Stable formulations comprising thiotepa
Inventors
Cunningham, Sharon • RYAN, Orlaith • Platteeuw, Johannes Jan
Assignees
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Publication Number
US-11975013-B2
Publication Date
2024-05-07
Expiration Date
Abstract
The present disclosure provides pharmaceutical compositions comprising thiotepa and one selected from PEG, such as PEG400 or PEG600, and DMSO, and optionally water or an aqueous saline solution and thiosulfate. The composition is free or substantially free of impurities. Also provided is a method for treating cancer in a subject, or myeloablation prior to bone marrow transplantation using the composition. A method for enhancing the stability of a thiotepa formulation is also contemplated.
Core Innovation
The invention relates to stable thiotepa pharmaceutical formulations comprising thiotepa and a selected solvent selected from dimethylsulfoxide (DMSO), polyethylene glycol 400 (PEG400), polyethylene glycol 600 (PEG600), dimethylacetamide (DMA), and N-methylpyrrolidone (NMP). The formulations contain thiotepa in an amount between about 1 and about 100 mg/mL and are substantially free of specified impurities, including formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxide, with defined ppm limits for each impurity component.
The disclosure further addresses formulation stability by providing compositions and stability approaches that maintain low impurity levels, including aqueous or waterless formulations in which selected solvents are used with optionally water or aqueous saline and thiosulfate. Stability is assessed using HPLC, including assay, RSD, and total/chloroethyl impurities, under refrigeration and at 25°C/60% RH, and impurity-profile comparisons of commercially sourced PEG400 batches affect stability.
In addition to the formulation concept, the document includes use in treating cancer and myeloablation prior to bone marrow transplantation. A method concept for enhancing thiotepa formulation stability is also described in the partial content, together with representative formulation tables and stability data showing stable thiotepa pharmaceutical formulations in the presence of tightly controlled impurity limits.
Claims Coverage
The partial claim set includes one independent claim directed to a thiotepa/solvent composition with substantially impurity-free specifications, with multiple dependent claims refining formulation components and quantitative constraints. The independent claim contains the core inventive constraints: selected solvent identity, thiotepa concentration range, and specific impurity species with ppm limits.
Substantially impurity-free thiotepa solvent composition
A composition comprising thiotepa and a solvent selected from dimethylsulfoxide (DMSO), polyethylene glycol 400 (PEG400), polyethylene glycol 600 (PEG600), dimethylacetamide (DMA), and N-methylpyrrolidone (NMP), wherein thiotepa is present between about 1 and about 100 mg/mL, the composition is substantially free of impurities, and the impurities are formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxide with less than about 150 ppm formic acid; less than about 15 ppm acetic acid; less than about 15 ppm formaldehyde; less than about 15 ppm acetaldehyde; and less than about 35 ppm peroxide.
Selected solvent refinement with DMSO
The composition further includes thiotepa and DMSO.
Water content upper limit
The composition includes water in an amount selected from specified upper limits of up to about 30%, 25%, 20%, 15%, 10%, or 5%.
Optional thiosulfate inclusion with concentration range
The composition further includes thiosulfate present at about 0.01% to about 1.0%.
The independent claim scope is defined by thiotepa at about 1 to about 100 mg/mL in a solvent selected from DMSO, PEG400, PEG600, DMA, or NMP, together with substantially impurity-free requirements specifying formic acid, acetic acid, formaldehyde, acetaldehyde, and peroxide impurity species and defined ppm thresholds. Dependent refinements add constraints on specific components such as water content and thiosulfate concentration, and identify DMSO as a solvent variant.
Stated Advantages
Stable thiotepa pharmaceutical formulations with tightly controlled impurity limits.
Maintains low impurity levels.
Documented Applications
Treating cancer.
Myeloablation prior to bone marrow transplantation.
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