Stability of Extemporaneously Prepared 0.5-Percent Caspofungin Eye Drops: a Potential Cost-Savings Exercise

Abstract

cWhile the successful use of topical caspofungin for patients has been reported, topical caspofungin is not commercially available and its stability is unknown, limiting its usefulness in treating fungal keratitis. Caspofungin (0.5%) eye drops were aseptically prepared, and the concentrations were measured using a validated high-performance liquid chromatography (HPLC) analysis. The preparations remained stable for 28 days under refrigerated condition but not at 25.0°C. Our study supports the cost-saving use of caspofungin eye drops in the clinical setting.F ungal keratitis is difficult to treat, with Candida, Aspergillus, and Fusarium species (1, 16) as the common causative pathogens. Current treatment options for keratomycosis are inadequate (3) given the restricted range of effective topical preparations (e.g., natamycin is the only commercially available antifungal eye drop). Caspofungin is active against a broad spectrum of fungi (MIC 90 , 60 to 2,000 ng/ml) (8,20). After topical delivery in animals, caspofungin has good penetration into eyes with inflammation or corneal abrasion (4, 20), and it has been shown previously to be effective in treating fungal keratitis in rabbits (5, 12). While penetration into intact human eyes may be limited (10), successful application of topical caspofungin alone (7) or in combination with voriconazole (11, 18) for patients with fungal keratitis has been reported. However, the stability of extemporaneously prepared caspofungin eye drops is unknown and the eye drops have to be freshly prepared and used within 24 h (7), making their use in clinical settings uneconomical. This study investigated the stability of 0.5% caspofungin eye drops to support the clinical use of topical caspofungin.The eye drops were prepared aseptically; 10.5 ml of water for injection was added to a 50-mg vial of caspofungin acetate (Cancidas) (2). Aliquots (0.5 ml) of the reconstituted 0.5% solution were then transferred into presterilized, lightproof, low-density polyethylene eye dropper bottles (Sik Hong Holding Pty. Ltd.). The bottles were kept sealed until the day of analysis, stored either (i) under refrigeration (at 4.0 Ϯ 1.0°C; n ϭ 18) or (ii) at room temperature (25.0 Ϯ 1.0°C; n ϭ 18). On days 0, 3, 7, 14, 28, and 56, 50 l of 0.5% caspofungin from each bottle was diluted with 450 l of water to obtain a concentration of 0.5 mg/ml; 10-l aliquots were injected into a high-performance liquid chromatograph (HPLC). Three bottles were analyzed in triplicate for each condition at the designated time points.The HPLC method of Spriet et al. (15) was adapted. A liquid chromatography (LC) system (Shimadzu, Japan) comprised an LC-10AD pump, a DGU-14A degasser, and a CTO-10AC column oven. A PhenoSphere-NEXT C 18 column (pore size, 120 Å; dimensions, 150 by 4.6 mm; and particle size, 5 m; Phenomenex) and a guard column (dimensions, 4 by 2 mm; Phenomenex) were used. The column temperature was 35.0°C, and the flow rate was 1.5 ml/min. The mobile phase comprised Milli-Q water-trifluoroacetic acid (mobile phase ...

Case Series of Rare Fungal Keratitides: Experiences from a Quaternary Eye Hospital in Sydney, Australia

“…These have a 14-day shelf-life and last only 3.5 days once opened. The drug is reconstituted in 0.9% sodium chloride instead of sterile water due to the low osmolality of the final product when prepared with water; hence, this formula replaces sterile water with 0.9% sodium chloride [31].…”

Echinocandins in antifungal pharmacotherapy

“…All the formulations contain excipients for pH adjustment, such as glacial acetic acid, citric acid, tartaric acid and sodium hydroxide (Table ). These excipients provide an acidic pH to the formulations (Cancidas™: pH: 6.6; Mycamine™: pH: 5–7; Eraxis™: pH: 4.5–4.6), to ensure their chemical stability (as they undergo ionization and ring‐opening at neutral or alkaline pH) . The bulking agents such as sucrose, mannitol and fructose are used to prevent hydrolysis of the drugs by sequestering water, to form an easily dispersible cake upon lyophilization and to prevent the dimerization of the drug leading to instability in solution .…”

“…The bulking agents such as sucrose, mannitol and fructose are used to prevent hydrolysis of the drugs by sequestering water, to form an easily dispersible cake upon lyophilization and to prevent the dimerization of the drug leading to instability in solution . As the osmolality of the reconstituted drug solution is low, it is administered using an electrolyte solution, to maintain iso‐osmolal conditions, during the IV administration …”

Caspofungin-Loaded Formulations for Treating Ocular Infections Caused by Candida spp.

“…The use of release systems for vaginal administration of CSP has already been reported [ 24 ]. The validity of CSP as an agent used to treat fungal keratitis is unknown, as no evidence is available on its ability to permeate into the aqueous humor ( Figure 1 ) when administered topically [ 25 ].…”