Glucocorticoids, drug delivery

G Hochhaus, S Suarez, RJ Gonzalez-Rothi, H Schreier. Pulmonary Targeting of Inhaled Glucocorticoids How Is It Influenced by Formulation Respiratory Drug Delivery VI, Hilton Head, SC, 1998, pp. 45-52. 

Pharmacokinetic Considerations in the Design of Pulmonary Drug Delivery Systems for Glucocorticoids... 

G. Hochhaus, S. Suarez, R. J. Gonzales-Rothi, and H. Schreier, Pulmonary targeting of inhaled glucocorticoids How is it influenced by formulation , Respiratory Drug Delivery VI(R. Dalby, P. Byron, and S. J. Farr, eds.), Interpharm Press, 1998, p. 45. 

To ensure optimal drug delivery, it is necessary to coordinate activation of the inhaler with inspiration and a final hold of breath. Many patients, especially the young and the elderly, find this very difficult and spacer devices are often used between the inhaler and lips these act as an aerosol reservoir and also reduce impaction of aerosol in the oropharynx. Topical deposition can cause local side effects in the mouth, particularly Candida with inhaled glucocorticoids a spacer abolishes this problem. 

The pharmacokinetic/dynamic parameters involved in pulmonary drug delivery of glucocorticoids have been reviewed. Among these, low oral bioavailability, high pulmonary deposition, pronounced clearance, and sustained pulmonary release are the most important parameters to be considered. 

Klyashchitsky, B. A., Owen, A. J., Nebulizer-compatible liquid formulations for aerosol pulmonary delivery of hydrophobic drugs glucocorticoids and cyclosporine,... 

A second example is the colon-specific delivery of glucocorticoids linked to dextran via a succinic acid or glutaric acid spacer [256a]. Such conjugates resist hydrolysis in the upper gastrointestinal tract, but are rapidly degraded by bacteria in the colon and caecum where little drug absorption occurs. 

The first inhaled glucocorticoid, beclomethasone dipropionate, revolutionized asthma therapy, when it was found that topical delivery to the lung resulted in reduced systemic side-effects (adrenal suppression, oseteoporosis and growth inhibition) typically seen with oral steroid treatments. Interestingly, a further reduction in systemic exposure was achieved with the introduction of fluticasone propionate (1). The evolution of this drug stemmed from observations with the steroid 17-carboxylates that showed that these esters were active topically when esterified, while the parent acids were inactive. Thus it was realized that enzymatic hydrolysis of the ester would lead to systemic deactivation. SAR studies led to a series of carbothioates, which were very active in vivo when topically applied to rodents, but were inactive after oral administration. It was shown that fluticasone propionate (1) underwent first pass metabolism in the liver to the corresponding inactive 173-carboxylic acid (la) (Scheme 1). This observation was... 

The systemic availability of an inhaled glucocorticoid represents the additive and complex combination of pulmonary and gastrointestinal drug absorption. Absorption is influenced by many factors, including delivery device, the use of a spacer, the particle size of the inhaled drug, and the absorption and metabolism of the swallowed drug (1). 

Macleod, A.D. Tolentino, L. Tozer, T.N. Glucocorticoid-dextran conjugates as potential prodrugs for colon-specific delivery steady-state pharmacokinetics in the rat. Biopharm. Drug Disp. 1994,15, 151-161. 

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