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Methazolamide 1% in Cyclodextrin Solution Lowers IOP in Human Ocular Hypertension

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Methazolamide 1% in Cyclodextrin Solution Lowers IOP in Human Ocular Hypertension Methazolamide 1% in Cyclodextrin Solution Lowers IOP in Human Ocular Hypertension Elı´nborg Guðmundsdo´ttir,1 Einar Stefa´nsson,1 Gyða Bjarnado´ttir,1 Jo´hanna F. Sigurjo´nsdo´ttir,2 Guðru´n Guðmundsdo´ttir,1 Mar Masson,2 and Thorsteinn Loftsson2 PURPOSE. To formulate aqueous eye drops containing methazolamide 1% in cyclodextrin solution and to evaluate their effect on intraocular pressure (IOP) in a double-blind randomized trial in humans. Methazolamide, a carbonic anhydrase inhibitor (CAI), has been used in oral doses in the treatment of glaucoma but hitherto has not been successfully formulated in eye drops. In this study the effects of methazolamide are compared with those of dorzolamide (Trusopt). METHODS. Methazolamide 1% was formulated in a 2-hydroxypropyl-␤-cyclodextrin with hydroxypro- pyl methylcellulose in aqueous solution. Eight persons with ocular hypertension were treated with the methazolamide-cyclodextrin eye drops and eight persons with dorzolamide (Trusopt), both groups at dosages of three times a day for 1 week. IOP was measured before treatment was begun and on days 1, 3, and 8 at 9 AM (peak) and 3 PM (trough). RESULTS. After 1 week of treatment, the peak IOP in the methazolamide group had decreased from 24.4 Ϯ 2.1 mm Hg (mean Ϯ SD) to 21.0 Ϯ 2.0 mm Hg, which is a 14% pressure decrease (P ϭ 0.006). In the dorzolamide group, the peak IOP decreased from 23.3 Ϯ 2.1 mm Hg to 17.2 Ϯ 3.1 mm Hg, which is a 26% pressure decrease (P Ͻ 0.001). On average, the IOP declined 3.4 Ϯ 1.8 mm Hg after methazolamide administration and 6.1 Ϯ 3.6 mm Hg after dorzolamide. CONCLUSIONS. Through cyclodextrin complexation, it is possible to produce topically active metha- zolamide eye drops that lower IOP. This is the first double-blind clinical trial that demonstrates the efficacy of the classic CAIs in eye drop formulation. (Invest Ophthalmol Vis Sci. 2000;41: 3552–3554) arbonic anhydrase inhibitors (CAIs) were invented dur- in the aqueous tear film and also somewhat lipid soluble to be ing the middle of the 20th century, and acetazolamide able to penetrate the lipophilic barriers of the cornea.6 Few Cand methazolamide were used as systemically adminis- drugs fulfill both criteria. However, cyclodextrin can serve as a tered glaucoma drugs for the latter half of the century. Numer- vehicle that carries a hydrophobic drug in aqueous solution ous attempts to formulate these drugs as eyedrops were un- and releases the lipophilic molecule to the biologic membrane successful, and it was thought by many that their formulation such as the cornea. Methazolamide is a good example of this 1,2 in eye drops was impossible. With the help of a cyclodex- drug delivery dilemma. The ocular bioavailability of methazol- trin-based drug delivery system we have successfully formu- amide can be improved with the aid of a cyclodextrin-based lated acetazolamide, methazolamide, and ethoxyzolamide in drug delivery vehicle. eye drops and tested these in experimental animals and in an 2-Hydroxypropyl-␤-cyclodextrin (HP␤CD) is a cyclic oligo- 3–5 open pilot study in humans. We now report a double-blind saccharide with a hydrophilic outer surface and a lipophilic randomized clinical trial comparing the effect of methazol- cavity in the center. It is capable of forming inclusion com- amide in a cyclodextrin eye drop formulation to dorzolamide plexes with many lipophilic drugs by taking up a drug mole- eye drops (Trusopt; Merck Inc., Whitehouse Station, NJ). cule, either the whole molecule or part of it, into the cavity. In Methazolamide is nearly insoluble in water and aqueous this way it is possible to form water-soluble drug–cyclodextrin tear fluid, and this has made formulation of methazolamide eye complexes with water-insoluble lipophilic drugs. No covalent drops impossible until now.3 A drug molecule in eye drops bounds are formed or broken during the complex formation, must be water soluble, at least to some degree, to be dissolved and in aqueous solutions the complexes are readily dissoci- ated.6,7 Adding hydroxypropyl methylcellulose (HPMC) to the From the Departments of 1Ophthalmology and 2Pharmacy, Uni- solution increases the stability of the drug–cyclodextrin com- versity of Iceland, Reykjavı´k. plexes.3,8 The larger stability constant results in increased Presented in part at the annual meeting of the Association for complexation