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Research Library

A-Z Conditions  Participate in ORR

Δ9-Tetrahydrocannabinol Derivative-Loaded Nanoformulation Lowers Intraocular Pressure in Normotensive Rabbits

  • Journal : Translational Vision Science & Technology
  • Publication Year : 2019
  • Authors : Pranjal S. Taskar, Akash Patil, Prit Lakhani, Eman Ashour, Waseem Gul, Mahmoud A. ElSohly, Brian Murphy, & Soumyajit Majumdar
Abstract

Purpose: Δ9-Tetrahydrocannabinol-valine-hemisuccinate, a hydrophilic prodrug of Δ9-tetrahydrocannabinol, synthesized with the aim of improving the ocular bioavailability of the parent molecule, was investigated in a lipid-based nanoparticle dosage form for ocular delivery.

Methods: Solid lipid nanoparticles (SLNs) of Δ9-tetrahydrocannabinol-valine-hemisuccinate and Δ9-tetrahydrocannabinol, along with a nanoemulsion of Δ9-tetrahydrocannabinol-valine-hemisuccinate, were tested for glaucoma management in a normotensive rabbit model by using a multiple-dosing protocol. Marketed formulations of timolol maleate and pilocarpine HCl were also tested for their pharmacodynamic profile, post-single dose administration.

Results: A peak intraocular pressure (IOP) drop of 30% from baseline was observed in rabbits treated with SLNs loaded with Δ9-tetrahydrocannabinol-valine-hemisuccinate at 90 minutes. Treated eyes of rabbits receiving Δ9-tetrahydrocannabinol-valine-hemisuccinate SLNs had significantly lower IOP than untreated eyes until 360 minutes, whereas the group receiving the emulsion formulation showed a drop in IOP until 90 minutes only. In comparison to marketed pilocarpine and timolol maleate ophthalmic solutions, Δ9-tetrahydrocannabinol-valine-hemisuccinate SLNs produced a greater effect on IOP in terms of both intensity and duration. In terms of tissue concentrations, significantly higher concentrations of Δ9-tetrahydrocannabinol-valine-hemisuccinate were observed in iris-ciliary bodies and retina-choroid with SLNs.

Conclusion: Δ9-Tetrahydrocannabinol-valine-hemisuccinate formulated in a lipid-based nanoparticulate carrier shows promise in glaucoma pharmacotherapy.

Translational Relevance: Glaucoma therapies usually focus on decreased aqueous humor production and increased outflow. However, such therapy is not curative, and there lies a need in preclinical research to focus efforts on agents that not only affect the aqueous humor dynamics but also provide neuroprotection. Historically, there have been bench-scale studies looking at retinal ganglion cell death post-axonal injury. However, for a smooth translation of this in vitro activity to the clinic, animal models examining IOP reduction, i.e., connecting the neuroprotective activity to a measurable outcome in glaucoma management (IOP), need to be investigated. This study investigated the IOP reduction efficacy of cannabinoids for glaucoma pharmacotherapy in a normotensive rabbit model, bringing forth a new class of agents with the potential of IOP reduction and improved permeation to the back of the eye, possibly providing neuroprotective benefits in glaucoma management.

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  • ∆9-tetrahydrocannabinol (THC)

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