International Journal of Pharmaceutics 416 (2011) 55–60 Contents lists available at ScienceDirect International Journal of Pharmaceutics jo ur nal homep a ge: www.elsevier.com/locate/ijpharm Encapsulation of poorly soluble basic drugs into enteric microparticles: A novel approach to enhance their oral bioavailability Mohamed A. Alhnan, Sudaxshina Murdan, Abdul W. Basit ∗ Department of Pharmaceutics, The School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX, United Kingdom a r t i c l e i n f o Article history: Received 5 March 2011 Received in revised form 26 May 2011 Accepted 28 May 2011 Available online 14 June 2011 Keywords: Microspheres o/o emulsion solvent evaporation pH responsive Wistar rats Site-specific IVIVC Enteric polymers a b s t r a c t Poorly water soluble basic drugs are very sensitive to pH changes and following dissolution in the acidic stomach environment tend to precipitate upon gastric emptying, which leads to compromised or erratic oral bioavailability. In this work, we show that the oral bioavailability of a model poorly soluble basic drug (cinnarizine) can be improved by drug encapsulation within highly pH-responsive microparticles (Eudragit L). The latter was prepared by emulsion solvent evaporation which yielded discrete spherical microparticles (diameter of 56.4 ± 6.8 m and a span of 1.2 ± 0.3). These Eudragit L (dissolution threshold pH 6.0) microparticles are expected to dissolve and release their drug load at intestinal conditions. Thus, the enteric microparticles inhibited the in vitro release of drug under gastric conditions, despite high cinnarizine solubility in the acidic medium. At intestinal conditions, the particles dissolved rapidly and released the drug which precipitated out in the dissolution vessel. In contrast, cinnarizine powder showed rapid drug dissolution at low pH, followed by precipitation upon pH change. Oral dosing in rats resulted in a greater than double bioavailability of Eudragit L microparticles compared to the drug powder sus- pension, although C max and T max were similar. The higher bioavailability with microparticles contradicts the in vitro results. Such an example highlights that although in vitro results are an indispensable tool for formulation development, an early in vivo assessment of formulation behaviour can provide better prediction for oral bioavailability. © 2011 Elsevier B.V. All rights reserved. 1. Introduction The oral delivery of poorly water soluble basic drugs is a com- mon challenge for pharmaceutical scientists as a result of their pH-dependent solubility. While soluble in the acid environment of the stomach (pH 1–2), partial or complete drug precipitation in the small intestine (pH 6.8–7.4) can occur following gastric emp- tying, which compromises oral bioavailability (Kostewicz et al., 2004). Clinically, the bioavailability of basic drugs has been proven to be dependent on gastric pH (Ogata et al., 1986). For instance, the bioavailability of dipyridamole is lower in achlorhydric elderly patients (Russell et al., 1994) while that of cinnarizine was com- promised in dogs with elevated gastric pH (Yamada et al., 1990). Previous approaches to address this problem have included the addition of acidic excipients to reduce gastric pH and thereby increase drug solubility. Formulation scientists exploited this approach by co-compressing the basic drug with an organic acid, this can reduce the local pH around the disintegrated particles to allow a faster ionization and dissolution of basic drugs (Derendorf et al., 2005). Other formulation strategies have included super- ∗ Corresponding author. Tel.: +44 20 7753 5865; fax: +44 20 7753 5865. E-mail address: abdul.basit@pharmacy.ac.uk (A.W. Basit). saturated lipid formulations (Porter et al., 2008), encapsulation in liposomes (Stozek and Krowczynski, 1986) or complexation with cyclodextrins (Fregnan and Berte, 1990; Ricevuti et al., 1991; Stracciari et al., 1989; Tokumura et al., 1984, 1985). We propose an additional approach to this problem: the use of highly pH-responsive microparticles which enhance the bioavail- ability of poorly soluble basic drugs through site-specific drug delivery in the gastrointestinal tract. The enteric microparticles would dissolve at the small intestinal pH conditions and release the drug at site of absorption. We have previously reported a novel pH responsive microparticle system which provides a unique plat- form to produce spherical and uniform microparticles with a broad ability to encapsulate drugs with a wide range of physicochemical properties (Nilkumhang et al., 2009; Alhnan et al., 2010). This sys- tem of Eudragit L microparticles showed enhanced bioavailability of a neutral drug in a rat model (Kendall et al., 2009). The micropar- ticles presented the poorly soluble drug in the amorphous form that dissolved rapidly in the small intestine leading to a fast plasma peak following oral dosing compared to a control drug suspension. In this manuscript, we show the ability of the microparticle sys- tem to enhance bioavailability of more challenging drugs; poorly water soluble basic drugs. The microparticles were tested in vitro and in vivo in rats. The basic drug cinnarizine (an antihistamine that has been used in the treatment of vestibular disorders, such 0378-5173/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2011.05.079