Solid forms and combination compositions containing beta-lactamase inhibitors and uses thereof

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]oxaborinin-8-carboxylic acid. In some embodiments, the crystalline form is formulated to treat a subject with a bacterial infection. [Selected Figure] Figure 2

Description

[Technical field]

[0001] cross reference This patent application claims the benefit of U.S. Provisional Patent Application No. 62 / 467,750, filed March 6, 2017; U.S. Provisional Patent Application No. 62 / 467,752, filed March 6, 2017; U.S. Provisional Patent Application No. 62 / 564,989, filed September 28, 2017; and U.S. Provisional Patent Application No. 62 / 564,990, filed September 28, 2017; each of which is incorporated by reference herein in its entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with U.S. Government support under Contract No. R43AI096679 from the National Institutes of Health (NIH), Contract No. R44AI096613 from the National Institutes of Health (NIH), and Contract No. HHSN272201300019C from the National Institutes of Health (NIH). The Government has certain rights in this invention.

[0003] FIELD OF THEINVENTION The present invention relates to boron-containing compounds, polymorphs, pharmaceutical compositions containing preparations and their use as inhibitors of β-lactamase enzymes and antibacterial agents in combination with β-lactam antibiotics. [Background technology]

[0004] Antibiotics are the most effective drugs for treating bacterial infections. Most of the antibiotics are used in clinics due to their good antibacterial effect with limited side effects. Among them, the β-lactam class of antibiotics (e.g. penicillins, cephalosporins, monobactams, and carbapenems) is preferred because its effect is bactericidal and its target is absent in eukaryotic cells with fairly low toxicity.

[0005] To counter the effects of various β-lactams, bacteria have evolved to produce variants of β-lactam deactivating enzymes, called β-lactamases, and have the ability to share this tool vertically and horizontally between and within species. These β-lactamases are classified as "serine" or "metallo", based on the presence of a key serine or zinc in the enzyme active site, respectively. The rapid introduction, selection, and dissemination of this mechanism of bacterial resistance could severely limit the entire class of β-lactam treatment options in hospitals and the community. Effective and safe therapeutic agents capable of treating such resistant infections are needed. Summary of the Invention

[0006] Disclosed herein is a pharmaceutical composition, the pharmaceutical composition comprising: (i) (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid:

[0007] [ka] a pharma- ceutically acceptable salt, solvate, or pharma-ceutically acceptable salt and solvate thereof; and (ii) Cefepime Includes.

[0008] In some embodiments of the pharmaceutical composition, the pharmaceutical composition is formulated as a homogenous liquid suitable for injection.

[0009] In some embodiments of the pharmaceutical composition, the pharmaceutical composition further comprises a pharma- ceutically acceptable excipient.

[0010] In some embodiments of the pharmaceutical composition, the pharma- ceutically acceptable excipient is an amino acid or a monosaccharide derivative.

[0011] In some embodiments of the pharmaceutical composition, the pharma- ceutically acceptable excipient is L-arginine.

[0012] In some embodiments of the pharmaceutical composition, the pharma- ceutically acceptable excipient is meglumine.

[0013] In some embodiments of the pharmaceutical composition, the pharmaceutical composition further comprises an aqueous carrier.

[0014] In some embodiments of the pharmaceutical composition, the aqueous carrier is water for injection, 0.9% saline for injection, 5% dextrose for injection, 10% dextrose for injection, sodium lactate for injection, 5% dextrose and 0.9% saline for injection, lactated Ringer's and 5% dextrose for injection, sodium chloride / sodium acetate / sodium gluconate / potassium chloride / magnesium chloride for injection, sodium chloride / potassium acetate / magnesium acetate in 5% dextrose for injection, or any combination thereof.

[0015] In some embodiments of the pharmaceutical composition, the pharmaceutical composition has a pH of about 4 to about 9.

[0016] In some embodiments of the pharmaceutical composition, the pharmaceutical composition has a pH of about 4 to about 6.

[0017] In some embodiments of the pharmaceutical composition, the pharmaceutical composition is formulated as a powder for reconstitution.

[0018] In some embodiments of the pharmaceutical composition, the pharmaceutical composition further comprises a pharma- ceutically acceptable excipient.

[0019] In some embodiments of the pharmaceutical composition, the pharma- ceutically acceptable excipient is an amino acid or a monosaccharide derivative.

[0020] In some embodiments of the pharmaceutical composition, the pharma- ceutically acceptable excipient is L-arginine.

[0021] In some embodiments of the pharmaceutical composition, the pharma- ceutically acceptable excipient is meglumine.

[0022] In some embodiments of the pharmaceutical composition, once reconstituted with an aqueous carrier, the pharmaceutical composition is suitable for injection.

[0023] In some embodiments of the pharmaceutical composition, the aqueous carrier is water for injection, 0.9% saline for injection, 5% dextrose for injection, 10% dextrose for injection, sodium lactate for injection, 5% dextrose and 0.9% saline for injection, lactated Ringer's and 5% dextrose for injection, sodium chloride / sodium acetate / sodium gluconate / potassium chloride / magnesium chloride for injection, sodium chloride / potassium acetate / magnesium acetate in 5% dextrose for injection, or any combination thereof.

[0024] 18. The pharmaceutical composition according to any one of claims 11 to 17, characterized in that the pharmaceutical composition is stable at about 25°C ± 2°C / 60% RH ± 5% RH for at least 12 months.

[0025] In some embodiments of the pharmaceutical composition, (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharma- ceutically acceptable salt, solvate, or a pharma-ceutically acceptable salt and solvate thereof is crystalline.

[0026] In some embodiments of the pharmaceutical composition, the crystalline (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid is in the form of a dihydrochloride or a solvate thereof.

[0027] In some embodiments of the pharmaceutical composition, the crystalline (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid dihydrochloride is in the form of a monohydrate solvate.

[0028] In some embodiments of the pharmaceutical composition, the crystals have an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG.

[0029] In some embodiments of the pharmaceutical composition, the crystals have an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG.

[0030] In some embodiments of the pharmaceutical composition, the crystals have an X-ray powder diffraction (XRPD) pattern including characteristic peaks at about 7.0°±0.1°2θ, about 14.1°±0.1°2θ, about 20.2°±0.1°2θ, about 24.6°±0.1°2θ, and about 27.7°±0.1°2θ.

[0031] In some embodiments of the pharmaceutical composition, the X-ray powder diffraction (XRPD) pattern further comprises characteristic peaks at about 10.5°±0.1°2θ, about 18.9°±0.1°2θ, about 23.7°±0.1°2θ, about 25.6°±0.1°2θ, and about 29.6°±0.1°2θ.

[0032] In some embodiments of the pharmaceutical composition, the pharmaceutical composition comprises about 500 mg of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborimine-8-carboxylic acid, a pharma- ceutically acceptable salt, solvate, or a pharma-ceutically acceptable salt and solvate thereof.

[0033] In some embodiments of the pharmaceutical composition, the pharmaceutical composition comprises about 750 mg of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborimine-8-carboxylic acid, a pharma- ceutically acceptable salt, solvate, or a pharma-ceutically acceptable salt and solvate thereof.

[0034] In some embodiments of the pharmaceutical composition, the pharmaceutical composition comprises about 2 g of cefepime.

[0035] Also disclosed herein is a method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a pharmaceutical composition described herein.

[0036] In some embodiments of the methods of treating a bacterial infection, the pharmaceutical composition is administered by intravenous (IV) infusion.

[0037] In some embodiments of the method of treating a bacterial infection, the period of infusion of the pharmaceutical composition is about 2 hours.

[0038] Also provided herein is (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid:

[0039] [ka] Crystalline forms of the pharma- ceutically acceptable salts, solvates, or pharma- ceutically acceptable salts and solvates thereof are disclosed.

[0040] Also provided herein is (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid:

[0041] [ka] Crystalline forms of the dihydrochloride or its solvates are disclosed.

[0042] In some embodiments of the crystalline form, the crystalline (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid dihydrochloride is in the form of a monohydrate solvate.

[0043] In some embodiments of the crystalline form, the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG.

[0044] In some embodiments of the crystalline form, the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG.

[0045] In some embodiments of the crystalline form, the crystalline form has an X-ray powder diffraction (XRPD) pattern including characteristic peaks at about 7.0°±0.1°2θ, about 14.1°±0.1°2θ, about 20.2°±0.1°2θ, about 24.6°±0.1°2θ, and about 27.7°±0.1°2θ.

[0046] In some embodiments of the crystalline form, the X-ray powder diffraction (XRPD) pattern further comprises characteristic peaks at about 10.5°±0.1°2θ, about 18.9°±0.1°2θ, about 23.7°±0.1°2θ, about 25.6°±0.1°2θ, and about 29.6°±0.1°2θ.

[0047] In some embodiments of the crystalline form, the crystalline (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid dihydrochloride is anhydrous.

[0048] In some embodiments of the crystalline form, the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG.

[0049] In some embodiments of the crystalline form, the crystal has an X-ray powder diffraction (XRPD) pattern including characteristic peaks at about 7.3°±0.1°2θ, about 14.5°±0.1°2θ, about 18.0°±0.1°2θ, about 19.7°±0.1°2θ, about 24.0°±0.1°2θ, and about 27.3°±0.1°2θ.

[0050] In some embodiments of the crystalline form, the X-ray powder diffraction (XRPD) pattern further comprises characteristic peaks at about 10.8°±0.1°2θ, about 16.6°±0.1°2θ, about 19.6°±0.1°2θ, about 23.3°±0.1°2θ, about 24.3°±0.1°2θ, and about 29.3°±0.1°2θ.

[0051] Also disclosed herein is a pharmaceutical composition, the pharmaceutical composition comprising: (i) a crystalline form disclosed herein, a pharma- ceutically acceptable salt, solvate, or a pharma-ceutically acceptable salt and solvate thereof; and (ii) Cefepime Includes.

[0052] In some embodiments of the pharmaceutical composition, the pharmaceutical composition is formulated as a homogenous liquid suitable for injection.

[0053] In some embodiments of the pharmaceutical composition, the pharmaceutical composition further comprises an aqueous carrier.

[0054] In some embodiments of the pharmaceutical composition, the pharmaceutical composition has a pH of about 4 to about 6.

[0055] In some embodiments of the pharmaceutical composition, the pharmaceutical composition is formulated as a powder for reconstitution.

[0056] In some embodiments of the pharmaceutical composition, once reconstituted with an aqueous carrier, the pharmaceutical composition is suitable for injection.

[0057] In some embodiments of the pharmaceutical composition, the pharmaceutical composition further comprises a pharma- ceutically acceptable excipient.

[0058] In some embodiments of the pharmaceutical composition, the pharma- ceutically acceptable excipient is an amino acid or a monosaccharide derivative.

[0059] In some embodiments of the pharmaceutical composition, the pharma- ceutically acceptable excipient is L-arginine.

[0060] In some embodiments of the pharmaceutical composition, the pharma- ceutically acceptable excipient is meglumine. [Brief description of the drawings]

[0061] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings in which: [Figure 1A] 1 shows the solubility values ​​of compound 1-dihydrochloride in IPA / water mixtures at 5, 25, 40, and 50° C. as a function of IPA / water content. [Figure 1B] Figure 2 shows the solubility values ​​of compound 1-dihydrochloride in IPA / water mixtures as a function of temperature. [Diagram 2] FIG. 1 shows an X-ray powder diffraction pattern collected for Form 1 at room temperature. [Diagram 3] 1 shows a simulated X-ray powder diffraction pattern from single crystal data for Form 1 collected at 100K. [Figure 4] 1 shows the TGMS thermogram (at a heating rate of 10° C. / min) of Form 1. [Diagram 5] 1 shows a DSC thermogram (at a heating rate of 10° C. / min) of Form 1. [Figure 6] 1 shows the DVS isotherm of Form 1. [Figure 7]1 shows stacked XRPD diffractograms of compound 1-dihydrochloride with varying RH (relative humidity). [Figure 8] FIG. 1 shows an X-ray powder diffraction pattern collected for Form 2 at room temperature. [Figure 9] 1 shows a DSC thermogram of Form 2. [Figure 10A] Figure 1 shows the recorded rate of mass change as a function of relative humidity level. Solid samples of Form 2 were incubated at 25°C at the indicated relative humidity values ​​while the rate of mass change was continuously recorded. [Figure 10B] The mass change rate recorded as a function of relative humidity level is shown. The conversion rate was calculated and plotted against the relative humidity values ​​(from the linear portion of the curve in FIG. 10A). The regression coefficient of the line is 0.9995. [Figure 11] FIG. 1 shows the water content of compound 1-dihydrochloride after incubation at different temperature and RH conditions. [Figure 12] 1 shows an X-ray powder diffraction pattern collected for Form 3. [Figure 13] 1 shows an X-ray powder diffraction pattern collected for Form 4. [Figure 14] 1 shows an X-ray powder diffraction pattern collected for Form 5. [Figure 15] 1 shows an X-ray powder diffraction pattern collected for Form 6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0062] Disclosed 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, a pharma- ceutically acceptable salt, solvate, or a pharma-ceutically acceptable salt and solvate thereof.

[0063] Also disclosed herein is 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, a pharma- ceutically acceptable salt, solvate, or a crystalline form of the pharma-ceutically acceptable salt and solvate.

[0064] Also disclosed herein is 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, a pharma- ceutically acceptable salt, solvate, or solid form of the pharma-ceutically acceptable salt and solvate thereof.

[0065] As used herein, (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid is as shown in the following structure:

[0066] [ka] In some implementations, (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid is also referred to as Compound 1. In some embodiments, Compound 1 exists in equilibrium between a "closed" ring form (as shown above) and an "open" acyclic form:

[0067] [ka] In some embodiments, compound 1 associates with intramolecular dimers, trimers, and any combination thereof. In some embodiments, compound 1 is in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt. In some embodiments, the pharmaceutically acceptable salt is a dihydrochloride salt. In some embodiments, compound 1 is in the form of a pharmaceutically acceptable solvate. A solvate contains a stoichiometric or non-stoichiometric amount of a solvent, and in some embodiments, is formed during a crystallization process using a pharmaceutically acceptable solvent, such as water or an organic solvent. In some embodiments, the solvent is not covalently bound to compound 1. In some embodiments, the solvent is covalently bound to compound 1. A hydrate is formed when the solvent is water, or an alcoholate is formed when the solvent is alcohol. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein. In some embodiments, the pharmaceutically acceptable solvate is a monohydrate solvate.

