Development and evaluation of novel surfactant-based elastic vesicular system for ocular delivery of fluconazole.

PURPOSE: Fluconazole is a bis-triazole antifungal agent with a low molecular weight (306 Da). It is hydrophilic in nature and has low protein binding. It is available as eye drops for the treatment of ocular mycoses, the second most common cause of blindness in developing countries. However, its administration often results in poor patient compliance and limited use due to its short half-life (15-30 min) and a low log P (0.25). Therefore, fluconazole was incorporated into a novel sorbitan (spans) based elastic (spanlastic) vesicular system with intent to achieve a prolonged and better effect. Spanlastics are to niosomes what Transfersomes(®) are to liposomes. METHODS: Developed spanlastics consisted of spans and an edge activator prepared by the ether injection method. Developed vesicles were characterized for size, shape, and the number of vesicles/ml by optical microscopy. Entrapment efficiency was determined by the dialysis method, and the ex vivo corneal permeability study was performed using porcine cornea. A 3-tier safety of the novel formulation was established by the Ames test, the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, and in rabbits according to the OECD guidelines 404 and 405. RESULTS: Spanlastics were smaller in size (3 times) and showed a better permeation in comparison to a corresponding niosomal formulation. The system showed an increase (3-fold) in the apparent permeability coefficient compared to the marketed formulation Zocon(®) (0.3% w/v solution of fluconazole) due to its elastic nature. The developed system was found to be stable for 2 months under refrigerated conditions and under extreme storage conditions. Safety was established in terms of genotoxicity (Ames test), cytotoxicity (MTT assay; mouse peritoneal macrophages), acute dermal/eye irritation/corrosion, and chronic eye irritation/corrosion tests (OECD guidelines). CONCLUSION: The developed system is novel and provides an effective and safe formulation of fluconazole.

Ocular preservatives: associated risks and newer options.

Presence of a preservative in an ocular medication has often been considered a culprit in damaging the epithelium. However, the inclusion of a preservative is equally necessary, especially in multiple-dose containers, in order to protect against dangerous organisms accidentally gaining access during instillation. Benzalkonium chloride (BAK), chlorobutanol, chlorhexidine acetate (CHA), and phenylmercuric nitrate or acetate are some commonly used preservatives in eye preparations. New preservatives with a wide range of activity and good safety profiles have been introduced in the market, such as stabilized oxychloro complex (SOC), sofZia, and sodium perborate. In the present review, we discuss various conventional and newly proposed and patented preservative molecules for ocular use. Reasons for discontinuing traditional preservatives and the need for less-toxic molecules are discussed at length, along with newer options coming up in this area.

Development of effective ocular preparations of antifungal agents.

In treating ophthalmic mycoses, the ultimate aim is to preserve vision, and this depends on rapid diagnosis and efficient antifungal therapy. Antifungal agents are used both for their superficial action as well as to treat infections of the internal eye. Their clinical efficacy would depend on the concentration achieved in ocular tissue, which, in turn, depends on the molecular mass, route of administration, duration of contact, and ability of the compound to penetrate the eye. Several of these agents have a high molecular mass exceeding 500 Da (such as amphotericin B, natamycin, and ketoconazole), resulting in their poor penetration (even if they are lipophilic in nature). In the present review, we present the physiochemical and pharmacokinetic profile and also the spectrum of antifungal activity of representative antifungal agents recommended for use in treatment of ocular infections. Suitable delivery systems, which can improve the effectiveness of these agents, are suggested as per the nature of each agent. These include liposomes/niosomes, lipid emulsions, nanoparticles including solid lipid nanoparticles, and use of cyclodextrin complexes. The advances made therein, followed by a critical appraisal and suggestions for achieving better therapy as per our expertise, are also included.