Virucidal activity and cytotoxicity of the liposomal formulation of povidone-iodine

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Abstract

Two drug formulations of povidone-iodine (PVP-I)—an aqueous PVP-I solution (Betaisodona®) and a liposomal PVP-I formulation—were tested for their virucidal activity and cytotoxicity in cell culture. As to the virudical activity against influenza A virus, herpes simplex virus type 1, adenovirus type 8 and human rhinovirus type 14, the liposomal formulation of PVP-I proved to be approximately as active as the aqueous one. Half maximum cytotoxic PVP-I concentrations were 0.01–0.07% for aqueous PVP-I and 0.03–0.27% for the liposomal PVP-I formulation (XTT reduction assay EZ4U). The detection of lactate dehydrogenase (LDH) release, DNA fragmentation (ELISA) and DNA strand breakage (TUNEL assay) after 24 h exposure of human embryonic lung fibroblasts to PVP-I revealed that necrosis predominates in cells treated with aqueous 0.08–0.32% PVP-I solutions, whereas apoptosis was the predominant type of cell death in cells treated with equivalent concentrations of liposomal PVP-I formulation. The favorable virucidal efficiency together with the preferred apoptotic route of cell death makes the liposomal PVP-I formulation a promising candidate for topical use in prevention and treatment of infections of the eye and the upper respiratory tract.

Introduction

Povidone-iodine (PVP-I) is a broad spectrum microbicide with in vitro activity against bacteria, viruses, fungi, and protozoans (Görtz et al., 1996). As an iodophore, PVP-I consists of elementary iodine bound to the carrier poly(1-vinyl-2-pyrrolidone) which increases the solubility and provides a reservoir of iodine. Due to its excellent antiseptic properties PVP-I is used in numerous topical formulations, e.g. for disinfection, wound antisepsis, the treatment of burns, leg ulcers and decubital ulcers. PVP-I has also been successfully applied in the treatment of bacterial and viral keratoconjunctivitis (Neuhann and Sommer, 1980, Schuhman and Vidic, 1985) but is not approved for repeated application on the eye. Possibly, PVP-I could be also suitable for the topical treatment of respiratory viral infections. However, due to its non-specific mechanism of cell killing by oxidizing effects of free iodine on SH-, OH- and NH-groups of amino acids and on double bounds of unsaturated fatty acids (Gottardi, 1991), PVP-I has a certain cytotoxic potential to mammalian cells.

Recently, a novel, liposomal PVP-I formulation was developed by liposomal drug encapsulation (Reimer et al., 1997). Liposomes are known to provide an enhanced site-specific activity, sustained release of drugs and less toxicity than conventional drug formulations in vivo. It was shown in a previous paper that the novel liposomal formulation is as virucidally active as the aqueous PVP-I solution and has a better cell tolerability (Wutzler et al., 2000). The present study was mainly directed to possible reasons for the different toxicological behavior of the two PVP-I formulations, in particular to the type of cell death. In addition, virucidal activities of aqueous and liposomal PVP-I formulations against several viruses related to infections of the eye or the respiratory tract were compared.

Section snippets

Test preparations

Following test preparations were provided by Mundipharma, Limburg, Germany: (1) the commercially available aqueous PVP-I solution Betaisodona® containing 10% (m/v) PVP-I; (2) a liposomal PVP-I formulation containing 5% resp. 4.5% PVP-I and 4% (m/v) fully hydrogenated soy bean phosphatidylcholine (Phospholipone 90 H, Rhöne-Poulenc Rorer); (3) a drug-free isotonic liposomal preparation containing 4% of the same phosphatidylcholine.

The liposomal PVP-I formulation was prepared by heating

Virucidal effectiveness

The virucidal activities of the PVP-I formulations are shown in Table 1. Influenza A virus and HSV-1 were inactivated by more than 4.0 log10 by 0.009 (influenza A virus) and 0.11% (HSV-1) liposomal or aqueous PVP-I preparations within 0.5 min. For inactivation of human adenovirus type 8 and human rhinovirus type 14 higher concentrations and longer exposure times were necessary. Following the 15 min exposure time to 0.23% liposomal PVP-I formulation, adenovirus type 8 was inactivated by more

Discussion

In view of the intended topical treatment of viral infections of the eye and the upper respiratory tract important concerns of PVP-I formulations are their virucidal efficacy as well as cytotoxicity including membrane-toxicity and apoptosis-inducing capacity. Although the aqueous PVP-I formulation has excellent antiseptic properties, overlapping microbicidal and cytotoxic concentrations have been reported in several studies (Sanchez et al., 1988). Therefore, the development of a novel,

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