Degradable delivery systems

Degradation and disappearance of a biodegradable polymer matrix occurs in a sequence of steps. Some of these steps are understood reasonably well as a consequence mathematical expressions can be used to describe some aspects of polymer degradation and drug release. These mechanisms will be illustrated using the pLGA system. 

Polymer molecules that are exposed to water will hydrolyze, causing the average molecular weight of the polymer to decrease with time. For polyester materials such as pLGA, the kinetics of degradation are first order [74]  

3 Examples of Drug Release from Degradable Materials 

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Kleimnan et al. 2008). In addition, synthetic siRNAs are also subject to degradation in vivo by nuclease activity. Besides side effects and instability, the efficient and specific delivery of the RNAi indncers to the target cell still requires optimization. Here we snmmarize the cnrrent statns of nncleic acid-based antiviral therapentics. The focns will be on antiviral strategies nsing antisense and RNAi technology. Additionally, antiviral ribozymes and aptamers will be discussed briefly, with a focus on recent studies. Gene therapy approaches and delivery systems are the subject of Chapter 11 of this book. 

A different approach to polyphosphazene-based drug delivery systems deals with hydrolytically unstable phosphazene substrates, able to degrade in a controlled way under physiological conditions in human body. A list of these bio-erodible substrates is reported in Table 21. 

These results open the exciting possibility of using degradable, tyrosine-derived polymers as "custom-designed" antigen delivery devices. On the other hand, our results indicate that the immunological properties of tyrosine-derived polymers will have to be carefully evaluated before such polymers can be considered for use as drug delivery systems or medical implants. 

YoUes, S., and Sartori, M. F., Degradable polymers for sustained drug release, in Drug Delivery Systems (R. L. Juliano, ed.), Oxford University Press, New York, 1980, pp. 84-111. 

Biodegradable polyurethanes have been proposed and studied before (9-72). The difference in our study is the inclusion of a phosphoester linkage instead of the commonly used polyester component. This seems to provide more flexibility as the side chain of the phosphate or phosphonate can be varied. For controlled drug delivery applications, drugs can be linked to this site to form a pendant delivery system. Moreover, for certain medical applications, fast degradation rate is obtainable by the introduction of these hydrolyzable phosphoester bonds. With the LDI based polyurethanes, drugs or other compounds of interest can also be coupled to the ester side chain of the lysine portion. 

A mathematical model has been developed which allows the calculation of the degradation of polymeric drug delivery systems. The model has been shown to accurately simulate both the drug release and molecular weight changes in such systems. The concentration of anhydride levels affect the erosion characteristics of... 

In this work we will focus on the use of the cubic phase as a delivery system for oligopeptides - Desmopressin, Lysine Vasopressin, Somatostatin and the Renin inhibitor H214/03. The amino acid sequences of these peptides are given in Table I. The work focuses on the cubic phase as a subcutaneous or intramuscular depot for extended release of peptide drugs, and as a vehicle for peptide uptake in the Gl-tract. Several examples of how the peptide drugs interact with this lipid-water system will be given in terms of phase behaviour, peptide self-diffusion, in vitro and in vivo release kinetics, and the ability of the cubic phase to protect peptides from enzymatic degradation in vitro. Part of this work has been described elsewhere (4-6). 

Poly-j3-malate is readily degraded completely to L-malic acid under both acid and base conditions [108], and it can also be hydrolyzed by enzymes within the cell [105,106]. Recently, several bacteria were isolated which were able to utilize poly-/i-malate as sole carbon source for growth [109]. Because the polymer is biodegradable and bioadsorbable, it is of considerable interest for pharmaceutical applications, especially in controlled-release drug delivery systems [97,98]. Chemical routes to poly-/ -malate are expected to provide materials with various properties [110]. 

Some active materials are carriers for drugs (drug delivery systems), some have immobilized peptides to enable cell adhesion or migration, some are degradable by hydrolysis or by specific enzyme action. Some contain bioactive agents (e.g., heparin, thrombomodulin) to prevent coagulation or platelet activation while others incorporate bioactive groups to enhance osteo-conduction. Many include polyethylene oxide to retard protein adsorption and this is perhaps the closest we have come to a kind of inertness. 

Figure 14.10 Overview of cellular entry of (non-viral) gene delivery systems, with subsequent plasmid relocation to the nucleus. The delivery systems (e.g. lipoplexes and polyplexes) initially enter the cell via endocytosis (the invagination of a small section of plasma membrane to form small membrane-bound vesicles termed endosomes). Endosomes subsequently fuse with golgi-derived vesicles, forming lysosomes. Golgi-derived hydrolytic lysosomal enzymes then degrade the lysosomal contents. A proportion of the plasmid DNA must escape lysosomal destruction via entry into the cytoplasm. Some plasmids subsequently enter the nucleus. Refer to text for further details...

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