CDs as solubilizers: effects of excipients and competing drugs.
In recent years cyclodextrins (CDs) have been acknowledged by the pharmaceutical industry as very useful enabling excipients for solubilization and stabilization of drugs in aqueous formulations. Their effect is however strongly influenced by other commonly used excipients. The purpose of this investigation was to examine the effects of excipients and drug combinations on the effects of CD solubilization of drugs and drug availability. The model drug was dexamethasone, the competing drugs tested were hydrocortisone, indomethacin and amphotericin B, and the sample CDs were gamma-cyclodextrin (gammaCD) and 2-hydroxypropyl-gamma-cyclodextrin (HPgammaCD). Benzalkonium chloride and hydroxypropyl methylcellulose enhance the solubilizing effect of the CDs whereas in general EDTA decreased the effect. The effect of second drug present in the aqueous formulation did depend on the affinity of that drug for the CD. Drugs which readily formed complexes with the CDs (e.g. hydrocortisone) decreased their ability to solubilize dexamethasone. Drugs that have little affinity for CDs (e.g. amphotericin B) did in some cases improve the CD solubilization of dexamethasone. Flux diagrams obtained through semi-permeable cellophane membrane indicated that drug/CD complexes self-assemble to form aggregates, especially at CD concentrations above 5% (w/v). This aggregate formation was affected by the excipients and did influence drug availability from the formulations.
Jansook
Phatsawee
P
Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, IS-107 Reykjavik, Iceland.
Loftsson
Thorsteinn
T
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000666:Amphotericin B / Q000737:chemistry; D001548:Benzalkonium Compounds / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003907:Dexamethasone / Q000008:administration & dosage / Q000737:chemistry*; D004492:Edetic Acid / Q000737:chemistry; D005079:Excipients / Q000737:chemistry*; D006854:Hydrocortisone / Q000737:chemistry; D065347:Hypromellose Derivatives; D007213:Indomethacin / Q000737:chemistry; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D012995:Solubility; D047392:beta-Cyclodextrins / Q000737:chemistry*; D047408:gamma-Cyclodextrins / Q000737:chemistry*
D001548:Benzalkonium Compounds; D005079:Excipients; D047392:beta-Cyclodextrins; D047408:gamma-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D065347:Hypromellose Derivatives; D003907:Dexamethasone; D000666:Amphotericin B; D008747:Methylcellulose; D004492:Edetic Acid; C023792:gamma-cyclodextrin; D006854:Hydrocortisone; D007213:Indomethacin