1509 JPP 2004, 56: 1509–1517 ß 2004 The Authors Received May 25, 2004 Accepted September 2, 2004 DOI 10.1211/0022357044896 ISSN 0022-3573 University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India Deepika Aggarwal, Indu P. Kaur School of Pharmacy, University of Auckland, Auckland-92019, New Zealand Alka Garg Correspondence: I. P. Kaur, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India. E-mail: indupalkaur@yahoo.com Funding: The authors wish to acknowledge the financial support provided by the Department of Science and Technology and Council of Scientific and Industrial Research (CSIR), New Delhi, India. Development of a topical niosomal preparation of acetazolamide: preparation and evaluation Deepika Aggarwal, Alka Garg and Indu P. Kaur Abstract Orally administered acetazolamide has a limited use in glaucoma due to the systemic side effects associated with its use. No topical formulation of acetazolamide is available, mainly because of it having a limited aqueous solubility and poor corneal permeation. To enhance the bioavailability of acetazolamide by the topical route and to improve the corneal permeability of the drug, niosomes of acetazolamide were prepared (employing span 60 and cholesterol) by different methods. Transmission electron microscopy (TEM) of the selected formulation was carried out to study the morphology. Niosomes were also prepared in the presence of dicetyl phosphate and stearylamine to obtain nega- tively and positively charged vesicles, respectively. It was found that the reverse-phase evaporation method (REV) gave the maximum drug entrapment efficiency (43.75%) as compared with ether injection (39.62%) and film hydration (31.43%) techniques. Drug entrapment efficiency varied with the charge and the percent entrapment efficiency for the REV method was 43.75, 51.23 and 36.26% for neutral, positively charged and negatively charged niosomes, respectively. Corneal permeability stud- ies, however, showed that the percent permeation and the apparent permeability coefficient for the charged niosomes were less than for the neutral ones. A bioadhesive niosomal formulation of acetazol- amide was also prepared and compared with the positively charged formulation, considering that both of them would have a prolonged stay in the cul-de-sac because of their expected interactions with mucin. The formulations were also compared based on their intraocular pressure (IOP)-lowering capacity. The positively charged niosomes (REV2), although showing good corneal permeability and pharmacodynamics, were however found to be inappropriate in terms of the corneal cell toxicity. The bioadhesive coated formulation (REV1bio) compared well with REV2 and also showed a much lesser toxicity. Further, the IOP-lowering effect of the developed formulations was compared with that of a marketed formulation of dorzolamide 2%, a topical carbonic anhydrase inhibitor. The developed niosomal formulations of acetazolamide showed a comparable physiological effect (33% reduction of IOP in REV1bio and 37% reduction in dorzolamide) with a duration of up to 6 h (the duration being 3 h for dorzolamide). Results of the study indicate that it is possible to develop a safe (as indicated by corneal toxicity studies) and physiologically active topical niosomal formulation of acetazolamide relative in efficiency to the newer local carbonic anhydrase inhibitor, dorzolamide. The developed formulations can form a cost effective treatment plan, which is especially important in the treatment of glaucoma, a chronic ailment affecting middle-aged to old patients. Introduction Acetazolamide, a carbonic anhydrase inhibitor, is a potent ocular hypotensive agent used to relieve the acute symptoms of open angle glaucoma, delay the onset of blindness in persons with advanced glaucoma and reduce intraocular pressure (IOP) preoperatively (Khaw & Cordiero 2000). Despite this, the use of acetazolamide for the treatment of glaucoma is limited as it is administered orally (no topical formulation being available) and, considering the large distribution of carbonic anhydrase enzyme in the various organs of the body, it causes a wide array of systemic side effects (Epstein & Grant 1977; Gamm 1984). The constraints in the development of a topical formulation of acetazolamide (Kaur et al 2002; Singla et al 2002) are its very low solubility (0.7 mg mL 1 ) in aqueous tear fluid and in water and its limited corneal penetration (log P ¼ 0.3) (Parasampuria 1993). Moreover, the degradation of acetazolamide increases many fold on the basic side (the highly soluble Downloaded from https://academic.oup.com/jpp/article/56/12/1509/6147501 by guest on 30 November 2021