[0068] Crystal morphology Disclosed 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, a pharma- ceutically acceptable salt, solvate, or a pharma- ceutically acceptable salt and solvate thereof. In some embodiments, the crystalline form is Form 1. In some embodiments, the crystalline form is Form 2. In some embodiments, the crystalline form is Form 3. In some embodiments, the crystalline form is Form 4. In some embodiments, the crystalline form is Form 5. In some embodiments, the crystalline form is Form 6.

[0069] Form 1 In some embodiments, the dihydrochloride salt of Compound 1 is made into a pure and stable crystalline form (Form 1) under controlled conditions. In some embodiments, Form 1 is a monohydrate form of the dihydrochloride salt of Compound 1. In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 1 is substantially the same as shown in FIG. 2, with corresponding tabulated peak data shown in Table 1. In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 1 is substantially the same as shown in FIG. 3. The X-ray powder diffraction (XRPD) pattern shown in FIG. 2 is substantially the same as the X-ray powder diffraction (XRPD) pattern shown in FIG. 3.

[0070] [Table 1-1]

[0071] [Table 1-2]

[0072] In some embodiments, Form 1 exhibits an X-ray powder diffraction pattern including at least three characteristic peaks selected from peaks at about 7.0°±0.1°2θ, about 10.5°±0.1°2θ, about 14.1°±0.1°2θ, about 18.9°±0.1°2θ, about 20.2°±0.1°2θ, about 23.7°±0.1°2θ, about 24.6°±0.1°2θ, about 25.6°±0.1°2θ, about 27.7°±0.1°2θ, and about 29.6°±0.1°2θ. In some embodiments, Form 1 exhibits an X-ray powder diffraction (XRPD) pattern including characteristic peaks at about 7.0°±0.1°2θ, about 14.1°±0.1°2θ, about 20.2°±0.1°2θ, about 24.6°±0.1°2θ, and about 27.7°±0.1°2θ. In some embodiments, Form 1 exhibits an X-ray powder diffraction (XRPD) pattern including further characteristic peaks at about 10.5°±0.1°2θ, about 18.9°±0.1°2θ, about 23.7°±0.1°2θ, about 25.6°±0.1°2θ, and about 29.6°±0.1°2θ. In some embodiments, Form 1 exhibits an X-ray powder diffraction pattern (XRPD) including characteristic peaks at about 10.5°±0.1°2θ, about 12.7°±0.1°2θ, about 16.1°±0.1°2θ, about 18.9°±0.1°2θ, about 19.3°±0.1°2θ, about 20.2°±0.1°2θ, about 20.6°±0.1°2θ, about 22.9°±0.1°2θ, about 23.7°±0.1°2θ, and about 25.6°±0.1°2θ. In some embodiments, Form 1 exhibits an X-ray powder diffraction pattern (XRPD) including characteristic peaks at about 10.5°±0.1°2θ, about 12.7°±0.1°2θ, about 14.9°±0.1°2θ, about 16.1°±0.1°2θ, about 18.9°±0.1°2θ, about 19.3°±0.1°2θ, about 20.2°±0.1°2θ, about 20.6°±0.1°2θ, about 22.9°±0.1°2θ, about 23.7°±0.1°2θ, about 25.0°±0.1°2θ, about 25.6°±0.1°2θ, about 25.9°±0.1°2θ, and about 26.1°±0.1°2θ.In some embodiments, Form 1 has a refractive index of about 8.6°±0.1°2θ, about 10.5°±0.1°2θ, about 12.7°±0.1°2θ, about 14.9°±0.1°2θ, about 16.1°±0.1°2θ, about 18.9°±0.1°2θ, about 19.3°±0.1°2θ, about 20.2°±0.1°2θ, about 20.6°±0.1°2θ, about 22.1°±0.1°2θ, about 22.6°±0.1°2θ, about 22.9°±0.1°2θ, about 23.7°±0.1°2θ, The compound exhibits an X-ray powder diffraction pattern (XRPD) including characteristic peaks at about 24.6°±0.1°2θ, about 25.0°±0.1°2θ, about 25.6°±0.1°2θ, about 25.9°±0.1°2θ, about 26.1°±0.1°2θ, about 26.5°±0.1°2θ, about 26.7°±0.1°2θ, about 28.1°±0.1°2θ, about 28.6°±0.1°2θ, about 29.6°±0.1°2θ, about 33.0°±0.1°2θ, and about 37.5°±0.1°2θ.

[0073] Form 2 In some embodiments, the dihydrochloride salt of Compound 1 can be made into a pure and stable crystalline form (Form 2) under controlled conditions. In some embodiments, Form 1 is an anhydrous form of the dihydrochloride salt of Compound 1. In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 2 is substantially the same as shown in FIG. 8, with corresponding tabulated peak data shown in Table 2.

[0074] [Table 2-1]

[0075] [Table 2-2]

[0076] In some embodiments, Form 2 exhibits an X-ray powder diffraction pattern including at least three characteristic peaks selected from peaks at about 7.3°±0.1°2θ, about 10.8°±0.1°2θ, about 14.5°±0.1°2θ, about 16.6°±0.1°2θ, about 18.0°±0.1°2θ, about 19.6°±0.1°2θ, about 19.7°±0.1°2θ, about 23.3°±0.1°2θ, about 24.0°±0.1°2θ, about 24.3°±0.1°2θ, about 27.3°±0.1°2θ, and about 29.3°±0.1°2θ. In some embodiments, Form 2 exhibits an X-ray powder diffraction (XRPD) pattern including characteristic peaks at about 7.3°±0.1°2θ, about 14.5°±0.1°2θ, about 18.0°±0.1°2θ, about 19.7°±0.1°2θ, about 24.0°±0.1°2θ, and about 27.3°±0.1°2θ. In some embodiments, Form 2 exhibits an X-ray powder diffraction (XRPD) pattern including further characteristic peaks at about 10.8°±0.1°2θ, about 16.6°±0.1°2θ, about 19.6°±0.1°2θ, about 23.3°±0.1°2θ, about 24.3°±0.1°2θ, and about 29.3°±0.1°2θ. In some embodiments, Form 2 exhibits an X-ray powder diffraction pattern (XRPD) including characteristic peaks at about 7.3°±0.1°2θ, about 10.8°±0.1°2θ, about 12.9°±0.1°2θ, about 15.9°±0.1°2θ, about 16.3°±0.1°2θ, about 16.6°±0.1°2θ, about 19.2°±0.1°2θ, about 19.7°±0.1°2θ, about 20.5°±0.1°2θ, about 21.1°±0.1°2θ, about 24.0°±0.1°2θ, and about 24.3°±0.1°2θ.In some embodiments, Form 2 has a refractive index of about 7.3°±0.1°2θ, about 10.8°±0.1°2θ, about 11.2°±0.1°2θ, about 12.9°±0.1°2θ, about 14.5°±0.1°2θ, about 15.9°±0.1°2θ, about 16.3°±0.1°2θ, about 16.6°±0.1°2θ, about 19.2°±0.1°2θ, about 19.7°±0.1°2θ, about 20.5°±0.1°2θ, about 21.5°±0.1°2θ, about 22.5°±0.1°2θ, about 23.5°±0.1°2θ, about 24.5°±0.1°2θ, about 25.5°±0.1°2θ, about 26.5°±0.1°2θ, about 27.5°±0.1°2θ, about 28.5°±0.1°2θ, about 29. The compound exhibits an X-ray powder diffraction pattern (XRPD) including characteristic peaks at 0.1°2θ, about 21.1°±0.1°2θ, about 22.8°±0.1°2θ, about 24.0°±0.1°2θ, about 24.3°±0.1°2θ, about 25.9°±0.1°2θ, about 26.3°±0.1°2θ, about 26.6°±0.1°2θ, about 29.3°±0.1°2θ, and about 32.3°±0.1°2θ.

[0077] Form 3 In some embodiments, the dihydrochloride salt of Compound 1 can be made into a new form (Form 3) under controlled conditions. In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 3 is substantially the same as shown in Figure 12, with corresponding tabulated peak data shown in Table 3.

[0078] [Table 3]

[0079] Form 4 In some embodiments, the dihydrochloride salt of Compound 1 can be made into a new form (Form 4) under controlled conditions. In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 4 is substantially the same as shown in Figure 13, with corresponding tabulated peak data shown in Table 4.

[0080] [Table 4]

[0081] Form 5 In some embodiments, the dihydrochloride salt of Compound 1 can be made under controlled conditions into a new form (Form 5). In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 5 is substantially the same as shown in Figure 14, with corresponding tabulated peak data shown in Table 5.

[0082] [Table 5]

[0083] Form 6 In some embodiments, the dihydrochloride salt of Compound 1 can be made into a crystalline form (Form 6) under controlled conditions. In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 6 is substantially the same as shown in Figure 15, with corresponding tabulated peak data shown in Table 6.

[0084] [Table 6]

[0085] Embodiment Embodiment P1: (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid:

[0086] [ka] Crystalline forms of its pharma- ceutically acceptable salts, and / or solvates.

[0087] Embodiment P2: (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid:

[0088] [ka] The crystalline form of the dihydrochloride and / or its solvates.

[0089] Embodiment P3: The crystalline form according to embodiment P2, wherein (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid dihydrochloride is in the form of a monohydrate solvate.

[0090] Embodiment P4: The crystalline form has the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. 2; or (b) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 3; or (c) an X-ray powder diffraction (XRPD) pattern including characteristic peaks at about 7.0°±0.1°2θ, about 14.1°±0.1°2θ, about 20.2°±0.1°2θ, about 24.6°±0.1°2θ, and about 27.7°±0.1°2θ; The crystalline form of embodiment P3, having at least one of:

[0091] Embodiment P5: The crystalline form of embodiment P4, wherein the X-ray powder diffraction (XRPD) pattern further comprises characteristic peaks at about 10.5°±0.1°2θ, about 18.9°±0.1°2θ, about 23.7°±0.1°2θ, about 25.6°±0.1°2θ, and about 29.6°±0.1°2θ.

[0092] Embodiment P6: A crystalline form according to any one of embodiments P3-P5, characterized in that the crystalline form is Form 1.

[0093] Embodiment P7: The crystalline form of embodiment P2, wherein (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid dihydrochloride is anhydrous.

[0094] Embodiment P8: The crystalline form has the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. 8; or (b) an X-ray powder diffraction (XRPD) pattern including characteristic peaks at about 7.3°±0.1°2θ, about 14.5°±0.1°2θ, about 18.0°±0.1°2θ, about 19.7°±0.1°2θ, about 24.0°±0.1°2θ, and about 27.3°±0.1°θ; The crystalline form of embodiment P7, having at least one of:

[0095] Embodiment P9: The crystalline form of embodiment P8, wherein the X-ray powder diffraction (XRPD) pattern further comprises characteristic peaks at about 10.8°±0.1°2θ, about 16.6°±0.1°2θ, about 19.6°±0.1°2θ, about 23.3°±0.1°2θ, about 24.3°±0.1°2θ, and about 29.3°±0.1°2θ.

[0096] Embodiment P10: A crystalline form according to any one of embodiments P7 to P9, wherein the crystalline form is form 2.

[0097] Pharmaceutical Compositions Disclosed herein is a pharmaceutical composition, the pharmaceutical composition comprising: (i) (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharma- ceutically acceptable salt, solvate, or pharma-ceutically acceptable salt and solvate thereof; and (ii) Contains cefepime.

[0098] In some embodiments, (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8-carboxylic acid, its pharma- ceutically acceptable salt, solvate, or its pharma- ceutically acceptable salt and solvate is amorphous. In some embodiments, (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8-carboxylic acid, its pharma- ceutically acceptable salt, solvate, or its pharma- ceutically acceptable salt and solvate is crystalline.

[0099] Also disclosed herein is a pharmaceutical composition, the pharmaceutical composition comprising: (i) crystalline (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharma- ceutically acceptable salt, solvate, or pharma-ceutically acceptable salt and solvate thereof; and (ii) Contains cefepime.

[0100] In some embodiments of the pharmaceutical composition, the (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8-carboxylic acid, its pharma- ceutically acceptable salt, solvate, or its pharma- ceutically acceptable salt and solvate is a crystal disclosed herein. In some embodiments, the crystalline form of the (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8-carboxylic acid, its pharma- ceutically acceptable salt, solvate, or its pharma- ceutically acceptable salt and solvate is Form 1. In some embodiments, the crystalline form of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharma- ceutically acceptable salt, solvate, or a pharma-ceutically acceptable salt and solvate thereof is Form 2.

[0101] In some embodiments, the pharmaceutical compositions described herein are provided in unit dosage form. As used herein, a "unit dosage form" is a composition comprising an amount of Compound 1 suitable for administration to an animal, preferably a mammalian subject, in a single dose in accordance with good medical practice. However, the preparation of a single dosage form or unit dosage form does not imply that the dosage form is administered once per day or once per treatment period. Such dosage forms are intended to be administered once, twice, three times, or more times per day, and may be administered as an infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours) or as a continuous infusion, and may be given more than once during a treatment period, although a single administration is not specifically excluded. In some embodiments, Compound 1 and cefepime are formulated in separate containers. In some embodiments, Compound 1 and cefepime are formulated in a single container.

[0102] In some embodiments, administration of Compound 1, its pharma- ceutically acceptable salts, solvates, or pharma- ceutically acceptable salts and solvates is via accepted modes of administration for agents that serve similar utilities, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, pulmonary, intravaginal, rectal, or intraocular. In some embodiments, administration is oral. In some embodiments, administration is intravenous. In some embodiments, administration is intramuscular.

[0103] Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), incorporated by reference for the disclosure.

[0104] In some embodiments, the pharmaceutical composition comprises a pharma- ceutically acceptable excipient. The term "pharma-ceutically acceptable excipient" as used herein means one or more compatible solid or encapsulating substances suitable for administration to a mammal. The term "compatible" as used herein means that the components of the composition are capable of mixing with the compound of interest and with each other in a manner such that there is no interaction that would substantially diminish the pharmaceutical effect of the composition under normal conditions of use. In some embodiments, the pharma-ceutically acceptable excipient is of sufficiently high purity and sufficiently low toxicity to be suitable for administration to the animal, preferably a mammal, being treated.

