Pharmaceutical Nanotechnology
The role of vehicle–nanoparticle interactions in topical drug delivery

https://doi.org/10.1016/j.ijpharm.2010.08.012Get rights and content

Abstract

Loading ‘difficult to deliver’ therapeutic agents into lipid nanoparticles (LN) is an attractive means to administer them to the skin. However, employing colloidal carriers to administer therapeutic agents from semi-solid preparations adds an extra dimension to the already complex process of topical drug delivery. The aim of this work was to understand how the mobility of nanoparticles influenced the delivery of a model drug when the carriers were suspended in a hyaluronic acid (HA) vehicle. Tocopheryl acetate (TA) was loaded into lipid nanoparticles (TALN) that were <100 nm in size and physically stable for more than 28 days. The TALN interacted with the HA polymeric chains to increase formulation macroviscosity. Nanoparticle tracking analysis confirmed that the gel hindered the TALN mobility. However, deliberate manipulation of the particle mobility in the gel by varying the concentration of HA had little effect on TA delivery. Only ca. 10 μg/cm2 of administered TA was delivered into porcine skin regardless of the vehicle characteristics and this suggested that drug release from the LN was the rate limiting step in the delivery process and not the nanoparticle–vehicle–skin interactions.

Introduction

There have been several reports that loading therapeutic agents into nanoparticles can enhance drug delivery into skin (Kreuter et al., 1983, Scherer, 1992, Santos Maia et al., 2000). However, in most cases, compared to when a drug is solubilised in a topical vehicle, the drug delivery rate is reduced when a particulate carrier is employed. This is because enclosing a therapeutic agent within a particle adds a second rate limiting step that retards the drug presentation to its intended site of delivery (Muller and Kreuter, 1999, Ricci et al., 2005). As a consequence of their greater complexity and slower drug release, particulate systems are usually only employed for topical delivery when attempting to deliver ‘difficult to formulate’ agents. Such compounds require the delivery system to be carefully designed in order to resolve a particular problem. In this context nanocarriers have been shown to be particularly effective at promoting: skin occlusion (Jenning et al., 1999); chemical protection (Dingler et al., 1998); controlled release (Jenning et al., 2000a); colour/odour masking and drug loading in topical vehicles (Dingler et al., 1996).

It is now widely accepted that nanoparticles with a size of greater than 10 nm do not penetrate the skin to any great extent (Baroli et al., 2007, Ryman-Rasmussen et al., 2006). However, the question of whether particle–skin interactions influence drug release from nanocarriers has yet to be answered. Very little is known about the rate of particle diffusion in topical formulations. As a consequence it is unclear if altering the diffusion of particles in semi-solid vehicles influences drug delivery. A good understanding of the nanoparticle–vehicle–skin interaction is important as it will dictate the size of the nanoparticles and the properties of the vehicles that should be used in topical preparations to achieve the desired release profile. For example, smaller particles may release a drug more rapidly due to a higher surface area, but if held immobile in a gel they may never reach the skin surface. As it is not known if the presentation of a particle at the lipid skin surface encourages drug release, it is unclear if viscous vehicles pose a problem to effective delivery of drugs from semi-solid preparations containing nanocarriers (Jenning et al., 2000b).

Nanoparticle mobility in simple matrices has been assessed by spectroscopic techniques but such methods have not been applied to topical gels (Spiedel et al., 2003). The current knowledge of particle mobility through gels is derived from traditional diffusion cell experiments. For example, Sanders et al. (2000), used sputum from cystic fibrosis patients to show that nanoparticle diffusion was extremely slow (<0.5% of particles diffused through the barrier). Nanoparticle diffusion in mucus demonstrates a strong dependence on particle size with the smallest sized particles being retarded the least by the complex crosslinked gel network of this viscous excretion. The gel network of semi-solid drug delivery vehicles is more homogeneous than respiratory mucus, but the rate of nanoparticle permeation will be dependent upon similar properties such as the gel viscosity, type and extent of cross linking and polymeric chain chemistry of the semi-solid vehicles.

