Abstract
A number of cyclodextrins were examined as to their ability to stabilize doxorubicin in solution and to enhance the rate of its dissolution. 2-Hydroxypropyl-β-cyclodextrin (HPβCD), 2-hydroxypropyl-γ-cyclodextrin (HPγCD) and γ-cyclodextrin (γCD) all acted to decrease degradation of doxorubicin in solution although the γ-cyclodextrin derivatives were decidedly more effective. Lineweaver-Burk analysis indicated that the incorporated anthracycline degraded 6–10-times more slowly than did doxorubicin in systems which did not contain Cyclodextrin. The chemically modified cyclodextrins were also shown to enhance the rate of dissolution of prototype lyophilized formulations. Thus, HPγCD, present in 5-fold excess relative to doxorubicin, acted to decrease dissolution time from 26 min (for a doxorubicin/lactose dosage form) to less than 9 min. Similarly, HPγCD decreased dissolution time for various prototype formulations. Finally, a complex of HPγCD and doxorubicin was found to be less toxic in a dermal extravasation model. These results, along with the accrued toxicity data which suggest HPγCD is innocuous even when given in large doses parenterally, highly support the use of the modified Cyclodextrin as a stabilizing and dissolution-enhancing excipient.
Published Version
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