Enhanced bioavailability of buspirone hydrochloride via cup and core buccal tablets: Formulation and in vitro/in vivo evaluation

Abstract

This work aims to prepare sustained release buccal mucoadhesive tablets of buspirone hydrochloride (BH) to improve its systemic bioavailability. The tablets were prepared according to 5 × 3 factorial design where polymer type was set at five levels (carbopol, hydroxypropyl methylcellulose, sodium alginate, sodium carboxymethyl cellulose and guar gum), and polymer to drug ratio at three levels (1:1, 2:1 and 3:1). Mucoadhesion force, ex vivo mucoadhesion time, percent BH released after 8 h (Q8h) and time for release of 50% BH (T_50%) were chosen as dependent variables. Additional BH cup and core buccal tablets were prepared to optimize BH release profile and make it uni-directional along with the tablets mucoadhesion. Tablets were evaluated in terms of content uniformity, weight variation, thickness, diameter, hardness, friability, swelling index, surface pH, mucoadhesion strength and time and in vitro release. Cup and core formula (CA10) was able to adhere to the buccal mucosa for 8 h, showed the highest Q8h (97.91%) and exhibited a zero order drug release profile. Pharmacokinetic study of formula CA10 in human volunteers revealed a 5.6 fold increase in BH bioavailability compared to the oral commercial Buspar^® tablets. Conducting level A in vitro/in vivo correlation showed good correlation (r² = 0.9805) between fractions dissolved in vitro and fractions absorbed in vivo.

Introduction

The buccal mucosa, lining of the oral cavity, is an attractive site for drug administration as it is highly vascular, easily accessible and suitable for retentive dosage forms administration. The buccal transmucosal drug delivery claims advantage over per-oral administration as it bypasses the first-pass effect and avoids the presystemic drug elimination within the gastrointestinal tract (Patel et al., 2012, Salamat-Miller et al., 2005, Sudhakar et al., 2006). Buccal mucoadhesive dosage forms include: tablets (Boyapally et al., 2010, Cilurzo et al., 2010), films (Rossi et al., 2003), patches (Nafee et al., 2003, Reddy et al., 2013, Shidhaye et al., 2008), gels (Perioli et al., 2008) and sponges (Portero et al., 2007). Dosage forms designed for buccal drug delivery should possess good bioadhesive properties, high drug loading capacity and cause no irritation. In addition, it should have controlled drug release properties preferably in a unidirectional way toward the mucosa and to be an erodible system so that the dosage form removal at the end of the desired dosing interval is not required (Salamat-Miller et al., 2005). Buccal tablets are the most common dosage forms for buccal drug delivery. Buccal tablets are usually prepared by direct compression and intended to dissolve or erode slowly. Buccal tablets may be prepared in different forms including, monolithic, bilayered and cup and core buccal tablets to achieve unidirectional drug release (Salamat-Miller et al., 2005).

Many mucoadhesive polymers are employed in the preparation of the buccal mucoadhesive systems: anionic such as carbopol (CP), sodium alginate (SALG) and sodium carboxymethyl cellulose (SCMC); cationic such as chitosan; and non-ionic polymers such as hydroxypropyl methylcellulose (HPMC) and guar gum (GG) (Andrews et al., 2009).

Buspirone HCl (BH) is an anxiolytic drug acting by modulating the serotonergic system (Shumilov and Touitou, 2010). It is used in the treatment of generalized anxiety disorder and for anxiety symptoms in depression (Nash and Nutt, 2005). BH undergoes extensive first-pass metabolism leading to very low oral bioavailability (4%) (Gannu et al., 2009, Moffat et al., 2011). The short and variable elimination half-life of BH (mean of 2.4 h) (Moffat et al., 2011, Sakr and Andheria, 2001), its low bioavailability and low molecular weight (422) (Moffat et al., 2011) recommend it a good candidate for sustained release buccal dosage forms.

In vitro/in vivo correlation (IVIVC) is the relation between the in vitro dissolution data and the in vivo input rate. A good IVIVC can be used as a surrogate for further bioequivalence studies and to predict in vivo results based on in vitro data. Four levels of IVIVC (level A, B, C and multiple level C) have been described in the FDA guidance. Of these levels, level A IVIVC is considered the most informative, representing a point to point relationship between the in vitro dissolution rate and the in vivo absorption rate (Shah et al., 2009, Uppoor, 2001).

In the present study, BH mucoadhesive buccal tablets of both matrix and cup and core designs were developed using: CP 934P, HPMC K4M, SALG, SCMC and GG. The effect of these polymers on BH release profile and on the mucoadhesion properties of the tablets was studied. The compatibility between BH and the tablet excipients was studied using differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). The buccal tablets were evaluated in term of content uniformity, weight variation, thickness, diameter, hardness, friability, surface pH, swelling index, mucoadhesion strength, ex vivo mucoadhesion time and in vitro drug release. The selected formula was further evaluated for its in vivo performance in four healthy human volunteers compared to commercially available BH tablet (Buspar^®, 15 mg BH, Glaxo-Smith Kline Co., Cairo, Egypt). Level A IVIVC was conducted between the in vitro dissolution data and the in vivo absorption data of the selected formula.