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Publication Number
US-12539276-B1
Publication Date
2026-02-03
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 provides a method for reducing toxic effects of methotrexate overdosage in a subject in need thereof by administering a pharmaceutical composition comprising a lyophilized composition suitable for injection. The lyophilized composition is prepared by mixing mannitol and levofolinic acid in sparged water under an inert atmosphere, adding aqueous sodium hydroxide to the mixture, filtering the solution, and lyophilizing the filtered solution to obtain the lyophilized composition.
During the mixing, addition, and filtering steps, the temperature of the mixture is maintained less than about 18° C, with a refined range of about 15° C to about 17° C during steps 1) through 3). The lyophilized composition includes 10-formyldihydrofolic acid in an amount from about 0.03% to about 0.5% mole fraction of the lyophilized composition.
Dependent aspects include dissolving the lyophilized composition in 0.9% saline or 5% dextrose and providing injection suitability for intramuscular, intravenous, or subcutaneous administration, including combinations.
Claims Coverage
Independent claim clm-00001 covers a method for reducing toxic effects of methotrexate overdosage using a specified lyophilized injectable composition prepared under defined mixing and processing conditions. The claim set further includes dependent features for selected diluents, injection routes, and a narrower preparation temperature range.
Lyophilized injectable composition for methotrexate overdosage rescue
A method for reducing toxic effects of methotrexate overdosage in a subject in need thereof, comprising administering a pharmaceutical composition comprising a lyophilized composition that is suitable for injection.
Inert-atmosphere lyophilization process with defined additives and temperature
The lyophilized composition is prepared by mixing mannitol and levofolinic acid in sparged water under an inert atmosphere, adding aqueous sodium hydroxide to the mixture, filtering the solution, and lyophilizing the filtered solution, while maintaining the temperature of the mixture less than about 18° C during steps 1) through 3).
Controlled 10-formyldihydrofolic acid mole fraction in lyophilized product
The lyophilized composition comprises 10-formyldihydrofolic acid in an amount from about 0.03% to about 0.5% mole fraction of the lyophilized composition.
Optional dissolution in selected diluents prior to injection
The method includes dissolving the lyophilized composition in a diluent selected from 0.9% saline or 5% dextrose.
Injection route selection for administration
The injection is intramuscular, intravenous, subcutaneous, or a combination thereof.
Narrower preparation temperature window for intermediate steps
The temperature of the mixture is maintained about 15° C to about 17° C during steps 1) through 3).
The claims center on administering a lyophilized, injection-suitable pharmaceutical composition for reducing methotrexate overdosage toxicity, with a defined inert-atmosphere process, aqueous sodium hydroxide, filtering, and lyophilization under a constrained temperature regime. The lyophilized product contains 10-formyldihydrofolic acid within a specified mole-fraction range, and dependent features further limit the dissolution diluents, injection routes, and intermediate preparation temperature range.
Stated Advantages
Reduces toxic effects of methotrexate overdosage in a subject in need thereof.
Documented Applications
Reducing toxic effects of methotrexate overdosage in a subject in need thereof.
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