Based delivery systems

Virtually all therapeutic proteins must enter the blood in order to promote a therapeutic effect. Such products must usually be administered parenterally. However, research continues on the development of non-parenteral routes which may prove more convenient, less costly and obtain improved patient compliance. Alternative potential delivery routes include transdermal, nasal, oral and bucal approaches, although most progress to date has been recorded with pulmonary-based delivery systems (Chapter 4). An inhaled insulin product ( Exubera , Chapters 4 and 11) was approved in 2006 for the treatment of type I and II diabetes. 

Tabosa do Egito ES, et al. In vitro and in vivo evaluation of a new amphotericin B emulsion-based delivery system. J Antimicrob Chemother 1996 38 485. 

Lamphear, B.J., Jilka, J.M., Kesl, L., Welter, M., Howard, J.A., and Streatfield, S.J. (2004). A corn-based delivery system for animal vaccines an oral transmissible gastroenteritis virus vaccine boosts lactogenic immunity in swine. Vaccine 22(19) 2420-2424. 

A corn-based delivery system for animal vaccines an oral transmissible gastroenteritis virus vaccine boosts lactogenic immunity in swine. Vaccine 22(19) 2420-2424. 

This approach, known as the chemical-based delivery system (CDS), has been... 

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. 

Nature itself gives us a spectacular example of a biopolymer-based delivery system in the form of the native casein micelle of mammalian milk (Lemay et al, 2007). This is primarily a colloidal delivery system for calcium, where the micronutrient is in the form of calcium phosphate, which does not give a bitter taste, and which provides good bioavailability owing to its colloidal size, amorphous state and quick dissolution in gastric conditions (pH 1-2). Nevertheless, the casein micelle structure is unique there are no other readily available natural delivery systems for most nutraceuticals. Therefore some new designs are clearly required (Velikov and Pelan, 2008 McClements et al, 2008, 2009). 

McClements, D.J., Decker, E.A. (2009). Controlling lipid bioavailability using emulsion-based delivery systems. In McClements, D.J., Decker, E.A. (Eds). Designing Functional Foods, Boca Raton, FL CRC Press, pp. 502-546. 

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. 

Ilium, L., et al. 2000. Novel chitosan based delivery systems for the nasal administration of a LHRH-analogue. STP Pharma Sci 10 89. 

It is possible to avoid incorporation of homopolynucleotide by using ternary complexes between polynucleotide, SPG, and polycation. It was recently demonstrated that such ternary complexes can be prepared with PEI and cationic cellulose (quatemized nitrogen is a charged functional group in cationic cellulose) [55]. However, this kind of approach is a step away from the non-cationic nature of schizophyllan-based delivery systems and will not be discussed here. 

The research performed by several groups on pullulans has demonstrated their potential as nucleic acid delivery vehicles. Although most of the pullulan-based delivery systems yielded low toxicity, some modifications of the backbone or introduction of substituents resulted in higher toxicity. Such modifications are unavoidable because the parent structure is incapable of efficient delivery and lacks target specificity. 

As of today, there are no commercially available pharmaceutical products of this technology. The pharmaceutical industry however, is involved in developing nanoparticle-based delivery systems. Use of nanospheres to modify the blood-brain barrier (BBB)—limiting characteristics of the drug enables targeted brain delivery via BBB transporters and provides a sustained release in brain tissue and vaccine delivery systems to deliver therapeutic protein antigens into the potent immune cells are under investigation.103... 

Polymer-based delivery systems (Fig. 11.1) include polymer-protein conjugates, polymer-drug conjugates, micelles consisting of polymeric surfactants, and complexes of cationic polymers and DNA (polyplexes).26... 

Polymer-based systems. Pulsatile release of medicaments can be obtained from polymer-based delivery systems. Based on the mechanism of drug release from the polymer, these systems can be divided into various classes and subclasses. Broadly, they can be classified into three classes delivery by hydrolysis of polymers, delivery by osmotic pressure, and delivery by both hydrolytic degradation and osmotic effects. 

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-... 

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