title: New injectable melphalan formulations utilizing (SBE)(7m)-beta-CD or HP-beta-CD.
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.
authors.affiliation: Higuchi Biosciences Center for Drug Delivery Research, Lawrence, KS, USA.
authors.forename: D Q
authors.initials: DQ
authors.lastname: Ma
authors.forename: R A
authors.initials: RA
authors.lastname: Rajewski
authors.forename: V J
authors.initials: VJ
authors.lastname: Stella
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D002712:Chlorides / Q000737:chemistry; D003505:Cyclodextrins / Q000737:chemistry*; D004339:Drug Compounding / Q000379:methods; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D005612:Freeze Drying; D007275:Injections, Intravenous; D007700:Kinetics; D008558:Melphalan / Q000008:administration & dosage / Q000737:chemistry*; D012997:Solvents; D013997:Time Factors; D047392:beta-Cyclodextrins
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002712:Chlorides; D003505:Cyclodextrins; D005079:Excipients; C103513:SBE7-beta-cyclodextrin; D012997:Solvents; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D008558:Melphalan