H S Lin1, C S Chean, Y Y Ng, S Y Chan, P C Ho. 1. Department of Pharmacy, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260.
Abstract
BACKGROUND: All-trans-retinoic acid (ATRA, vitamin A acid or tretinoin) is effective in the treatment of acute promyelocytic leukaemia (APL). Unfortunately, the oral absorption of ATRA is highly variable. Its poor aqueous solubility also makes it difficult to be formulated into parenteral formulation. To date, there is no parenteral formulation of ATRA available commercially. OBJECTIVE: To undertake the preformulation work necessary for developing such a product. METHOD: We investigated the solubility and stability profile of ATRA in various formulations. RESULTS: The aqueous solubility of ATRA could be greatly increased by the inclusion of ATRA in 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD). Adjusting the pH value further improved the water solubility of ATRA. The photostability of HP-beta-CD-based formulation of ATRA was evaluated and it was found that inclusion ATRA into HP-beta-CD did improve the photostability of ATRA. CONCLUSION: These results showed that it is possible to develop a parenteral formulation and/or an aqueous oral formulation of all-trans-retinoic acid by using 2-hydroxypropyl-beta-cyclodextrin. However, the biopharmaceutical properties of such a formulation would be necessary before its use.
BACKGROUND:All-trans-retinoic acid (ATRA, vitamin A acid or tretinoin) is effective in the treatment of acute promyelocytic leukaemia (APL). Unfortunately, the oral absorption of ATRA is highly variable. Its poor aqueous solubility also makes it difficult to be formulated into parenteral formulation. To date, there is no parenteral formulation of ATRA available commercially. OBJECTIVE: To undertake the preformulation work necessary for developing such a product. METHOD: We investigated the solubility and stability profile of ATRA in various formulations. RESULTS: The aqueous solubility of ATRA could be greatly increased by the inclusion of ATRA in 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD). Adjusting the pH value further improved the water solubility of ATRA. The photostability of HP-beta-CD-based formulation of ATRA was evaluated and it was found that inclusion ATRA into HP-beta-CD did improve the photostability of ATRA. CONCLUSION: These results showed that it is possible to develop a parenteral formulation and/or an aqueous oral formulation of all-trans-retinoic acid by using 2-hydroxypropyl-beta-cyclodextrin. However, the biopharmaceutical properties of such a formulation would be necessary before its use.