Loading poorly water soluble compounds in an aqueous topical gel can be facilitated by encapsulation within nanoparticles. A nanocarrier system is preferable to an ointment, which would traditionally be employed to solubilise a hydrophobic agent, in terms of cosmetic acceptability. Previous work has shown that nanoparticles can alter the viscosity of a gel as a consequence of the particles facilitating association of the macromolecular chains in the matrix (Chi and Jun, 1991, Rafiee-Tehrani and Mehramizi, 2000). How such changes in the gel macroviscosity influence drug delivery has not been elucidated. Therefore, the aim of this study was to characterise the interactions of loaded lipid nanoparticle with a hydrophilic gel suitable for topical drug delivery. In order to achieve this aim, TA was chosen as a model lipophilic active; the active was loaded into lipid nanoparticles (LN) and formed into a homogeneous HA gel. HA–nanoparticle interactions were characterised by traditional ‘cone and plate’ rheometry, while nanoparticle tracking analysis (NTA) measured the nanoparticle mobility in the gel. TA delivery from two gels that restricted the freedom of the drug loaded nanoparticles to very different degrees was assessed using porcine skin as a model.

Section snippets

Materials

A mixture of medium chain acid triglycerides (Labrafac® WL 1349) was provided by Gattefossé S.A. (France). Soybean lecithin (Lipoid® S75-3) was donated by Lipoid Gmbh (Germany), a mixture of free polyethylene glycol 660 and polyethylene glycol 660 hydroxystearate (Solutol® HS 15) were provided by BASF (Univar, UK) and d-α tocopheryl acetate (96.0–102.0% purity) by Roche (Adina chemicals, UK). Sodium chloride, ethanol and methanol (high performance liquid chromatography, HPLC grade) were

Nanoparticle production and loading

Both placebo (PLN) and TA loaded LN (TALN) were prepared by a phase-inversion process described previously by Heurtault et al. (2002). Briefly, TA oil (4%, w/w, if required) was dissolved in a Labrafac (16.5%, w/w), Lipoid S-75 (1.75%, w/w) and Solutol (16.25%, w/w) mixture that was dispersed in an aqueous phase (NaCl in water, at 61.5%, w/w). The dispersion was heated and stirred to just above the phase inversion temperature (PIT) of the system (ca. 90 °C). The emulsion was homogenised by

Nanoparticle production

The phase inversion process of the emulsions was monitored by measuring the conductivity of the emulsion's external phase as a function of temperature. At the start of the heating cycles, i.e. at 55 °C, the emulsions displayed high conductivity values (3000 μS/cm for 2% NaCl, 4000 μS/cm for 3% NaCl, 5000 μS/cm for 5%), which was indicative of the mixture components forming an o/w emulsion. Increasing the temperature of the emulsion resulted in a rapid decrease in conductivity. For example, in the

Discussion

Nanoparticle production is often problematic as it is difficult to generate particles with a size of <100 nm that efficiently incorporate an active molecule, whilst retaining their physical stability during manufacture, storage and use. The phase inversion method, previously described by Heurtault et al. (2002), is a very robust means to fabricate nanoparticles. It generates nanosized particles from a highly stable nanoemulsion in a ‘one pot’ reaction. The specific nanoemulsion employed in this

Conclusions

The phase-inversion method used here was suitable for producing monodisperesed TA lipid nanoparticles of less than 100 nm in diameter. Adding purified TA nanoparticles to sodium hyaloranate led to a one step production system of a gel without any additives. Rheology measurements showed that LN interacted with the HA gel network and this reduced the LN mobility. However, reducing the mobility of the LN by increasing the HA gel viscosity did not affect the TA permeation. Drug release from lipid

Acknowledgements

The authors would like to acknowledge the financial support from University of the Arts, London and thank Matthew Wright from Nanosight for performing the nanotracking measurements.

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