Rifabutin treatment methods, uses, and compositions
Inventors
Dale, Glenn E. • Lociuro, Sergio • Gitzinger, Marc • Biondi, Stefano • BOUROTTE, Marilyne
Assignees
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Publication Number
US-12403133-B2
Publication Date
2025-09-02
Expiration Date
Abstract
The invention provides formulations containing highly concentrated solutions of rifabutin and methods of making such formulations. The invention also provides methods of using such formulations to treat a bacterial infection in a subject.
Core Innovation
The invention concerns producing a rifabutin formulation from a rifabutin powder in the presence of an acid, water, and a solvent, achieving a rifabutin concentration greater than or equal to about 250 mg/mL. The formulation is described as highly concentrated and made as a non-oral rifabutin formulation.
The disclosed formulation specifies multiple acid and solvent options, including hydrochloric acid, methanesulfonic acid, phosphoric acid, L-tartaric acid, D-glucuronic acid, L-malic acid, D-gluconic acid, L-lactic acid, and acetic acid, and solvent options include dimethyl isosorbide (DMI), transcutol HP, and Tween 80, among other listed solvents.
The highly concentrated formulation can be suitable for dilution ad libitum with saline or water for intravenous or inhalation use. The formulation approach is described with a focus on rapid dissolution and maintaining solubility and clarity after storage and dilution.
Experimental results are described, including solubility screening, reconstitution/dilution stability, and additional stability/impurity results for a terminally sterilized, large-scale vial process. The document links the formulation approach to achieving high pharmacokinetic exposures (AUC, Cmax) and prevention of resistance.
Claims Coverage
The independent claim covers producing a rifabutin formulation from rifabutin powder in the presence of an acid, water, and a solvent, where the rifabutin concentration is at least about 250 mg/mL. The claim set includes multiple inventive features further constrained by solvent selection, acid selection, and quantitative component ratios, along with at least one preparation sequence limitation and route-related suitability through dilution.
Rifabutin concentration of at least about 250 mg/mL
A rifabutin formulation produced from a rifabutin powder in the presence of an acid, water, and a solvent, with a rifabutin concentration greater than or equal to about 250 mg/mL.
Molar ratio of rifabutin to acid
The formulation has a molar ratio of rifabutin to acid between about 3:1 and about 1:3.
Rifabutin-to-solvent ratio (w/v)
The formulation has a ratio of rifabutin to solvent within about 4:1 to about 1:4 (w/v).
Solvent selected from a defined group
The formulation includes a solvent selected from PEG, propylene glycol, NMP, ethanol, DMA, transcutol HP, or dimethyl isosorbide (DMI).
Acid selected from a defined group
The formulation includes an acid chosen from hydrochloric, methanesulfonic, phosphoric, L-tartaric, D-glucuronic, L-malic, D-gluconic, L-lactic, and acetic acids.
Preparation by adding an acid/water/solvent solution to rifabutin powder
Preparing the formulation by making a solvent/water/acid solution and adding it to rifabutin powder to produce the formulation of claim 1.
Overall claim coverage centers on a highly concentrated rifabutin formulation prepared from rifabutin powder with acid, water, and a solvent, with the concentration threshold of at least about 250 mg/mL. Dependent features narrow the formulation through specified acid and solvent selections, quantitative rifabutin-to-acid and rifabutin-to-solvent ratios, and at least one defined preparation sequence involving addition of a solvent/water/acid solution to rifabutin powder.
Stated Advantages
Improved rapid dissolution.
Maintained solubility and clarity after storage and dilution.
Achieves high pharmacokinetic exposures (AUC, Cmax).
Prevention of resistance.
Documented Applications
Non-oral administration of bacterial infections via intravenous or inhalation routes, with the document explicitly referencing bacterial infections including bacteremia and meningitis and other named infection contexts such as periprosthetic joint infections (PJI).
Dilution of the concentrated formulation ad libitum with saline or water for intravenous or inhalation use.
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