US-20260124144-A1 - COMPOSITIONS COMPRISING DISODIUM LEVOFOLINATE

US20260124144A1US 20260124144 A1US20260124144 A1US 20260124144A1US-20260124144-A1

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.

Inventors

Ramsharan Singh
Bahman Shimiaei

Assignees

Acrotech Biopharma Inc.

Dates

Publication Date: 20260507
Application Date: 20251229

Claims (11)

1 - 9 . (canceled)
10 . A method for treating folic acid deficiency in a subject in need thereof, comprising administering a lyophilized composition suitable for injection; wherein the lyophilized composition was prepared by a process comprising: 1) mixing mannitol and levofolinic acid in sparged water under an inert atmosphere, wherein the ratio of mannitol to levofolinic acid is 3:5 w/w; 2) adding aqueous sodium hydroxide to the levofolinic acid and mannitol mixture; 3) filtering the solution; and 4) lyophilizing the filtered solution of step (3) to obtain lyophilized composition; and wherein the temperature of the mixture is maintained less than about 18° C. during steps 1) through 3); and the 10-formyldihydrofolic acid is not more than about 0.5% of the mole fraction of the lyophilized composition.
11 . (canceled)
12 . The method of claim 10 , wherein the lyophilized composition is dissolved in a diluent.
13 . The method of claim 12 , wherein the diluent is 0.9% saline or 5% dextrose.
14 . The method of claim 10 , wherein said injection is intramuscular, intravenous, subcutaneous, or a combination thereof.
15 . The method of claim 14 , wherein said injection is intramuscular.
16 . The method of claim 14 , wherein said injection is intravenous.
17 . The method of claim 14 , wherein said injection is subcutaneous.
18 . The method of claim 10 , wherein the 10-formyldihydrofolic acid is not more than about 0.4% mole fraction of the lyophilized composition.
19 . The method of claim 10 , wherein the lyophilized composition comprises 10-formyldihydrofolic acid in an amount of about 0.03% to about 0.5% mole fraction by weight of the lyophilized composition.

Description

RELATED APPLICATIONS This application is a division of U.S. application Ser. No. 18/072,085, filed on Nov. 30, 2022, which is a continuation of U.S. application Ser. No. 16/257,684, filed Jan. 25, 2019, and issued as U.S. Pat. No. 11,541,012 on Dec. 14, 2022, which claims priority to U.S. Provisional Patent Application No. 62/622,720, filed Jan. 26, 2018, the entire content of which are incorporated herein by reference. SUMMARY Described herein are compositions comprising disodium levofolinate (i.e., disodium levoleucovorin) and one or more of an additional component(s), which may be considered as an impurity(ies). In some embodiments, the additional components can be one or more of 4-aminobenzoylglutamic acid, folic acid, 10-formylfolic acid, formyltetrahydropteroic acid, diformyltetrahydrofolic acid, 10-formyldihydrofolic acid, 7,8-dihydrofolic acid, methylenetetrahydrofolic acid, tetrahydropteridine-5-oxide, carboxy-leucguan, hydroxyleucovorin or 7,8-dihydroxanthopterin. In some embodiments, the additional components can be not more than three of the enumerated components. In some embodiments, pharmaceutical compositions described herein may comprise a disodium levofolinate and one or two additional components. One of the additional components can be 10-formyldihydrofolic acid. One of the additional components can be 4-aminobenzoylglutamic acid. In some embodiments, the compositions are pharmaceutical compositions. In some embodiments, the compositions are lyophilized compositions. In some embodiments, the compositions are aqueous compositions. Also described herein are processes to prepare a lyophilized composition including disodium levofolinate. In some embodiments, the process can be accomplished at a temperature of less than about 18° C. In some embodiments, the compositions described herein can be used in the preparation of a medicament for the treatment of cancer, methotrexate toxicity rescue, or folic acid deficiency. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates a DSC thermogram of disodium levofolinate showing a glass transition occurring at −17.88° C. FIG. 2 illustrates a DSC thermogram of disodium levofolinate and 10 mg/mL mannitol showing a glass transition occurring at −24.10° C. DETAILED DESCRIPTION Definitions Listed below are definitions of various terms used to describe the compositions and methods provided herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which the compositions and methods provided herein pertain. Generally, the nomenclature used herein and the laboratory procedures in pharmaceutical sciences, organic chemistry, and analytical chemistry are those well-known and commonly employed in the art. As used herein, the articles “a” and “an” refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. As used herein, the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the specified value, as such variations are appropriate to perform the disclosed compositions and methods. As used herein, the terms “effective amount,” “pharmaceutically effective amount” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction, alleviation, or both, of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. As used herein, the term “patient,” “individual” or “subject” refers to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. Preferably, the patient, subject or individual is human. As used herein, the term “treatment” or “treating,” is defined as the application or administration of a therapeutic agent, i.e., a compound or composition thereof provided herein, to a subject in need thereof, or application or administration of a therapeutic agent to an isolated tissue or cell line from the subject (e.g., for