Pharmaceutical NanotechnologySilica-lipid hybrid microcapsules: Influence of lipid and emulsifier type on in vitro performance
Graphical abstract
Introduction
According to recent estimates, approximately 40–70% of the newly discovered chemical entities are poorly soluble in water and the percentage is estimated to increase (Leuner and Dressman, 2000, Takagi et al., 2006, Hauss, 2007). Poorly water-soluble drugs generally have low and erratic bioavailability because of various challenges such as: (i) poor drug dissolution in the intestinal milieu despite the aid of mixed micelles as natural surfactants; (ii) precipitation when passing through the unstirred water layer; (iii) transporter-mediated efflux and oxidative metabolism in the intestinal wall which affects drug absorption; and (iv) first pass metabolism (Porter et al., 2007, Dahan and Hoffman, 2008, Trevaskis et al., 2008, Chakraborty et al., 2009).
Lipid-based delivery systems are attractive formulation strategies as they have been shown to enhance dissolution and simulate the positive food effect, i.e. increased drug bioavailability in the fed state (Fatouros et al., 2007, Porter et al., 2008). Lipid-based drug delivery systems potentially improve the bioavailability of poorly water-soluble drugs via several mechanisms: (i) prolongation of gastric residence time, (ii) enhanced drug solubilisation via the formation of various lipophilic colloidal systems in the gastrointestinal tract, and (iii) stimulation of the lymphatic absorption pathway in which drug molecules avoid the first pass metabolism (Humberstone and Charman, 1997, MacGregor et al., 1997, Porter et al., 2007, Porter et al., 2008, Chakraborty et al., 2009).
Lipid emulsions have proved to be effective in enhancing drug bioavailability mainly via an increased total surface area for enhanced drug diffusional release as well as lipid–enzymatic interactions (Humberstone and Charman, 1997). Due to the physical and microbiological instability of wet emulsions, dry emulsions are preferred to confer storage stability and dosage precision. The formation of dry emulsions can be achieved by using various drying techniques such as rotary evaporation (Myers and Shively, 1992), lyophilisation (Molina and Cadorniga, 1995) or spray drying (Takeuchi et al., 1992a, Takeuchi et al., 1992b, Pedersen et al., 1998). Dry emulsions are usually prepared in combination with a water-soluble carrier such as gelatin and sugars, or a water-insoluble carrier such as colloidal silica. Ideally, a dry emulsion formulation can be easily reconstituted in water prior to administration or readily redispersed in the gastrointestinal fluids after administration (Christensen et al., 2001). Dry emulsions are potentially useful in providing light (Takeuchi et al., 1992a, Takeuchi et al., 1992b) and oxidation protection (Heinzelmann and Franke, 1999), as well as improving dissolution and bioavailability of drugs (Jang et al., 2006).
Considering the various advantages associated with solid state lipid-based formulations, our previous work has led to the establishment of a dry, porous silica-lipid hybrid (SLH) microcapsule system, composed of medium-chain triglycerides (MCT) and lecithin, encapsulated by hydrophilic silica nanoparticles (Simovic et al., 2009, Simovic et al., 2010, Tan et al., 2009, Tan et al., 2010). For two model BCS Class II drugs, i.e. celecoxib (Tan et al., 2009) and indomethacin (Simovic et al., 2009, Simovic et al., 2010), the SLH formulations have been shown to offer several physicochemical and biopharmaceutical advantages in comparison with unmodified drug as well as conventional lipid-based solutions and emulsions. Orally dosed absorption studies in fasted rats demonstrated significantly improved bioavailability of celecoxib and indomethaicn resulting from the SLH microcapsules as compared to the aqueous drug suspension (Simovic et al., 2009, Tan et al., 2009). The major advantages of the SLH formulations are (i) physical stability of the oil-based formulation, (ii) preservation of drug molecules in the amorphous state in the microcapsule matrix, (iii) high porosity of the microcapsule structure resulting in an enhanced lipid digestibility and drug solubilisation by the lipolysis products, (iv) potential drug delivery into the lymphatic system by varying lipid composition and drug type, and (v) the absence of synthetic surfactants which eliminates the safety issues associated with chronic dosage form administration.
Recent mechanistic studies have demonstrated the role of hydrophilic fumed silica in controlling the digestion kinetics of lipid-based formulations (Mohanraj et al., 2010, Tan et al., 2010). Silica nanoparticles in the dispersed state produced an inhibitory effect on the digestion of submicron lipid emulsions and liposomes due to the formation of a protection layer at the oil–water interface. In contrast, the porous SLH microcapsules enhanced lipolysis; this emphasizes the significance of the internal porous silica-lipid matrix structure in enhancing lipid digestibility. In another study, indomethacin-loaded SLH microcapsules were engineered using a cationic emulsifier, oleylamine (Simovic et al., 2010). This resulted in the formation of (anionic) drug-(cationic) lipid electrostatic complexes that leads to an enhanced bioavailability of indomethacin, possibly via controlled drug release and hence minimisation of drug precipitation in the intestinal lumen.
In this study, various types of lipid and emulsifier were incorporated into the SLH formulation to investigate the resultant physicochemical as well as in vitro drug release and lipid digestion properties. Investigations were conducted for soybean oil, a long chain triglyceride and Capmul MCM, a mixed medium chain mono-/di-/triglycerides as the lipid phase; in combination with either cationic oleylamine or anionic lecithin as the emulsifier. The fluorescent compound coumarin 102 (log P = 4.09) was used in this study to represent a highly lipophilic drug. Significantly, the current investigation provides a sound platform on which the SLH microcapsules can be tailored to optimise the release and solubilisation of poorly water-soluble drugs through a versatile selection of lipids and emulsifiers.
Section snippets
Materials
Coumarin 102 (dye content 99%) and soybean oil (C18 triglyceride) were purchased from Sigma Aldrich (Australia). Miglyol® 812 (C8/C10 triglyceride) was obtained from Hamilton Laborotaries (Australia). Capmul MCM (58% monoglyceride, 36% diglyceride, and 5% triglyceride) was a gift from Abitec Corporation. Soybean lecithin (containing 94% phosphatidylcholine and <2% triglycerides) and oleylamine (primary amine purity >98%) were obtained from BDH Merck (Australia) and Sigma Aldrich (Australia),
Preparation and physicochemical characterisation of SLH microcapsules
The average hydrodynamic diameters and zeta-potentials of drug-free submicron emulsions prepared using various lipids and emulsifiers are shown in Table 1. The average particle size for LCT-based emulsions (≈360 nm) is relatively larger than that of the MCT- and MCMDG-based emulsions (≈187 nm and ≈250 nm, respectively). This is ascribable to the longer acyl chain length of LCT which results in a larger molecular spatial arrangement in comparison with MCT- and MCMDG-based emulsions. Each emulsion
Conclusions
SLH microcapsules with an internal porous matrix structure can be effectively prepared using different types of lipid (i.e. MCT, LCT or MCMDG) and emulsifier (i.e. anionic lecithin or cationic oleylamine). Under sink conditions, the in vitro release study indicates an immediate and complete release of lipophilic drug (log P = 4.09) from the SLH microcapsules regardless of the types of lipid and emulsifier used. Under simulated fasted-state intestinal lipolysis conditions, the SLH microcapsules
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