Formulation Strategies to Address Physiological and Anatomical Constraints for Improved Topical Ocular Drug Delivery
Date of Award
Ph.D. in Pharmaceutical Sciences
Pharmaceutics and Drug Delivery
S. Narasimha Murthy
Delivery of therapeutic molecules to the eye has been a complicated task owing to its anatomical and physiological barriers. This dissertation delineates several formulation strategies to circumvent dynamic and static constraints hampering the ocular drug delivery. Advanced vesicular systems, bilosomes and transfersomes, were prepared to improve the ocular pharmacotherapy of natamycin (NT). NT bilosomes and transfersomes were further loaded into in situ gel systems which transformed immediately to hydrogel, in the simulated tear fluid, with good viscoelastic and mucoadhesive properties.In vitro corneal transport studies confirmed the superior permeability characteristics of NT from the optimized bilosome and transfersome in situ gel formulations, over control marketed (5 % w/v NT) suspension. In the ocular distribution studies, considerably higher mean dose normalized drug levels in the ocular tissues from bilosome and transfersome in situ gel formulations for 6h, compared to that from the control suspension, demonstrated the effectiveness of ion-sensitive in situ hydrogels of bilosomes and transfersomes as potential carrier systems for improved and prolonged topical ocular drug delivery. The magnitude of P-glycoprotein (P-gp) and multidrug resistance protein (MRP1) were investigated by comparative ocular distribution studies in the P-gp and MRP1 gene knock out (KO) and wild type (WT) rats. The blood ocular penetration of paclitaxel (PTX), a P-gp substrate and, methotrexate (MTX), an MRP 1 substrate, were significantly higher in the KO rats compared to WT rats. These results suggested that the penetration of anticancer substrate drugs across the BOB is restricted by efflux transporter proteins. Further, the concurrent intravenous administration of specific P-gp and MRP 1 inhibitors, along with PTX or MTX, in the WT rats resulted in improved blood ocular penetration of substrate anticancer drugs by effective inhibition of efflux protein activity in the BOB. The electroretinography (ERG) studies demonstrated that the inhibitor and substrate interactions did not induce any toxic effects on retina functions. However, at higher concentration of PTX and MTX shotoxic effects on the retina functions. Feasibility of coadministration of topical ocular inserts of P-gp inhibitors and intravenous anticancer substrate drug, PTX, was investigated in rats to examine the potential of this strategy to improve blood ocular penetration of PTX. Ocular films of P-gp inhibitors were fabricated by melt cast method and the transocular membrane permeability of the P-gp inhibitors, elacridar (EQ) and tariquidar (TQ), was investigated in the isolated rabbit cornea. Both EQ and TQ shotranscorneal permeability but no penetration through Sclera-choroidal retinal pigmented epithelium (RPE) tissue. The ocular distribution studies in rats shoimproved blood ocular penetration of PTX in the rats co-administered with EQ and TQ. These results demonstrated that the topically administered P-gp inhibitor effectively inhibits the P-gp activity and thereby improves ocular chemotherapy. ERG and Ultrastructure analyses of RPE confirmed that the PTX-EQ/TQ interactions were compatible with retina. TA protransfersome gel formulations were successfully prepared with at least two-fold higher drug load, compared to the marketed topical dosage form, which allows higher, localized, concentration gradients. Microscopic studies confirmed complete drug dissolution in the lipid phase and rapid formation of transfersomes on hydration. Significantly higher trans-eyelid TA permeation with the protransfersome gel formulation – demonstrated their potential in enhancing drug delivery to the ocular surface and deeper tissues via the eyelid. Experiments in dead rabbits confirmed that TA efficiently penetrated into the eyelid and formed a depot leading to increasing concentration-time profiles in all ocular tissues tested. The overall results suggest that trans-eyelid protransferosome gel formulations can provide a platform for the sustained delivery of therapeutic agents to both the surface of the eye as well as the anterior and posterior segment ocular tissues.
Janga, Karthik Yadav, "Formulation Strategies to Address Physiological and Anatomical Constraints for Improved Topical Ocular Drug Delivery" (2019). Electronic Theses and Dissertations. 1701.