title: In vivo evaluation and in-depth pharmaceutical characterization of a rapidly dissolving solid ocular matrix for the topical delivery of timolol maleate in the rabbit eye model.
abstract: The purpose of this study was to investigate the in-depth pharmaceutical properties and in vivo behavior of a novel lyophilized rapidly dissolving solid ocular matrix (RD-SOM) as a 'solid eye drop' formulation comprising timolol maleate as the model drug. Thermal and molecular transition analysis displayed similar findings with no incompatibility between formulation components. Porositometric studies confirmed the presence of interconnecting pores across the matrix surface. The HETCAM test indicated an irritation score of 0 with the inference of good tolerability for the RD-SOM in the New Zealand White albino rabbit eye model. Ex vivo permeation across excised rabbit cornea showed an improved steady state drug flux (0.00052 mg cm(-2)min(-1)) and permeability co-efficient (1.7 × 10(-4)cmmin(-1)) for the RD-SOM compared to pure drug and a marketed eye drop preparation. UPLC analysis quantitatively separated timolol maleate and the internal standard (diclofenac sodium) and gamma irradiation was used as a terminal sterilization procedure. In vivo results revealed a peak concentration of timolol was reached at 104.9 min. In the case of a typical eye drop formulation a lower Cmax was obtained (1.97 ug/mL). Level A point-to-point IVIVC plots via the Wagner-Nelson method revealed a satisfactory R(2) value of 0.84. In addition, the biodegradability and ocular compatibility of the RD-SOM was confirmed by histopathological toxicity studies.
authors.affiliation: University of the Witwatersrand, Faculty of Health Sciences, Department of Pharmacy and Pharmacology, 7 York Road, Parktown 2193, Johannesburg, South Africa.
authors.forename: Raeesa M
authors.initials: RM
authors.lastname: Moosa
authors.affiliation: University of the Witwatersrand, Faculty of Health Sciences, Department of Pharmacy and Pharmacology, 7 York Road, Parktown 2193, Johannesburg, South Africa.
authors.forename: Yahya E
authors.initials: YE
authors.lastname: Choonara
authors.affiliation: University of the Witwatersrand, Faculty of Health Sciences, Department of Pharmacy and Pharmacology, 7 York Road, Parktown 2193, Johannesburg, South Africa.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: du Toit
authors.affiliation: University of the Witwatersrand, Faculty of Health Sciences, Department of Pharmacy and Pharmacology, 7 York Road, Parktown 2193, Johannesburg, South Africa.
authors.forename: Lomas K
authors.initials: LK
authors.lastname: Tomar
authors.affiliation: University of the Witwatersrand, Faculty of Health Sciences, Department of Pharmacy and Pharmacology, 7 York Road, Parktown 2193, Johannesburg, South Africa.
authors.forename: Charu
authors.initials: C
authors.lastname: Tyagi
authors.affiliation: University of the Witwatersrand, Faculty of Health Sciences, Department of Pharmacy and Pharmacology, 7 York Road, Parktown 2193, Johannesburg, South Africa.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kumar
authors.affiliation: University of the Witwatersrand, Faculty of Health Sciences, Division of Ophthalmology, Department of Neurosciences, 7 York Road, Parktown 2193, Johannesburg, South Africa.
authors.forename: Trevor R
authors.initials: TR
authors.lastname: Carmichael
authors.affiliation: University of the Witwatersrand, Faculty of Health Sciences, Department of Pharmacy and Pharmacology, 7 York Road, Parktown 2193, Johannesburg, South Africa. Electronic address: viness.pillay@wits.ac.za.
authors.forename: Viness
authors.initials: V
authors.lastname: Pillay
mesh_terms: D060433:Administration, Ophthalmic; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000187:drug effects; D016503:Drug Delivery Systems; D005123:Eye / Q000378:metabolism*; D066298:In Vitro Techniques; D009883:Ophthalmic Solutions / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010539:Permeability; D011817:Rabbits; D012995:Solubility; D013999:Timolol / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000959:Antihypertensive Agents; D009883:Ophthalmic Solutions; D013999:Timolol
keywords: HET-CAM; In vitro in vivo correlation; Lyophilized polymer matrix; Ocular delivery; Timolol maleate