Dibenzo azepine compounds and their use in the treatment of otic diseases and disorders

1. Crystalline Compound I having the formula:

characterized by an x-ray powder diffraction pattern with peaks at 8.2, 13.8, 14.0, 18.4, and 20.9±0.15 degrees two-theta; and characterized as having a differential scanning calorimetry endotherm onset at about 238.5° C.

2. Crystalline Compound I, according to claim 1 , characterized by an x-ray powder diffraction pattern with peaks at 4.6, 8.2, 9.2, 13.8, 14.0, 18.2, 18.4, 20.9, 23.8, and 27.7±0.15 degrees two-theta.

3. Crystalline Compound I, according to claim 1 , characterized by an x-ray powder diffraction pattern with peaks at 3.0, 4.6, 8.2, 9.2, 10.4, 13.8, 14.0, 16.4, 18.2, 18.4, 18.8, 19.1, 20.9, 21.5, 22.2, 22.7, 23.0, 23.8, 24.3, 24.7, 25.2, 26.5, 26.6, 27.1, 27.7, 28.1, 28.3, 28.6, 29.0, 30.0, 31.2, 31.5, 31.8, 32.1, 32.4, 35.1, 35.6, 35.8, 36.4, 36.7, 38.4, 38.8, 39.8, 40.5, and 40.8±0.15 degrees two-theta.

4. Crystalline Compound II having the formula:

characterized by an x-ray powder diffraction pattern with peaks at 8.4, 15.2, 16.0, 20.6, and 22.6±0.15 degrees two-theta; and characterized as having a differential scanning calorimetry endotherm onset at about 173° C.

5. Crystalline Compound II, according to claim 4 characterized by an x-ray powder diffraction pattern with peaks at 6.5, 8.4, 15.2, 16.0, 19.9, 20.6, 22.6, 24.5, 25.1, and 30.6±0.15 degrees two-theta.

6. Crystalline Compound II, according to claim 4 , characterized by an x- ray powder diffraction pattern with peaks at 6.5, 8.4, 10.1, 13.1, 14.6, 15.0, 15.2, 16.0, 17.6, 18.0, 18.4, 19.6, 19.9, 20.1, 20.6, 20.9, 21.2, 22.2, 22.6, 23.3, 23.5, 23.8, 24.5, 24.9, 25.1, 25.8, 26.1, 26.7, 26.8, 27.5, 27.8, 29.6, 30.6, 31.2, 32.3, 32.9, 33.2, 33.9, 34.4, 35.4, 36.3, 36.7, 37.3, 37.7, 38.0, 38.9, 40.0, 40.2, 40.8, and 41.6±0.15 degrees two-theta.

7. An aqueous pharmaceutical composition comprising:

(1) an active agent selected from:

a crystalline Compound I having the formula:

characterized by an x-ray powder diffraction pattern with peaks at 8.2, 13.8, 14.0, 18.4, and 20.9±0.15 degrees two-theta; or

a crystalline Compound II having the formula:

characterized by an x-ray powder diffraction pattern with peaks at 8.4, 15.2, 16.0, 20.6, and 22.6±0.15 degrees two-theta; and

(2) a pharmaceutically acceptable aqueous solution.

8. The aqueous pharmaceutical composition according to claim 7 wherein said aqueous solution comprises:

(A) approximately 15% to 25% by weight (w/w) of poloxamer 407; or

(B) (i) approximately 15% to 25% by weight (w/w) of poloxamer 407 and

(ii) approximately 0.5% to 4% by weight (w/w) of hydroxypropyl methylcellulose having a nominal viscosity of 40-60 cP or grade 80-120 cP; or

(C) (i) approximately 10%-20% by weight (w/w) of poloxamer 407, and

(ii) approximately 0.1%-0.3% by weight (w/w) of Carbopol® 974P.

9. The aqueous pharmaceutical composition according to claim 7 , wherein said aqueous solution comprises approximately 15% to 25% by weight (w/w) of poloxamer 407.

10. The aqueous pharmaceutical composition according to claim 7 , wherein the pH of said aqueous solution is between about 7.0 and 8.0.