[0105] Some examples of substances that can function as pharma- ceutically acceptable excipients include: Amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In some embodiments, the amino acid is arginine. In some embodiments, the amino acid is L-arginine. · Monosaccharides such as glucose (dextrose), arabinose, mannitol, fructose (levulose), and galactose. Monosaccharide derivatives, such as monosaccharides, in which one or more -OH groups have been replaced. In some embodiments of the monosaccharide derivatives, one or more -OH groups on the monosaccharide are replaced with one or more -NH2 or -NH-CH3 groups. In some embodiments, the monosaccharide derivative is meglumine. Other examples of monosaccharide derivatives include amino alcohols. Cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; · Solid lubricants such as talc, stearic acid, and magnesium stearate. Polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol. · Emulsifiers such as polysorbates. · Wetting agents such as sodium lauryl sulfate. Diluents such as calcium carbonate, sodium carbonate, mannitol, and lactose. · Binding agents such as starch (corn starch and potato starch), gelatin, and sucrose. Disintegrants such as starch, alginic acid, and croscarmellose. Lubricants such as silicon dioxide. ·Coloring agents, such as FD&C dyes. Sweeteners and flavorings, such as aspartame, saccharin, menthol, peppermint, and fruit flavors. ·Preservatives such as benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, parabens, and sodium benzoate. Tonicity adjusters such as sodium chloride, potassium chloride, mannitol, and glycerin. · Antioxidants such as sodium sulfite, acetone sodium sulfite, sodium formaldehyde, sulfoxylates, thiourea, and EDTA. ·pH adjusters such as NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. · Cryoprotectants, such as sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran.

[0106] In some embodiments of the pharmaceutical composition, the pharmaceutical composition is formulated as a homogenous liquid suitable for injection. In some embodiments, the pharmaceutical composition is formulated for intravenous / intramuscular administration. In some embodiments of the pharmaceutical composition, the pharmaceutical composition further comprises a pharma- ceutically acceptable excipient. In some embodiments of the pharmaceutical composition, the pharma- ceutically acceptable excipient is an amino acid, a monosaccharide, or a monosaccharide derivative. In some embodiments of the pharmaceutical composition, the pharma- ceutically acceptable excipient is an amino acid or a monosaccharide derivative. In some embodiments of the pharmaceutical composition, the pharma- ceutical acceptable excipient is an amino acid. In some embodiments of the pharmaceutical composition, the pharma- ceutical acceptable excipient is arginine. In some embodiments of the pharmaceutical composition, the pharma- ceutical acceptable excipient is L-arginine. In some embodiments of the pharmaceutical composition, the pharma- ceutical acceptable excipient is a monosaccharide or a monosaccharide derivative. In some embodiments of the pharmaceutical composition, the pharma- ceutical acceptable excipient is a monosaccharide derivative. In some embodiments of the pharmaceutical composition, the pharma- ceutical acceptable excipient is meglumine.

[0107] liquid composition In some embodiments, the pharmaceutical composition for intravenous / intramuscular administration is formulated as a homogenous liquid suitable for injection. In some embodiments, the pharmaceutical composition further comprises an aqueous carrier. In some embodiments, the aqueous carrier is water for injection, 0.9% saline for injection, 5% dextrose for injection, 10% dextrose for injection, sodium lactate for injection, 5% dextrose and 0.9% saline for injection, lactated Ringer's and 5% dextrose for injection, sodium chloride / sodium acetate / sodium gluconate / potassium chloride / magnesium chloride for injection, sodium chloride / potassium acetate / magnesium acetate in 5% dextrose for injection, or any combination thereof. In some embodiments, the aqueous carrier is water for injection. In some embodiments, the aqueous carrier is 0.9% saline injection.

[0108] pH of the liquid composition In some embodiments, the pH of the homogenous liquid is about 4 to about 9. In some embodiments, the pH of the homogenous liquid is about 4, about 4.4, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, or about 9. In some embodiments, the pH of the homogenous liquid is about 4 to about 6.

[0109] Powder for reconstitution In some embodiments, pharmaceutical compositions for intravenous / intramuscular administration are formulated as a powder for optimal suitability, hi some embodiments, the pharmaceutical compositions are suitable for injection once reconstituted with an aqueous carrier.

[0110] In some embodiments, the aqueous carrier is 0.9% saline for injection, 5% dextrose for injection, 10% dextrose for injection, sodium lactate for injection, 5% dextrose and 0.9% saline for injection, lactated Ringer's and 5% dextrose for injection, sodium chloride / sodium acetate / sodium gluconate / potassium chloride / magnesium chloride for injection, sodium chloride / potassium acetate / magnesium acetate in 5% dextrose for injection, or any combination thereof.

[0111] Powder stability for reconstitution The pharmaceutical compositions described herein are stable under various storage conditions, including frozen conditions, ambient conditions, and accelerated conditions. In some embodiments, frozen conditions include about 2°C, about 2.1°C, about 2.2°C, about 2.3°C, about 2.4°C, about 2.5°C, about 2.6°C, about 2.7°C, about 2.8°C, about 2.9°C, about 3°C, about 3.1°C, about 3.2°C, about 3.3°C, about 3.4°C, about 3.5°C, about 3.6°C, about 3.7°C, about 3.8°C, about 3.9°C, about 4°C, about 4.1°C, about 4.2°C, about 4.3°C, about 4.4°C, about 4.5°C, about 4.6°C, about 4.7°C, about 4.8°C, about Accelerated conditions include temperatures and / or relative humidity (RH) at or above ambient conditions (e.g., 25±5° C.; 55±105% RH). In some examples, the accelerated conditions are about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, or about 60°C. In other examples, the accelerated conditions are above 55% RH, about 65% RH, about 70% RH, about 75% RH, or about 80% RH. In further examples, the accelerated conditions are about 40°C or 60°C with ambient humidity. In yet further examples, the accelerated conditions are about 40°C±2°C / 75% RH±5% RH. In yet further examples, the accelerated conditions are about 30°C±2°C / 65% RH±5% RH.

[0112] In some embodiments, the pharmaceutical composition is stable at about 5° C.±3° C. for at least 12 months. In some embodiments, the pharmaceutical composition is stable at about 25° C.±2° C. / 60% RH±5% RH for at least 12 months. In some embodiments, the pharmaceutical composition is stable at about 30° C.±2° C. / 65% RH±5% RH for at least 6 months. In some embodiments, the pharmaceutical composition is stable at about 40° C.±2° C. / 75% RH±5% RH for at least 6 months.

[0113] Embodiment Embodiment P'1: A pharmaceutical composition comprising: (i) (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid:

[0114] [ka] Pharmaceutically acceptable salts, and / or solvates thereof; and (ii) A pharmaceutical composition comprising cefepime.

[0115] Embodiment P'2: The pharmaceutical composition according to embodiment P'1, wherein the pharmaceutical composition is formulated as a homogenous liquid suitable for injection.

[0116] Embodiment P'3: A pharmaceutical composition according to embodiment P'1 or P'2, further comprising a pharma- ceutically acceptable excipient.

[0117] Embodiment P'4: A pharmaceutical composition according to embodiment P'3, characterized in that the pharma- ceutically acceptable excipient is selected from amino acids.

[0118] Embodiment P'5: The pharmaceutical composition according to embodiment P'4, wherein the amino acid is L-arginine.

[0119] Embodiment P'6: A pharmaceutical composition according to any one of embodiments P'1 to P'5, further comprising an aqueous carrier.

[0120] Embodiment P'7: The pharmaceutical composition of embodiment P'6, wherein the aqueous carrier is selected from water for injection, 0.9% saline for injection, 5% dextrose for injection, 10% dextrose for injection, sodium lactate for injection, 5% dextrose and 0.9% saline for injection, lactated Ringer's and 5% dextrose for injection, sodium chloride / sodium acetate / sodium gluconate / potassium chloride / magnesium chloride for injection, sodium chloride / potassium acetate / magnesium acetate in 5% dextrose for injection, and any combination thereof.

[0121] Embodiment P'8: A pharmaceutical composition according to any one of embodiments P'2 to P'7, characterized in that it has a pH of about 4 to about 9.

[0122] Embodiment P'9: A pharmaceutical composition according to any one of embodiments P'2 to P'8, characterized in that it has a pH of about 4 to about 6.

[0123] Embodiment P'10: The pharmaceutical composition of embodiment P'1, wherein the pharmaceutical composition is formulated as a powder for reconstitution.

[0124] Embodiment P'11: A pharmaceutical composition according to embodiment P'10, further comprising a pharma- ceutically acceptable excipient.

[0125] Embodiment P'12: A pharmaceutical composition according to embodiment P'11, characterized in that the pharma- ceutically acceptable excipient is selected from amino acids.

[0126] Embodiment P'13: The pharmaceutical composition according to embodiment P'12, wherein the amino acid is L-arginine.

[0127] Embodiment P'14: A pharmaceutical composition according to any one of embodiments P'10 to P'13, characterized in that the pharmaceutical composition, once reconstituted with an aqueous carrier, is suitable for injection.

[0128] Embodiment P'15: The pharmaceutical composition of embodiment P'14, wherein the aqueous carrier is selected from water for injection, 0.9% saline for injection, 5% dextrose for injection, 10% dextrose for injection, sodium lactate for injection, 5% dextrose and 0.9% saline for injection, lactated Ringer's and 5% dextrose for injection, sodium chloride / sodium acetate / sodium gluconate / potassium chloride / magnesium chloride for injection, sodium chloride / potassium acetate / magnesium acetate in 5% dextrose for injection, and any combination thereof.

[0129] Embodiment P'16: A pharmaceutical composition according to any one of embodiments P'10 to P'15, wherein the pharmaceutical composition is stable at about 5°C ± 3°C for at least 12 months.

[0130] Embodiment P'17: A pharmaceutical composition described in any one of embodiments P'10 to P'15, characterized in that the pharmaceutical composition is stable at about 25°C ± 2°C / 60% RH ± 5% RH for at least 12 months.

[0131] Embodiment P'18: A pharmaceutical composition described in any one of embodiments P'10 to P'15, characterized in that the pharmaceutical composition is stable at about 30°C ± 2°C / 65% RH ± 5% RH for at least 6 months.

[0132] Embodiment P'19: A pharmaceutical composition described in any one of embodiments P'10 to P'15, characterized in that the pharmaceutical composition is stable at about 40°C ± 2°C / 75% RH ± 5% RH for at least 6 months.

[0133] Embodiment P'20: A method of administering a pharmaceutical composition to a subject in need thereof, the pharmaceutical composition comprising: (i) (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, pharma- ceutically acceptable salts, and / or solvates thereof; and (ii) A method comprising cefepime.

[0134] Embodiment P'21: The method of embodiment P'20, wherein (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, its pharma- ceutically acceptable salts, and / or solvates, and cefepime are formulated in separate containers.

[0135] Embodiment P'22: The method of embodiment P'20 or P'21, wherein (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8-carboxylic acid, its pharma- ceutically acceptable salts, and / or solvates are formulated in a first container.

[0136] Embodiment P'23: The method of any one of embodiments P'20 to P'22, characterized in that (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8-carboxylic acid, its pharma- ceutically acceptable salts, and / or solvates are in the form of a first powder for reconstitution.

[0137] Embodiment P'24: The method of any one of embodiments P'20 to P'23, wherein the cefepime is formulated in a second container.

[0138] Embodiment P'25: The method of any one of embodiments P'20 to P'24, wherein the cefepime is in the form of a second powder for reconstitution.

[0139] Embodiment P'26: (a) mixing a first powder for reconstitution with a second powder for reconstitution to obtain a third powder for reconstitution; (b) reconstituting the third powder for reconstitution of step (a) with an aqueous carrier to obtain a homogenous liquid; and (c) administering the homogenous liquid of step (b) to a subject in need thereof. The method of embodiment P'23 or P'25, comprising:

[0140] Embodiment P'27: (a) reconstituting a first powder for reconstitution with a first aqueous carrier to obtain a first homogenous liquid; (b) reconstituting the second powder for reconstitution with a second aqueous carrier to obtain a second homogenous liquid; (c) mixing the first homogenous liquid of step (a) and the second homogenous liquid of step (b) to obtain a third homogenous liquid; and (d) administering the third homogenous liquid of step (c) to a subject in need thereof. The method of embodiment P'23 or P'25, comprising:

[0141] Embodiment P'28: The method of embodiment P'26 or P'27, wherein each of the aqueous carriers is independently selected from water for injection, 0.9% saline for injection, 5% dextrose for injection, 10% dextrose for injection, sodium lactate for injection, 5% dextrose and 0.9% saline for injection, lactated Ringer's and 5% dextrose for injection, sodium chloride / sodium acetate / sodium gluconate / potassium chloride / magnesium chloride for injection, sodium chloride / potassium acetate / magnesium acetate in 5% dextrose for injection, and any combination thereof.

[0142] Embodiment P'29: The method of embodiment P'20, wherein (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, its pharma- ceutically acceptable salts, and / or solvates, and cefepime are formulated in a single container.

[0143] Embodiment P'30: The method of embodiment P'29, wherein the (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, its pharma- ceutically acceptable salts, and / or solvates, and cefepime are in the form of powders for reconstitution.

[0144] Embodiment P'31: (a) reconstituting the powder for reconstitution with an aqueous carrier to obtain a homogenous liquid; and (b) administering the homogenous liquid of step (a) to a subject in need thereof. The method of embodiment P'30, comprising:

[0145] Embodiment P'32: The method of embodiment P'31, wherein the aqueous carrier is selected from water for injection, 0.9% saline for injection, 5% dextrose for injection, 10% dextrose for injection, sodium lactate for injection, 5% dextrose and 0.9% saline for injection, lactated Ringer's and 5% dextrose for injection, sodium chloride / sodium acetate / sodium gluconate / potassium chloride / magnesium chloride for injection, sodium chloride / potassium acetate / magnesium acetate in 5% dextrose for injection, and any combination thereof.

[0146] Embodiment P'33: The method according to any one of embodiments P'20 to P'32, wherein the pharmaceutical composition further comprises a pharma- ceutically acceptable excipient.

[0147] Embodiment P'34: The method according to embodiment P'33, wherein the pharma- ceutically acceptable excipient is selected from amino acids.

[0148] Embodiment P'35: The method of embodiment P'34, wherein the pharma- ceutically acceptable excipient is L-arginine.

[0149] Embodiment P'36: A method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a pharmaceutical composition described in any one of embodiments P'1 to P'19.

[0150] Embodiment P'37: A method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to the method of any one of embodiments P'20 to P'35.

