An efficient ternary complex of acetazolamide with HP-ss-CD and TEA for topical ocular administration.
In order to enhance the ocular bioavailability of acetazolamide (ACZ), a multicomponent complex with hydroxypropyl-ss-cyclodextrin (HP-ss-CD) and triethanolamine (TEA) was prepared to be applied topically. In vitro corneal permeation across isolated rabbit cornea of proposed ACZ formulations and the marketed AZOPT(R) formulation (1% w/v brinzolamide) was studied. Formulations were also tested for their effect on the intraocular pressure (IOP) in rabbits. (1)H- and (13)C-NMR experiments were undertaken to verify the real inclusion of ACZ in the ACZ-HP-ss-CD-TEA multicomponent complex. The binding of ACZ to HP-ss-CD in the presence of TEA is described. The increase of TEA concentration decreases the apparent equilibrium constant for the ACZ-HP-ss-CD complex. The ternary system ACZ-HP-ss-CD-TEA seemed to be able to reduce IOP in about 30%. This effect was sustained for 4 h after instillation. In vitro corneal permeation studies demonstrated that the ACZ permeation was increased. RMN experiments indicated that TEA can weaken the association between ACZ and HP-ss-CD increasing the drug ocular hypotensive effect by increasing the free drug available for absorption. Our formulations were considered practically non-irritant. These results indicate that the ternary system ACZ-HP-ss-CD-TEA might be a useful tool for formulating aqueous ACZ eye drop solutions.
Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, (5000) Córdoba, Argentina.
Santiago D
SD
Palma
Luis I
LI
Tartara
Daniela
D
Quinteros
Daniel A
DA
Allemandi
Marcela R
MR
Longhi
Gladys E
GE
Granero
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000086:Acetazolamide / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D000287:Administration, Topical; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D003315:Cornea / Q000187:drug effects / Q000378:metabolism*; D004983:Ethanolamines / Q000737:chemistry*; D007429:Intraocular Pressure / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D009994:Osmolar Concentration; D011817:Rabbits; D047392:beta-Cyclodextrins / Q000737:chemistry*
D002257:Carbonic Anhydrase Inhibitors; D004983:Ethanolamines; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C009546:triethanolamine; D000086:Acetazolamide