Prodrugs pilocarpine

Fig. 8.6. Two-step activation of pilocarpine prodrugs [123]. The prodrugs are diesters of pilocarpic acid (8.86). Enzymatic hydrolysis (Reaction a) cleaves the acyl carrier group. The product is a monoester of pilocarpic acid that undergoes cyclization to pilocarpine (8.87) upon intramolecular nucleophilic attack and loss of the alcohol carrier. 

H. Bundgaard, E. Falch, C. Larsen, G. L. Mosher, T. J. Mikkelson, Pilocarpine Prodrugs. II. Synthesis, Stability, Bioconversion, and Physicochemical Properties of Sequentially Labile Pilocarpine Acid Diesters , J. Pharm. Sci. 1986, 75, 775 - 783. 

P. Saarinen-Savolainen, T. Jarvinen, P. Suhonen, A. Urtti, Amphiphilic Properties of Pilocarpine Prodrugs , Int. J. Pharm. 1996, 133, 171-178. 

Bundgaard, H., Falch, E., Larsen, C., and Mikkelson, T. J. Pilocarpine prodrugs I. Synthesis, physicochemical properties and kinetics of lactonization of pilocarpic acid esters. J. Pharm. Sci. 75 36-43, 1986. 

Jarho, P., Jarvinen, K., Urtti, A., Stella, V. J., and Jarvinen, T. (1996), Modified beta-cyclodextrin (SBE7-beta-CyD) with viscous vehicle improves the ocular delivery and tolerability of pilocarpine prodrug in rabbits, J. Pharm. Pharmacol., 48(3), 263-269. 

Suhonen, P., T. Jarvinen, K. Lehmussaari, T. Reunamaki, and A. Urtti. 1995. Ocular absorption and irritation of pilocarpine prodrug is modified with buffer, polymer, and cyclodextrin in the eyedrop. Pharm. Res. 12 (4) 529-530. 

FIG. 16 Comparison of the miotic effect after ocular administration of a submi-crometer emulsion containing 1.2% (w/v) pilocarpine prodrug or aqueous solutions containing 0.5% (w/v) or 2.0% (w/v) pilocarpine HCl. (From Ref. 133 with permission from Elsevier Science.)... 

Pilocarpine and dipivefrin, a prodrug of epinephrine, are used as third-line therapies because of adverse events or reduced efficacy as compared with newer agents. 

Loftssona et al. [98] found that with increases in the concentration of HP-(3-CD, the flux of a hydrophobic drug arachidonylethanolamide increased. Later, Tirucherai and Mitra [99] found that HP-(3-CD could also enhance the corneal permeation of the lipophilic drug ganciclovir dibutyrate (acyl ester prodrug of ganciclovir). Aktas [100] also found that addition of HP-(3-CD to the simple aqueous solution of pilocarpine nitrate increased the permeation of pilocarpine nitrate by four times in an in vitro permeability study using isolated rabbit cornea. 

Jarvinen and co-workers [136] synthesized unique O, 0 -(xylylene)bispilocarpic acid esters containing two pilocarpic acid monoesters linked with one moiety. The found that prodrug showed a two- to seven-fold higher corneal permeability than pilocarpine itself despite the high molecular weight. 

Jarvinen, T., Suhonen, P, Auriola, S., Vepsalainen, J., Peura, P, et al. (1991), 0,0 -( 1,4-Xylylene)bispilocarpic acid esters as new potential double prodrugs of pilocarpine for improved ocular delivery. Part 1. Synthesis and analysis, Int. I. Pharm., 75(2-3), 249-258. 

To improve the ocular bioavailability and prolong the duration of action, various pilocarpic acid mono- and diesters were evaluated as prodrugs for pilocarpine. As shown in Scheme 24, the pilocarpic acid monoesters (138) undergo a quantitative... 

Pilocarpine is widely used as a topical miotic for controlling the elevated intraocular pressure associated with glaucoma. Beside its low lipophilicity, which stimulated the search for prodrugs,pilocarpine has a short duration of action, its lactonic ring being rapidly opened to yield pilo-carpic acid. In pilocarpine, by substituting the lactonic ester function by its carbamate equivalent, a much more stable analog, which is as effective as pilocarpine, was obtained. ... 

A nice example of this approach has been reported for two-step prodrugs of pilocarpine (47) (Fig. 13.41), aimed at improving ocular delivery (215). The prodrugs were lipophilic diesters of pilocarpic acid (46). The first activation step was enzymatic regiospecific 0-acyl hydrolysis to remove the acyl carrier (reaction A). In a second step, intramolecular nucleophilic substitution-elimination led to loss of the alcohol carrier and to ring closure to pilocarpine (reaction B). Efficient enzymatic hydrolysis was seen in various ocular tissue preparations, confirming the potential of these diesters as prodrugs for ocular delivery. 

Prodrugs have been designed to improve corneal absorption. This approach has been applied with epinephrine (226-230), terbutaline (231), various prostaglandins (232), phenylephrine (233-235), and pilocarpine (236-241). For some pilocarpine derivatives the double prodrug approach has been used to overcome eye irritation and improve on poor water solubility (240,241) (Section 5.4). 

Stability in aqueous solutions. This stability problem was solved by forming double prodrug pilocarpic acid esters. Because of their blocked hydroxyl group, these compounds are unable to undergo cyclizationto pilocarpine in the absence of hydro lytic enzymes. 

Pilocarpine Acid diesters Prodrug developed to increase aqueous stability... 

Which of the following agents is a prodrug that is much less toxic in mammals than in insects (A) Malathion Nicotine Parathion Physostigmine Pilocarpine... 

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