Enhanced oral bioavailability of flurbiprofen by combined use of micelle solution and inclusion compound

Abstract

The main purpose of this study was to evaluate the effect of a mixed drug solution containing a surfactant and beta-cyclodextrin (beta-CD) on the solubility and bioavailability of a poorly water soluble drug, flurbiprofen. Solubility, dissolution and in vivo pharmacokinetics of flurbiprofen in the presence of surfactant, beta-CD or mixture of surfactant and beta-CD were investigated. Among the surfactants tested, Tween 80 produced the highest improvement in the aqueous solubility of flurbiprofen. The solubility of flurbiprofen increased linearly as a function of beta-CD, resulting in B8 type that suggested a formation of inclusion complex in a molar ratio of 1:1. The solubility of flurbiprofen increased further when Tween 80 was included in addition to beta-CD, suggesting that a micelle formation in the presence of Tween 80 was the likely reason for additional increase. Furthermore, the data suggested that Tween 80 did not interfere with the inclusion interaction between flurbiprofen and beta-CD. The solubility of flurbiprofen was the highest in the mixed system containing 1.3 mM beta-CD and 0.3% w/v Tween 80, and the maximum solubility of 160 microg/mL was achieved. Consistent with the enhanced solubility, the plasma exposure (both AUC and Cmax) of flurbiprofen when dosed as the mixed system was significantly higher (as much as 2 to 3-fold) than that without surfactant or beta-CD, with surfactant alone, or with beta-CD alone. Therefore, the mixed system consists of surfactant and beta-CD could be used as an effective oral dosage form to improve bioavailability of poorly water soluble drugs such as flurbiprofen.

Solid-state flurbiprofen and methyl-β-cyclodextrin inclusion complexes prepared using a single-step, organic solvent-free supercritical fluid process

“…The favourable effect of natural β-cyclodextrin (Muraoka et al, 2004;Cirri et al, 2005;Tokumura et al, 2009;Li et al, 2010;Baek et al, 2011) and its derivatives, such as hydroxypropyl-β-cyclodextrin (Govindarajan and Nagarsenker, 2005;Vega et al, 2013), hydroxyethyl-β-cyclodextrin and methyl-β-cyclodextrin (Cirri et al, 2005) on its pharmaceutical properties has been previously reported. For example, Cirri et al (2005) reported that flurbiprofen and methyl-β-cyclodextrin (Me-β-CD) complexes prepared in the 1:1 molar ratio using kneading and co-evaporation techniques exhibit higher solubility and dissolution profiles than flurbiprofen alone or in a state of a physical mixture.…”

“…Several formulation strategies have been reported to improve the solubility and dissolution rate of flurbiprofen, such as dry elixir (Kim and Yoon, 1995), solid dispersion (Habib et al, 1998;Oh et al, 2011), salt formation (Gupta et al, 1997), microemulsion (Park et al, 1997;Ambade et al, 2008), inclusion complex with cyclodextrins (Tokumura et al, 2009;Li et al, 2010) and cycloamyloses (Baek et al, 2011).…”

Hybrid systems based on “drug – in cyclodextrin – in nanoclays” for improving oxaprozin dissolution properties

“…Combined strategies exploiting at the same time both CD complexation, and encapsulation of the complexed drug into micro/nanocarriers, such as polymeric micro/nanoparticles Vega et al, 2013), classic or ultradeformable liposomes Maestrelli et al, 2010), niosomes (Marianecci et al, 2015), micelles (Li et al, 2010), solid lipid nanoparticles (SLN) (Cavalli et al, 1999), or nanostructured lipid carriers (NLC) proved to be successful in improving the effectiveness of the two carriers, overcoming the related problems associated with their use. In particular, this approach was fruitfully applied by loading OXA as CD complex into PLGA nanoparticles, where the presence of CD showed to be useful not only to promote but also to regulate the drug release rate from the delivery system, depending on the type of CD used .…”

The Enhancement Effect of Castor Oil on the Permeability of Flurbiprofen as Transdermal Gel

“…Therefore, to improve its bioavailability, the drug formulated as a transdermal gel. The absorbed drug appears to be adequate for therapeutic uses in spite of its amount required for therapeutic effect in transdermal drug delivery system is less bioavailable as compared to the oral route of administration [6]. The gel is a solid jelly-like material that can have properties ranging from soft and weak to hard and tough.…”

“…It also possesses a degree of flexibility very similar to natural tissue due to their significant water content. Drug penetration via transdermal route can be improved using penetration enhancers [6][7][8].…”