Eflornithine and sulindac, fixed dose combination formulation
Inventors
Shannon, Patrick • Bravo González, Roberto Carlos • Ducassou, Jean
Assignees
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Publication Number
US-11925613-B2
Publication Date
2024-03-12
Expiration Date
Abstract
Provided herein are fixed-dose combination formulations of a pharmaceutically effective amount of eflornithine together with a pharmaceutically effective amount of sulindac. Also provided are methods of use and of methods of manufacture of these formulations.
Core Innovation
The invention relates to fixed-dose combination (FDC) formulations and single dosage unit tablets combining eflornithine, including eflornithine hydrochloride monohydrate and eflornithine hydrochloride monohydrate racemate, with sulindac for prevention and/or treatment of cancers, especially colon cancer and familial adenomatous polyposis (FAP). The document describes unit tablets that include an FDC amount of eflornithine hydrochloride monohydrate together with sulindac.
A core aspect is a producing method for a single dosage unit tablet that forms a first mixture by pre-mixing sulindac with a first excipient, then mixing the first mixture with a second mixture comprising eflornithine hydrochloride monohydrate and a second excipient to obtain a blend. The method further includes screening the blend to form a granulated blend, adding magnesium stearate to obtain a final blend, and applying a compression force to form the tablet, where the magnesium stearate amount is about 1 to about 1.5 weight percent.
The method is refined by incorporating a pre-compression step before main compression to address tablet capping, including applying a compression force relationship in which the pre-compression compression force is about 5% to about 15% of the compression force used to form the tablet. The document also discusses excipient and coating compatibility using XRPD and HPLC, together with dissolution comparison to single-API references.
Claims Coverage
The provided claim content includes one independent claim directed to a producing method for a single dosage unit tablet that includes specific eflornithine hydrochloride monohydrate and sulindac amounts and a defined magnesium stearate percentage, with blend preparation, granulation, and compression. Dependent claims further refine excipients, coating composition, and compression-force relationships via pre-compression constraints.
Single dosage unit tablet composition and magnesium stearate level
A method producing a single dosage unit tablet comprising about 375 mg of eflornithine hydrochloride monohydrate, about 75 mg of sulindac, and about 1 to about 1.5 weight percent magnesium stearate.
Two-mixture formation with screening to granulated blend
Pre-mixing sulindac with a first excipient to form a first mixture; mixing the first mixture with a second mixture comprising eflornithine hydrochloride monohydrate and a second excipient to form a blend; screening the blend to form a granulated blend.
Magnesium stearate addition and compression into the tablet
Adding magnesium stearate to the granulated blend to obtain a final blend and applying a compression force to the final blend to form the tablet.
Pre-compression step using a constrained force relationship
Applying a pre-compression step after adding magnesium stearate and before forming the tablet, where a pre-compressed blend is formed and then the compression force used in forming the tablet is applied to the pre-compressed blend.
Pre-compression force quantified as percentage and absolute range
Using a pre-compression compression force of about 5% to about 15% of the compression force used to form the tablet, with the pre-compression compression force being about 2.5 to about 3.5 kN.
Across the provided claim set, the inventive coverage centers on producing an FDC single dosage unit tablet containing defined eflornithine hydrochloride monohydrate and sulindac amounts with a specified magnesium stearate range, using sequential mixture formation, screening to a granulated blend, and compression to form the tablet, with further dependent refinements including a pre-compression step and quantitative pre-compression force relationships.
Stated Advantages
Provides a producing method that supports tablet performance metrics including disintegration time, friability, and tablet hardness.
Shows improved stability behavior versus a single-API reference tablet, described as lower water uptake over 6 months.
Supports excipient/coating compatibility using XRPD/HPLC and provides dissolution overlap with single-API references.
Provides a co-formulated versus single-agent bioequivalence and discusses tolerability/safety outcomes.
Documented Applications
Prevention and/or treatment of cancers, including colon cancer and familial adenomatous polyposis (FAP).
Patient-selection concepts tied to administration of the FDC, including pharmacogenomic/biomarker-guided treatment using ODC1 promoter genotype at position +316 and its association with adenoma recurrence response.
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