Background on Conventional Self-Emulsifying Drug Delivery Systems and the Supersaturatable Formulations

Low water solubility is widely recognized as the main reason for the poor oral absorption of many new chemical entities. Conventional solubilization approaches such as salt formation, cosolvents and, more recently, surfactant-based micellar systems, are now widely employed in enhancing the oral absorption of drugs, primarily poorly soluble drugs. In particular, self-emulsifying drug delivery systems (SEDDS) are commonly employed in improving the oral exposure of poorly soluble, lipophilic drugs (1-5). However, a high surfactant level is needed in the conventional SEDDS formulations in order to prevent precipitation of the drug on dilution with water in the gastrointestinal (GI) tract. The surfactants that are commonly employed in SEDDS formulations can increase the incidence of

GI side-effects (6,7) and, therefore, a reduced amount of surfactant in the formulations should minimize the surfactant-induced GI side-effects (8-10).

The potential of increasing the thermodynamic activity of drug formulations and, thereby, increasing the bioavailability of poorly soluble drugs through supersaturation was recognized by Higuchi more than four decades ago (11). Since then, a number of publications have appeared in the literature employing supersaturated formulations as a means of enhancing bioavailability. While most work on supersaturation reported in the literature has been devoted to topical delivery (11-22), less attention has been focused on the use of supersaturation for improving oral delivery of poorly soluble drugs (23-29).

Polyvinylpyrrolidone (PVP) was found useful in generating a supersaturated state with a number of poorly soluble drugs (12-16,23,24,30). Other studies reported the use of the water soluble cellulosic polymers such as HPMC (17-20,22,25,26,31), methylcellulose (20), hydroxypropyl methylcellulose phthalate (28,29), and sodium carboxymethylcellulose (32). The cellulosic polymers are excellent crystal growth inhibitors and they are effective in maintaining the supersaturated state of the drugs (16,18,31,32).

One of the most promising approaches for enhancing the oral bioavailabi-lity of poorly soluble drugs is the use of the principle of supersaturation in the development of supersaturatable formulations (33,34). It should be clearly recognized that supersaturatable formulations differ from supersaturated formulations. Supersaturated formulations are not thermodynamically stable and drugs in supersaturated formulations can crystallize on storage. Therefore, the physical stability of such formulations is fundamentally challenging and this limits their practical utility. In contrast, supersaturatable formulations are thermodynamically stable dosage forms; they yield a supersaturated state only after administration in vivo.

Development of Supersaturatable Self-Emulsifying Drug Delivery Systems

To take advantage of supersaturation, the generation and maintenance of a supersaturated system in vivo from supersaturatable dosage forms is a prerequisite. In our studies, we found that reducing the amount of surfactant in a SEDDS formulation in order to generate a supersaturated state on dilution of the formulation with an aqueous medium can result in rapid precipitation of the poorly soluble drug. However, we found that incorporation of hydroxypropyl methyl cellulose (HPMC) or other cellulosic polymeric excipients in the SEDDS formulations can sustain the supersaturated state by preventing precipitation of the drug. These formulations are termed supersaturatable SEDDS or S-SEDDS formulations.

This chapter describes the development of supersaturatable S-SEDDS formulations using three poorly soluble drugs, namely, PNU-91325, paclitaxel, and Drug X along with the behavior of these S-SEDDS formulations in an in vitro dissolution/precipitation test. These studies show that the S-SEDDS formulations containing a reduced amount of surfactant along with a supersaturation promoting polymer can generate a supersaturated drug solution on contact with water and the resulting supersaturated state can be maintained sufficiently long to achieve enhanced absorption. These S-SEDDS formulations of poorly soluble drugs have the potential of improving the tox/safety profile of the product due to a reduced amount of surfactant and they can show higher oral bioavailability as compared with the corresponding conventional SEDDS formulation of the same drug. The studies described below clearly demonstrate that the supersaturatable S-SEDDS formulation approach is a powerful approach for improving the oral absorption of poorly soluble, lipophilic drugs.

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