MAGL inhibitor NanoMicellar formulation (MAGL-NanoMicellar) for the development of an antiglaucoma eye drop

Int J Pharm. 2022 Sep 25:625:122078. doi: 10.1016/j.ijpharm.2022.122078. Epub 2022 Aug 3.

Abstract

The ocular endocannabinoid system (ECS) including enzymes and CB1/CB2 receptors determines various substantial effects, such as anti-inflammatory activity and reduction of the intraocular pressure (IOP). The modulation of 2-arachidonoylglycerol (2-AG) levels obtained via MAGL inhibition is considered as a promising pharmacological strategy to activate the ECS. Within the scope of this study, the effect of a selective monoacylglycerol lipase (MAGL) inhibitor (MAGL17b) was investigated by measuring the IOP reduction in normotensive rabbits after performing a solubilisation process of the molecule with non-ionic surfactants, to produce suitable eye drops containing the highest possible concentration of the drug. Furthermore, the study involved the evaluation of cytotoxicity and of in vitro/ex vivo corneal permeation of MAG17b of selected formulations based on polyoxyl(35)castor oil (C-EL) and polyethylene glycol (80) sorbitan monolaurate (TW80). The solubilisation of 0.5 mM MAGL17b with 3 % w/w TW80 (TW80/3-17b), through the formation of NanoMicellar structures (diameter of 12.3 nm), determined a significant permeation of MAGL17b, both through excised rabbits corneas and reconstituted corneal epithelium, with a limited corneal epithelial cells death. The blockade of MAGL activity induced a IOP reduction up to 4 mmHg in albino and pigmented rabbits after topical instillation, thus confirming the potential efficacy of the MAGL inhibition approach in the treatment of ocular pathologies.

Keywords: COR-100 EpiCorneal; In vitro/ex vivo ocular permeation; Intraocular pressure; MAGL inhibitor; Nanomicelles; Rabbit; Surfactant.

MeSH terms

  • Animals
  • Cornea
  • Endocannabinoids
  • Enzyme Inhibitors
  • Intraocular Pressure
  • Monoacylglycerol Lipases*
  • Monoglycerides*
  • Ophthalmic Solutions
  • Rabbits

Substances

  • Endocannabinoids
  • Enzyme Inhibitors
  • Monoglycerides
  • Ophthalmic Solutions
  • Monoacylglycerol Lipases