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. A monohydrate 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 monohydrate crystalline form of claim 1 , wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at about 10.5°±0.1°2θ, about 16.1°±0.1°2θ, and about 19.3°±0.1°2θ.
3. The monohydrate crystalline form of claim 2 , wherein the X-ray powder diffraction (XRPD) pattern further comprises characteristic peaks at about 12.7°±0.1°2θ, about 14.9°±0.1°2θ, and about 18.90°±0.1°2θ.
4. The monohydrate 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 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 20.6°±0.1°2θ, about 22.9°±0.1°2θ, about 23.7°±0.1°2θ, and about 25.6°±0.1°2θ.
5. A pharmaceutical composition comprising:
(i) monohydrate (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.
6. The pharmaceutical composition of claim 5 , further comprising L-arginine.
7. The pharmaceutical composition of claim 5 , formulated as a homogeneous liquid suitable for injection.
8. The pharmaceutical composition of claim 5 , further comprising an aqueous carrier.
9. The pharmaceutical composition of claim 8 , having a pH from about 4 to about 9.
10. 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.
11. 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.
12. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition comprises about 2 g of cefepime.
13. A method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of claim 5 .
14. A pharmaceutical composition comprising:
(i) a monohydrate 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.
15. The pharmaceutical composition of claim 14 , further comprising L-arginine.
16. A method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of claim 14 .
17. A pharmaceutical composition comprising:
(i) a monohydrate 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 about 10.5°±0.1°2θ, about 16.1°±0.1°2θ, and about 19.3°±0.1°2θ; and
(ii) cefepime.
18. The pharmaceutical composition of claim 17 , wherein the X-ray powder diffraction (XRPD) pattern further comprises characteristic peaks at about 12.7°±0.1°2θ, about 14.9°±0.1°2θ, and about 18.9°±0.1°2θ.
19. The pharmaceutical composition of claim 17 , further comprising L-arginine.
20. A method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of claim 17 .