Surface modification of liposomes increases drug efficacy in local vaginal therapy

Abstract

<p>The vaginal inflammation and infection are one of the major female health issues, and unfortunately rather neglected. The anatomical structure and physiological conditions make vagina vulnerable to inflammation and infection, which if not successfully treated, can lead to deteriorating female health conditions. In pregnant patients, the pregnancy outcome can be severely affected. Although a standard treatment for vaginal infection is available, it is often not successful and recurrence rates are high. Therefore, a patientfocused drug development targeted at the vaginal inflammation and infection is the current social demand. Research and practice have shown that the topical treatment by the drugs against vaginal inflammation and infection can be superior comparing to the classical oral drug administration. However, the thick vaginal mucus lining the luminal surface of vagina and cervix, which protects the underlying tissue, limits the ability of a drug to reach vaginal mucosa. The success of mucosal delivery is highly dependent on a suitable drug carrier. Current dosage forms suffer from limited residence time at administration site and unpleasant leakage of dosage forms residues due to the self-cleansing action of the vagina, resulting in a reduced therapeutic effect. Therefore, liposomal drug delivery systems, with the ability to incorporate poorly soluble drugs and assure their stability, would be suitable for this purpose. Moreover, the modification of liposomal surface with mucoadhesive or mucoresistant polymers, might further enable improved mucosal drug delivery by providing prolonged residence time or rapid mucuspenetration, respectively. <p>We selected chitosan as a mucoadhesive polymer due to its biocompatibility, low toxicity and intrinsic anti-microbial potential. By combining the liposomal carrier and the mucoadhesive chitosan, an optimized vaginal drug delivery system with specific, prolonged and controlled drug release properties might be developed. Alternatively, improved drug delivery to vaginal mucosa can be provided through mucoresistant properties of the delivery system. Polyethylene glycol (PEG) plays an important role in this approach, and PEGylated liposomes enable controlled drug release in close proximity to the vaginal epithelium. Three model drugs/active ingredients were tested in mucoadhesive/mucoresistant liposomebased delivery systems, namely clotrimazole, resveratrol and interferon. Particularly interesting were the anti-oxidative and anti-inflammatory properties of resveratrol, which has a great potential in the treatment of vaginal inflammation and infection, however, its low solubility and poor bioavailability accompanied by poor stability limit its therapeutic effects. Liposomal system enhanced its activities and confirmed its potential. <p>The <i>in vitro</i> drug release and <i>ex vivo</i> penetration confirmed a sustained release of all liposomallyassociated drugs/active molecules. PEGylated liposomes (mucoresistant) assured improved penetration of interferon. By modulation of liposomal surface properties to be either mucoadhesive or mucoresistant it is possible to achieve prolonged residence time or deeper penetration of drug within vaginal epithelium, respectively. Moreover, the system can be modified for the different drugs, regardless of their molecular size and physicochemical characteristics.