Category: Formulation and Quality
Purpose: Glaucoma is an optic neuropathy that can lead to vision loss. Increased intraocular pressure (IOP), a hallmark of the disease, results in a buildup of aqueous fluid due to change in aqueous humor secretion or drainage dynamics. Currently the marketed treatments are aimed at lowering the IOP by aiding in the removal of the excess fluid build-up through reduction in aqueous humor production or increase of drainage. Δ9-Tetrahydrocannabinol (THC) is emerging as a potential new class of IOP lowering agents. Recently, Δ9-Tetrahydrocannabinol-Valine-Hemisuccinate (THC-VHS, NB 1111), a prodrug of THC, has demonstrated a better permeation profile and better IOP lowering activity, as well as the ability to reach inner ocular tissues in higher quantities, than THC. The objective of this study was to investigate the IOP profile on multi-day application of THC-VHS nanoemulsion (THC-VHS-NE) or THC-VHS-NE with Carbopol (THC-VHS-NEC) and latanoprost (Lat).
Methods: THC-VHS was incorporated into a NE or a NEC by hot homogenization followed by probe sonication method. The THC-VHS-NE and THC-VHS-NEC formulations were instilled into the eye of the rabbits (normotensive New Zealand white) twice a day - once in the morning and once in the evening - every day for 6 days. Lat was instilled once a day in the morning every day for 6 days. On the 7th day, rabbits received only one dose in the morning and were sacrificed 2 hours after instillation, corresponding to the peak drop in IOP. The ocular tissues, were collected from the rabbits receiving the THC-VHS formulation and were analyzed for THC-VHS and THC content to establish the correlation between the concentrations of THC/THC-VHS in the various ocular tissues with the drop in IOP. All animal procedures followed IACUC approved protocols.
Results: THC-VHS was incorporated into a nanoemulsion (NE) and further optimized with Carbopol (NEC). The THC-VHS-NE and THC-VHS-NEC formulations showed a similar IOP lowering ability while Lat generated a smaller drop in IOP; 4.3 ± 0.7, 4.2 ± 0.4, and 3.4 ± 0.5 mmHg, respectively. THC-VHS-NE produced a similar duration of action as Lat, 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. THC and THC-VHS were detected in significant levels in all ocular tissues collected except in vitreous humor where only small concentrations of THC-VHS were detected from both formulations. (one rabbit in the NEC group showed detectable levels of THC in the vitreous humor).
Conclusion: Overall, THC-VHS-NE and the marketed ophthalmic latanoprost solution demonstrated similar qualities in terms of duration of activity. THC-VHS-NE, however, elicited a greater drop in IOP in comparison to Lat. The THC-VHS-NEC formulation, on the other hand, demonstrated significantly (p< 0.05) longer duration of activity as well as a greater intensity in IOP drop in comparison with Lat.
Corinne Sweeney– Graduate student, University of Mississippi, Ocford, Mississippi
Ruchi Thakkar– Graduate Research Assistant, The University of Mississippi, University, Mississippi
Tabish Mehraj– Graduate Student, University of Mississippi, University, Mississippi
Sushrut Marathe– Mr., University of Mississippi, University, Mississippi
Iram Shahzadi– Oxford, Mississippi
Waseem Gul– Oxford, Mississippi
Mahmoud ElSohly– Oxford, Mississippi
Brian Murphy– Long Beach, California
Soumyajit Majumdar– Professor and Associate Dean, Department of Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi. Oxford, MS, University, Mississippi