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Publication Number
US-12564556-B1
Publication Date
2026-03-03
Expiration Date
Abstract
Provided herein are compositions comprising disodium levofolinate. Also provided are processes for preparing compositions comprising disodium levofolinate. Also provided are compositions comprising disodium levofolinate prepared by the processes provided herein.Also provided are methods of treating folic acid deficiency in a subject in need thereof, comprising administering a composition provided herein to the subject. Also provided are methods of treating cancer in a subject in need thereof, comprising administering 5-fluorouracil and a composition provided herein to the subject. Also provided are methods of reducing the immediate toxic effects of methotrexate overdose in a subject in need thereof, comprising administering a composition provided herein to the subject. Also provided are methods of treating cancer in a subject in need thereof, comprising administering high-dose methotrexate and a composition provided herein to the subject. Also provided are methods of treating megaloblastic anemia in a subject in need thereof, comprising administering a composition provided herein to the subject.
Core Innovation
The disclosure relates to pharmaceutical compositions comprising disodium levofolinate (disodium levoleucovorin; levofolinic acid) and controlled levels of one or more specified folate-related components that are impurities. The compositions are described as lyophilized formulations prepared in a way that maintains limited mole fractions of the specified impurities, including specific combinations such as disodium levofolinate with 10-formyldihydrofolic acid and/or 4-aminobenzoylglutamic acid.
A related aspect is a method of preparing lyophilized disodium levofolinate formulations, including mixing mannitol and levofolinic acid in sparged water under an inert atmosphere, adding aqueous sodium hydroxide, filtering, and lyophilizing to prepare the lyophilized composition. The lyophilized composition further comprises 10-formyldihydrofolic acid at a mole fraction from about 0.03% to about 0.5% of the lyophilized composition.
The document also provides treatment use for the resulting lyophilized levofolinic acid compositions, including administration as part of an admixture with 5-fluorouracil. The stated use includes treating colorectal cancer by administering to a patient a therapeutically effective amount of an admixture comprising 5-fluorouracil and a lyophilized composition of levofolinic acid in 0.9% saline. The disclosure further reports stability and compatibility evaluations, including maintenance of assay and impurity limits over defined conditions and microbiological evaluation results.
Claims Coverage
The provided claims include one independent claim directed to a treatment method for colorectal cancer and dependent refinements that further define stability and compatibility time thresholds for the admixture.
Colorectal cancer treatment with 5-fluorouracil and lyophilized levofolinic acid in 0.9% saline
A method for the treatment of colorectal cancer comprising administering to a patient in need thereof a therapeutically effective amount of an admixture of 5-fluorouracil and a lyophilized composition of levofolinic acid in 0.9% saline.
Inert, sparged water preparation of mannitol and levofolinic acid lyophilized composition
The lyophilized composition is prepared by mixing mannitol and levofolinic acid in sparged water under an inert atmosphere, adding aqueous sodium hydroxide to the levofolinic acid and mannitol mixture, filtering the solution, and lyophilizing the filtered solution.
Controlled 10-formyldihydrofolic acid impurity level in the lyophilized composition
The lyophilized composition further comprises 10-formyldihydrofolic acid in an amount from about 0.03% to about 0.5% mole fraction of the lyophilized composition.
Stability and compatibility of the 5-fluorouracil/levofolinic acid admixture for at least 24 hours
The method further specifies that the admixture is stable and compatible for at least 24 hours.
Stability and compatibility of the 5-fluorouracil/levofolinic acid admixture for at least 48 hours
The method further specifies that the admixture is stable and compatible for at least 48 hours.
Stability and compatibility of the 5-fluorouracil/levofolinic acid admixture for at least 72 hours
The method further specifies that the admixture is stable and compatible for at least 72 hours.
The claimed coverage centers on colorectal cancer treatment using an admixture of 5-fluorouracil and a lyophilized levofolinic acid composition in 0.9% saline, with a controlled mole fraction of 10-formyldihydrofolic acid and additional refinements covering stability and compatibility duration.
Stated Advantages
Maintains limited mole fractions of specified folate-related impurities in the lyophilized disodium levofolinate composition.
Maintains assay/impurity limits over defined storage/hold times for the lyophilized product.
Provides levofolinate plus 5-fluorouracil admixture compatibility that is stable for specified durations in 0.9% saline.
Provides microbiological stability results showing no growth over a tested time for the tested organisms.
Documented Applications
Treatment of colorectal cancer by administering a therapeutically effective amount of an admixture comprising 5-fluorouracil and a lyophilized composition of levofolinic acid in 0.9% saline.
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