Pharmaceutical compositions comprising L-leucovorin
Inventors
Gupta, Pramod Kumar • Shimiaei, Bahman • Xie, Shaofeng
Assignees
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Publication Number
US-9713616-B2
Publication Date
2017-07-25
Expiration Date
Abstract
Compositions comprising a calcium salt of L-leucovorin may be prepared that have a higher concentration of L-leucovorin than may be prepared using racemic leucovorin under similar conditions. Thus, some pharmaceutical compositions described herein may comprise a calcium salt of L-leucovorin at a relatively high concentration, such as at least about 15 mg/mL. Such a composition may be a stable aqueous solution, and may have near physiological pH, such as about 6 to about 8. Some pharmaceutical compositions may be substantially free of D-leucovorin, and may contain either: a) no EDTA, or b) less than about 1 mg/ml of EDTA. These compositions may be prepared, for example, by sonicating a mixture comprising the solid calcium salt of L-leucovorin and water. In some compositions, a calcium salt of L-leucovorin may be sufficiently soluble that it does not precipitate when it is injected.
Core Innovation
The invention relates to pharmaceutical compositions comprising a calcium salt of L-leucovorin formulated as a stable aqueous solution. The composition is characterized by an L-leucovorin concentration greater than about 20 mg/mL and an aqueous solution pH of about 6 to about 8.
The composition is substantially free of D-leucovorin and contains either no EDTA or less than about 1 mg/mL EDTA. The formulation is defined to avoid calcium complexation while maintaining the stability of the aqueous solution.
The aqueous solution remains free of precipitates for at least about 20 hours. The disclosed formulations enable higher L-leucovorin concentrations in substantially free of D-leucovorin stable near-physiological aqueous solutions.
Claims Coverage
The independent claim is clm-00001. The claim covers a calcium-salt L-leucovorin pharmaceutical composition that is stable, high-concentration, substantially free of D-leucovorin, and free of precipitates for a specified duration, with specific constraints on EDTA content and pH.
High-concentration calcium salt of L-leucovorin stable aqueous solution
A pharmaceutical composition comprising a calcium salt of L-leucovorin at a concentration greater than about 20 mg/mL, wherein the composition is a stable aqueous solution having a pH of about 6 to about 8.
Substantially D-leucovorin-free composition with controlled EDTA
The composition is substantially free of D-leucovorin and contains either no EDTA or less than about 1 mg/mL of EDTA.
Precipitate-free aqueous stability for at least 20 hours
The aqueous solution remains free of precipitates for at least about 20 hours.
Across the independent claim, the core inventive coverage is directed to a stable aqueous formulation of a calcium salt of L-leucovorin at > about 20 mg/mL, at pH about 6–8, substantially free of D-leucovorin, with either no EDTA or < about 1 mg/mL EDTA, and remaining free of precipitates for at least about 20 hours.
Stated Advantages
Provides stable aqueous solutions at high L-leucovorin concentrations (greater than about 20 mg/mL) while remaining free of precipitates for at least about 20 hours.
Maintains substantially free of D-leucovorin composition in a pH of about 6 to about 8 aqueous solution.
Avoids calcium complexation by using either no EDTA or less than about 1 mg/mL of EDTA.
Documented Applications
The partial content associates the compositions with clinical use contexts including intravenous injection and use with high-dose methotrexate rescue and 5-fluorouracil combination therapy.
The partial content also associates the use contexts with folic acid deficiency treatment and mentions osteosarcoma and metastatic colorectal cancer.
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