European Journal of Pharmaceutical Sciences 21 (2004) 251–260 Influence of hydroxypropyl--cyclodextrin complexation on piroxicam release from buccoadhesive tablets Mario Jug, Mira Be´ cirevi´ c-La´ can ∗ Department of Pharmaceutics, Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovaˇ ci´ ca 1, 10 000 Zagreb, Croatia Received 9 May 2003; received in revised form 12 October 2003; accepted 20 October 2003 Abstract Interaction of piroxicam (PX) and hydroxypropyl--cyclodextrin (HPCD) was investigated in solution and in the solid state. Solubility studies demonstrated the formation of the PX–HPCD inclusion complex with 1:1 stoichiometry. Equimolecular PX–HPCD solid systems were prepared and characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, and X-ray diffractometry. Modification of the release of a sparingly water-soluble drug, PX, from hydrophilic matrices using cyclodextrin complexation was evaluated. The buccoadhesive controlled release tablets for the delivery of PX were prepared by direct compression of hydroxypropylmethyl cellulose (HPMC) and Carbopol 940 (C940), which showed superior bioadhesion properties compared to HPMC. The tablets were evaluated for their dissolution, swelling and mucoadhesive properties. The in vitro release results demonstrated that matrix tablets containing the PX–HPCD solid complex displayed faster PX release compared to those containing a physical mixture or “free” drug. Differences in release rates of PX from the tablets could be attributed to the presence of the polymers and to cyclodextrin complexation. The effect of the polymers on PX release can affect the drug solubility (complexation) and polymer water uptake (swelling). Higher polymer water uptake may result in higher drug solubility and diffusivity in a hydrated polymeric environment. Drug complexation affected also its diffusivity through the semipermeable membrane. © 2003 Elsevier B.V. All rights reserved. Keywords: Piroxicam; Cyclodextrin complexation; Buccal drug delivery; Mucoadhesion 1. Introduction Buccal mucosa is a potential site for the delivery of drugs to the systemic circulation. A drug administered through the buccal mucosa enters directly the systemic circulation, thereby minimizing the first-pass hepatic metabolism and adverse gastro-intestinal effect (Voorspoels et al., 1996; Singh and Ahuja, 2002). However, oral mucosal perme- ability of drugs is too low to allow plasma concentration to reach therapeutic levels. Buccal permeation can be im- proved by using various classes of transmucosal and trans- dermal penetration enhancers such as bile salts, surfactants, fatty acids and derivatives, chelators and cyclodextrins (Lee et al., 1991; Senel et al., 1998; Sridevi and Divan, 2002; Senel and Hincal, 2001). ∗ Corresponding author. Tel.: +385-146-12608; fax: +385-146-12691. E-mail address: mira becirevic@Yahoo.com (M. Be´ cirevi´ c-La´ can). Cyclodextrins are capable of forming inclusion complexes with many drugs by taking up a whole drug molecule, or a part of it, into the cavity of the cyclodextrin molecule. Drug cyclodextrins complexes can improve the clinical usage of drugs by increasing their aqueous solubility, dissolution rate, and pharmaceutical availability (Loftsson and Brewster, 1996; Rajewski and Stella, 1996). Testosterone complex with 2-hydroxypropil--cyclodextrin was readily absorbed sublingually, resulting in a rapid increase of testosterone levels in plasma (Pitha et al., 1986). Solubilization of poorly water-soluble drugs by complexation with cyclodextrins and then delivery via the buccal or sublingual mucosa may be advantageous for increasing drug absorption. However, the buccal route of administration using drug-cyclodextrin complexes has not been evaluated extensively. The buccal bioavailability of danazol from an aqueous solution of the danazol hydroxypropyl--cyclodextrin complex was found to be 26% in rats (Badawy et al., 1996). Attempts to study danazol bioavailability using a fast dissolving buccal patch in dogs were not successful. The patch was swallowed, and 0928-0987/$ – see front matter © 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2003.10.029