Improving the Performance of Lipid Formulations: Nanoparticle Layers and Solid Hybrid Particles

• Ian Wark Research Institute, University of South Australia

Introduction

Lipid-based drug delivery systems are developed to mimic the food (or post-prandial) effect to address the oral bioavailability challenges of low solubility drugs and vitamins. That is, the molecules are effectively solubilized in the lipophilic microenvironment generated by the presence of fat and their corresponding digested fatty acid products mixed with endogenous micellar components [1, 2].

The diversity of commercialized lipid excipients (e.g. fatty acids, glycerides, polyoxyethylene glycols derivatives, ethoxylated glycerides and polyalcohol fatty acid esters) has created a large platform for lipid-based formulation design, such as in the forms of emulsions, microemulsions, micelles, liquid crystalline particles, solid lipid particles and various self-emulsifying systems [3-7]. Successfully marketed oral lipid-based drug products, currently comprising ≤ 4% of the global pharmaceutical market, are mostly formulated as bulk liquid solutions or liquid-filled gelatin capsules [3]. Clinical translation of novel lipid-based formulations is clearly behind the rate of discovery of pipeline drugs exhibiting poor aqueous solubility, which is predicted to increase from 30% to 70% [3, 8]. Major barriers to attaining full commercial potential for lipid-based formulations are associated with challenges in their physical stability, non-ideal drug encapsulation and unpredictable delivery performance.

Here we report on the application of engineered silica nanoparticle layers and specific nanostructures to integrate several attractive biopharmaceutical functions into lipid colloidal systems. Specifically, hybrid silica-lipid particles with nanoporous interiors have been engineered to optimize encapsulation of drugs in their dissolved form as well as to manipulate enzymatic digestion of lipid-based carriers, hence facilitating improved solubilization and absorption of poorly soluble drugs (Figure 1).

Figure 1. Schematic depiction of key factors affecting the rate of drug dissolution, lipid digestion and relative bioavailability of a poorly water-soluble drug: crystallinity of drug molecules, droplet size of lipid carriers and nanostructure confinement.

Such specific nanostructures can be fabricated by forming at the droplet interface an adlayer of silica nanoparticles of different size, porosity or chemistry based on their self-assembly from the aqueous bulk, followed by a drying process to remove the aqueous phase (e.g. high heat spray-drying, lyophilization under vacuum, or phase coacervation) [9-11]. The fact that pharmaceutical food effects may be mitigated when drug absorption is optimized towards the maximum is an important clinical implication for such solid hybrid particles. These multifaceted functions principally stem from the nanostructure confinement of lipid colloids, where their specific surface area is significantly enhanced and the structured lipid arrangement is ideal for facilitating endogenous formulation processing and absorption. In the following, successful proof-of-concept studies are presented to highlight some key roles of silica nanoparticle coating in improving the performance of lipid-based formulations.

Hybrid particles enhancing solidstate amorphous drug encapsulation

For drugs demonstrating low solubility in both aqueous and oily media, the practicability of orally dosing a lipid-based formulation could be hindered by the large volume or amount of excipients required. A majority of lipid-based formulations typically produce ≤ 10% of drug loading levels [12]. Currently marketed oral lipid-based products have been reported to contain up to 5g or 20mL of lipid excipients in capsule dosage forms or solution products, respectively [3]. Some of these products have limited shelf-life at room temperature. Colloidal silica particles, being a chemically inert and biocompatible inorganic solid carrier, have found great application in encapsulating lipid-based formulations in a dry, powdery form. The advantages of such an encapsulation approach are multi-fold. Firstly, powdered lipid-based formulations confer longer term storage stability and potentially enhance chemical protection of volatile and photosensitive drugs [13-17]. Powdered formulations also fulfil industrial and consumer needs by enabling simpler formulation handling and processing using conventional (and thus more economic) equipment to produce convenient unit dosage forms such as tablets and powder-filled capsules [12, 18-20].

Interestingly, the interplay in surface charges between lipid droplets, silica nanoparticles and ionizable drug molecules is exploitable to improve drug loading efficiency. This was demonstrated for a weak base molecule, albendazole, which has a pH-dependent solubility and is practically insoluble in most pharmaceutical solvents at neutral pH (Figure 2). Initial acidification of lipids with hydrochloric acid enhanced albendazole solubility to ~40mg/g; subsequent electrostatic adsorption of the free drug molecules (in its cationic form) onto anionic silica nanoparticle adlayers effectively afforded a 6-fold higher, supersaturated loading level in the dry hybrid formulation [21]. Such an electrostatic approach has also been applied in another study to enhance molecular interaction between lipid droplets and silica nanoparticles, where triglyceride emulsion droplets were made positively charged by incorporating oleylamine as an emulsifier. The formation of electrostatic attraction with the anionic silica nanoparticles allowed the use of significantly lower mass of solid carriers for lipid encapsulation while minimizing material loss during processing under strong mechanical forces [10].

