Pharmacological Evaluation of a New Timolol/Pilocarpine Formulation

Abstract

A new formulation (HYA) based on timolol hyaluronate and pilocarpine hyaluronate salts has been shown to improve the bioavailability of the drugs and to extend the duration of their action. Extent of the intraocular pressure lowering effect, duration of action and aqueous bioavailability of timolol and pilocarpine of HYA were compared with a commercial preparation. Ocular hypertension in the rabbit was induced by α-chymotrypsin or by water loading. The hypotensive effect of HYA treatment was significantly greater and longer than that observed in rabbit eyes treated with the commercial preparation both in the normotensive and in the hypertensive animals. Furthermore, we evaluated the miotic response; due to pilocarpine, normotensive rabbits showed a greater miotic response and an extended duration when the eyes were treated with HYA. The new formulation increased the aqueous availability of timolol and pilocarpine compared to the commercial preparation as determined by HPLC. The pharmacodynamic and pharmacokinetic profiles of HYA indicate an increase in efficacy and duration of action along with an increase in bioavailability of timolol and pilocarpine in comparison with the commercial preparation.

Hyaluronic acid: a unique topical vehicle for the localized delivery of drugs to the skin

“…HA has also been extensively studied in ophthalmic, 81–95 nasal 96,97 and parenteral drug delivery 98–107 . In addition, more novel applications including, pulmonary, 108,109 implantation 110,111 and gene delivery 112,113 have also been suggested.…”

“…Summary of the drug delivery applications of hyaluronic acid Jarvinen et al, 1995,81 Sasaki et al, 1996, 82 Gurny et al, 1987, 83 Camber et al, 1987,84 Camber and Edman, 1989,85 Saettone et al, 1994,86 Saettone et al, 1991,87 Bucolo et al, 1998,88 Bucolo and Mangiafico, 1999, 89 Herrero-Vanrell et al, 2000,90 Moreira et al, 1991, 91,92 Bernatchez et al, 1993,93 Gandolfi et al, 1992, 94 Langer et al, 1997 95. Sakurai et al, 1997,99 Luo and Prestwich, 1999,100 Luo et al, 2000101 Prisell et al, 1992, 102 Yerushalmi et al, 1994, 103 Yerushalmi and Margalit, 1998,104 Peer and Margalit, 2000,105 Eliaz and Szoka, 2001,106 Peer et al, 2003.…”

Hyaluronan: Pharmaceutical Characterization and Drug Delivery

“…HA has been used as a vehicle for topical ophthalmic drugs due to its viscoelasticity and mucoadhesive capacity (Lapcik et al 1998;Kaur and Smitha 2002). Numerous studies have reported that HA is capable of prolonging the precorneal residence and/or increasing the bioavailability of pilocarpine (Gurny et al 1987;Camber and Edman 1989;Camber et al 1987Camber et al , 1994Saettone et al 1989Saettone et al , 1991Saettone et al , 1994Bucolo and Mangiafico 1999;Bucolo et al 1998), tropicamide (Saettone et al 1989;Herrero-Vanrell et al 2000), timolol (Bucolo et al 1998), gentimycin (Moreira et al 1991a(Moreira et al , 1991bBernatchez et al 1993), tobramycin (Gandolfi et al 1992), arecaidine propargyl ester (Langer et al 1997) and {S}-aceclidine (Langer et al 1997) in solution form. The mucoadhesion together with the increased structure conferred by HA are thought to be primarily responsible for the prolonged precorneal residence of the drugs.…”

L-Carnosine: multifunctional dipeptide buffer for sustained-duration topical ophthalmic formulations

“…[44] Correlation of well-established pharmacokinetic and doseresponse relationships for topical ocular timolol supports these findings. [45][46][47] L-Carnosine-mediated lowering of IOP and reduction of prostaglandin-induced ocular hypertension in normotensive rabbits has been previously reported. These studies, however, used 0.2 ml intracameral injections of 10 mM L-carnosine to modulate IOP.…”