Electronic Theses and Dissertations

Date of Award

1-1-2021

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

First Advisor

Soumyajit Majumdar

Second Advisor

Michael A. Repka

Third Advisor

Walter Chambliss

Relational Format

dissertation/thesis

Abstract

The use of Δ9-Tetrahydrocannabinol (THC) and Δ9-Tetrahydrocannabinol-Valine-Hemisuccinate (THC-VHS; NB1111) has recently been investigated in the management of intraocular pressure (IOP) lowering activity. The current studies were undertaken to develop a THC-VHS loaded nanoemulsion (NE; THC-VHS-NE) with and without Carbopol® 940 as mucoadhesive agent (NEC; THC-VHS-NEC) that could increase the drug load and the duration of activity. The physical and chemical stability and sterilization of the lead formulation THC-VHS-NE and THC-VHS-NEC were observed under refrigerated conditions (4°C) for sixty days. Further, the pharmacodynamic (PD) effect of the lead formulations were studied in normotensive Albino New Zealand White (NZW) male rabbits following topical administration. The IOP lowering activity of THC-VHS-NE, THC-VHS-NEC, and THC-NEC and commercial timolol and latanoprost ophthalmic solutions, as well as THC-VHS incorporated into a marketed Tocrisolve™ emulsion (THC-VHS-TOC), were used as comparators in NZW male rabbits. All studies involving animals were conducted under University IACUC approved protocols. THC-VHS-TOC showed a similar drop in IOP (20% below baseline) to THC-VHS-NE but had a shorter duration of action (180 minutes, p < 0.0001). THC-VHS-NE produced a greater drop in IOP (23%) compared to latanoprost (13%) and timolol (14%) and a longer duration of action compared to timolol (360 and 90 minutes, respectively). The THC-VHS-NEC formulation showed a significant (p < 0.0001) improvement in the duration of IOP lowering activity, compared to THC-NEC and THC-VHS-NE. Moreover, THC-VHS-NEC was more effective than the commercially available latanoprost ophthalmic formulation (0.005 %w/v), in terms of both duration of activity and intensity of IOP lowering effect (p < 0.0001). THC-VHS-NE, THC-VHS-NEC and latanoprost formulations were then evaluated in a multiday administration. THC-VHS-NE (4.7 mmHg) and THC-VHS-NEC (4.4 mmHg) formulations showed a similar IOP lowering ability while latanoprost (3.6 mmHg) showed a smaller drop in IOP. The duration of action of THC-VHS-NE was not significantly different from latanoprost (p=0.893), returning to a baseline within 8 hours, while THC-VHS-NEC had the longest duration of action with IOP remaining below 10% of baseline even after 8 hours post-instillation. Overall, THC-VHS-NEC formulation demonstrated significantly (p < 0.0001) longer duration of activity as well as a greater intensity (p < 0.0001) in max drop of IOP in comparison with latanoprost.

Concentration/Emphasis

Pharmaceutical sciences

Available for download on Friday, February 17, 2023

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