Lipid-based delivery systems

Anwer, K., C. Meaney, G. Kao, N. Hussain, R. Shelvin, R.M. Earls, R Leonard, A. Quezada, A.P. Rolland, and S.M. Sullivan, Cationic lipid-based delivery system for systemic cancer gene therapy. Cancer Gene Ther, 2000. 7(8) 1156-64. 

Liposomes and micelles are lipid vesicles composed of self-assembled amphiphilic molecules. Amphiphiles with nonpolar tails (i.e., hydrophobic chains) self-assemble into lipid bilayers, and when appropriate conditions are present, a spherical bilayer is formed. The nonpolar interior of the bilayer is shielded by the surface polar heads and an aqueous environment is contained in the interior of the sphere (Figure 10.3A). Micelles are small vesicles composed of a shell of lipid the interior of the micelle is the hydrophobic tails of the lipid molecules (Figure 10.3B). Liposomes have been the primary form of lipid-based delivery system because they contain an aqueous interior phase that can be loaded with biomacromolecules. The ability to prepare liposomes and micelles from compounds analogous to pulmonary surfactant is frequently quoted as a major advantage of liposomes over other colloidal carrier systems. 

Caillot, D., Chavanet, P, Casasnovas, O., Solary, E., Zanetta, G., Buisson, M., Wagner, O., Cuisenier, B., Bonnin, A., Camerlynck, P, et al. (1992) Clinical evaluation of a new lipid-based delivery system for intravenous administration of amphotericinEUr. J. Clin. Microbiol. Infect. Dis., 11 722-725. 

Classification of Lipid-Based Delivery Systems Developed by C. Pouton (Pouton, 2000)... 

Hauss, D.J., Fogal, S.E., Ficorilli, J.V., Price, C.A., Roy, T., Jayara, A.A., and Keirns, J.J. (1998) Lipid-based delivery systems for improving the bioavailability and lymphatic transport of a poorly water-soluble LTB4 inhibitor. J. Pharm. Sci., 87 164-169. 

Kossena, G. A., W. N. Charman, B. J. Boyd, D. E. Dunstan, and C. J. H. Porter. 2004. Probing drug solubilization patterns in the gastrointestinal tract after administration of lipid-based delivery systems A phase diagram approach).. Pharm. Sci93 332-348. 

Hauss, D.J., et al. 1998. Lipid-based delivery systems for improving the bioavailability and lymphatic transport of a poorly water-soluble LTB4 inhibitor. J Pharm Sci 87 164. 

Lipids, unlike many excipients, whether present in food or as discreet pharmaceutical additives, are processed both chemically and physically within the GIT before absorption and transport into the portal blood (or mesenteric lymph). Indeed, most of the effects mediated by formulation-based lipids or the lipid content of food are mediated by means of the products of lipid digestion—molecules that may exhibit very different physicochemical and physiological properties when compared with the initial excipient or food constituent. Therefore, although administered lipids have formulation properties in their own right, many of their effects are mediated by species that are produced after transformation or activation in the GIT. An understanding of the luminal and/or enterocyte-based processing pathways of lipids and lipid systems is therefore critical to the effective design of lipid-based delivery systems. 

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. 

Although lipids and lipid-based formulations cannot promote drug association with intestinal lipoproteins in the absence of the requisite physicochemical dmg properties, lipid-based delivery systems can have an appreciable effect on the extent of drug absorption into the enterocyte as described in the previous section. The eventual extent of lymphatic drug transport therefore is the product of the sequential processes of drug diffusion and dissolution in the GIT, drug absorption and metabolism within the enterocyte, and partition of the drug mole-... 

Airway administration of liposome complexes was used for the treatment of pulmonary diseases including cystic fibrosis. Cationic liposome/DNA complex showed no adverse effect towards airway epithelial integrity (190) therefore, the cationic lipid-based delivery system proved to be appropriate for use in human trials for cystic fibrosis (CF). A series of pre-clinical trials were done in CF patients with intranasal instillation to evaluate the risk factors associated with the treatment (191-193). Because there was no apparent toxicity associated with lipoplexes as was seen from these trials, progress had been made in delivering the complexes to the entire lung by aerosol in CF patients (192,194,195). By nebulization, the DNA-liposome complex was delivered into the airways of mutant mice to obtain human cystic fibrosis transmem-... 

The degree of dispersion of a lipid-based delivery system appears to have the most marked effect on the bioavailability of a co-administered drug, and this has stimulated many of the most recent articles in the literature. Clearly, by decreasing the particle size of a dispersed formulation, the surface area available for lipid digestion and drug release or transfer is enhanced. In this regard, the bioavailability of griseofulvin [32, 33], phenytoin [23], penclomedine [30], dana-zol [34], REV 5901 [35], and, more recently, ontazolast [36] has been shown to be enhanced after administration in an emulsion formulation compared with a tablet, aqueous solution, or suspension formulation. It is not clear in these cases how much more efficient the emulsion formulation would have been compared with a simple lipid solution. 

Lipid/DNA particles represent a nonliposomal but lipid-based delivery system for gene transfer. Monomeric or micellar lipids are allowed to interact with DNA in the presence of detergent or some other surface-active agent that is then removed by dialysis. As the surface-active agent diffuses out, solid, condensed particles of lipid and DNA form (17). These can be prepared such that they are smaller and more homogeneous than liposome/DNA complexes yet transfect cells equally well (F. Wong, unpublished observations). 

In recent years there has been an increased interest in the utility of lipid-based delivery systems to enhance oral bioavailability (4). It is generally known that membrane permeability is directly correlated to a drug s water-lipid partition coefficient however, the systemic availability of highly lipophilic drugs is impeded by their low aqueous solubility. In an effort to improve this solubility-limited bio-availabiliy,formulators have turned to the use of lipid excipients to solubilize the compounds before oral administration. Several formulations are currently on the market, for example, Sandimmun/Neoral (cyclosporin microemulsion), Norvir (ritonavir), and Fortovase (saquinavir)... 

Pouton CW and Porter CJ. (2008). Formulation of lipid-based delivery systems for oral administration Materials, methods and strategies. Advanced Drug Delivery Review, 60, 625-637. 

Fathi, M. Mozafari, M. R. Mohebbi, M., Nanoencapsulation of food ingredients using lipid based delivery systems. Trends in Food Science and Technology (2012) 23,13-27. 

Porter, C.J., Pouton, C.W., Cuine, J.F., Charman, W.N., 2008. Enhancing intestinal drug solubilisation using lipid-based delivery systems. Adv. Drug Deliv. Rev. 60, 673—691. 

It is well known, that the co-administration of poorly water soluble drugs with a meal rich in fat can enhance the oral bioavailability of poorly water soluble drugs and lipid based delivery systems mostly based on complex lipid mixtures are intensively studied to enhance the bioavailability of poorly water soluble drugs. ° ° A couple of lipid based formulations are already on the market, e.g. for cyclosporine (Neoral ), retonavir (Norvir ), saquinavir (Fortovase ) and amprenavir (Agenerase ). Formulations of solid lipid nanoparticles may present a further alternative for oral delivery of poorly water soluble drugs as well as for proteins and peptides with low oral bioavailability due to degradation in the intestinal fluids. ... 

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