Sustained-release prodrugs

Figure 16.2 Dihydropyridine-pyridinium salt redox system for site-specific and sustained delivery to the brain. The prodrug A is delivered directly to the brain, where it is oxidized and trapped as the prodrug B. The quaternary ammonium salt is slowly cleaved by chemical/enzymatic action with sustained release of the biologically active phenylethylamine C and the facile elimination of the carrier molecule D. Elimination of the drug from the general circulation is by comparison accelerated, either as A or B or as cleavage products...

L-Dopa is a prodrug of dopamine and is known as the drug of choice for the treatment of Parkinson s disease. L-Dopa has a narrow absorption window and is actively absorbed from the upper part of the small intestine. The large fluctuations in L-Dopa plasma concentration cause severe side effects. Hence, there is a PK rationale to elevate the extent of absorption while minimizing the maximum plasma concentration (Cmax) obtained, following oral administration of a sustained release (SR) formulation of L-Dopa. 

This approach can be used to prolong the release of compounds with limited aqueous solubility. A suspension of a compound in its saturated solution can provide both immediate-release and sustained-release components of a dose (Madan 1985). A number of water-insoluble prodrugs are also formulated as suspensions, including hydrocortisone acetate and medroxyprogesterone acetate. As with any other type of suspension, excipients will usually be required to ensure the physical stability of the formulation. Strickley s (1999) article provides a table of parenteral suspension formulations the most popular excipient combinations are clearly polyethylene glycol/Tween 80 and carboxymethylcellulose/Tween 80. 

Generalizing the dihydropyridine pyridinium salt redox delivery system, successfully applied to 2-PAM, Bodor and his coworkers proposed an astute sustained release methodology for brain delivery, based on the mixed-t3q)e prodrugs. The biologically active compound is linked to a... 

M. L. Forrest et ah, Paclitaxel prodrugs with sustained release and high solubility in poly(ethylene glycol)-b-p>oly(epsilon-caprolactone) micelle nanocarriers pharmacokinetic dispxjsition, tolerability, and cytotoxicity. Pharm. Res., 25(1), 194-206 (2008). 

ZT-1, a semisynthetic prodrug of hupA, is transformed nonenzymaticafly into hupA. It has been administered by i.v., oral, immediate-release and by sustained-release formulations in the form of implants [76]. In vitro studies show that ZT-1 inhibits AChE similar to hupA, but a weaker BuChE inhibition was observed. Pharmacokinetic studies suggest that ZT-1 has similar properties to hupA regarding oral bioavailability, the ability to cross the BBB, and longevity of action [8]. 

Luo Q, Wang P, Miao Y, He H, Tang X. A novel 5-fluorouracil prodrug using hydroxy-ethyl starch as a macromolecular carrier for sustained release. Carbohydr Polym... 

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