EFFECT OF VARIOUS CYCLODEXTRINS ON SOLUTION STABILITY AND DISSOLUTION RATE OF DOXORUBICIN HYDROCHLORIDE

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-beta-cyclodextrin (HP-beta-CD), 2-hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD) and gamma-cyclodextrin (gamma-CD) all acted to decrease degradation of doxorubicin in solution although the gamma-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, HP-gamma-CD, 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, HP-beta-CD decreased dissolution time for various prototype formulations. Finally, a complex of HP-beta-CD and doxorubicin was found to be less toxic in a dermal extravasation model. These results, along with the accrued toxicity data which suggest HP-beta-CD is innocuous even when given in large doses parenterally, highly support the use of the modified cyclodextrin as a stabilizing and dissolution-enhancing excipient.