut, "α-TOCOPHEROL SUCCINATE NANO STRUCTURED LIPID CARRIERS FOR THE OCULAR DELIVERY OF THE ANTICANCER AGENTS AND STATISTICAL MODELING OF RELEASE STUDY PROFILES BY LINEAR MIXED MODELS" (2022). Electronic Theses and Dissertations. 2248.
Available for download on Thursday, August 15, 2024