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Monday, 02 December 2013 15:08

Technical Report: The Antimicrobial Activity of Itraconazole and LoxaSperse™ Against Biofilms of C. albicans

Introduction:

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Local delivery of medication to the sinuses and lungs is highly desirable, especially in patients with specific sinus and pulmonary diseases such as cystic fibrosis, asthma, chronic sinus and pulmonary infections, and lung cancer. The principal advantages include reduced systemic side effects and higher doses of the applicable medication at the site of drug action (Harvey and Schlosser, 2009; Pilcer and Amighi, 2010).

Many existing APIs and an increasing number of new drugs are often poorly water-soluble drugs (Zhang et al., 2011). Drug insolubility, regardless of the administration route, commonly generates bioavailability or efficacy problems. Different techniques exist to increase drug dissolution and/or solubility, which often require the use of specific excipients. In the ear, nose and throat (ENT) injuries and illness field, excipients should be chemically and physically stable, inert to the API and exhibit no side effects (Duret et al., 2012).

LoxaSperse is a proprietary excipient manufactured by PCCA for use as a chemical dispersing or solubilizing agent in oral, sinus, inhalation, rectal and topical formulations. It consists of a blend of micronized xylitol and micronized poloxamers, designed to be mixed with APIs in order to improve their water solubility and dispersability (PCCA, 2013). Xylitol is a 5-carbon sugar with low transepithelial permeability which is poorly metabolized by bacteria (Durairaj et al., 2007). Poloxamers are a series of synthetic block copolymers of poly(ethyleneoxide-b-propylene oxide-b-ethylene oxide) (PEO–PPO–PEO) with varying molecular weights and block ratios. They are nonionic amphiphilic surfactants possessing excellent wetting, antifoaming and solubilizing properties (Moebus et al., 2009). The use of xylitol and poloxamers in nebulization and irrigation is thoroughly referenced in the literature and there is evidence of their safety. (Durairaj et al., 2007; Jagannath et al., 1995; Plataki et al., 2011; Zabner et al., 2000). LoxaSperse is a base that allows for the preparation of non-sterile capsules and powder sachets that are added to sterile water or normal saline by the patient at the moment of administration (PCCA, 2013).

Candida infections have increased dramatically over the past years, being reported as the fourth most common nosocomial bloodstream pathogen. Candidemia represents 10% of all nosocomial blood-stream infections (Burgess et al., 2000). The traditional treatment uses amphotericin B, but it has changed to relatively less toxic alternatives, such as the triazole antifungals itraconazole and fluconazole (Wroblewska et al., 2002).

Itraconazole has a broader spectrum of activity than other azole antifungals (De Beule, 1996). However, poor oral bioavailability, variable absorption and gastrointestinal toxicity due to the hydroxypropyl-β-cyclodextrin component of the oral solution limit itraconazole to a second or third line treatment option for invasive fungal infections (Vaughn et al., 2007).

Itraconazole is a typical Biopharmaceutical Classification System (BCS) Class II drug with low solubility–high permeability (Amidon et al., 1995). An inhaled itraconazole delivery system has shown an interesting potential for treating pulmonary invasive fungal infections with improvement of its efficacy (Duret et al., 2012).

Abstract:

Itraconazole is a broad-spectrum, triazole antifungal agent, class II drug molecule (low solubility–high permeability) according to the Biopharmaceutical Classification System (BCS). LoxaSperse is an excipient manufactured by PCCA and can be used as a chemical dispersing or solubilizing agent in irrigation or nebulization formulations, improving the solubility and dispersibility of poorly water soluble Active Pharmaceutical Ingredients (APIs). The in vitro antimicrobial activity of itraconazole in a LoxaSperse formulation was evaluated against Candida albicans biofilms and compared to the same activity of reference antifungal drugs (itraconazole, fluconazole and amphotericin B), in order to verify the benefits of the LoxaSperse formulation. The LoxaSperse formulation reduced Minimum Biofilm Inhibitory Concentration (MBIC) 10-fold compared to the value of itraconazole alone. Improvement in antimicrobial activity of the LoxaSperse/itraconazole formulation could be attributed to the improved dissolution rate and solubility enhancement caused by the base over the poorly water-soluble itraconazole.

Conclusions:

Itraconazole has an increased in vitro antimicrobial activity against Candida biofilms when associated with the LoxaSperse excipient. It may be due to the benefits caused by the base in terms of the dissolution rate and saturation solubility of the poorly water-soluble itraconazole, providing a higher in vitro dissolved drug concentration that induced an enhanced inhibition of microbial growth.

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