In vitro ocular biocompatibility of novel HP-β-CD acetazolamide complexes

JAVIER A. CALLES, MARIA J. MORA, ANTONIO LOPEZ-GARCÍA, SANTIAGO D. PALMA, ENRIQUE M. VALLÉS, MARCELA R. LONGHI, GLADYS E. GRANERO, YOLANDA DIEBOLD

Conferencia; X Spanish-Portuguese Conference on Controlled Drug Deliery; 2013

INTRODUCTION Cyclodextrins (CDs) are a group of natural products formed during bacterial digestion of starch. These cyclic oligosaccharides consist of (α-1,4)-linked α-D glucopyranose units with a hydrophilic outer surface and a lipophilic central cavity1. CDs are able to solubilize many lipophilic water-insoluble drugs otherwise is hard to formulate in aqueous eyedrop solutions2,3. Acetazolamide (ACZ) is a carbonic anhydrase inhibitor used orally for the reduction of intraocular pressure (IOP) in patients suffering from glaucoma4. The two major problems that hinder the topical effectiveness of ACZ are its poor aqueous solubility (w0.7 mg/ml) and a low corneal permeability coefficient of 4.1x10-6 cm/s5. In order to enhance the ocular bioavailability of ACZ, a multicomponent complex with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and triethanolamine (TEA) was prepared for ocular topical application. The aim of this work was to evaluate the in vitro ACZ delivery performance and the bio-compatibility between ocular surface cells and ACZ complexes as a first step in the design of a topical DDS for ocular administration. RESULTS AND DISCUSSION Cell viability: Human corneal cells exposed to ACZ complexes (ACZ-HP-ß-CD and ACZ-HP-ß-CD-TEA) in concentrations of 0,1%, 0,5% and 1% (ACZ), for 24 h exhibited viabilities around 100% in all cases. Morphological details of exposed cells remained intact. Viability was not reduced when cells were exposed to higher concentrations of complexes solutions. Proliferation: Proliferation rate of human corneal cells exposed to 0,1% or 0,5% ACZ-CD complexes was equivalent to that of controls. Cells exposed to ACZ-HP-ß-CD 1% solutions showed a marked reduction in proliferation rate. Cells exposed to ACZ-HP-ß-CD-TEA 1% solutions also showed an important reduction in proliferation through the first 24 h, although they recovered their normal proliferation rate in the following 24 h. Drug delivery: CD-free formulations showed a slower ACZ release profile than those of HP-ß-CD-containing formulations, being the drug release from the physical mixture the lowest. This decrease in drug release is probably a result from the formation of an ion pair between ACZ and TEA, whose hydrophilicity and relatively larger size than the free drug might be responsible for its poor membrane permeability. REFERENCES 1. T. Loftsson, T. Järvinen, Cyclodextrins in ophthalmic drug delivery, Adv. Drug Deliv. Rev. 36 (1999) 59?79. 2. T. Loftsson, E. Stefánsson, Cyclodextrins in eye drop formulations: enhanced topical delivery if corticosteroids to the eye, Acta Ophthalmol. Scand. 80 (2002) 144?150. 3. M.E. Brewster, T. Loftsson, Cyclodextrins as pharmaceutical solubilizers, Adv. Drug Deliv. Rev. 59 (2007) 645?666. 4. I.P. Kaur, R. Smitha, D. Aggarwal, M. Kapil, Acetazolamide: future prespective in topical glaucoma therapeutics, Int. J. Pharm. 248 (2002) 1-14. 5. M.W. Duffel, I.S. Ing, T.M. Segarra, J.A. Dixson, C.F. Barfkenecht, R.D. Schoenwald, N-Substituted sulfonamide carbonic anhydrase inhibitors with topical effects on intraocular pressure, J. Med. Chem. 29 (1986) 1488-1494. 6. S. Cohen, E. Lobel, A. Trevgoda, Y. Peled, A novel in situ-forming ophthalmic drug delivery system from alginates undergoing gelation in the eye, J. Control. Release 44 (1997) 201-208.