title: Development of a Δ9-Tetrahydrocannabinol Amino Acid-Dicarboxylate Prodrug With Improved Ocular Bioavailability.
abstract: The aim of the present study was to evaluate the utility of the relatively hydrophilic Δ9-tetrahydrocannabinol (THC) prodrugs, mono and di-valine esters (THC-Val and THC-Val-Val) and the amino acid (valine)-dicarboxylic acid (hemisuccinate) ester (THC-Val-HS), with respect to ocular penetration and intraocular pressure (IOP) lowering activity. THC, timolol, and pilocarpine eye drops were used as controls.
  
  
  
  THC-Val, THC-Val-Val, and THC-Val-HS were synthesized and chemically characterized. Aqueous solubility and in vitro transcorneal permeability of THC and the prodrugs, in the presence of various surfactants and cyclodextrins, were determined. Two formulations were evaluated for therapeutic activity in the α-chymotrypsin induced rabbit glaucoma model, and the results were compared against controls comprising of THC emulsion and marketed timolol maleate and pilocarpine eye drops.
  
  
  
  THC-Val-HS demonstrated markedly improved solubility (96-fold) and in vitro permeability compared to THC. Selected formulations containing THC-Val-HS effectively delivered THC to the anterior segment ocular tissues in the anesthetized rabbits: 62.1 ng/100 μL of aqueous humor (AH) and 51.4 ng/50 mg of iris ciliary bodies (IC) (total THC). The duration and extent of IOP lowering induced by THC-Val-HS was 1 hour longer and 10% greater, respectively, than that obtained with THC and was comparable with the pilocarpine eye drops. Timolol ophthalmic drops, however, exhibited a longer duration of activity. Both THC and THC-Val-HS were detected in the ocular tissues following multiple dosing of THC-Val-HS in conscious animals. The concentration of THC in the iris-ciliary bodies at the 60- and 120-minute time points (53 and 57.4 ng/50 mg) were significantly greater than that of THC-Val-HS (24.2 and 11.3 ng/50 mg). Moreover, at the two time points studied, the concentration of THC was observed to increase or stay relatively constant, whereas THC-Val-HS concentration decreased by at least 50%. A similar trend was observed in the retina-choroid tissues.
  
  
  
  A combination of prodrug derivatization and formulation development approaches significantly improved the penetration of THC into the anterior segment of the eye following topical application. Enhanced ocular penetration resulted in significantly improved IOP-lowering activity.
authors.affiliation: Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, University, Mississippi, United States.
authors.forename: Goutham R
authors.initials: GR
authors.lastname: Adelli
authors.affiliation: Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, University, Mississippi, United States.
authors.forename: Prakash
authors.initials: P
authors.lastname: Bhagav
authors.affiliation: Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, University, Mississippi, United States.
authors.forename: Pranjal
authors.initials: P
authors.lastname: Taskar
authors.affiliation: Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, University, Mississippi, United States.
authors.forename: Tushar
authors.initials: T
authors.lastname: Hingorani
authors.affiliation: Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, United States.
authors.forename: Sara
authors.initials: S
authors.lastname: Pettaway
authors.affiliation: ElSohly Laboratories, Inc., Oxford, Mississippi, United States.
authors.forename: Waseem
authors.initials: W
authors.lastname: Gul
authors.affiliation: Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, University, Mississippi, United States 3ElSohly Laboratories, Inc., Oxford, Mississippi, United States.
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: ElSohly
authors.affiliation: Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, University, Mississippi, United States 4Research Institute of Pharmaceutical Sciences, University of Mississippi, University, Mississippi, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Repka
authors.affiliation: Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, University, Mississippi, United States.
authors.forename: Soumyajit
authors.initials: S
authors.lastname: Majumdar
mesh_terms: D000818:Animals; D001082:Aqueous Humor / Q000187:drug effects / Q000378:metabolism*; D001682:Biological Availability; D063386:Cannabinoid Receptor Agonists / Q000493:pharmacokinetics; D003315:Cornea / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D013759:Dronabinol / Q000493:pharmacokinetics*; D004353:Drug Evaluation, Preclinical; D005901:Glaucoma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D009883:Ophthalmic Solutions; D011355:Prodrugs / Q000493:pharmacokinetics*; D011817:Rabbits; D014822:Vitreous Body / Q000187:drug effects / Q000378:metabolism*
chemical_list: D063386:Cannabinoid Receptor Agonists; D009883:Ophthalmic Solutions; D011355:Prodrugs; D013759:Dronabinol