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Monday, 02 December 2013 14:51

Technical Report: Improvement of Dissolution Properties of Ketoconazole Using a New Excipient (LoxOral™) in Comparison with Microcrystalline Cellulose

Introduction:

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Poor aqueous solubility of an active pharmaceutical ingredient (API) is one of the most pressing problems in pharmaceutical R&D, with as many as 90% of new API candidates in this category (Lobmann et al., 2013). Dissolution rate in the gastrointestinal tract is the rate limiting factor for the absorption of many of these drugs (Zimmermann et al., 2009), which may limit their bioavailability after oral administration (Holm et al., 2011).

In order to enhance the dissolution of poorly water-soluble drugs, an increasing number of pharmaceutical formulation technologies are being developed to address this drug development challenge (Uchiyama et al., 2010). Many pharmaceutical studies have focused their attention on the production of multifunctional excipients, once the choice of excipients becomes critical in terms of delivery system functionality and quality. Excipients with multiple functional properties confer many advantages such as manufacturing efficiency and reduced production costs (Builders et al., 2010).

Microcrystalline cellulose (MCC) is a purified, partially depolymerized cellulose prepared by treating alpha cellulose, obtained as pulp from fibrous plant material, with mineral acids (Gohel et al., 2007). It is widely used as a filler, disintegrant and binder of oral tablets, pellets and capsules (Nikolakakis et al., 2006). MCC is considered one of the most useful fillers due to its excellent compatibility at low pressures, high dilution potential, chemical inertness and compatibility with most drugs (Kalita et al., 2013). However, according to Chamsai & Sriamornsak (2013), most drugs prepared with MCC show a tendency toward prolonged release due to a lack of disintegration.

LoxOral, manufactured by PCCA, is an innovative excipient for use in capsule formulations. It improves dissolution of all types of APIs, including drugs with poor water solubility. It is gluten- and casein-free, Sodium Lauryl Sulfate (SLS)-free, lactose-free, soy-free, dye-free and magnesium stearate-free. It also contains an ingredient (isomalt) which has shown potential prebiotic effects (Gibson et al., 2010). LoxOral is an all-in-one base with improved dissolution, excellent flowability and reduced static. It is minimally hygroscopic, resisting moisture absorption and providing optimal stability.

Ketoconazole, an imidazole antifungal agent, is administered both orally and topically. It is known to be orally active in the treatment of systemic blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, paracoccidioidomycosis, and tinea of skin and nails (Van den Mooter et at., 2001). According to the Biopharmaceutic Drug Classification System (BCS) proposed by Amidon et al. (1995), ketoconazole is a class II drug, characterized by low solubility–high permeability. It is difficult to dissolve in water, and gastrointestinal fluids under normal conditions (Van den Mooter et al., 2001). Furthermore, ketoconazole exhibits solubility which is strongly pH dependent (Dressman & Reppas, 2000). It has been reported that poor water solubility can cause problems with drug release and bioavailability in various pharmaceutical forms and there have been numerous efforts to resolve this issue (Balata et al., 2010).

Abstract:

Ketoconazole is an imidazole antifungal drug that can be administered orally and is characterized by low solubility, high permeability (class II by BCS). The capability of a new excipient, LoxOral, manufactured by PCCA, to enhance the dissolution of drugs with poor water solubility was investigated by USP dissolution testing and compared to microcrystalline cellulose (MCC). The capsules containing ketoconazole in LoxOxal produced a higher in vitro dissolution when compared to corresponding mixture with MCC. It was also the only combination which complied with the USP dissolution specification for the drug (80.78% at 30 min). The results suggest that LoxOral, is a useful and powerful excipient tool to accelerate dissolution and potentially improve the oral bioavailability of drugs with poor water solubility.

Conclusions:

LoxOral was shown to be a successful excipient to improve the dissolution rate of ketoconazole. The increase in rate would potentially provide rapid bioavailability and onset of action after the drug is taken orally. LoxOral-based formulations have proven to be a most promising delivery system for oral bioavailability enhancement of BCS Class II drugs such as ketoconazole.

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