Figure 2. Drug loading enhancement via lipid solubilization and electrostatic adsorption onto silica-lipid hybrid (SLH) microparticles for a model low solubility drug, albendazole. Data adapted from [21].

Nanostructure effects on drug dissolution and lipid Carrier digestion

An important consideration in attempts to “solidify” lipid-based formulations is whether their drug release or solubilization performance from the solid state could be at least as preserved as in the original liquid state. When a solid carrier (such as silica particles) is acting fully “inert” and not impeding the diffusion of the embedded lipid colloids and drug molecules, fast and complete drug dissolution (or release) could be achieved from the solid state for application in immediaterelease or fast-acting formulations (Figure 3). The efficiency of formulation hydration (or dispersion) and release tend to decrease with increasing carrier particle sizes (hence reduced specific surface area) and pore lengths [22, 23].

For digestible lipid-based formulations, integrating nanoparticles adlayers or nanostructures into lipid droplets may provide effective control over their enzymatic digestion kinetics, which offer merits in manipulating drug solubilization or precipitation in the gastrointestinal environment [11, 25]. Hybrid silica-lipid particles designed with different internal nanostructures have been shown to enhance the rate of lipid digestion in comparison with dispersed coarse oil droplets (Figure 4). The enhancement in lipid digestibility is predominantly related to the specific surface area of the silica nanostructured network. The core-shell structured microparticles (based on non-porous Ludox silica, ~22nm) with a resultant BET surface area of 66m²/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/g [11].

Figure 3. Drug release enhancement with silica-lipid hybrid (SLH) formulations for three low solubility drugs: (A) unionized weak base, celecoxib; (B) pH-dependent weak base, albendazole; and (C) pH-dependent weak acid, indomethacin. Modified from [9], [21] and [24] respectively.

Figure 4. Controlling lipid digestion with silica-lipid hybrid (SLH) carriers of diff erent internal nanostructures: dispersed mediumchain triglyceride coarse droplets (0), core-shell structured Ludoxbased SLH microparticles (n), and matrix structured Aerosil-based SLH microparticles (p). Modifi ed from [11].

Nanostructure effects on drug absorption and Food effects

There is increasing preclinical evidence that demonstrates significant 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 effects 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 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 offer 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.

Table 1. Examples of lipid emulsions and self-emulsifying drug delivery systems encapsulated by silica particles in the solid state

While the extent of positive food effects generated by many lipidbased 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 emulsified lipid solution and the effect of dietary fats (Figure 5). The fact that the hybrid formulation contained less than 1g lipid dose in comparison with 35g of fat content present in the food clearly highlights the important role of the nanostructured carrier network in maximizing the “food-mimicking effect”, which has potential implication for removing the fed-fasted variations in drug absorption.

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].

Conclusion

Lipid-based dosage forms represent an important class of solubilized formulations for low solubility drugs when other physical modification approaches (e.g. micronization and crystal habit modification) produce only modest improvements in their gastrointestinal dissolution and absorption. The coupling of lipid colloids with silica nanoparticle adlayers and specific nanostructures potentially improves the performance of lipid formulations in terms of drug loading efficiency, control of enzymatic digestion kinetics, and drug release behavior in comparison with lipids in their bulk or original states. Importantly, such nanostructured hybrid formulations have demonstrated attractive potential in maximizing oral drug bioavailability while mitigating pharmaceutical food effects, hence offering new options in the formulation and delivery of challenging molecules.

Author Biographies

Dr. Clive Prestidge is the Professor of Colloid and Pharmaceutical Science at the University of South Australia and the Associate Director for Nanomedicine at the Ian Wark Research Institute. Clive’s research group focuses on nanomaterials for biological application. He has contributed over 120 journal articles and is the inventor of a number of patent families for drug encapsulation and delivery.

Dr. Angel Tan is a post-doctoral Research Associate in nanomedicine research at the Ian Wark Research Institute, University of South Australia. Her primary research interests are in the design and mechanistic investigation of functional hybrid nanomaterials for the oral delivery of poorly water-soluble therapeutics, with a focus on their translation into clinical applications.

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