Synergistic role of solid lipid and porous silica in improving the oral delivery of weakly basic poorly water soluble drugs

Abstract

Oral absorption of weakly basic drugs (e.g. cinnarizine (CIN)) is limited by their pH dependent precipitation in intestinal conditions. To overcome this challenge, a novel drug delivery system composed of solid lipid and porous silica, namely silica encapsulated solid lipid (SESL) particles, was developed via hot homogenization of melted lipid dispersion, followed by ultra-sonication of the silica stabilized homogenized melted lipid dispersion. Scanning electron microscope (SEM) images of the SESL formulation revealed non-spherical and aggregated hybrid particles, with rough exterior and structured nanoparticles visible on the surface. A 1.5, 2.2 and 7-fold improvement in the dissolution of CIN was observed for the SESL particles, under simulated intestinal non-digesting conditions, in comparison to the drug loaded in solid lipid (CIN-SL) matrix, drug loaded in porous silica (CIN-PS) and pure drug powder. Under simulated intestinal digestive condition, significant improvement in the drug solubilization was reported for the SESL formulation in compared to the individual drug loaded systems i.e. CIN-PS and CIN-SL. Thereby, silica encapsulated solid lipid system provides a promising oral delivery approach for poorly water soluble weakly basic drugs.

Introduction

40% to 70% of the new chemical entities and active pharmaceutical ingredients (APIs) available from the drug delivery pipeline show poor aqueous solubility and high permeability, therefore are categorized as Biopharmaceutical Classification Systems (BCS) class II drugs (Amidon et al., 1995). Traditional formulations of these drugs are often unable to achieve satisfactory oral absorption due to their limited dissolution and rapid precipitation in intestinal fluids. For ionisable drugs that are either weak acids or weak bases (e.g. cinnarizine, halofantrine, carvedilol, loratidine), the pH of the medium plays a vital role in their solubility and subsequent oral absorption (Avdeef, 2007). For example, weakly basic drugs are protonated at low pH, hence leading to rapid solubilization and a high degree of supersaturation in the stomach. During transit into the small intestine, the metastable supersaturated state of the solubilised drug shows a higher tendency to convert in a thermodynamically stable crystalline state (Pouton, 2006). Moreover, in the intestinal pH, which is close to or beyond the pKa of the drug, the drug is no longer in an ionized state. As the free base reaches the primary site of absorption in the small intestine, the rate of nucleation and crystal growth is intensified and causes a sharp decrease in solubility and the concentration of drug in solution may, in fact, exceed its aqueous solubility, which results in rapid precipitation, with the drug no longer available for absorption (Gao and Shi, 2012).

Cinnarizine (CIN), a weakly basic antihistaminic agent, has been widely used to inhibit the vasoconstrictor responses to various pharmacological stimuli by peripheral blood vessels. It is a highly lipophilic compound having a log P of 5.8 and pKa's of 2 and 7.5 (Branchu et al., 2007). CIN is practically insoluble in neutral water, showing a pH dependent solubility profile i.e. 52.3 and 2.2 μg/ml at pH 3 and 6.8 respectively (Ogata et al., 1986). Due to poor solubility in intestinal pH, CIN shows limited absorption when taken orally and, together with the short half-life of 3–6 h, leads to the requirement of frequent dosing which has negative consequences for patience compliance.