[0151] Embodiment P'38: The method of any one of embodiments P'20 to P'37, wherein the pharmaceutical composition comprises about 500 mg of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8-carboxylic acid.

[0152] Embodiment P'39: The method of any one of embodiments P'20 to P'37, wherein the pharmaceutical composition comprises about 750 mg of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8-carboxylic acid.

[0153] Embodiment P'40: The method according to any one of embodiments P'20 to P'39, wherein the pharmaceutical composition comprises about 2 g of cefepime.

[0154] Embodiment P'41: The method according to any one of embodiments P'20 to P'10, wherein the pharmaceutical composition is administered by intravenous (IV) infusion.

[0155] Embodiment P'42: The method according to embodiment P'41, wherein the infusion period of the pharmaceutical composition is about 2 hours.

[0156] Intravenous / intramuscular administration method In some embodiments, the pharmaceutical composition is administered via intravenous / intramuscular injection. In some embodiments, the pharmaceutical composition is infused into the patient over a period of time. In various embodiments, the infusion time (duration of infusion) ranges from 5 minutes to continuous infusion, 10 minutes to 8 hours, 30 minutes to 4 hours, and 1 hour to 3 hours. In one embodiment, the pharmaceutical composition is infused over a 30 minute period. In one embodiment, the pharmaceutical composition is infused over a 1 hour period. In one embodiment, the pharmaceutical composition is infused over a 1.5 hour period. In one embodiment, the pharmaceutical composition is infused over a 2 hour period. In one embodiment, the pharmaceutical composition is infused over a 3 hour period. In one embodiment, the pharmaceutical composition is infused over a 4 hour period. In some embodiments, the infusion is repeated at a desired dosing interval, including, for example, every 6 hours, 8 hours, 12 hours, or 24 hours.

[0157] In some embodiments, the pharmaceutical composition is administered over a one day period. In some embodiments, the pharmaceutical composition is administered over a two day period. In some embodiments, the pharmaceutical composition is administered over a three day period. In some embodiments, the pharmaceutical composition is administered over a four day period. In some embodiments, the pharmaceutical composition is administered over a five day period. In some embodiments, the pharmaceutical composition is administered over a six day period. In some embodiments, the pharmaceutical composition is administered over a seven day period. In some embodiments, the pharmaceutical composition is administered over an eight day period. In some embodiments, the pharmaceutical composition is administered over a nine day period. In some embodiments, the pharmaceutical composition is administered over a ten day period. In some embodiments, the pharmaceutical composition is administered over an eleven day period. In some embodiments, the pharmaceutical composition is administered over a twelve day period. In some embodiments, the pharmaceutical composition is administered over a thirteen day period. In some embodiments, the pharmaceutical composition is administered over a fourteen day period. In some embodiments, the pharmaceutical composition is administered over a twenty-eight day period. In some embodiments, the pharmaceutical composition is administered over a twenty-nine day period or more.

[0158] In some embodiments, the infusion is repeated at a desired dosing interval, including, for example, 6 hours, 8 hours, 12 hours, or 24 hours, for a period of 1 day. In some embodiments, the infusion is repeated at a desired dosing interval, including, for example, 6 hours, 8 hours, 12 hours, or 24 hours, for a period of 2 days. In some embodiments, the infusion is repeated at a desired dosing interval, including, for example, 6 hours, 8 hours, 12 hours, or 24 hours, for a period of 3 days. In some embodiments, the infusion is repeated at a desired dosing interval, including, for example, 6 hours, 8 hours, 12 hours, or 24 hours, for a period of 4 days. In some embodiments, the infusion is repeated at a desired dosing interval, including, for example, 6 hours, 8 hours, 12 hours, or 24 hours, for a period of 5 days. In some embodiments, the infusion is repeated at a desired dosing interval, including, for example, 6 hours, 8 hours, 12 hours, or 24 hours, for a period of 6 days. In some embodiments, the infusion is repeated at a desired dosing interval, including, for example, 6 hours, 8 hours, 12 hours, or 24 hours, for a period of 7 days. In some embodiments, the infusion is repeated at a desired dosing interval, including, for example, 6 hours, 8 hours, 12 hours, or 24 hours, for a period of 8 days. In some embodiments, the infusion is repeated at a desired dosing interval, including, for example, 6 hours, 8 hours, 12 hours, or 24 hours, for a period of 9 days. In some embodiments, the infusion is repeated at a desired dosing interval, including, for example, 6 hours, 8 hours, 12 hours, or 24 hours, for a period of 10 days. In some embodiments, the infusion is repeated at a desired dosing interval, including, for example, 6 hours, 8 hours, 12 hours, or 24 hours, for a period of 11 days. In some embodiments, the infusion is repeated at a desired dosing interval, including, for example, 6 hours, 8 hours, 12 hours, or 24 hours, for a period of 12 days. In some embodiments, the infusions are repeated at desired dosing intervals, including, for example, 6, 8, 12, or 24 hours, over a 13 day period, hi some embodiments, the infusions are repeated at desired dosing intervals, including, for example, 6, 8, 12, or 24 hours, over a 14 day period.In some embodiments, the infusions are repeated at desired dosing intervals, including, for example, 6 hours, 8 hours, 12 hours, or 24 hours, over a period of 28 days. In some embodiments, the infusions are repeated at desired dosing intervals, including, for example, 6 hours, 8 hours, 12 hours, or 24 hours, over a period of 29 days or more. In certain embodiments, only a single infusion is administered on the last day of the treatment period.

[0159] In some embodiments, the injection is repeated every 8 hours for a period of 1 day. In some embodiments, the injection is repeated every 8 hours for a period of 2 days. In some embodiments, the injection is repeated every 8 hours for a period of 3 days. In some embodiments, the injection is repeated every 8 hours for a period of 4 days. In some embodiments, the injection is repeated every 8 hours for a period of 5 days. In some embodiments, the injection is repeated every 8 hours for a period of 6 days. In some embodiments, the injection is repeated every 8 hours for a period of 7 days. In some embodiments, the injection is repeated every 8 hours for a period of 8 days. In some embodiments, the injection is repeated every 8 hours for a period of 9 days. In some embodiments, the injection is repeated every 8 hours for a period of 10 days. In some embodiments, the injection is repeated every 8 hours for a period of 11 days. In some embodiments, the injection is repeated every 8 hours for a period of 12 days. In some embodiments, the injection is repeated every 8 hours for a period of 13 days. In some embodiments, the injection is repeated every 8 hours for a period of 14 days. In some embodiments, the infusion is repeated every 8 hours for a period of 28 days. In some embodiments, the infusion is repeated every 8 hours for a period of 29 days or more. In some embodiments, only a single infusion is administered on the last day of the administration period. In some embodiments, the infusion is repeated every 8 hours for a period of 10 days, with three administrations on days 1-9 and one administration on day 10.

[0160] In some embodiments, the injection is repeated every 12 hours for a period of 1 day. In some embodiments, the injection is repeated every 12 hours for a period of 2 days. In some embodiments, the injection is repeated every 12 hours for a period of 3 days. In some embodiments, the injection is repeated every 12 hours for a period of 4 days. In some embodiments, the injection is repeated every 12 hours for a period of 5 days. In some embodiments, the injection is repeated every 12 hours for a period of 6 days. In some embodiments, the injection is repeated every 12 hours for a period of 7 days. In some embodiments, the injection is repeated every 12 hours for a period of 8 days. In some embodiments, the injection is repeated every 12 hours for a period of 9 days. In some embodiments, the injection is repeated every 12 hours for a period of 10 days. In some embodiments, the injection is repeated every 12 hours for a period of 11 days. In some embodiments, the injection is repeated every 12 hours for a period of 12 days. In some embodiments, the injection is repeated every 12 hours for a period of 13 days. In some embodiments, the infusion is repeated every 12 hours for a period of 14 days. In some embodiments, the infusion is repeated every 12 hours for a period of 28 days. In some embodiments, the infusion is repeated every 12 hours for a period of 29 days or more. In some embodiments, only a single infusion is administered on the last day of the administration period.

[0161] In some embodiments, the injections are repeated every 24 hours for a period of 1 day. In some embodiments, the injections are repeated every 24 hours for a period of 2 days. In some embodiments, the injections are repeated every 24 hours for a period of 3 days. In some embodiments, the injections are repeated every 24 hours for a period of 4 days. In some embodiments, the injections are repeated every 24 hours for a period of 5 days. In some embodiments, the injections are repeated every 24 hours for a period of 6 days. In some embodiments, the injections are repeated every 24 hours for a period of 7 days. In some embodiments, the injections are repeated every 24 hours for a period of 8 days. In some embodiments, the injections are repeated every 24 hours for a period of 9 days. In some embodiments, the injections are repeated every 24 hours for a period of 10 days. In some embodiments, the injections are repeated every 24 hours for a period of 11 days. In some embodiments, the injections are repeated every 24 hours for a period of 12 days. In some embodiments, the injections are repeated every 24 hours for a period of 13 days. In some embodiments, the infusion is repeated every 24 hours for a period of 14 days. In some embodiments, the infusion is repeated every 24 hours for a period of 28 days. In some embodiments, the infusion is repeated every 24 hours for a period of 29 days or more.

[0162] In some embodiments, the injections are repeated every 48 hours for a period of 2 days. In some embodiments, the injections are repeated every 48 hours for a period of 4 days. In some embodiments, the injections are repeated every 48 hours for a period of 6 days. In some embodiments, the injections are repeated every 48 hours for a period of 8 days. In some embodiments, the injections are repeated every 48 hours for a period of 10 days. In some embodiments, the injections are repeated every 48 hours for a period of 12 days. In some embodiments, the injections are repeated every 48 hours for a period of 14 days. In some embodiments, the injections are repeated every 48 hours for a period of 28 days or more.

[0163] In some embodiments, the pharmaceutical composition comprises 100-5000 mg of cefepime. In some embodiments, the pharmaceutical composition comprises 250-2000 mg of cefepime. In some embodiments, the pharmaceutical composition comprises 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of cefepime. In some embodiments, the pharmaceutical composition comprises 250 mg of cefepime. In some embodiments, the pharmaceutical composition comprises 500 mg of cefepime. In some embodiments, the pharmaceutical composition comprises 750 mg of cefepime. In some embodiments, the pharmaceutical composition comprises 1000 mg of cefepime. In some embodiments, the pharmaceutical composition comprises 1250 mg of cefepime. In some embodiments, the pharmaceutical composition comprises 1500 mg of cefepime. In some embodiments, the pharmaceutical composition comprises 1750 mg of cefepime. In some embodiments, the pharmaceutical composition comprises 2000 mg of cefepime.

[0164] In some embodiments, the daily dose of cefepime is 250 mg to 12 g. In some embodiments, the daily dose of cefepime is 250 mg, 500 mg, 750 mg, 1000 mg, 1250 mg, 1500 mg, 1750 mg, 2000 mg, 2250 mg, 2500 mg, 2750 mg, 3000 mg, 3.5 g, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g. In some embodiments, the daily dose of cefepime is 250 mg. In some embodiments, the daily dose of cefepime is 500 mg. In some embodiments, the daily dose of cefepime is 1 g. In some embodiments, the daily dose of cefepime is 2 g. In some embodiments, the daily dose of cefepime is 4 g. In some embodiments, the daily dose of cefepime is 6 g. In some embodiments, the daily dose of cefepime is 8 g. In some embodiments, the daily dose of cefepime is 10 g. In some embodiments, the daily dose of cefepime is 12 g.

[0165] In some embodiments, the pharmaceutical composition comprises 100-2000 mg of compound 1. In some embodiments, the pharmaceutical composition comprises 125-1000 mg of compound 1. In some embodiments, the pharmaceutical composition comprises 125, 187.5, 200, 250, 300, 350, 375, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of compound 1. In some embodiments, the pharmaceutical composition comprises 100 mg of compound 1. In some embodiments, the pharmaceutical composition comprises 125 mg of compound 1. In some embodiments, the pharmaceutical composition comprises 150 mg of compound 1. In some embodiments, the pharmaceutical composition comprises 187.5 mg of compound 1. In some embodiments, the pharmaceutical composition comprises 200 mg of compound 1. In some embodiments, the pharmaceutical composition comprises 250 mg of compound 1. In some embodiments, the pharmaceutical composition comprises 300 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 350 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 375 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 400 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 450 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 500 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 550 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 600 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 650 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 750 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 800 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 850 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 900 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 950 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 1000 mg of Compound 1.

[0166] In some embodiments, the pharmaceutical composition comprises 100-2000 mg of compound 1 and 0.5-5 g of cefepime. In some embodiments, the pharmaceutical composition comprises 125-1000 mg of compound 1 and 0.5-2.5 g of cefepime. In some embodiments, the pharmaceutical composition comprises 125, 150, 187.5, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of compound 1 and 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of compound 1. In some embodiments, the pharmaceutical composition comprises 250 mg of compound 1 and 2 g of cefepime. In some embodiments, the pharmaceutical composition comprises 500 mg of compound 1 and 2 g of cefepime. In some embodiments, the pharmaceutical composition comprises 750 mg of compound 1 and 2 g of cefepime. In some embodiments, the pharmaceutical composition comprises 125 mg of compound 1 and 1 g of cefepime. In some embodiments, the pharmaceutical composition comprises 250 mg of compound 1 and 1 g of cefepime. In some embodiments, the pharmaceutical composition comprises 375 mg of compound 1 and 1 g of cefepime. In some embodiments, the pharmaceutical composition comprises 62.5 mg of compound 1 and 2 g of cefepime. In some embodiments, the pharmaceutical composition comprises 125 mg of compound 1 and 2 g of cefepime. In some embodiments, the pharmaceutical composition comprises 187.5 mg of compound 1 and 2 g of cefepime.

[0167] In some embodiments, the daily dose of compound 1 is about 200 mg to 5 g. In some embodiments, the daily dose of compound 1 is about 200 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 1250 mg, 1500 mg, 1750 mg, 2000 mg, 2250 mg, 2500 mg, 2750 mg, 3000 mg, 3.5 g, 4 g, 4.5 g, or 5 g. In some embodiments, the daily dose of compound 1 is 250 mg. In some embodiments, the daily dose of compound 1 is 500 mg. In some embodiments, the daily dose of compound 1 is 750 mg. In some embodiments, the daily dose of compound 1 is 1000 mg. In some embodiments, the daily dose of compound 1 is 1250 mg. In some embodiments, the daily dose of compound 1 is 1500 mg. In some embodiments, the daily dose of compound 1 is 1750 mg. In some embodiments, the daily dose of compound 1 is 2000 mg. In some embodiments, the daily dose of compound 1 is 2250 mg. In some embodiments, the daily dose of compound 1 is 2500 mg. In some embodiments, the daily dose of compound 1 is 2750 mg. In some embodiments, the daily dose of compound 1 is 3000 mg. In some embodiments, the daily dose of compound 1 is 3.5 g. In some embodiments, the daily dose of compound 1 is 4 g. In some embodiments, the daily dose of compound 1 is 4.5 g. In some embodiments, the daily dose of compound 1 is 5 g.

