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New injectable melphalan formulations utilizing (SBE)(7m)-beta-CD or HP-beta-CD.

D Q Ma·R A Rajewski·V J Stella
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Abstract

The objective of this work was to evaluate the potential of using (SBE)(7m)-beta-CD and HP-beta-CD as enabling excipients to improve on the current melphalan injectable formulation. Melphalan is an anti-neoplastic agent formulated for parenteral use as a sterile, non-pyrogenic, freeze-dried powder. It is marketed by Glaxo-Wellcome as ALKERAN((R)) for Injection (Alkeran). A major concern with melphalan therapy, other than its intrinsic cytotoxicity and biocompatibility, arises from its marginal aqueous solubility and chemical stability; thus, co-solvents are used in the current two-vial formulation. Because of the two-vial system, the product is also inconvenient to use. Two approaches to improve melphalan's formulation utilizing cyclodextrins, including the use of aqueous (SBE)(7m)-beta-CD or HP-beta-CD solutions as the reconstitution diluents, and/or the use of (SBE)(7m)-beta-CD as a freeze-drying excipient in a melphalan formulation, are presented. Results showed that, when the cyclodextrins were used as diluents, the use of organic co-solvents can be eliminated and the shelf-life of the reconstituted melphalan greatly enhanced. When the freeze-dried melphalan/(SBE)(7m)-beta-CD formulation was prepared, the formulation was found to be stable; and a simplified one-vial delivery system was achieved. In conclusion, the parenterally safe beta-cyclodextrins derivatives can provide promising alternatives and improved formulations for melphalan injectable and perhaps similar problematic drugs.

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2-Hydroxypropyl-beta-cyclodextrinAntineoplastic Agents, AlkylatingChemistry, PharmaceuticalChloridesCyclodextrinsDrug CompoundingDrug StabilityExcipientsFreeze DryingInjections, IntravenousKineticsMelphalanSolventsTime Factorsbeta-CyclodextrinsComparative StudyJournal ArticleResearch Support, Non-U.S. Gov't

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D Q Ma, R A Rajewski, V J Stella. 1999-11-05. New injectable melphalan formulations utilizing (SBE)(7m)-beta-CD or HP-beta-CD.. https://doi.org/10.1016/s0378-5173(99)00255-0

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