Mesoporous silicon microparticles for oral drug delivery: Loading and release of five model drugs

Abstract

Mesoporous silicon (PSi) microparticles were produced using thermal carbonization (TCPSi) or thermal oxidation (TOPSi) to obtain surfaces suitable for oral drug administration applications. The loading of five model drugs (antipyrine, ibuprofen, griseofulvin, ranitidine and furosemide) into the microparticles and their subsequent release behaviour were studied. Loading of drugs into TCPSi and TOPSi microparticles showed, that in addition to effects regarding the stability of the particles in the presence of aqueous or organic solvents, surface properties will affect compound affinity towards the particle. In addition to the surface properties, the chemical nature of the drug and the loading solution seems to be critical to the loading process. This was reflected in the obtained loading efficiencies, which varied between 9% and 45% with TCPSi particles. The release rate of a loaded drug from TCPSi microparticles was found to depend on the characteristic dissolution behaviour of the drug substance. When the dissolution rate of the free/unloaded drug was high, the microparticles caused a delayed release. However, with poorly dissolving drugs, the loading into the mesoporous microparticles clearly improved dissolution. In addition, pH dependency of the dissolution was reduced when the drug substance was loaded into the microparticles.

Introduction

The application of nanotechnology in biomedical research carries tremendous potential for drug administration. While most of the research has been focused on diagnostic systems (lab-on-chip), interest in microdevices for therapeutic applications has also increased [1], [2]. Initially, therapeutic applications of silicon-based systems were directed towards implanted devices [3], [4], with other administration routes, such as oral delivery emerging [5]. Recent reports on the advantages of mesoporous materials as drug delivery vehicles have encouraged research in novel applications, supporting also conventional dosage forms, and several potential materials for this purpose have been reported [6], [7], [8], [9].

Main efforts in the studies of mesoporous materials as drug delivery vehicles have been focused on sustained/controlled drug release [7], [8], [9]. The potential of mesoporous materials to improve the permeability of large, hydrophilic drug substances has also been explored in combination with classical permeation enhancers [6]. Further, mesoporous materials offer a potential means to increase the dissolution of poorly soluble drug via effects on surface area or crystallinity. At pore sizes only a few times larger than the drug molecule, the formation of crystalline material is restricted by the confined space of the pores, thus retaining the drug in its noncrystalline, amorphous form. The amorphous form is known to exhibit higher dissolution rates than the crystalline phase, especially when solubility is limited by high crystal energy [10]. Drug delivery strategies providing the potential to tailor the physical state of a compound will be of increasing importance in drug development, since it is estimated that 40% of potential lead candidates suffer from poor solubility, a great part of which may be related to high crystal energy [11].

Porous silicon (PSi) has some advantages compared to synthesised mesoporous materials when drug delivery vehicles are considered. The fabrication of PSi is a simple procedure, where the porosity and pore size can easily be tuned by anodization parameters [12]. Depending on the morphology, PSi could be tailored as a biodegradable, bioactive or stable material [13], [14]. In addition, the surface chemistry of PSi can easily be modified to produce surfaces favourable for drug adsorption [15], [16]. In this work, we will describe a simple fabrication method to produce mesoporous silicon microparticles with a surface stabilisation suitable for oral drug administration applications. Five model drugs, antipyrine, ibuprofen, griseofulvin, ranitidine and furosemide, were used to study drug loading into the microparticles and subsequent drug release behaviour. The compounds were chosen to represent a wide range of solubilities with additional differences in acid/base character and lipophilicity, while also representing drugs of different biopharmaceutical classification (BCS) (Table 1) [17]. Dissolution was studied at the pH-values 5.5, 6.8 and 7.4 representative of different parts of the small intestine.