[0168] In some embodiments, the pharmaceutical composition is stored in a sterile container. In some embodiments, Compound 1, a pharma- ceutically acceptable salt, solvate, or a pharma- ceutically acceptable salt and solvate thereof is co-administered with an antibiotic. In some embodiments, the antibiotic is a β-lactam antibiotic. In some embodiments, the β-lactam antibiotic is cefepime.

[0169] In some embodiments, Compound 1, its pharma- ceutically acceptable salt, solvate, or its pharma- ceutically acceptable salt and solvate are provided in separate containers. In some embodiments, Compound 1, its pharma- ceutically acceptable salt, solvate, or its pharma- ceutically acceptable salt and solvate are provided in one container. In some embodiments, the container is an IV bag. In some embodiments, the container is a glass bottle. In some embodiments, the container is an amber glass bottle.

[0170] Disclosed herein is a method of administering to a subject in need thereof a pharmaceutical composition comprising: (i) (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharma- ceutically acceptable salt, solvate, or pharma-ceutically acceptable salt and solvate thereof; and (ii) Cefepime Includes.

[0171] In some embodiments of the method of administering a pharmaceutical composition, (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8-carboxylic acid, a pharma- ceutically acceptable salt, solvate, or a pharma- ceutically acceptable salt and solvate thereof, and cefepime are formulated in separate containers. In some embodiments of the method of administering a pharmaceutical composition, (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8-carboxylic acid, a pharma- ceutically acceptable salt, solvate, or a pharma- ceutically acceptable salt and solvate thereof, is a crystalline form as disclosed herein. In some embodiments of the method of administering a pharmaceutical composition, the crystalline form is Form 1. In some embodiments of the method of administering a pharmaceutical composition, (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8-carboxylic acid, a pharma- ceutically acceptable salt, solvate, or a pharma- ceutically acceptable salt and solvate thereof is formulated in a first container. In some embodiments of the method of administering a pharmaceutical composition, (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8-carboxylic acid, a pharma- ceutically acceptable salt, solvate, or a pharma- ceutically acceptable salt and solvate thereof is in the form of a first powder for reconstitution. In some embodiments of the method of administering a pharmaceutical composition, cefepime is formulated in a second container. In some embodiments of the method of administering a pharmaceutical composition, the cefepime is in the form of a second powder for reconstitution.

[0172] In some embodiments of the method of administering a pharmaceutical composition, the method comprises: (a) mixing a first powder for reconstitution with a second powder for reconstitution to obtain a third powder for reconstitution; (b) reconstituting the third powder for reconstitution of step (a) with an aqueous carrier to obtain a homogenous liquid; and (c) administering the homogenous liquid of step (b) to a subject in need thereof. Includes.

[0173] In some embodiments of the method of administering a pharmaceutical composition, the method comprises: (a) reconstituting a first powder for reconstitution with a first aqueous carrier to obtain a first homogenous liquid; (b) reconstituting the second powder for reconstitution with a second aqueous carrier to obtain a second homogenous liquid; (c) mixing the first homogenous liquid of step (a) and the second homogenous liquid of step (b) to obtain a third homogenous liquid; and (d) administering the third homogenous liquid of step (c) to a subject in need thereof. Includes.

[0174] In some embodiments of the method of administering a pharmaceutical composition, each of the aqueous carriers is independently water for injection, 0.9% saline for injection, 5% dextrose for injection, 10% dextrose for injection, sodium lactate for injection, 5% dextrose and 0.9% saline for injection, lactated Ringer's and 5% dextrose for injection, sodium chloride / sodium acetate / sodium gluconate / potassium chloride / magnesium chloride for injection, sodium chloride / potassium acetate / magnesium acetate in 5% dextrose for injection, or any combination thereof. In some embodiments of the pharmaceutical composition, the pharmaceutical composition further comprises a pharma- ceutical acceptable excipient. In some embodiments of the pharmaceutical composition, the pharma-ceutical acceptable excipient is an amino acid or monosaccharide derivative. In some embodiments of the pharmaceutical composition, the pharma-ceutical acceptable excipient is L-arginine. In some embodiments of the pharmaceutical composition, the pharma-ceutical acceptable excipient is meglumine.

[0175] Also disclosed herein is a method of administering to a subject in need thereof a pharmaceutical composition comprising: (i) (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharma- ceutically acceptable salt or solvate thereof; and (ii) Cefepime Includes.

[0176] In some embodiments of the method of administering a pharmaceutical composition, (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8-carboxylic acid, a pharma- ceutically acceptable salt, solvate, or a pharma- ceutically acceptable salt and solvate thereof, and cefepime are formulated in one container. In some embodiments of the method of administering a pharmaceutical composition, (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-8-carboxylic acid, a pharma- ceutically acceptable salt, solvate, or a pharma- ceutically acceptable salt and solvate thereof, is a crystalline form as disclosed herein. In some embodiments of the method of administering a pharmaceutical composition, the crystalline form is Form 1. In some embodiments of the method of administering a pharmaceutical composition, the (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, a pharma- ceutically acceptable salt, solvate, or a pharma- ceutically acceptable salt and solvate thereof, and cefepime are in the form of a powder for reconstitution. In some embodiments of the method of administering a pharmaceutical composition, the method comprises: (a) reconstituting the powder for reconstitution with an aqueous carrier to obtain a homogenous liquid; and (b) administering the homogenous liquid of step (a) to a subject in need thereof. Includes.

[0177] In some embodiments of the method of administering the pharmaceutical composition, the aqueous carrier is water for injection, 0.9% saline for injection, 5% dextrose for injection, 10% dextrose for injection, sodium lactate for injection, 5% dextrose and 0.9% saline for injection, lactated Ringer's and 5% dextrose for injection, sodium chloride / sodium acetate / sodium gluconate / potassium chloride / magnesium chloride for injection, sodium chloride / potassium acetate / magnesium acetate in 5% dextrose for injection, or any combination thereof. In some embodiments of the pharmaceutical composition, the pharmaceutical composition further comprises a pharma- ceutical acceptable excipient. In some embodiments of the pharmaceutical composition, the pharma-ceutical acceptable excipient is an amino acid or monosaccharide derivative. In some embodiments of the pharmaceutical composition, the pharma-ceutical acceptable excipient is L-arginine. In some embodiments of the pharmaceutical composition, the pharma-ceutical acceptable excipient is meglumine.

[0178] Treatment Method The present disclosure also provides a method for inhibiting bacterial growth, for example by reducing bacterial resistance to β-lactam antibiotics, comprising contacting a bacterial cell culture, or a bacterially infected cell culture, tissue, or organism, with Compound 1, a pharma- ceutically acceptable salt, solvate, or a pharma- ceutically acceptable salt and solvate thereof. In some embodiments, the bacteria inhibited by administration of Compound 1, a pharma- ceutically acceptable salt, solvate, or a pharma- ceutically acceptable salt and solvate thereof are bacteria that are resistant to β-lactam antibiotics. The term "resistant" is well understood by those skilled in the art (see, for example, Payne et al., Antimicrobial Agents and Chemotherapy 38 767-772 (1994), Hanaki et al., Antimicrobial Agents and Chemotherapy 30 1120-1126 (1995)).

[0179] These methods are useful for inhibiting bacterial growth in a variety of contexts. In certain embodiments, Compound 1, its pharma- ceutically acceptable salts, solvates, or pharma- ceutically acceptable salts and solvates are administered to laboratory cell cultures in vitro to prevent the growth of β-lactam resistant bacteria. In other particular embodiments, Compound 1, its pharma- ceutically acceptable salts, solvates, or pharma- ceutically acceptable salts and solvates are administered to a mammal, including a human, to prevent the growth of β-lactam resistant bacteria in vivo. The method according to this embodiment includes administering to a mammal, including a human, a therapeutically effective amount of a β-lactamase inhibitor for a therapeutically effective period of time. Preferably, the β-lactamase inhibitor is in the form of a pharmaceutical composition as described above. In some embodiments, an antibiotic is co-administered with the β-lactamase inhibitor. In some embodiments, the antibiotic is a β-lactam antibiotic. In some embodiments, the β-lactam antibiotic is cefepime.

[0180] In another aspect, provided herein is a method of treating a bacterial infection, the method comprising administering to a subject a pharmaceutical composition comprising Compound 1, a pharma- ceutically acceptable salt, solvate, or a pharma- ceutically acceptable salt and solvate thereof, as described above, and a pharma- ceutically acceptable excipient. In some embodiments, the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intraperitoneal infection, or a skin infection.

[0181] The most common types of strains are Elizabethkingia meningoseptica, Pseudomonas aeruginosa, and Pseudomonas fluorescens、Pseudomonas acidovorans、Pseudomonas alkaligenes、Pseudomonas putida、Stenotrophomonas maltophilia、Burkholderia cepacia、Aeromonas hydrophilia、Escherichia coli、Citrobacter freundii、Salmonella typhimurium、Salmonella typhi、Salmonella paratyphi、Salmonella enteritidis、Shigella dysenteriae、Shigella flexneri、Shigella sonnei、Enterobacter cloacae、Enterobacter aerogenes、Klebsiella pneumoniae、Klebsiella oxytoca、Serratia marcescens、Francisella tularensis、Morganella morganii、Proteus mirabilis、Proteus vulgaris、Providence alcalifaciens、Providence rettgeri、Providence stuartii、Acinetobacter baumannii、Acinetobacter calcoaceticus、Acinetobacter haemolyticus、Yersinia enterocolitica、Yersinia pestis、Yersinia pseudotuberculosis、Yersinia intermedia、Bordetella pertussis、Bordetella parapertussis、Bordetella bronchiseptica、Haemophilus influenzae、Haemophilus parainfluenzae、Haemophilus haemolyticus、HaemophilusVibrio parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A's同族群, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicusThe bacteria include Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus.

[0182] In some embodiments, to treat or prevent infection, Elizabethkingia meningoseptica, Pseudomonas aeruginosa, Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio parahaemolyticus、Legionella pneumophila、Listeria monocytogenes、Neisseria gonorrhoeae、Neisseria meningitidis、Moraxella、Bacteroides fragilis、Bacteroides vulgatus、Bacteroides ovalus、Bacteroides thetaiotaomicron、BacteroidesThe bacteria include Bacteroides uniformis, Bacteroides eggerthii, or Bacteroides splanchnicus.

[0183] In one aspect, provided herein is a method of treating a bacterial infection by administering Compound 1, a pharma- ceutically acceptable salt, solvate, or a pharma- ceutically acceptable salt and solvate thereof in combination with a β-lactam antibiotic. In some embodiments, the β-lactam antibiotic is cefepime. In certain embodiments, the bacterial infection is a complicated intraperitoneal infection, a complicated urinary tract infection (including pyelonephritis), pneumonia, an uncomplicated urinary tract infection, or an uncomplicated skin and skin tissue infection. In certain embodiments, the bacterial infection is a complicated intraperitoneal infection, or a complicated urinary tract infection (including pyelonephritis). In certain embodiments, the bacterial infection is a complicated intraperitoneal infection. In certain embodiments, the bacterial infection is a complicated urinary tract infection (including pyelonephritis).

[0184] In another aspect, provided herein are methods of treating a febrile neutropenic patient by administering Compound 1, a pharma- ceutically acceptable salt, solvate, or a pharma- ceutically acceptable salt and solvate thereof, in combination with a β-lactam antibiotic. In some embodiments, the β-lactam antibiotic is cefepime.

[0185] Specific Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods similar or equivalent to those described herein can be used in the practice or testing of the embodiments described herein, certain preferred methods, devices, and materials are described herein.

[0186] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "an excipient" is a reference to one or more excipients and equivalents thereof known to those skilled in the art, and so forth.

[0187] The term "about" is used to indicate that a value includes a standard level of error for the device or method being utilized to determine the value.

[0188] Use of the term "or" in the claims is used to mean "and / or" unless expressly intended to refer to alternatives only or the alternatives are not mutually exclusive, however, the present disclosure supports a definition that refers to alternatives only or "and / or."

[0189] The terms "comprise," "have," or "include" are open-ended linking verbs. One or more forms or tenses of these verbs, such as "comprises," "comprising," "has," "having," "includes," or "including," are also open-ended. For example, a method that "comprises," "has," or "includes" one or more steps is not limited to having only those one or more steps, but also encompasses other unlisted steps.

[0190] "Optional" or "optionally" may be taken to mean that the subsequently described structure, event, or circumstance may or may not occur, and that the description includes instances in which the event occurs and instances in which the event does not occur.

[0191] As used herein, the term "therapeutic agent" means an agent utilized to treat, halt, ameliorate, prevent, or ameliorate an unwanted disease or disorder in a patient.

[0192] "Administering," when used in conjunction with a therapeutic agent, can mean administering the therapeutic agent systemically or locally, such as directly into or onto a target tissue, or can mean administering the therapeutic agent to a patient so that it positively affects the tissue to which it is targeted. "Administering" a pharmaceutical composition can be accomplished by injection, topical administration, and oral administration or other methods, alone or in combination with other known techniques.

[0193] The term "animal" as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic, and livestock animals. As used herein, the terms "patient," "subject," and "individual" are intended to include biological systems in which a particular disease may occur as described herein. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In a preferred embodiment, the patient is a primate. In a particular embodiment, the primate or subject is a human. In a particular example, the human is an adult. In a particular example, the human is a child. In a further example, the human is 12 years of age or younger. In a particular example, the human is an elderly person. In another example, the human is 60 years of age or older. Other examples of subjects include laboratory animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows.

[0194] By "pharmacologically acceptable" the carrier, diluent or excipient must be compatible with the other ingredients of the composition and not deleterious to the recipient.

[0195] The term "pharmaceutical composition" refers to a composition that includes at least one active ingredient, such as Compound 1, whereby the composition is amenable to testing for a particular efficacious outcome in a mammal (such as, but not limited to, a human). Those of skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based on the needs of the artisan.

