Hydrolysis-activated drug delivery systems

In addition to solvent uses, esters of lactic acid can be used to recover pure lactic acid via hydrolysis, which in-tum is used to make optically active dilactide and subsequently polylactic acid used for drag delivery system.5 This method of recovery for certain lactic acid applications is critical in synthesis of medicinal grade polymer because only optically active polymers with low Tg are useful for drug delivery systems. Lactic acid esters themselves can also be directly converted into polymers, (Figure 1), although the commercial route proceeds via ring-opening polymerization of dilactide. 

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. 

Chitosan is a second abundant heteropolysaccharide composed of /3-[l-4]-2-deoxy-2-amino and -2-acetamino D-glucopyranose units [31]. Chitosan is the partial deacetylated (involving alkaline hydrolysis] product of chitin. Chltln is the main component of outer skeleton of small insects, cuticles, and the shells of shrimp, crab, lobster, etc. Chitosan has been expansively investigated in the pharmaceutical industries for the development of various sustained and controlled release drug delivery systems due to its versatile biological activity [as food and non-food items] and excellent biocompatibility. Hirano [22] conducted an experiment with both healthy and infected skin and found the LD50 in case of orally administered mouse to be [>16 g/kg]. Wu et al. [76] worked on... 

The oxidation of dihydropyridine-based chemical delivery systems (CDSs) pioneered by Bodor and co-workers [176] has been discussed in a previous book (Chapt. 13 in [81]). There, we examined the principles by which such compounds function to deliver drugs to the brain. Here, we focus our attention to the last step in the activation of these double prodrugs, namely hydrolysis to release the drug. 

Fig. 8.14. Stepwise activation of dihydrotrigonelline-based chemical delivery systems, first by oxidation to a pyridinium cation (Reaction a), and then by hydrolysis to trigonelline and the drug ROH (Reaction b). Direct hydrolysis (Reaction c) is slow in comparison to the Reactions...

Capecitabine is an example of a prodrug chemical delivery system that requires a series of enzymatic steps for conversion to the active antitumor drug species. S-fluorouracil (Scheme 5-24). Tumors located in tissues with high levels of the required enzymes. should respond best to treaunent with capecitabine. Esterase activity occurs primarily in the liver, allowing the intact e.ster capecitabine to be the absorbed species following oral administration. The ester hydrolysis product itself shows some specific toxicity towani... 

When the transdermal penetration of a drug is inadequate to achieve and maintain a plasma concentration above the minimum therapeutic concentration required to produce the desired effect, a lipophilic prodrug that will be metabolized in the epidermis to the active drug could be used in the development of a controlled-release transdermal delivery system. This approach has been applied to estradiol esters (diacetate and valerate) which are rapidly converted by esterases in the skin tissue to estradiol (Chien et al, 1985). The prodrug serves to increase the transdermal bioavailability of the active drug to which it is converted by metabolism (generally ester hydrolysis) during the percutaneous absorption process. 

Briefly, upon release of the macromolecular drug from the delivery system, the drug should withstand hydrolysis and enzymatic activity in the extracellular milieu at the site of absorption. In the case of nonparenteral delivery, the unstirred water layer and especially the viscous mucin layer in particular, both present at the surface of epithelia constitute a barrier for absorption of biotechnology-based pharmaceuticals and must be permeated for the biomacromolecule to reach the surface of the epithelial membrane. A... 

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