Solid forms and combination compositions comprising a beta-lactamase inhibitor and uses thereof
Described herein are crystalline forms of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid. In some embodiments, the crystalline forms are formulated for treating a subject in need thereof with a bacterial infection.
1. An anhydrous 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, dihydrochloride:
2. The anhydrous crystalline form of claim 1 , wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at about 7.3°±0.1° 2θ, about 10.8°±0.1° 2θ, and about 16.6±0.1° 2θ.
3. The anhydrous crystalline form of claim 2 , wherein the X-ray powder diffraction (XRPD) pattern further comprises characteristic peaks at about 16.3°±0.1° 2θ, about 19.7°±0.1° 2θ, and about 21.1°±0.1° 2θ.
4. The anhydrous crystalline form of claim 1 , wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern having at least five peaks selected from about 7.3°±0.1° 2θ, about 10.8°±0.1° 2θ, about 14.5°±0.1° 2θ, about 16.3°±0.1° 2θ, about 16.6°±0.1° 2θ, about 19.7°±0.1° 2θ, about 21.1°±0.1° 2θ, about 24.0°±0.1° 2θ, about 24.3°±0.1° 2θ, and about 29.3°±0.1° 2θ.
5. A pharmaceutical composition comprising:
(i) anhydrous (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid, dihydrochloride; and
(ii) cefepime; and
(iii) L-arginine.
6. A pharmaceutical composition comprising:
(i) an anhydrous 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, dihydrochloride; and
(ii) cefepime.
7. A pharmaceutical composition comprising:
(i) an anhydrous 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, dihydrochloride having an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at about 7.3°±0.1° 2θ, about 10.8°±0.1° 2θ, and about 16.6±0.1° 2θ; and
(ii) cefepime.
8. The pharmaceutical composition of claim 7 , wherein the X-ray powder diffraction (XRPD) pattern further comprises characteristic peaks at about 16.3°±0.1° 2θ, about 19.7°±0.1° 2θ, and about 21.1°±0.1° 2θ.
9. The pharmaceutical composition of claim 5 formulated as a homogeneous liquid suitable for injection.
10. The pharmaceutical composition of claim 5 further comprising an aqueous carrier.
11. The pharmaceutical composition of claim 10 having a pH from about 4 to about 9.
12. The pharmaceutical composition of claim 5 , 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]oxaborinine-8-carboxylic acid.
13. The pharmaceutical composition of claim 5 , 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]oxaborinine-8-carboxylic acid.
14. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition comprises about 2 g of cefepime.
15. A method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of claim 5 .
16. The pharmaceutical composition of claim 6 further comprising L-arginine.
17. A method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of claim 6 .
18. The pharmaceutical composition of claim 7 further comprising L-arginine.
19. A method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of claim 7 .