[0196] A "therapeutically effective amount" or "effective amount," as used herein, refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which response includes one or more of the following: (1) prevention of a disease; e.g., preventing a disease, illness, or disorder in an individual who may be prone to the disease, illness, or disorder but has not yet experienced or exhibited the symptoms or symptomology of the disease; (2) inhibition of a disease; e.g., inhibiting a disease, illness, or disorder (i.e., halting further progression of the symptoms and / or symptomology) in an individual who is experiencing or exhibiting the symptoms or symptomology of the disease, illness, or disorder; and (3) amelioration of a disease; e.g., ameliorating a disease, illness, or disorder (i.e., reversing the symptoms and / or symptoms) in an individual who is experiencing or exhibiting the symptoms or symptomology.

[0197] The terms "treat", "treated", "treatment", or "treating" as used herein refer to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, the purpose of which is to prevent or slow (alleviate) an undesirable physiological disease, disorder, or condition, or to produce a beneficial or desired clinical outcome. For purposes described herein, beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms; reduction in the extent of the disease, disorder, or condition; stabilization (i.e., not worsening) of the disease, disorder, or condition; delay in onset or slowing of progression of the disease, disorder, or condition; improvement of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable, or whether the disease, disorder, or condition is enhanced or improved. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment further includes extending survival time as compared to expected survival time in the absence of treatment. Prophylactic benefits of treatment include prevention of disease, slowing the progression of disease, stabilizing disease, or reducing the likelihood of disease occurrence. As used herein, "treat," "treated," "treatment," or "treating" includes prevention, in some embodiments.

[0198] The term "substantially the same" as used herein refers to an X-ray powder diffraction pattern or a differential scanning calorimetry pattern that is not identical to that depicted herein, but is within the limits of experimental error as would be considered by one of ordinary skill in the art. EXAMPLES

[0199] Analysis method X-ray powder diffraction XRPD patterns were obtained using a high-throughput XRPD (HT-XRPD) setup. The plate was mounted on a Bruker GADDS diffractometer equipped with a Hi-Star area detector. The XRPD platform was calibrated using Silver Behenate for long d-spacings and Corundum for short d-spacings.

[0200] Data collection was performed at room temperature using monochromatic CuKα radiation in the 2θ region between 1.5° and 41.5°, which is the most characteristic part of the XRPD pattern. Diffraction patterns for each well were collected in two 2θ ranges (1.5°≦2θ≦21.5° for the first frame, and 19.5°≦2θ41.5° for the second frame) with an exposure time of 90 s for each frame. No background subtraction or curve smoothing was applied to the XRPD patterns.

[0201] The support material used during the XRPD analysis was transparent to X-rays and contributed only negligible background.

[0202] High-resolution X-ray powder diffraction (HR-XRPD) Powder data were collected on a D8 Advance diffractometer using Cu Ka1 radiation (1.54016A) with a germanium monochromator at room temperature. Data were collected from 4 to 45° with 0.016° 2θ steps, 3426.5 s per step on a solid-state LynxEye detector in 2θ only (detector scan) mode. Samples were measured in 8 mm long glass capillaries with an outer diameter of 0.5 mm.

[0203] Variable Temperature X-ray Powder Diffraction (VT-XRPD) For the variable temperature experiments, an ANSYCO HT chamber was used, designed with Brag-Brentano geometry and mounted in a D8 Advance system diffractometer (Bruker) equipped with a LynxEye solid-state detector. The radiation used to collect the data was CuKα1 (λ=1.54056A) monochromated by a germanium crystal. The material was placed on a fixed sample holder mounted in the chamber.

[0204] VT-XRPD: The temperature ramp rate was 10° C. / min. Patterns were collected in the range 9-41° 2θ with a step of 0.01569° 2θ and a measurement time per step of 8 seconds. Data collection time was 2 * It was 60 minutes.

[0205] Differential scanning calorimetry (DSC) analysis Melting characteristics were obtained from DSC thermograms and recorded on a heat flow DSC822e instrument (Mettler-Toledo GmbH, Switzerland). The DSC822e was calibrated for temperature and enthalpy with indium chips (melting point of 156.6°C; ΔHf=28.45 Jg-1). Samples were sealed in standard 40 μl aluminum pans, pin-holed, and heated in the DSC from 25°C to 300°C at a heating rate of 10°C min-1. Dry N2 gas was used at a flow rate of 50 ml min-1 to purge the DSC instrument during the measurements.

[0206] Thermogravimetric analysis coupled with mass spectrometry (TGMS) The corrosion weight loss by solvent or water loss from the crystals was determined by TGA / SDTA (TGA: Thermogravimetric Analysis; SDTA: Single Differential Thermal Analysis). Sample weight was monitored during heating in a TGA / SDTA851e instrument (Mettler-Toledo GmbH, Switzerland), resulting in a weight vs. temperature curve. The TGA / SDTA851e was calibrated for temperature with indium and aluminum. Samples were weighed into 100 μl aluminum crucibles and sealed. A pinhole was made in the seal and the crucibles were heated in the TGA from 25 to 300 or 400 °C (depending on the experiment) at a heating rate of 10 °C min-1. Dry N2 gas was used for purging.

[0207] The evolved gases from the TGA samples were analyzed by a mass spectrometer Omnistar GSD 301 T2 (Pfeiffer Vacuum GmbH, Germany), the latter being a quadrupole mass spectrometer that resolves masses in the range 0-200 amu.

[0208] Dynamic Vapor Sorption (DV) Analysis Differences in hygroscopicity (moisture absorption) of various forms of solid materials provided a measure of their relative stability at increasing relative humidity. Moisture sorption isotherms of small samples were obtained using a DVS-1 system from Surface Measurement Systems (London, UK); this instrument is suitable for use with samples as small as a few milligrams, with an accuracy of 0.1 μg.

[0209] The following humidity profile was applied: relative humidity was cycled from 45% to 95% (adsorption), back to 0% (desorption) and back to 45% at a constant temperature of 25 °C. Steps consisted of 10% RH (45%-75% RH), 5% RH (0-45% RH) and 20% (75%-95% RH). Weight balance per step was established with a minimum residence time of 1 h. At the end of the DVS experiment, the recovered solid material was measured by HT-XRPD.

[0210] Example 1: Preparation of Compound 1-Dihydrochloride Salt

[0211] [ka]

[0212] To a solution of tert-butyl 3-((R)-2-(2-((1r,4R)-4-((tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino)ethyl)amino)cyclohexyl)acetamido)-2-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)ethyl)-2-methoxybenzoate (structure 2, 110.9 g, 136.7 mmol) in 1,4-dioxane (137 mL) was added hydrochloric acid (540 mL, 3 M in water). The resulting mixture was heated to reflux and stirred at this temperature for 100 min. The resulting mixture was cooled to room temperature over 30 min and extracted with methyl tert-butyl ether (3×200 mL). The aqueous phase was concentrated under vacuum (57-29 mmHg and external bath temperature of 20-72° C.). The residue was diluted with water to a total weight of 130 g. To this solution was added isopropanol (90 mL) over about 10 minutes. This solution was seeded with compound 1-(HCl)2 crystals (100 mg). To this mixture was added isopropanol (100 mL) over about 5 minutes. The resulting slurry was stirred for about 15 hours, filtered under vacuum, and the solid was washed with isopropanol (2×200 mL) followed by methyl tert-butyl ether (400 mL). The solid was further dried under high vacuum to give the title compound (Structure 1) (43.9 g) as a white crystalline solid as a mixture of Form 1 and Form 2.

[0213] Example 2: Compound 1-Dihydrochloride Crystalline Form Example 2A: Solubility of Compound 1-Dihydrochloride in IPA / Water Mixtures The solubility of API in these combinations was determined to design the recrystallization process of Compound 1-dihydrochloride salt from water as solvent and from IPA as anti-solvent. Suspensions in various water / IPA mixtures were prepared and incubated at 5°C, 25°C, 40°C, and 50°C for 24 hours. After completion of the incubation time, the solids were separated from the mother liquor by centrifugation and filtration, and the concentration of Compound 1 in the solution was determined by HPLC analysis. The remaining solids were analyzed by HT-XRPD. The results of the solubility determination as a function of anti-solvent content and temperature are shown in Table 6, Figure 1A, and Figure 1B.

[0214] [Table 7]

[0215] Example 2B: Preparation of Crystalline Compound 1-Dihydrochloride To compound 1-dihydrochloride from Example 1 (675 g, Sample A) was added 1.85 L of isopropanol / water (40 / 60 v / v). The mixture was stirred at 19-26° C. until a clear solution was obtained. The solution was filtered through a membrane filter (5 microns). To the filtrate was added isopropanol (550 mL) followed by seed crystals (6.75 g). To this mixture was added isopropanol (8.7 L) over 1 hour. The resulting mixture was stirred for 63 hours and filtered under vacuum. The wet cake was deliquored under vacuum for 1 hour 20 minutes. The solid was washed with isopropanol (700 mL) followed by methyl tert-butyl ether (700 mL). The solid was dried under ambient air flow for 2 hours 45 minutes. 612 g of compound 1-dihydrochloride monohydrate (Sample B) was recovered. Chloride by ion chromatography 14.8% w / w. Water content by Karl Fischer analysis = 3.8% w / w.

[0216] Example 2C: Impurity Profile of Crystalline Compound 1-Dihydrochloride Monohydrate Table 7 shows the impurity profile of Compound 1-dihydrochloride (Sample A) and crystalline Compound 1-dihydrochloride (Sample B) as assessed by the HPLC method described in Table 8.

[0217] [Table 8]

[0218] [Table 9]

[0219] Example 2D: XRPD Characterization Crystalline Compound 1-dihydrochloride (Example 2B) was analyzed by HR-XRPD (Figure 2). Based on the available single crystal data for the monohydrate (Figure 3), it was concluded that the crystalline form represents a monohydrate of the dihydrochloride salt of Compound 1. This was designated Form 1. Table 1 lists the peak positions and their intensities for Form 1.

[0220] Example 2E: TG / MS and DSC Analysis Analysis of compound 1-dihydrochloride monohydrate by TG / MS (Figure 4) showed that a mass loss of 3.4% was recorded between 25 °C and 80 °C. This mass is due to the loss of one molecule of water per molecule of compound 1-dihydrochloride. This result confirms by XRPD analysis that the material consisted of the monohydrate form. The compound decomposed at temperatures above 280 °C.

[0221] FIG. 5 shows the DSC trace of Form 1 for a programmed ramp in temperature from 0° C. to 400° C. The DSC trace shows an endothermic event with an onset temperature of about 50° C. This event corresponds to the onset of dehydration of the monohydrate. This dehydration process is followed by the formation of the compound at about 290° C., which is indicated by a large endothermic event. From this experiment, we conclude that Form 1 is stable up to high temperatures of up to about 50° C.

[0222] Example 2F: Dynamic Vapor Sorption Analysis Compound 1-dihydrochloride monohydrate was analyzed by dynamic vapor sorption (FIG. 6) by subjecting it to an isothermal desorption / sorption profile at 25° C. and 45%-95%-0%-45% relative humidity (5% steps at low relative humidity (RH)).

[0223] The temperature was kept constant at about 25° C. for the duration of the experiment. The curve with diamond markers shows the change in mass of a sample of Form 1 when exposed to increasing relative humidity levels (45% to 95% RH). The mass uptake was fairly small, confirming that compound 1-dihydrochloride remained as Form 1 at high humidity levels. This is confirmed by the mass stability and performance of VH-XRPD experiments (see FIG. 7).

[0224] The curve with square markers shows the change in mass of a sample of Form 1 when exposed to a series of decreases in relative humidity from 95% RH to 0% RH. It can be seen that the sample mass does not change significantly between about 55% RH and 15% RH. After subsequent exposure to humidity values ​​of 10, 5, and 0% RH, the sample loses about 4% mass, corresponding to the loss of a single molecule of water per Compound 1-dihydrochloride salt. VH-XRPD experiments confirmed that the loss of water is accompanied by a transformation to the anhydrous form (Form 2) (see Figure 7).

[0225] The curve with triangular markers shows the change in mass of Form 2 resulting from dehydration of crystalline Form 1 when exposed to increasing relative humidity (0% RH to 50% RH). When Form 2 was exposed to 30% RH, there was a slight increase in mass up to 25% RH, followed by a sharp increase in mass. VH-XRPD experiments showed that Form 2 converts to Form 1 at % RH values ​​in the 25-35% RH range (see FIG. 7). These observations demonstrate that Form 2 undergoes substantial changes in moisture content and physical form at relative humidity values ​​that represent values ​​specified in pharmaceutical processing facilities.

[0226] Example 2G: Variable Humidity XRPD Analysis To confirm the hypothesis of a solid form change from 40% to 0% relative humidity, variable humidity XRPD (VH-XRPD) analysis was performed. Samples were exposed to a humidity profile of 45-75-20-15-10-30--35-45% relative humidity levels at 30°C. At each step, two diffractograms were recorded. The first diffractogram was recorded upon achievement of the target humidity and the second diffractogram was recorded after the sample was equilibrated at each humidity level for 1 hour. When a phase change appeared and the rate of transformation was faster than the scan time, the diffractogram showed a peak of the starting form (low 2θ angle) at the start and a peak of the converted form (high 2θ angle) at the end of the diffractogram. The most intense peak of Form 1 (dihydrochloride monohydrate) is in the range of 9.5 to 24.5° 2θ.

[0227] The layered diffractograms recorded at different relative humidity levels are shown in Figure 7. The measured RH levels and the type of RH variation process in progress (adsorption or desorption) are seen on the right. The material displays clear changes in the diffractogram indicating that moisture adsorption caused a phase transition. After desorption, the material converted to Form 2, the anhydrous form, at 20%-15% relative humidity. After adsorption, Form 2 converted to Form 1 at 30%-35% relative humidity. DVS analysis showed significant moisture adsorption in the range of 40%-95% RH. VH-XRPD results gave no evidence for additional form changes at these values.

[0228] Example 2H: Characterization of Form 2 A second crystalline form of Compound 1-dihydrochloride was discovered from variable humidity X-ray powder diffraction experiments performed on Form 1. This form was designated Form 2. For further characterization of Form 2, some material was prepared by vacuum drying Form 1 at 40° C. for 18 hours. FIG. 8 shows the XRPD diffractogram of Form 2. Analysis of a solid sample of Form 2 by TGA demonstrated the anhydrous nature of the solid. Thermogravimetric and thermograms obtained by DSC analysis showed the absence of thermal events prior to decomposition at 280° C. and the absence of weight loss during drying (FIG. 9). Table 2 lists the peak positions and their intensities for Form 2.

