Solid forms and combination compositions comprising a beta-lactamase inhibitor and uses thereof
Inventors
Burns, Christopher J. • Pevear, Daniel C. • XERRI, Luigi • Henkel, Timothy • McGarry, Daniel • Rosen, Lawrence • Brenner, Gerald • Arlin, Jean-Baptiste • Fernandez Casares, Ana
Assignees
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Publication Number
US-12187752-B2
Publication Date
2025-01-07
Expiration Date
Abstract
Described herein are crystalline forms of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid. In some embodiments, the crystalline forms are formulated for treating a subject in need thereof with a bacterial infection.
Core Innovation
The document describes crystalline solid forms and equilibria for (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl) acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Compound 1), including a closed cyclic and open acyclic equilibrium. It further describes salt and solvate states of Compound 1, including the dihydrochloride monohydrate Form 1 and anhydrous form Form 2, and identifies additional Forms 3 to 6. Solid-form identification is supported by XRPD peak sets, thermogravimetric analysis (TGMS), differential scanning calorimetry (DSC), and interconversion characterization.
The solid-form interconversion is described as being driven by relative humidity, using DVS and variable-humidity XRPD (VH-XRPD). The document reports dehydration/hydration hysteresis, physical stability under multiple relative humidity and temperature conditions, and that many transient forms convert to Form 1 under stress. The solid-state characterization is used to define and manage the presence of specific forms within the pharmaceutical composition context.
The document further provides combination pharmaceutical compositions for treating bacterial infections that include Compound 1 in a crystalline form or salt/solvate together with cefepime and L-arginine. Injectable pharmaceutical composition formats are described, including a homogeneous liquid suitable for injection and a powder for reconstitution, and can include other formulation components such as meglumine and aqueous carriers.
Claims Coverage
The claims coverage centers on a pharmaceutical composition containing Compound 1, cefepime, and L-arginine, with dependent claims refining the compound form and formulation characteristics.
Pharmaceutical composition with Compound 1, cefepime, and L-arginine
A pharmaceutical composition comprising (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl) acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid or a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof; cefepime; and L-arginine.
Dihydrochloride salt form of the compound
The pharmaceutical composition further comprises the compound in the form of the dihydrochloride salt.
Homogeneous injectable liquid formulation
The pharmaceutical composition is characterized as a homogeneous liquid suitable for injection.
pH between about 4 and about 9
The pharmaceutical composition is characterized by having a pH between about 4 and about 9.
Specific aqueous carrier selection
The aqueous carrier is selected from specified water-based injection formulations, including 0.9% sodium chloride injection, 5% dextrose injection, 10% dextrose injection, sodium lactate injection, and combinations including lactated Ringers and other enumerated electrolyte/dextrose mixtures.
The claims cover the specified Compound 1 or pharmaceutically acceptable salt/solvate combined with cefepime and L-arginine, with dependent claims further constraining the dihydrochloride salt form and injectable formulation characteristics.
Stated Advantages
Physical stability under multiple relative humidity and temperature conditions.
Dehydration/hydration hysteresis and reversible moisture-driven interconversion between Form 1 and Form 2.
Combination efficacy is supported by MIC tables against multiple organisms.
Pharmacokinetic interaction findings are reported for Compound 1 with cefepime.
Documented Applications
Treatment of bacterial infections.
Administration by intravenous (IV) infusion.
Phase 1 clinical/PK and drug-drug interaction study of Compound 1 with cefepime.
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