of the drug, and thus a higher concentration of Research in Vision and Ophthalmology in Fort Lauderdale, Florida, on the drug can be dissolved in a given amount of cyclodextrin.3 May 12 1999. Submitted for publication December 6, 1999; revised May 19, In general, cyclodextrin molecules do not penetrate biologic 2000; accepted May 22, 2000. membranes but act as penetration enhancers by assuring high Commercial relationships policy: P (ES, TL); all others N. ES and concentration of dissolved drug at the membrane surface. TL hold a patent for the drug delivery technology used in this study. Cyclodextrins increase the aqueous solubility of lipophilic wa- Corresponding author: Einar Stefa´nsson, Department of Ophthal- mology, University of Iceland, Landspı´tali, 101 Reykjavı´k, Iceland. ter-insoluble drugs without decreasing the drug molecules’ [email protected] ability to penetrate lipophilic biologic membranes. Investigative Ophthalmology & Visual Science, October 2000, Vol. 41, No. 11 3552 Copyright © Association for Research in Vision and Ophthalmology Downloaded from iovs.arvojournals.org on 09/30/2021 IOVS, October 2000, Vol. 41, No. 11 Methazolamide in Ocular Hypertension 3553 TABLE 1. Intraocular Pressure at Baseline and After Administration of Eye Drops (8 ؍ Methazolamide (n (8 ؍ Dorzolamide (n Change from Change from IOP Baseline P IOP Baseline P Baseline day 0 9 AM, peak 23.3 Ϯ 2.1 24.4 Ϯ 2.1 3 PM, trough 23.2 Ϯ 2.4 22.7 Ϯ 2.3 Treatment day 1 9 AM, peak 17.5 Ϯ 2.9 25% P Ͻ 0.001 21.9 Ϯ 1.6 10% P ϭ 0.017 3 PM, trough 18.2 Ϯ 1.8 21% P Ͻ 0.001 20.9 Ϯ 2.9 8% P ϭ 0.187 Treatment day 3 9 AM, peak 17.1 Ϯ 2.0 27% P Ͻ 0.001 21.2 Ϯ 2.2 13% P ϭ 0.012 3 PM, trough 17.6 Ϯ 1.6 24% P Ͻ 0.001 21.1 Ϯ 3.9 7% P ϭ 0.313 After 1 week 9 AM, peak 17.2 Ϯ 3.1 26% P Ͻ 0.001 21.0 Ϯ 2.1 14% P ϭ 0.006 3 PM, trough 17.2 Ϯ 1.5 26% P Ͻ 0.001 20.6 Ϯ 3.8 9% P ϭ 0.196 Data are means Ϯ SD. The purpose of this study was to formulate eye drops study days with the baseline value at 9 AM on the baseline day containing methazolamide 1% in cyclodextrin solution and to 0, and a similar comparison was made for the 3 PM measure- evaluate its effect on IOP in humans with ocular hypertension ments, which were compared with the 3 PM measurement on and to compare it with dorzolamide in a double-blind random- day 0. ized clinical trial. The IOP was measured by Goldmann applanation tonom- etry two times at each measurement point, and the mean value recorded. Possible toxic effects were monitored throughout MATERIALS AND METHODS the study with evaluation of symptoms, best corrected Snellen visual acuity, and slit lamp examinations at all time points on study The institutional review board of Landspitali University Hospi- days. Student’s t-test was used for statistical analysis of the data. tal and the State Committee on Pharmaceutics in Reykjavı´k approved the protocol, which conformed to the tenets of the Declaration of Helsinki. Methazolamide eye drops were formu- RESULTS lated in an aqueous solution of HP␤CD with HPMC. One gram of methazolamide was added to 100 ml of an aqueous solution Table 1 shows the IOP data. Data are expressed as means Ϯ SD. containing 23 g HP␤CD (Encapsin; Janssen Biotech, Beerse, After 1 week of treatment, the peak IOP in the methazolamide Belgium), 0.1 g HPMC, 0.01 g benzalkonium chloride, and group had decreased from 24.4 Ϯ 2.1 to 21.0 Ϯ 2.1 mm Hg, 0.05 g EDTA. The solution was heated in an autoclave at 121°C which is a 14% pressure decrease (P ϭ 0.006). In the dorzol- for 40 minutes to promote the complexation between HP␤CD amide group, the peak IOP decreased from 23.3 Ϯ 2.1 to and methazolamide.3,8,9 The resultant solution was filtered 17.2 Ϯ 3.1 mm Hg, which is a 26% pressure decrease (P Ͻ through a 0.45-␮m nylon membrane and aseptically divided 0.001). On average, the IOP declined 3.4 Ϯ 1.8 mm Hg after into eye drop vials. Finally, the eye drop vials and their con- methazolamide administration and 6.1 Ϯ 3.6 mm Hg after dorzol- tents were sterilized in an autoclave at 121°C for 20 minutes amide. The difference between the methazolamide and dorzol- Patients with ocular hypertension (IOP Ͼ21 mm Hg) were amide groups did not reach statistical significance (P ϭ 0.07). recruited. Inclusion criteria included no previous treatment to Figure 1 shows the effect of methazolamide and dor- lower ocular pressure and no concurrent ocular therapy other zolamide on peak IOP. Looking at the trough effect (IOP at 3 than the study drug. Informed consent was obtained from each PM, just before the administration of the second drop) the IOP subject.
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