[0229] VH-XRPD and DVS analyses performed on the starting materials suggested that there was a dynamic and reversible relationship between anhydrous Form 2 and monohydrate Form 1. The conversion rate from Form 2 to Form 1 as a function of relative humidity value was studied by isothermal moisture sorption experiments at fixed relative humidity values. Briefly, solid samples of Form 2 were prepared by drying Form 1. The samples were placed in a DVS machine and incubated at the indicated humidity levels for 1 h, during which the weight change was recorded. The results are provided in Figures 10A and 10B. The conversion rate was dependent on the relative humidity level. The highest rate was achieved at 45% RH, while the lowest rate was achieved at 30% RH. The right panel shows the linear relationship between the applied humidity level and the conversion rate.

[0230] overview Compound 1-dihydrochloride was physically characterized by X-ray powder diffraction, thermal analysis, and dynamic vapor sorption techniques. Loss on drying studies performed by TG / MS analysis demonstrated that the material consisted of a monohydrated crystalline solid form of Compound 1-dihydrochloride. This particular form was designated as Form 1. The material showed decomposition at temperatures above 280°C. Characterization by DVS analysis showed a dehydration / hydration pattern at relative humidity values ​​of 0% to 40% at 25°C with a clear hysteresis. The presence of hysteresis suggested a phase change from the monohydrate to anhydrous crystalline form. This phase transition was confirmable by variable X-ray powder diffraction studies that showed the conversion of Form 1 (monohydrate) to Form 2 (anhydrous).

[0231] Physical characterization of compound 1-dihydrochloride confirmed the presence of two crystalline forms. The predominant form is form 1, designated as the monohydrate, the other form being form 2, which is an anhydrous form. Dynamic vapor sorption studies showed that under ambient conditions, the monohydrate form of compound 1-dihydrochloride is the most stable form. Only at low relative humidity levels, or at elevated temperatures and / or drying under vacuum, is the anhydrous form observed in this study. Interconversion between the two solid forms is fast and reversible.

[0232] Example 3: Aqueous solubility of Compound 1-dihydrochloride monohydrate as a function of pH A known amount of Compound 1 was weighed directly into a 5 ml vial and 1 ml of each phosphate buffer was added; the resulting solutions were maintained at controlled temperature (25° C.) and magnetically stirred for up to 24 hours. Aliquots of the resulting suspensions or solutions were centrifuged (14000 rpm 10 min) and withdrawn at two predefined time points (4 hours and 24 hours) that were appropriately diluted and analyzed by HPLC-UV using the analytical method parameters summarized in Table 9.

[0233] [Table 10]

[0234] The solubility data and pH values ​​of Compound 1-dihydrochloride monohydrate are reported in Table 10.

[0235] [Table 11]

[0236] Example 4: Physical Stability of Compound 1-Dihydrochloride A physical stability study was performed on compound 1-dihydrochloride (mixture of Form 1 and Form 2). Solid samples of compound 1-dihydrochloride were incubated under four relative humidity and temperature conditions: 5°C / ambient RH, 25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH. At equal intervals, the compound was analyzed by HR-XRPD and TGMS. After 3 days of exposure, the initial crystalline form of compound 1-dihydrochloride showed complete conversion to Form 1 (monohydrate) in all four conditions tested. No significant change in the solid form was observed after long-term incubation (at least up to 1 month).

[0237] The water content of each sample was determined by TGMS analysis and is presented in Figure 11. After 3 days of exposure, the water content increased from 3.1% to values ​​between 3.8-4.1% (corresponding to 1 or 1.1 molecules of water per molecule of Compound 1-dihydrochloride). The water content is consistent with the monohydrate nature of Compound 1-dihydrochloride Form 1. TGMS analyses recorded for 2 weeks and 1 month of incubation are also in line with 3.8% water (1 molecule of water per molecule of API).

[0238] The data indicate that Form 1 is physically stable and non-hygroscopic under the conditions tested. No change in crystalline phase was observed for samples incubated for 4 weeks. Furthermore, no significant change in water content was recorded after exposure to the various conditions and times.

[0239] Example 5: Polymorph Screen of Compound 1-Dihydrochloride Preparation of Compound 1-Dihydrochloride Amorphous Powder Approximately 20 mg of compound 1-dihydrochloride was weighed into nine separate 1.8 mL glass vials, and nine selected solvent systems were added to these glass vials in multiple steps until a clear solution was observed. In the various solvent systems (2-propanol-water, 1,4-dioxane / water, tetrahydrofuran / water, ethanol / water, acetone / water, and acetonitrile / water; all in 90 / 10 v / v ratio), the API did not dissolve. Therefore, these experiments were discarded. The solutions (methanol / water, 90 / 10 v / v ratio; dimethylsulfoxide / water, 1 / 1 v / v ratio; and water) were frozen in liquid nitrogen and then dried using Crys Alpha 2-4 LO for 24 hours. Extra drying at 50° C. and 5 mbar was applied for 4 hours. The resulting solids were analyzed by HT-XRPD. An amorphous solid was obtained from one solvent, namely water. These conditions were scaled up to produce 1600 mg of amorphous solid for the polymorph screen.

[0240] Polymorph screening experiments The design of a comprehensive polymorph screen is characterized by utilizing different crystallization techniques in combination with a variety of solvents and solvent mixtures. The diversity of the screen depends on the solubility profile of the API. Certain crystallization forms such as suspension equilibrium require intermediate solubility, while antisolvent crystallization relies on solvents with good solubility and solvents with near-zero solubility.

[0241] The polymorph screen consisted of the following crystallized forms: · Solvent equilibration at RT and 50 °C in 25 solvent systems; · Evaporative crystallization; · Cooling crystallization with hot filtration; Crash-crystallization with antisolvent addition; Crystallization by thermal cycling; · Sonic shattering; · Vapor diffusion onto solids; -Vapor diffusion into liquid.

[0242] The solids obtained from the various crystallization experiments were analyzed by high-throughput XRPD (HT-XRPD). Where relevant, the mother liquors were completely evaporated and the remaining solids were analyzed by HT-XRPD. All solids were subsequently subjected to accelerated aging conditions (AAC) at 40°C and 75% RH for 48 hours.

[0243] From the polymorph screen, four new diffractograms were identified in addition to the two known forms of compound 1-dihydrochloride, Form 1 and Form 2. Form 1 was the most abundant solid form discovered in this polymorph screen. The new diffractograms were designated Forms 3, 4, 5, and 6. All of these forms were found at low frequencies and were poorly crystalline. All of them were physically unstable, as conversion to Form 1 was observed after exposure to short-term stress conditions (2 days at 40° C. and 75% RH). The HT-XRPD patterns of the new Forms 3, 4, 5, and 6 are shown in Figures 12, 13, 14, and 15, respectively. Table 11 provides a summary of the experimental conditions under which these forms were obtained.

[0244] [Table 12]

[0245] All the above mentioned forms except for Form 3 were further analyzed by DSC, TGMS and HPLC. A brief description of the analytical characterization is given below.

[0246] Form 3 was obtained as a pure crystalline phase in a single experiment. Due to physical stability limitations, no further analysis could be performed on this form. This form was found in the solid obtained from iso-amyl alcohol after drying under ambient conditions. After drying under vacuum, conversion to form 1 occurred. Form 3 also transformed into form 1 after exposure to short-term stress conditions.

[0247] Form 4 was found in a few crystallization experiments carried out in TFE, 1,4-dioxane, and IPA / water. Thermal analysis confirmed that Form 4 is a mixed solvate / hydrate form. Based on the different solvents / water determined for various Form 4 samples, it was hypothesized that Form 4 is a class of isostructural mixed hydrate / solvate.

[0248] A mixed hydrated / iso-amyl alcohol solvated form was identified from solvent equilibration experiments performed in iso-amyl alcohol. This new solid form was designated Form 5, and Form 5 appeared to be physically stable after drying under vacuum; however, conversion to Form 1 was observed after exposure to AAC.

[0249] Form 6 was found primarily during hydrate screen experiments performed in IPA / water mixtures and was identified in a few solvent equilibration experiments performed in different solvents such as 1,2-dimethoxyethane, DMSO / DCM, and DMF / anisole. Form 6 was found primarily from solids dried under vacuum; however, conversion to Form 1 was observed after AAC. Analytical characterization suggested that Form 6 is a mixed hydrate / solvate form. Based on the different solvents that can be incorporated into the structure of Form 6, it was hypothesized that this form clusters a class of isostructural mixed hydrate / solvates containing different organic solvent molecules.

[0250] Hydrate Screen To study the formation of other hydrated forms, solvent equilibration experiments were carried out in various water / organic solvent mixtures. Suspensions of amorphous compound 1-dihydrochloride were prepared in 15 water / solvent mixtures with different water activities. The suspensions were stirred at 5°C, 20°C, 35°C, and 50°C for 7 days.

[0251] After completion of the equilibration period, the remaining solids were analyzed by HT-XRPD drying under vacuum and dried under ambient conditions. The mother liquor was analyzed by Karl Fischer titration for determination of water content. Three experiments showed no solids after equilibration conditions. The solutions for these experiments were evaporated under vacuum (200 mBar) and the resulting dried solids were analyzed by HT-XRPD. All solids were then exposed to 40° C. and 75% RH for two days.

[0252] Monohydrate form 1 was crystallized from the majority of crystallization conditions.

[0253] From IPA / water mixtures, Form 4, Form 6, and their mixtures with Form 1 were identified at low water content (<5%). At water activity values ​​above 0.5, monohydrate Form 1 was identified in all cases. Based on analytical characterization, Forms 4 and 6 appeared to be mixed hydrated / solvated forms that were converted to Form 1 after exposure to short-term stress conditions.

[0254] Solvent equilibration experiments performed in ethyl acetate / water showed differences in the solid forms evaluated for solids dried under ambient and vacuum. Form 1 was identified in the majority of solids dried under ambient conditions. After drying under vacuum, a mixture of Forms 1 and 2 was identified. Form 6 was identified in a mixture with Form 1 at water activity values ​​below 0.3 at temperatures above 35° C. The presence of Form 2 was observed when high temperatures and moisture contents were used, but also at temperatures below 20° C. and low moisture contents.

[0255] A similar trend was observed for experiments performed in acetonitrile / water. All solids dried under ambient conditions were attributed to Form 1. After drying the solids under vacuum, in some cases partial conversion to Form 2 was observed. This observation was noted for solvent equilibration experiments performed at temperatures above 35° C. Experiments performed below 25° C. did not show solid form conversion after drying.

[0256] A physical stability study carried out at 40° C. / 75% RH for 2 days led to the identification of Form 1. All new powder patterns detected in this study indicated conversion to the initial Form 1.

[0257] Example 6: Stability of combined formulations The stability of aqueous solutions of Compound 1-dihydrochloride in combination with meropenem at pH 5.0 vs. Compound 1-dihydrochloride in combination with cefepime at pH 5.0 after 24 hours was investigated. The results are shown in Table 12.

[0258] [Table 13]

[0259] Example 7: Effect of combined preparations The results presented in Examples 7A-7D indicate that the cefepime / Compound 1 combination is more effective against a variety of organisms than the meropenem / Compound 1 combination.

[0260] Example 7A: Elizabethkingia meningoseptica Elizabethkingia meningoseptica is a Gram-negative rod that expresses two chromosomal metallo-β-lactamases (both carbapenemases) and a class A serine cephalosporinase CME (AAC, 2012, 1686-1692). MIC test results (N=10 strains) are shown in Table 13.

[0261] [Table 14]

[0262] Example 7B: Stenotrophomonas maltophilia Stenotrophomonas maltophilia is a gram-negative rod. It is an opportunistic MDR pathogen. It has been associated with infections with high morbidity and mortality in severely immunocompromised and debilitated individuals. MIC test results are shown in Table 14.

[0263] [Table 15]

[0264] Example 7C: Pseudomonas aeruginosa 507 isolates were not susceptible to meropenem (MIC values ​​for meropenem >8 μg / mL). The MIC test results are shown in Table 15.

[0265] [Table 16]

[0266] Example 7D: Pseudomonas aeruginosa 554 isolates were not susceptible to cefepime (MIC values ​​for cefepime >8 μg / mL). The MIC test results are shown in Table 16.

[0267] [Table 17]

[0268] Example 8: A randomized drug-drug interaction study to evaluate the safety and pharmacokinetics of Compound 1 in healthy adult volunteers Example 8A: Overview of Phase 1 Clinical Study Example 8 describes four Phase 1 clinical studies designed to evaluate the safety, tolerability, and PK of various dose levels of Compound 1, when administered as single or multiple doses, alone or in combination with cefepime, which contain the following components (and are outlined in Table 17): 1) single ascending doses (SAD) and multiple ascending doses (MAD) of Compound 1 in healthy volunteers; and 2) Drug-drug interactions in healthy volunteers of single doses of compound 1, cefepime, and metronidazole alone, and of compound 1 in combination with cefepime alone and with and without metronidazole (part 1), and of repeated doses of compound 1 in combination with cefepime over a 10-day period (part 2)

[0269] [Table 18]

[0270] Evaluation of human pharmacokinetics and pharmacokinetic / pharmacodynamic target attainment of compound 1 Results from in vitro and in vivo nonclinical PK / PD studies, human PK data collected in Phase 1 trials, and human crystal binding data will be used to determine the human therapeutic dose required to achieve the PK / PD targets. In vitro studies demonstrated that human serum protein binding of Compound 1 was 37%, with 63% remaining in the free fraction. Table 18 shows the overall AUC 0-24 , the corresponding free fraction (fAUC 0-24 ), and fAUC 0-24 The calculated values ​​for the estimation of the / MIC ratio are summarized.

[0271] [Table 19]

[0272] fAUC for all doses ≥ 250 mg q8 hr 0-24 The fAUC / MIC ratio (based on a MIC value of 8 mg / L) exceeds the PK / PD target required to achieve bacteriostasis for the isolates studied to date. Similarly, the fAUC for a dose of approximately 375 mg q8 hr (interpolated from the data shown) 0-24 / MIC value is the fAUC required to achieve 1 log bacterial kill 0-24 Based on these data, a dose of 500 mg q8hr would provide approximately three times the drug exposure required to achieve PK / PD targets for bacteriostasis.

