Hydrocortisone prodrugs

Johnson, K., G L. Amidon, and S. Pogany. 1985. Solution kinetics of a water-soluble hydrocortisone prodrug hydrocortisone-21-lysinatel. Pharm. Sci74 87-89. 

Benzoic acids substituted with a basic side chain also are also of interest as pro-moieties whose physicochemical properties and rates of enzymatic hydrolysis can readily be modulated. A number of drugs have been converted to prodrugs with this type of pro-moiety, e.g., hydrocortisone, prednisolone, acyclovir, chloramphenicol, and paracetamol [148] [149], These prodrugs appear well suited as parenteral formulations, being water-soluble, stable in slightly acidic solution, and readily hydrolyzed enzymatically. As examples, we consider here the hydrolysis in human plasma of a number of (aminomethyl)ben-zoates of metronidazole (8.109-8.115, Sect. 8.5.5.1, Table 8.9) [138], These prodrugs are very rapidly activated, which may be beneficial for parenteral administration. However, this type of pro-moiety may be cleaved too rapidly after oral administration to be of interest for poorly absorbed drugs. 

Synthetic glucocorticoids are prednisolone, prednisone, methylprednisolone, dexamethasone, betamethasone and triamcinolone (Table 13.2). Hydrocortisone is available as either succinate or phosphate salts for oral and intravenous administration. It is the drug of choice when a rapid effect is required, e.g. acute adrenal insufficiency, or as peri-operative replacement therapy. Prednisolone can also be given intravenously. It has about 0.8 of the mineralocorticoid activity of hydrocortisone. Prednisone is a prodrug that is converted to prednisolone in the body. For chronic therapy, synthetic steroids without mineralocorticoid activity are preferred, such as dexamethasone, betamethasone or triamcinalone. Beclo-metasone passes membranes poorly and is more active topically than when given orally. It is used as an aerosol for chronic rhinitis and asthma, and topically in severe eczema. Fludrocortisone is a synthetic halogenated derivate of cortisol that is used for its mineralocorticoid effect. 

Pharmacokinetic studies in dogs demonstrated a 3.5-fold increase in oral bioavailability of phenytoin when administered as the disodium phosphate prodrug versus sodium phenytoin [54]. A few additional examples of investigations with this strategy include the steroids betamethasone [55] and hydrocortisone [56], HIV protease inhibitors [57], and the anticancer drug etoposide [58,59]. Comprehensive reviews of this strategy are also available [52,60,61]. 

Thiazolidines Thiazolidines of some a,P-unsaturated 3-ketone steroids including progesterone, testosterone, and hydrocortisone (112, 113) were prepared from the reaction with cysteine alkyl esters and cysteamines as potential prodrugs.67,68 The thiazolidines readily reverted to their parent steroidal ketones,... 

Many other polymers have been tested as backbonesfor prodrugs. As examples, one may list poly-L-(glutamic acid) for clonidine controlled release (52), hyaluronic acid for hydrocortisone and derivatives (53-55), or the synthetic polyanionic polymer pyran for the antitumor, antibacterial, and antiviral agent muramyl dipeptide (56). Hyaluronic acid and pyran are interesting in the sense that they add a new dimension to the macromolecular prodrug approach. Hyaluronic acid is believed to be potentially useful for the control of infec-... 

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. 

QTie kinetics of hydrolysis of imidazole-l-carboxylic acid esters of hydrocortisone and testosterone were studied to assess their suitability as prodrug forms. The pH-rate profiles of tiie 2 derivatives were derived in the range pH 1-12 and were accounted for by assuming spontaneous hydrolysis of the protonated forms (pKa 33-3.5) and hydroxide ion-catalyzed hydrolysis of the free base forms "... 

Cited in Klixbull U and Bundgaard H, Prodrugs as drug delivery systems XXIX. Imidazole-l-carboxylic acid esters of hydrocortisone and testosterone. Arch. Pharm. Chem., Sci. Edn., 11, 101-110 (1983). 

Hydrocortisone hydrogen succinate (C25H34O8) Hydrocortisone, imidazole-1-carboxylic acid prodrug (C25H32N2O6)... 

Silybin Meclizine Cefoperazone Amiodarone KHL 8430 Butaclamol Nefazodone Dextromoramide Levomoramide Plydrocortisone, imidazole-1-carboxylic acid prodrug Hydrocortisone hydrogen succinate Mebeverine... 

---