Brinzolamide nanocrystal formulations for ophthalmic delivery: reduction of elevated intraocular pressure in vivo

Int J Pharm. 2014 Jun 5;467(1-2):34-41. doi: 10.1016/j.ijpharm.2014.03.048. Epub 2014 Mar 26.

Abstract

Nanocrystal-based drug delivery systems provide important tools for ocular formulation development, especially when considering poorly soluble drugs. The objective of the study was to formulate ophthalmic, intraocular pressure (IOP) reducing, nanocrystal suspensions from a poorly soluble drug, brinzolamide (BRA), using a rapid wet milling technique, and to investigate their IOP reducing effect in vivo. Different stabilizers for the nanocrystals were screened (hydroxypropyl methylcellulose (HPMC), poloxamer F127 and F68, polysorbate 80) and HPMC was found to be the only successful stabilizer. In order to investigate both the effect of an added absorption enhancer (polysorbate 80) and the impact of the free drug in the nanocrystal suspension, formulations in phosphate buffered saline (PBS) at pH 7.4 and pH 4.5 were prepared. Particle size, polydispersity (PI), solid state (DSC), morphology (SEM) as well as dissolution behavior and the uniformity of the formulations were characterized. There was rapid dissolution of BRA (in PBS pH 7.4) from all the nanocrystal formulations; after 1 min 100% of the drug was fully dissolved. The effect was significantly pronounced at pH 4.5, where the dissolved fraction of drug was the highest. The cytotoxicity of nanocrystal formulations to human corneal epithelial cell (HCE-T) viability was tested. The effects of the nanocrystal formulations and the commercial product on the cell viability were comparable. The intraocular pressure (IOP) lowering effect was investigated in vivo using a modern rat ocular hypertensive model and elevated IOP reduction was seen in vivo with all the formulations. Notably, the reduction achieved in experimentally elevated IOP was comparable to that obtained with a marketed product. In conclusion, various BRA nanocrystal formulations, which all showed advantageous dissolution and absorption behavior, were successfully formulated.

Keywords: Brinzolamide; Glaucoma; Intraocular pressure; Nanocrystal suspension; Ophthalmic delivery.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Ophthalmic
  • Animals
  • Calorimetry, Differential Scanning
  • Carbonic Anhydrase Inhibitors / administration & dosage*
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / toxicity
  • Cell Line
  • Cell Survival / drug effects
  • Chemistry, Pharmaceutical
  • Disease Models, Animal
  • Epithelium, Corneal / drug effects
  • Epithelium, Corneal / pathology
  • Excipients / chemistry
  • Glaucoma / drug therapy*
  • Glaucoma / enzymology
  • Glaucoma / physiopathology
  • Humans
  • Hypromellose Derivatives / chemistry
  • Intraocular Pressure / drug effects*
  • Male
  • Microscopy, Electron, Scanning
  • Nanoparticles*
  • Nanotechnology
  • Particle Size
  • Polysorbates / chemistry
  • Rats, Wistar
  • Solubility
  • Sulfonamides / administration & dosage*
  • Sulfonamides / chemistry
  • Sulfonamides / toxicity
  • Surface Properties
  • Technology, Pharmaceutical / methods
  • Thiazines / administration & dosage*
  • Thiazines / chemistry
  • Thiazines / toxicity
  • Time Factors

Substances

  • Carbonic Anhydrase Inhibitors
  • Excipients
  • Polysorbates
  • Sulfonamides
  • Thiazines
  • Hypromellose Derivatives
  • brinzolamide