Tebipenem pivoxil crystalline forms, compositions including the same, methods of manufacture, and methods of use
Inventors
Jain, Akash • Hecker, Evan • Edwards, Richard • Bonnaud, Thierry
Assignees
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Publication Number
US-10889587-B2
Publication Date
2021-01-12
Expiration Date
Abstract
The disclosure is directed to new crystalline tebipenem pivoxil salt forms, including a crystalline tebipenem pivoxil ethane sulfonate salt form (Form A), a crystalline tebipenem pivoxil ketoglutarate salt form (Form A), tebipenem pivoxil maleate salt forms (Form A and Form B), a tebipenem pivoxil malate salt form (Form A), a tebipenem pivoxil methane sulfonate salt form (Form B), a tebipenem pivoxil hydrobromide salt form (Form B), and a tebipenem pivoxil edisylate salt form (Form A). The disclosure also includes a composition, comprising a crystalline tebipenem pivoxil salt and a pharmaceutically acceptable carrier and further includes a method for treating an antibiotic resistant bacterial infection, comprising administering to a patient in need of such treatment a therapeutically effective amount of a crystalline tebipenem pivoxil salt.
Core Innovation
The invention relates to crystalline solid salt forms of tebipenem pivoxil. The disclosed salt forms include ethane sulfonate (ESA) Form A, ketoglutarate (KTG) Form A, maleate Form A and Form B, malate Form A, methane sulfonate (MSA) Form B, hydrobromide (HBr) Form B plus additional HBr forms C and D, and edisylate Form A.
The disclosed crystalline salt forms are characterized using XPRD/XRPD from a Cu Kb1 source, with identification based on characteristic 2b8 peak values. The disclosure also reports DSC/TGA characterization, including characteristic thermal behavior and purity information reported as levels.
The disclosure further reports stability and deliquescence behavior and polymorphic conversion under storage, including an example of maleate Form A to Form B and deliquescence of certain forms. Crystalline salt forms and characterization results are presented in the context of pharmaceutical use for treating antibiotic-resistant bacterial infections, including Gram-negative infections.
Claims Coverage
The independent claims are directed to a crystalline tebipenem pivoxil hydrobromide salt form defined by an XPRD signature using a Cu Kb1 source, and a crystalline tebipenem pivoxil hydrobromide salt form defined by an XPRD diffractogram containing specified 2b8 peak values, with additional inventive characterization features and composition/dosage form embodiments in dependent claims.
XPRD-defined crystalline hydrobromide salt form using Cu Kb1 characteristic values
A crystalline tebipenem pivoxil hydrobromide salt form wherein the XPRD of the form, obtained from a Cu Kb1 source, has the characteristic 2b8 values of FIG. 14.
XPRD diffractogram with specified Cu Kb1 peak positions for the crystalline hydrobromide salt form
A crystalline tebipenem pivoxil hydrobromide salt form characterized by an XPRD diffractogram obtained from a Cu Kb1 source which comprises peaks at 2b8 values of 9.3, 13.0, 17.6, 20.8, and 26.8b10.2 degrees, or 2b8 values of 10.7, 14.0, 18.7, 20.0, and 23.5b10.2 degrees.
Across the independent claims, the inventive scope is defined by XPRD/XRPD signatures for crystalline tebipenem pivoxil hydrobromide salt forms using a Cu Kb1 source and specified characteristic 2b8 peak values. Dependent claims further include additional characterization, pharmaceutical composition thresholds, and therapeutic use including treatment of bacterial infections and combination therapy with a second active agent.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating antibiotic-resistant bacterial infections, including Gram-negative infections.
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