[0273] Protocol Overview Population: The 42 subjects were divided overall between the two study parts as follows: Part 1: Single-dose, five-period crossover: 18 healthy male and female subjects Part 2: Randomized repeated dose 10-day study: 24 healthy male and female subjects

[0274] Inclusion criteria No waivers to the inclusion / exclusion criteria will be granted. The following inclusion criteria must be met for a subject to be eligible to participate in the study: 1. Willing to participate in the study, willingly provide written informed consent, and willingly comply with the study terms 2. Gender: Male or female with a negative serum pregnancy test (β-human chorionic gonadotropin [β-hCG]) at screening and on day -1; females may be of childbearing potential or non-childbearing potential. 3. Age: 18-55 years at screening 4.Weight:≧50kg 5. Body mass index (BMI): ≥ 18.5kg / m2 and < 30.0kg / m2 6. Normotensive (Screening and Day -1), defined as systolic values ​​≧90 mmHg and ≦140 mmHg, and diastolic values ​​<90 mmHg. Out-of-range values ​​for inclusion may be retested once there is a clinical rationale for the out-of-range values. 7. Urine dipstick results for protein are negative or trace at screening and day -1. 8. All values ​​for blood and urine hematology and clinical chemistry tests will be within normal ranges or as defined by allowed exceptions in Table 3 at Screening and Day -1. Values ​​outside these ranges may be retested once there is a clinical rationale for the range values. Screening laboratories are defined in Tables 9 and 10. 9. Ability and willingness to abstain from alcohol for 48 hours (2 days) prior to admission to the Clinical Trials Center until the follow-up visit. 10. Men who are not surgically sterilized, and women of childbearing potential, must agree to use highly effective contraception during the study and for 90 days after the last dose of study drug. Women are considered to be of childbearing potential unless they are postmenopausal (no menses for ≥ 1 year) or have been surgically sterilized via bilateral oophorectomy, hysterectomy, bilateral tubal ligation, or successful Essure® placement with documented confirmatory testing at least 3 months after treatment. Highly effective contraception is defined as a contraceptive method that has a failure rate of < 1% when used consistently and correctly. These methods are: Hormonal contraceptives (e.g., combined oral contraceptives, patches, vaginal rings, injectables, and implants); · Intrauterine device (IUD) or intrauterine system (IUS); · Double barrier contraception (e.g. male condom with diaphragm, male condom with cervical cap) Monogamous relationships with a partner who has had a vasectomy Total abstinence according to the subject's lifestyle 11. All over-the-counter [OTC] medications, dietary supplements, and herbal remedies (e.g., St. John's Wort extract) must be discontinued at least 14 days prior to admission to the Clinical Trial Center. An exception will be made for acetaminophen, which will be permitted at a dose of ≦3 g daily until admission to the Clinical Trial Center. 12. Have veins suitable for cannulation / multiple venipunctures as assessed by the investigator at screening.

[0275] Exclusion criteria Subjects who meet any of the following exclusion criteria are ineligible for study participation: 1. Employee or Principal Investigator of the sponsor 2. Females who are pregnant, breastfeeding, or planning to become pregnant during this study or within 90 days after receiving the study drug 3. Men with a female partner who is pregnant, breastfeeding during the study, or planning to conceive during the study or within 90 days after study drug administration 4. Use of any investigational drug or device within 30 days prior to screening (90 days for injectable biologic agents). 5. Presence of congenital or acquired immune deficiency syndrome. 6. Presence of a current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, autoimmune, hematological, neoplastic, or neurological disorder 7. Any disease that, in the investigator's opinion, poses an unacceptable risk to the subject 8. Clinically significant ECG abnormalities defined as a Mean QTcF of 450 msec, short QTcF (<300 msec), or ECG evidence of atrial fibrillation, atrial flutter, complete right or left bundle branch block, Wolff-Parkinson-White syndrome, or a cardiac pacemaker (at Screening or Day -1) 9. Current or prior history of second and third degree heart block, and / or clinically relevant prolongation of the PR interval as determined by the investigator (at Screening or Day -1) 10. History of drug allergies severe enough to require emergency medical treatment, such as treatment with epinephrine in an emergency department 11. History of any hypersensitivity reaction following administration of cephalosporins, penicillins, or other β-lactam antibacterial agents 12. History of hypersensitivity to metronidazole or other nitroimidazole derivatives. 13. Requires regular use of medication for a chronic condition or has taken a prescription or received a vaccination within 14 days prior to Day -1. Hormonal contraception is permitted. 14. Use of acetaminophen >3 grams on 3 or more days in the 14 days prior to screening. 15. Strenuous activity, sun exposure, and contact sports within 48 hours (2 days) prior to admission to the Clinical Trials Center and throughout the duration of the study. 16. History of donating more than 450mL of blood within 60 days prior to administration at the clinical trial center, or scheduled to donate within 30 days of the investigator's last administration 17. Donate plasma or platelets within 7 days of dosing and throughout the study 18. Currently suspected of drug or alcohol intoxication as specified by the criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision 19. Recent history of alcohol consumption exceeding 2 standard drinks (1 standard drink = 10 grams of alcohol) per day on average 20. Positive alcohol or drug test result at screening or day -1 21. A positive screening test for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) antibodies, or type 1 and type 2 anti-human immunodeficiency virus (HIV) antibodies. 22. Body temperature >38.5°C or sudden illness at the time of admission (day -1) 23. Have previously participated in a study on Compound 1

[0276] Investigational Drug Identity of investigational drug and placebo Compound 1 was provided in a glass vial containing 500 mg of lyophilized solid. Compound 1 was reconstituted at the site with water for injection. The site obtained the following products from commercial pharmacies or wholesalers: Cefepime for IV infusion Metronidazole 500mg immediate release tablet United States Pharmacopoeia (USP) Saline Injection 0.9% ·Water for injection.

[0277] the purpose: Part 1: Primary: -Evaluation of the pharmacokinetics (PK) of compound 1 and cefepime after single dose administration alone and in combination (Part 1A). Secondary: · Evaluation of the PK of metronidazole following single dose administration of metronidazole alone and in combination with compound 1 and cefepime (Part 1B). -Evaluation of the PK of compound 1 and cefepime following single doses of coadministered compound 1 and cefepime when coadministered with metronidazole (Part 1B). To evaluate the safety and tolerability of a single dose of Compound 1 in combination with cefepime, with and without metronidazole, compared with Compound 1, cefepime, and metronidazole alone in healthy adult volunteers. Part 2:

[0278] Primary: -Evaluation of the safety and tolerability of repeated dosing (10 days) of two dose levels of Compound 1 in combination with cefepime in healthy adult volunteers

[0279] Secondary: Evaluation of plasma trough concentrations of Compound 1 and cefepime following repeated dosing (10 days) of two dose levels of Compound 1 co-administered with cefepime in healthy adult volunteers.

[0280] search: -Evaluation of serum and urine bactericidal activity at peak and trough concentrations.

[0281] Research design: This is a phase 1, randomized, single-center drug-drug interaction study in healthy adult male and female volunteers. The study consists of two independent parts. Each part enrolled a separate group of subjects. Eligible subjects were allowed to participate in either part 1 or 2, but not both.

[0282] Part 1 Part 1 enrolled 18 subjects in a randomized, single-dose evaluation of five treatments in a sequential 3-period crossover (Part 1A) and 2-period crossover (Part 1B) design. Subjects who did not meet any stopping rules in Part 1A were eligible for re-randomization to Part 1B.

[0283] Part 2 Part 2 enrolled 24 subjects in a randomized, double-blind evaluation of three treatments in a parallel group design.

[0284] Rationale In view of the available nonclinical data and data from single and multiple doses in humans, further development of compound 1 in combination with β-lactam antibiotics was warranted. This study provided an evaluation of the safety and pharmacokinetics of compound 1 in combination with cefepime with and without metronidazole in a multiple-period, single-dose, crossover design in part 1, and the safety, tolerability, and pharmacokinetics (PK) of multiple doses of compound 1 administered in combination with cefepime in part 2.

[0285] Compound 1 was administered as an intravenous (IV) infusion over a period of 2 hours.

[0286] Rationale for subject selection Healthy subjects were selected for this study population due to the study design, the low risk of clinically significant toxicity at the expected exposure levels, and the absence of any potential treatment effects. Furthermore, the use of healthy subjects, as opposed to patients, allowed for a clearer interpretation of the study results, as there were no confounding factors resulting from changing disease status and / or concomitant medications.

[0287] Example 8B: Part 1 of a Multiple Dose Study Part 1A All treatments in Part 1A were administered as a single 2-hour IV infusion and included the treatments in Table 19. All subjects received all three treatments. Dosing occurred on days 1, 4, and 7. The order of dosing was randomized.

[0288] Descriptions of treatments for Part 1A are shown in Table 19.

[0289] [Table 20]

[0290] Part 1B Part 1B included two treatments, which were administered according to the treatment sequence specified by the randomization code. Dosing occurred on days 10 and 13. Treatments are listed in Table 20.

[0291] [Table 21]

[0292] Research Notes: Certain assessments were repeated at each treatment period. Subjects were released after completing all Day 15 evaluations. If a subject discontinued the study before Day 15, all ET assessments were completed at the time of discontinuation. Scheduled assessments collected within 1 day of the ET may be used in place of the ET assessment. Additional general or symptom-specific examinations may be performed at other times at the discretion of the principal investigator. Screening included height, weight, and BMI calculation. Day -1 included weight and BMI calculation. · Clinical laboratories included serology (HBsAg, anti-HCV, and anti-HIV types 1 and 2 antibodies) at screening. PK samples were collected prior to administration of each treatment and at 0.5, 1, 2 (end of infusion), 2.25, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours after the start of the infusion. Adverse events (AEs) were collected from admission (Day -1) until completion of the follow-up visit. Any AEs continuing at follow-up were followed until resolution or stabilization. Subjects received their assigned randomized treatment once on days 1, 4, 7, 10, and 13. All subjects received all treatments in a pre-specified order according to the randomization schedule. Compound 1 and cefepime were administered IV. Metronidazole was administered orally. Included FSH levels at screening in postmenopausal women.

[0293] Example 8C: Part 2 of a Multiple Dose Study In Part 2, subjects were randomized in a 5:5:2 ratio to one of the three treatments in Table 21.

[0294] [Table 22]

[0295] Treatment was administered as a 2-hour IV infusion every 8 hours (q8h) for 10 days. Subjects received a total of 28 doses, with a single dose administered on day 10. Subjects were released after laboratory and ECG review on Day 10 and after completion of all Day 11 evaluations. If a subject discontinued the study before Day 11, ET assessments were completed at the time of discontinuation for subjects who did not have an assessment performed after the last dose of study drug. Discontinued subjects had to complete a follow-up visit 7 days (± 1 day) after their last dose of study medication. Additional general or symptom-specific examinations may be performed at other times at the discretion of the principal investigator. Height and BMI calculations were done at screening only. Weight was done at screening and on day -1 (admission). ECGs on days 1 and 10 were completed after the first infusion administration on those days. Vital signs included resting systolic and diastolic blood pressure, pulse, temperature, and respiratory rate. On days 1-9, vitals were collected prior to and 2 hours after the start of the first infusion of the day. On day 10, vitals were collected pre- and post-dose (at any time point). The study drug was administered as a 2-hour intravenous infusion every 8 hours (28 doses total, last dose in the morning on day 10). Samples were collected pre-dose on days 1 and 2, and pre-dose in the morning on days 3, 5, and 10. Blood samples were collected pre-dose on day 1, and at the end of the infusion and 8 hours after the start of the infusion on day 10. Urine samples were collected pre-dose on day 1 (single sample within 12 hours of dosing), and on day 10 as a pooled collection of all urine at intervals 0-4 and 4-8 hours after the start of the infusion. AEs were collected from admission (Day -1) until completion of the follow-up visit. Any AEs continuing at follow-up were followed until resolution or stabilization. Included FSH levels at screening in postmenopausal women.

[0296] result: There were no significant differences in the pharmacokinetic parameters of AUC(0-inf) and Cmax for Compound 1 or cefepime upon coadministration of the two drugs compared to administration of either drug alone.

[0297] There was no significant pharmacokinetic interaction between metronidazole and cefepime / Compound 1 upon administration of metronidazole alone or the cefepime / Compound 1 combination without metronidazole.

[0298] Both single and repeated doses of study drug were well tolerated. There were no clinically significant vital sign, ECG, or laboratory abnormalities. All adverse events were mild in intensity.

[0299] Example 9: Treatment of bacterial infections with combination therapy of cefepime and Compound 1 Subjects with infections at multiple anatomical sites caused by resistant pathogens, including lower respiratory tract infections, complicated intra-abdominal infections (cIAI), and complicated urinary tract infections (cUTI), such as pyelonephritis, are administered a cefepime / Compound 1 combination as follows in Table 22:

[0300] [Table 23]

[0301] The treatments in Table 22 will be administered as a 2-hour IV infusion every 8 hours (q8h) for 10 days. Subjects will receive a total of 28 doses, with a single dose administered on day 10.

Claims

1. (i) anhydrous crystalline, and (ii) cefepime A pharmaceutical composition comprising: wherein the anhydrous crystal is an anhydrous crystal of the dihydrochloride salt of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, 【Chemistry 1】 10. An X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 7.3°±0.1°2θ, 10.8°±0.1°2θ, 14.5°±0.1°2θ, 16.6°±0.1°2θ, 18.0°±0.1°2θ, 19.6°±0.1°2θ, 19.7°±0.1°2θ, 23.3°±0.1°2θ, 24.0°±0.1°2θ, 24.3°±0.1°2θ, 27.3°±0.1°2θ, and 29.3°±0.1°2θ, wherein the crystalline form of the anhydrous crystal is Form 2.

2. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated as a powder.

3. 3. The pharmaceutical composition according to claim 1, further comprising L-arginine.

4. A pharmaceutical composition described in any one of claims 1 to 3, characterized in that the amount of the anhydrous crystals is 500 mg and the amount of the cefepime is 2 g.

5. The pharmaceutical composition of claim 1, wherein the amount of the anhydrous crystals is 750 mg and the amount of the cefepime is 2 g.

6. 13. Use of a pharmaceutical composition according to any one of claims 1 to 5 in the manufacture of a medicament for treating a bacterial infection in a subject in need thereof.

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