Injectable nitrogen mustard compositions comprising a cyclodextrin derivative and methods of making and using the same
Inventors
Pipkin, James D. • Machatha, Stephen G.
Assignees
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Publication Number
US-11020363-B2
Publication Date
2021-06-01
Expiration Date
Abstract
The present disclosure is directed to pharmaceutical compositions comprising a nitrogen mustard and a cyclodextrin derivative, and methods of making and using the same.
Core Innovation
The invention provides injectable aqueous pharmaceutical formulations containing melphalan and a sulfobutyl ether β-cyclodextrin derivative in an aqueous solution at a defined pH of 5. The formulations include sodium chloride and melphalan at specified concentrations, and the sulfobutyl ether β-cyclodextrin and melphalan are present in a weight ratio of at least 54:1. The formulations are described as stable at room temperature compared to a reference melphalan standard.
The formulations are further characterized by stability for at least one hour and, in certain embodiments, at least 4 hours, with quantitative degradation limits provided for melphalan after defined room temperature holding periods. The described embodiments include melphalan hydrochloride and aqueous solutions with melphalan concentrations of 5 mg/mL or 0.45 mg/mL. The disclosed compositions are presented as solid or sterile pharmaceutical compositions and as injectable aqueous pharmaceutical formulations.
Upon dilution using sodium chloride solution and administration to a subject, the formulations are stated to increase melphalan systemic exposure. Specifically, the cyclodextrin-containing formulation provides a melphalan AUC0-t at least 20% greater than a melphalan formulation containing an equivalent dose of melphalan and lacking the sulfobutyl ether β-cyclodextrin.
Claims Coverage
The independent claims include three inventive formulation claims. Across these claims, the key inventive features are the injectable aqueous pH 5 composition with sulfobutyl ether β-cyclodextrin and melphalan at specified concentrations or weight ratios, room-temperature stability versus a reference melphalan standard, and a stated melphalan AUC0-t increase of at least 20% after dilution and administration.
Injectable aqueous formulation at pH 5 with sulfobutyl ether β-cyclodextrin and melphalan
An injectable aqueous pharmaceutical formulation at a pH of 5 consisting of sodium chloride, a sulfobutyl ether-β-cyclodextrin, and melphalan; or an injectable aqueous pharmaceutical formulation comprising an aqueous solution with a pH of 5, consisting of sulfobutyl ether-β-cyclodextrin and melphalan with a weight ratio of at least 54:1 and a melphalan concentration of 0.45 mg/mL; or an injectable aqueous pharmaceutical formulation comprising an aqueous solution at a pH of 5, consisting of sodium chloride, a sulfobutyl ether-β-cyclodextrin, and 5 mg/mL melphalan.
Sulfobutyl ether β-cyclodextrin to melphalan weight ratio of at least 54:1
The sulfobutyl ether-β-cyclodextrin and melphalan are present in a weight ratio of at least 54:1 in the claimed formulations where that ratio is explicitly required.
Room-temperature stability versus a reference melphalan standard
The injectable aqueous pharmaceutical formulation is stable at room temperature for at least one hour, as compared to a reference melphalan standard, and in certain embodiments stable at room temperature for at least 4 hours, as compared to a reference melphalan standard.
Increased melphalan exposure measured by AUC0-t after dilution and administration
When the injectable aqueous pharmaceutical formulation is diluted using sodium chloride solution to prepare a composition having 0.45 mg/mL melphalan concentration and administered to a subject, the subject provides a melphalan AUC0-t that is at least 20% greater than a melphalan formulation containing an equivalent dose of melphalan and lacking the sulfobutyl ether-β-cyclodextrin.
Taken together, the independent claims cover injectable aqueous pH 5 formulations combining sodium chloride, sulfobutyl ether β-cyclodextrin, and melphalan at specified concentration and weight-ratio requirements, defined room-temperature stability relative to a reference melphalan standard, and a stated increase in melphalan systemic exposure measured as melphalan AUC0-t at least 20% greater than an equivalent-dose melphalan formulation lacking sulfobutyl ether β-cyclodextrin after dilution and administration.
Stated Advantages
Increased melphalan exposure, where administering the diluted cyclodextrin-containing formulation provides a melphalan AUC0-t at least 20% greater than an equivalent-dose melphalan formulation lacking sulfobutyl ether β-cyclodextrin.
Room-temperature stability of the injectable aqueous formulation at least one hour, and in certain embodiments at least 4 hours, compared to a reference melphalan standard.
Quantitative control of melphalan degradation after room-temperature holds, including less than 2% by weight degradation after 5 hours and less than 4% by weight degradation after 10 hours.
Documented Applications
Treatment of neoplastic disorders, including multiple myeloma, using the described melphalan cyclodextrin-containing formulations.
Conditioning for stem cell transplantation using the described melphalan cyclodextrin-containing formulations.
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