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LIPIDS
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Figure 4. Controlling lipid digestion with silica-lipid hybrid (SLH) carriers of diff erent internal nanostructures: dispersed medium- chain triglyceride coarse droplets (¡), core-shell structured Ludox- based SLH microparticles (n), and matrix structured Aerosil-based SLH microparticles (p). Modifi ed from [11].
core-shell structured microparticles (based on non-porous Ludox silica, ~22nm) with a resultant BET surface area of 66m2
/g [11].
Figure 5. Bioavailability enhancement of celecoxib (3 mg/kg) in male beagle dogs based on food-mimicking eff ect: relative
bioavailability (bars, left axis) and maximum plasma concentration (circle, right axis). (* denotes p<0.05 compared with pure drug in fasted state; ** denotes p<0.05 compared with pure drug in fed
and fasted states and oil solution in fasted state). Reproduced with permission from [11].
/g exhibited
a more sustained lipid digestion behavior than the matrix structured microparticles (based on mesoporous Aerosil fumed silica, ~50nm) with a BET surface area of 184m2
Nanostructure Eff ects on Drug Absorption and Food Eff ects
There is increasing preclinical evidence that demonstrates signifi cant oral bioavailability enhancement of poorly soluble drugs when delivered using lipid colloids encapsulated by silica particles in the solid state. Based on selected examples (Table 1), we highlight some important insights into the eff ects of nanostructured silica particles on drug absorption which may be important in guiding future formulation design: (i) hydrophilic silica nanoparticles appeared to be an ideal
Drug
choice of solid carrier for lipid colloids that a higher bioavailability was obtained in comparison with a sugar-based dry emulsion, a lipid solution and an aqueous suspension [9]; (ii) porous silica particles off er great versatility in the loading methodology for various lipid-based formulations owing to their high adsorbing capacities (e.g. spray-drying, lyophilization and physical adsorption); (iii) formulation desorption and dispersion could be adversely impacted by too large particle size and pore length [23]; and (iv) possible chemical interactions between lipid excipients (especially surfactants) and the carrier particles should be taken into consideration for avoiding inconsistent or inhomogenous formulation release.
While the extent of positive food eff ects generated by many lipid- based formulations remains unclear, a recent study performed in dogs has shown remarkable bioavailability enhancement of celecoxib (i.e. 2- to 6.5-times higher) resulting from an Aerosil silica-based hybrid formulation in comparison with a readily emulsifi ed lipid solution and
Table 1. Examples of lipid emulsions and self-emulsifying drug delivery systems encapsulated by silica particles in the solid state Lipid formulation
Type of silica particle Particle specifi c surface area (BET) Drug bioavailability/ effi cacy Enhanced absorption
Celecoxib (log P = 3.5)
Simvastatin (log P = 4.7)
Nitrendipine (log P = 2.9)
Spray-dried SLH microparticles (Miglyol 812/ Capmul MCM/ lecithin)
Physically adsorbed solid SMEDDS (Soybean oil/ Capryol 90/ Tween 80/ Cremophor EL)
Physically adsorbed and extruded/ spheronized solid SEDDS pellet (Miglyol 812/ Cremophor RH40/ Tween 80/ TranscutolP)
Reduced absorption Danazol
(log P = 4.2)
Physically adsorbed solid SEDDS (Captex 355/ Capmul MCM/ Cremophor EL/ ethanol) (Soybean oil/ Maisine 35-1/ Cremophor EL/ ethanol)
Aerosil 380 fumed silica Aerosil 200 fumed silica Syloid 244FP 380 m2 /g (7 nm primary particles) 200 m2 /g (12 nm primary particles)
320 m2 pores)
/g (2–5 µm particles of ~20 nm
Signifi cantly higher than maltodextrin-based dry emulsion, lipid solution and aqueous suspension
Reduction in total cholesterol signifi cantly greater than aqueous suspension and placebo
Signifi cantly higher than conventional tablet and comparable to liquid SEDDS
[9] [26] [27] Ref.
Neusilin US2 magnesium aluminium silicate
300 m2 pores)
/g (44–177 µm particles of ~5 nm
Signifi cantly lower than liquid SEDDS
[23]
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| November/December 2013
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