Date of Award
1-1-2023
Document Type
Dissertation
Degree Name
Ph.D. in Pharmaceutical Sciences
First Advisor
Soumyajit Majumdar
Second Advisor
Michael A. Repka
Third Advisor
Dr. Walter Chambliss
School
University of Mississippi
Relational Format
dissertation/thesis
Abstract
Nanoformulations such as nanoemulsions (NE), solid lipid nanoparticles (SLN), and nanostructured lipid carriers (NLCs) are colloidal particulate systems in the submicron size range and act as carriers of drug molecules. Their size varies from 10 to 1,000 nm (1). The capacity of these nanoparticles to permeate through many anatomical barriers, the prolonged release of their contents, and their stability on the nanometer scale have widely contributed to their efficacy in drug delivery. Owing to the advantages of nanoformulations, they were further explored in our studies to target different diseases like Dry eye disease (DED), glaucoma, and malaria.
Chapter 2 discusses the formulation development of novel cyclosporine nanoemulsion (CSA-NE) for the treatment of DED, which is a multifactorial ocular disease characterized by unstable tear film due to decreased tear production (aqueous DED) or excessive tear evaporation (evaporative DED). CSA and retinyl palmitate (RP) have been known to treat aqueous and evaporative DED, respectively. The commercial formulations available for moderate to severe DED, however, only focus on increasing tear production. Therefore, the current study aimed to prepare and characterize a novel CSA nanoemulsion (NE; CSA-NE) with RP as the co-lipid that could potentially treat both aqueous and evaporative DED. The CSA-NE was prepared using hot homogenization followed by probe sonication technique, and the lead CSA-NE was screened using the HLB technique. The CSA-NE formulation exhibited a globule size of 80 ± 2.0 nm, PDI of 0.22 ± 0.01, and zeta potential of -18 mV, and was stable at 25°C pre- and post-sterilization. In-vitro CSA drug release from CSA-NE showed a sustained drug release of 80% within 24 hours, thus showing potential for a once-a-day dose regimen. Thus, 0.1% w/v CSA-NE with RP as co-lipid was successfully developed, characterized, and found to be stable for 90 days at 25°C. Combining RP with CSA could provide a formulation that is effective against both aqueous as well as evaporative DED.
In previously reported literature, Δ9-Tetrahydrocannabinol-valine-hemisuccinate (THC-VHS), a prodrug of Δ9-Tetrahydrocannabinol (THC), was incorporated into nanoemulsion (NE; THC-VHS-NE) and nanoemulsion with Carbopol® (NEC; THC-VHS-NEC) formulations. These formulations successfully decreased the IOP in male normotensive New Zealand albino rabbits. In Chapter 3, the previously optimized formulation was further evaluated in pigmented normotensive Dutch Belted (DB) male rabbits to determine the effect of melanin binding, if any, on the IOP-lowering effect of THC-VHS. Additionally, the THC and THC-VHS formulations' activity was compared against commercially available ophthalmic formulations latanoprost and Rhopressa® (netarsudil). THC-NEC (0.6 %w/v), THC-VHS-NE (1.0 % w/v), and THC-VHS-NEC (1.0 %w/v), formulations were prepared using hot homogenization followed by probe sonication method and characterized. THC-NEC, THC-VHS-NE, THC-VHS-NEC, latanoprost, and Rhopressa® demonstrated an average max drop in IOP (%) of 21, 26, 23.5, 17.3 and 25.8 %, respectively, in the treated eye compared to the baseline. THC-VHS-NEC demonstrated a superior IOP lowering profile in the DB rabbits, compared to the standard of care, latanoprost. Thus, due to its superior IOP-lowering activity, THC-VHS-NEC holds significant promise in the management of glaucoma.
Chapter 4 discusses the formulation development and effect of Cannabidiol (CBD) nanoemulsion on IOP-lowering activity in pigmented Dutch belted rabbits. In literature, contradictory reports with respect to CBD’s effect on intraocular pressure (IOP) has raised concerns and halted research exploring its use in ocular therapeutics. Therefore, the current investigation aimed to further evaluate CBD’s impact on the IOP in the rabbit model. CBD-NE containing Carbopol® 940 NF as a mucoadhesive agent (CBD-NEC), was prepared using hot-homogenization followed by probe sonication. The stability of the formulations post moist-heat sterilization, in terms of physical and chemical characteristics, was studied at three different storage conditions. The lead CBD-NEC formulation (1 % w/v CBD) exhibited a globule size of 259 ± 2.0 nm, 0.27 ± 0.01 PDI, and 23.2 ± 0.4 cP viscosity, and was physically and chemically stable for one month (last time point tested) at 4°C, 25°C, and 40°C. CBD-NEC significantly lowered the IOP in the treated eyes for up to 360 minutes, with a peak drop in IOP of 4.5 mmHg observed at the 150 min time point, post topical application. Overall, topically administered CBD, formulated in a mucoadhesive nanoemulsion formulation, reduced the IOP in the animal model studied.
Chapter 5 discusses the formulation development of various nanoformulations containing NPC1161B succinate salt for potentially treating malaria. NPC1161B succinate salt derived from primaquine is known to show transmission-blocking activity by acting on oocyst and blocking sporozoite production in the mosquito host (2). Even though NPC 1161B shows great potential for the treatment, prevention, and control of malaria, its major drawback of hemolytic toxicity in glucose-6-phosphate-dehydrogenase (G6PD) deficient humans is the major hurdle for the widespread use of the drug for treating malaria (3). In this study, lipid-based nanoformulations were explored as an alternative formulation strategy to overcome the hemolytic toxicity that is caused by NPC 1161B in patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd). The lead NLC, SLN, and NE formulations were compared with pure NPC for effect on the generation of reactive oxygen species (ROS) inside normal, and G6PD deficient erythrocytes in the presence and absence of human liver microsomes.
Recommended Citation
Senapati, Samir, "Novel Formulation Strategies for Oral and Ocular Drug Delivery" (2023). Electronic Theses and Dissertations. 2578.
https://egrove.olemiss.edu/etd/2578