11. The aqueous pharmaceutical composition according to claim 7 , wherein said aqueous solution further comprises a buffering agent selected from sodium phosphate monobasic, sodium phosphate dibasic, and sodium chloride, or a combination thereof.

12. The aqueous pharmaceutical composition according to claim 7 , wherein said active agent is present in approximately 0.1% to 5% w/v.

13. The aqueous pharmaceutical composition according to claim 7 comprising:

(1) a crystalline Compound I having the formula:

characterized by an x-ray powder diffraction pattern with peaks at 8.2, 13.8, 14.0, 18.4, and 20.9±0.15 degrees two-theta; and

(2) a pharmaceutically acceptable aqueous solution comprising approximately 15% to 25% by weight (w/w) of poloxamer 407, wherein the pH is between about 7.0 and 8.0; and wherein said crystalline Compound I is present in approximately 0.01% to 20% w/v of said aqueous solution.

14. The aqueous pharmaceutical composition according to claim 13 wherein said aqueous solution comprises approximately 15% to 18% by weight of poloxamer 407, and wherein said crystalline Compound I is present in approximately 0.1% to 5% w/v.

15. The aqueous pharmaceutical composition according to claim 7 comprising:

(1) crystalline Compound II having the formula:

characterized by an x-ray powder diffraction pattern with peaks at 8.4, 15.2, 16.0, 20.6, and 22.6±0.15 degrees two-theta; and

(2) a pharmaceutically acceptable aqueous solution comprising approximately 15% to 25% by weight (w/w) of poloxamer 407, wherein the pH is between about 7.0 and 8.0; and wherein said crystalline Compound II is present in approximately 0.01% to 20% w/v of said aqueous solution.

16. The aqueous pharmaceutical composition according to claim 15 wherein said aqueous solution comprises approximately 15% to 18% by weight of poloxamer 407, and wherein said crystalline Compound II is present in approximately 0.1% to 5% w/v.

17. A method for the treatment of otic disorders which comprises intratympanic administration of a therapeutically effective amount of an active agent selected from:

a crystalline Compound I having the formula:

characterized by an x-ray powder diffraction pattern with peaks at 8.2, 13.8, 14.0, 18.4, and 20.9±0.15 degrees two-theta; or

a crystalline Compound II having the formula:

characterized by an x-ray powder diffraction pattern with peaks at 8.4, 15.2, 16.0, 20.6, and 22.6±0.15 degrees two-theta, to a patient in need thereof.

18. The method of claim 17 , wherein the otic disorder is hearing loss.

19. The aqueous pharmaceutical composition of claim 7 , wherein the aqueous pharmaceutical composition is formulated for intratympanic administration.

20. The aqueous pharmaceutical composition of claim 7 , wherein the pharmaceutically acceptable aqueous solution comprises:

(A) approximately 15% to 25% by weight (w/w) of poloxamer 407; or

(B) (i) approximately 15% to 25% by weight (w/w) of poloxamer 407 and

(ii) approximately 0.5% to 4% by weight (w/w) of hydroxypropyl methylcellulose having a nominal viscosity of 40-60 cP or grade 80-120 cP; or

(C) (i) approximately 10%-20% by weight (w/w) of poloxamer 407, and

(ii) approximately 0.1%-0.3% by weight (w/w) of Carbopol® 974P; or

(D) (i) approximately 0.5% to 8% by weight (w/w) of a hyaluronic acid; or

(E) (i) approximately 0.5% to 4% by weight (w/w) of a hyaluronic acid, and

(ii) approximately 5% to 20% by volume of polyethylene glycol 400.

21. The method of claim 20 , wherein said active agent is present in approximately 0.01% to about 20% w/v of said aqueous solution.

22. The method of claim 17 , wherein the intratympanic administration is intratympanic injection.

23. The method of claim 22 , wherein the intratympanic injection is administered at or near the round window membrane in the ear of said patient.

24. The method of claim 17 , wherein the otic disorder is selected from the group consisting of hearing loss, deafness, and conditions associated with vestibular dysfunction.