Several attempts have been made to address the pH dependent precipitation and consequent poor oral absorption of CIN, including self-emulsifying lipid systems (Sassene et al., 2010, Shahba et al., 2012, Larsen et al., 2013, Sassene et al., 2015), liquid crystalline lipid dispersions (Nguyen et al., 2011, Bhatt et al., 2015), lipophilic ionic liquids (Sahbaz et al., 2015), solid lipid nanoparticles (Wang et al., 2010), silica-stabilized cubosomes (Bhatt et al., 2015) and silica lipid hybrid (SLH) microparticles (Rao et al., 2015). SLH microparticles have been reported as a novel approach to improve the oral delivery of poorly soluble drugs, which uses the solubilizing effect of lipid and stabilizing effect of silica nanoparticles. SLH solid dosage formulations have been prepared using adsorption of silica nanoparticles onto the o/w emulsion of liquid lipid during homogenization and drying process (Prestidge and Simovic, 2006, Simovic et al., 2009, Tan et al., 2009). Even with 80% liquid lipid content, a freeze dried SLH formulation was a free flowing powder and stable for at least one year (Yasmin et al., 2014). Addition of mannitol improved the flowability of this powder for preparation of standard quality tablets (Bremmell et al., 2013). By modifying the morphology using a different silica component, fine tuning of drug release was achievable for several poorly soluble moieties such as indomethacin (Simovic et al., 2009, Simovic et al., 2010), lovastatin (Rao et al., 2014) and celecoxib (Tan et al., 2009, Yasmin et al., 2014). The three dimensional internal porous structure of these microparticles provides extensive interfacial area and a solid support for lipase adsorption and catalysis of its action. The SLH structure aids optimal formation of the mixed micellar phase composed of lipid digestion products along with the endogenous bile salts and phospholipids, and hence enhanced solubilization was achieved for these poorly soluble drugs. Lately, Rao et al. (2015) developed a Pluronic functionalized SLH microparticle system for the oral delivery of CIN. Improved CIN solubilization was achieved in simulated intestinal mediums in both digestive and non-digestive conditions. The effect of Pluronic F127 in inhibiting the precipitation of the drug in neutral pH was demonstrated to contribute towards the improved solubilization of CIN in intestinal conditions. A 2-fold improvement in the oral bioavailability of CIN was reported in rats compared to the powdered drug. Additionally, a recent investigation for silica-stabilized cubosomes reported significant improvement in CIN dissolution under simulated intestinal non-sink conditions, in compared to the powdered CIN (Bhatt et al., 2015). The non-porous Ludox silica provided a shielding effect to the glyceryl monooleate (GMO) based cubosomes and sustained the enzymatic digestion by limiting the lipase adsorption. Moreover, silica nanoparticle preserved the non-crystalline state of CIN in the post digestion precipitates.

On the other hand, solid lipid-based carriers, such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) have proven efficacy in encapsulating poorly soluble drugs in a molecularly dispersed state and providing protection from the surrounding aqueous environment (Müller et al., 2011, Müller et al., 2016). The solid lipid matrix can improve solid state stability of the encapsulated drug in aqueous media, thereby sustaining drug release and subsequent supersaturation (Müller et al., 2000). This would prevent drug precipitation in both in vitro and in vivo conditions (Lim et al., 2012). Additionally, a recent investigation reported that a hybrid formulation composed of solid lipid and nanostructured porous silica improved the poor digestability of solid lipid by 2-fold and was also controllable by changing the lipid loading level in the porous silica (Yasmin et al., 2016). The synergistic role of solid lipid and porous silica in the improved solubilization of the poorly soluble drug, lovastatin, LOV (log P 4.8) was reported. Encapsulation of LOV in a non-crystalline state in the hybrid formulation resulted in a 3–6 fold enhancement in the dissolution of LOV in non-digesting intestinal conditions, whereas in intestinal digesting conditions drug solubilization was improved by 2.7–3.5 folds, compared to the lipid-drug suspension and unformulated drug.

In the current study, we aimed to investigate the synergistic effect of silica carriers and solid lipids in improving the oral delivery of CIN. By learning from an extending silica-lipid hybrid delivery systems, the study will explore for the first time the suitability of the silica encapsulated solid lipid (SESL) particles as a potential carrier for the oral delivery of poorly soluble weakly basic drugs. Investigating the role of porous silica nanostructure and solid lipid matrix will provide further understanding and mechanistic insight of the solubilization and oral bioavailability of poorly water soluble drugs.