title: Brinzolamide nanocrystal formulations for ophthalmic delivery: reduction of elevated intraocular pressure in vivo.
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.
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland. Electronic address: annika.tuomela@helsinki.fi.
authors.forename: Annika
authors.initials: A
authors.lastname: Tuomela
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Jooseppi
authors.initials: J
authors.lastname: Puranen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Rönkkö
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Laaksonen
authors.affiliation: Department of Ophthalmology, Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Giedrius
authors.initials: G
authors.lastname: Kalesnykas
authors.affiliation: Santen Oy, Tampere, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Oksala
authors.affiliation: Oy Medfiles Ltd., Kuopio, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Ilkka
authors.affiliation: Orion Pharma R&D, Formulation Research, Espoo, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Laru
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Järvinen
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
authors.forename: Jouni
authors.initials: J
authors.lastname: Hirvonen
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
mesh_terms: D060433:Administration, Ophthalmic; D000818:Animals; D002152:Calorimetry, Differential Scanning; D002257:Carbonic Anhydrase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D019573:Epithelium, Corneal / Q000187:drug effects / Q000473:pathology; D005079:Excipients / Q000737:chemistry; D005901:Glaucoma / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D006801:Humans; D065347:Hypromellose Derivatives / Q000737:chemistry; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles; D036103:Nanotechnology; D010316:Particle Size; D011136:Polysorbates / Q000737:chemistry; D017208:Rats, Wistar; D012995:Solubility; D013449:Sulfonamides / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D013499:Surface Properties; D013678:Technology, Pharmaceutical / Q000379:methods; D013843:Thiazines / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D013997:Time Factors
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D005079:Excipients; D011136:Polysorbates; D013449:Sulfonamides; D013843:Thiazines; D065347:Hypromellose Derivatives; C111827:brinzolamide
keywords: Brinzolamide; Glaucoma; Intraocular pressure; Nanocrystal suspension; Ophthalmic delivery