Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and ‘self-microemulsifying’ drug delivery systems

Abstract

‘Lipid’ formulations for oral administration of drugs generally consist of a drug dissolved in a blend of two or more excipients, which may be triglyceride oils, partial glycerides, surfactants or co-surfactants. The primary mechanism of action which leads to improved bioavailability is usually avoidance, or partial avoidance, of the slow dissolution process which limits the bioavailability of hydrophobic drugs from solid dosage forms. Ideally the formulation allows the drug to remain in a dissolved state throughout its transit through the gastrointestinal tract. The availability of the drug for absorption can be enhanced by presentation of the drug as a solubilizate within a colloidal dispersion. This objective can be achieved by formulation of the drug in a self-emulsifying system or alternatively by taking advantage of the natural process of triglyceride digestion. In practice ‘lipid’ formulations range from pure oils, at one extreme, to blends which contain a substantial proportion of hydrophilic surfactants or cosolvents. Knowledge of the efficiency of emulsification of these formulations, the nature of the colloidal system formed by dispersion, their susceptibility to digestion, and the subsequent fate of the drug is desirable for formulation. Yet the literature on this subject is limited, so this article represents part review and part commentary on current status of lipid formulations. A simple classification system for lipid formulations, based on the polarity of the blend and reviewed here, will help comparison of data between laboratories. Priorities for future work are discussed. More data is needed on the solubility of drugs in various types of formulations, and in particular, on the relationship between the physical chemistry of the drug and its fate, subsequent to dilution and digestion of the formulation in the lumen of the gastrointestinal tract. The mechanisms of action and practical uses of each type of lipid formulation are discussed.

Introduction

In recent years several successful oral pharmaceutical products have been marketed as lipid systems, notably cyclosporin A (originally marketed as ‘Sandimmune™’ and now as the improved product ‘Neoral™’) and the two HIV protease inhibitors, ritonavir and saquinavir. Consequently, there is now considerable interest in the potential of lipid formulations for oral administration. It was not always so; the potential of self-emulsifying drug delivery systems has been evident for at least 15 years (Pouton, 1985a, Pouton, 1985b), and in the earlier literature there were many references to the beneficial effects of food or oils on bioavailability of hydrophobic drugs (Humberstone and Charman, 1997). Nevertheless a preference for solid dosage forms prevailed until the case of cyclosporin A emerged, when it became clear that its formulation with lipids or surfactants had been crucial to the success of the oral capsule product. The literature on the mechanisms of action, optimisation and performance of lipid formulations for oral administration is relatively small. In particular there are very few reports of systematic bioavailability studies in man. Considerable growth can be anticipated over the next decade. In this article I aim to describe the current status of lipid formulations, and discuss aspects of their use which will require further evaluation in the future.

The use of lipid systems has been reviewed on various occasions. Prior to the emergence of self-emulsifying systems, Armstrong and James (1980), reviewed the release of drugs from lipids. Several useful reviews have been published in recent years. Humberstone and Charman (1997) reviewed the biopharmaceutical literature. Strategies for formulation of self-emulsifying systems, and efforts to understand their mechanisms of action, have been reviewed by Constantinides (1995), Pouton (1997), Craig et al. (2000) and Gershanik and Benita (2000). In practice ‘lipid’ formulations are a diverse group of formulations which have a wide range of properties. These result from the blending of up to five classes of excipients; ranging from pure triglyceride oils, through mixed glycerides, lipophilic surfactants, hydrophilic surfactants and water-soluble cosolvents. Table 1 describes one method of classifying different lipid formulations. Myself and my research group use this classification system, which was first described last year (Pouton, 1999), to aid comparison of published data from other laboratories. The virtues of each type of formulation are discussed below. One general working hypothesis which can be applied to the use of all lipid formulations, relates to their general mechanism of action; that their advantage results from their ability to ensure that the drug remains in solution throughout its transit within the gastro-intestinal tract. Stated another way, if the drug precipitates within the gut, the dissolution form the crystalline form will result in slower, more variable absorption. The significance of this hypothesis in relation to formulation will be discussed below.