Lipid-based formulations approach systems

In conclusion, the recent increase in the number of water-insoluble drug candidates will doubtless enhance the importance of oral lipid-based formulations in the coming years. If a candidate has adequate solubility in the vehicles described in this chapter, lipid-based systems will usually provide an attractive approach for efLcient in-house development of clinical and commercial formulations. 

As reviewed in this chapter, certain means can be utilized to improve the bioavailability of lipophilic drugs, whether by formulative approach or molecular changes strategies. These means present a number of attractive propositions to the scientist, ranging from an enhancement of drug dissolution and solubilization by lipid-based formulation, increased solubility via the synthesis of a prodrug, specific delivery to the intestinal lymphatics, and reduction in enterocyte-hepatic presystemic metabolism and efflux systems. 

Hormones, proteins, and small peptides are not suitable for oral administration without complex modifications in the formulation. A variety of approaches for insulin delivery, as a model drug, have been attempted to improve on its bioavailability. Advances have been realized in the delivery of insulin through oral, nasal, rectal, dermatologic, and ocular routes. Proteins can also be delivered transdermally, using a lipid-based, biphasic delivery system in therapeutic quantity. 

In this chapter we will provide a brief overview of the early approaches to bioavailability enhancement by use of simple lipid-based delivery systems (lipid solutions, emulsions etc), and then describe recent progress in the application of self-emulsifying- and microemulsion-based formulations. The effects of lipids on the oral bioavailability of co-administered poorly water-soluble drugs may also be classified from a mechanistic (and to a degree, historical) perspective as physicochemically mediated effects (solubility, dissolution, surface area) and biochemically mediated effects (metabolism, transport related events), and these will be approached separately. It is readily apparent, however, that in many cases physicochemically and biochemically mediated mechanisms will operate side by side. In some instances, bioavailability may also be enhanced by the stimulation of intestinal lymphatic transport, and these studies will be addressed in a separate section. 

The most recent development (in terms of physicochemical/particle size approaches) in the design of lipid-based delivery systems has been the use of microemulsions, microemulsion preconcentrates, or self-microemulsifying drug delivery systems (SMEDDS), typified by the Sandimmun Neoral formulation. 

Segura el al. combines Tarazona s WDA DFT for hard-spheres with Wertheim s thermodynamic perturbation theory and has been used in a number of studies of associating fluids in pores and with functionalized walls in the limit of complete association a DFT for polymeric fluids is obtained in this method. Based on these works, Chapman and co-workers have presented the interfacial-SAFT (iSAFT) equation, which is a DFT for polyatomic fluids formulated by considering the polyatomic system as a mixture of associating atomic fluids in the limit of complete association this approach allows the study of the microstructure of chain fluids. Interfacial phenomena in complex mixtures with structured phases, including lipids near surfaces, model lipid bilayers, copolymer thin films and di-block copolymers, have all been studied with the iSAFT approach. 

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