Oral particulate delivery: status and future trends

Abstract

Oral delivery of complex molecules such as peptides and proteins is one of the most intensively studied research subjects. However, its success has been hampered by the degradation of these molecules in the gastrointestinal tract. As a result, various types of particulate systems such as biodegradable microspheres and liposomes have been proposed as potential delivery vehicles to protect these drugs in the gastrointestinal tract. Unfortunately, these particulates generally display low oral absorption efficiencies. This renders most encapsulated drugs ineffective after oral administration and therefore remains as the main obstacle to their practical application as oral delivery vehicles. In attempts to improve particle absorption efficiency, strategies such as using mucoadhesive polymers and targeted delivery systems have been studied in animals. In this chapter, the usefulness of these strategies are briefly reviewed. Potential applications and future prospects of particulates in oral delivery of complex molecules are also highlighted.

Introduction

Oral delivery is by far the easiest and most convenient way for drug delivery, especially when repeated or routine administration is necessary [1]. Despite these advantages, most peptide and protein drugs available today are not administered orally due to their gastrointestinal degradation by digestive enzymes.

As a result, new formulations consisting of different kinds of delivery vehicles are therefore being developed to attempt to overcome these difficulties. Many of these formulations utilize various forms of particulates. These particulates can be replicating or non-replicating in nature. The replicating systems are mainly attenuated or genetically modified strains of viruses or bacteria which continue to propagate in vivo after administration. Examples of these include genetically engineered Vaccina virus and attenuated strains of Salmonella. These systems have been reviewed elsewhere [2]and therefore will not be discussed further in this chapter. Instead, we will focus on non-replicating particulate systems, such as polymeric particles and lipid-containing particles. These systems encapsulate the drugs within the particles and therefore protect them from the harsh environmental elements in the gastrointestinal (G-I) tract.

Due to the unique physiological conditions in the G-I tract, the particulate systems are required to meet the following criteria before they can be used as effective oral delivery vehicles: firstly, they need to be resistant to degradation in the G-I tract and in turn protect the encapsulated drugs from degradation. This is especially important for lipid-containing particulates such as liposomes, since the presence of bile salts in the small intestine is known to destroy most of the particles administered 3, 4. In comparison, this is not as critical for polymeric particles such as biodegradable microspheres since their degradation typically takes place on a time scale of days and sometimes weeks. Secondly, the encapsulated drugs in the particles need to be absorbed with high efficiency in the G-I tract to be therapeutically effective. In other words, the particles themselves need to be absorbed at an efficient rate in the G-I tract in order to deliver the encapsulated drugs to their in vivo targets. Currently, it is believed that less than one percent of the particles can be absorbed after oral administration [5]. This extremely low absorption efficiency proves to be the largest obstacle toward the potential application of particulates in oral delivery of complex molecules such as proteins and peptides.

Due to the critical role that particle absorption phenomenon plays in oral delivery of protein and peptide drugs, we will devote our discussion to this topic in the following sections of this chapter. We will first briefly address the current understanding of particle absorption mechanisms in the G-I tract. This is followed by a brief summary of the various types of non-replicating oral particulate systems that have appeared in the literature and their advantages as well as disadvantages. Strategies that have been used to improve particle absorption efficiency are then discussed. We will conclude with a description of potential applications and some future prospects of oral particulate delivery.