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Claims for Patent: 7,981,905

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Claims for Patent: 7,981,905

Title:Pharmaceutical formulations: salts of 8-[{1-(3,5-bis-(trifluoromethyl)phenyl)-Ethoxy}-methyl]-8-phenyl-1,7-diaz- a-spiro[4.5]decan-2-one and treatment methods using the same
Abstract: Pharmaceutical formulations containing salts of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl]-ethoxy}-methyl]-8-ph- enyl-1,7-diazaspiro[4.5]decan-2-one, represented by Formula I, are disclosed. Disclosed also are methods of treatment utilizing such dosage forms.
Inventor(s): Qiu; Zhihui (Bridgewater, NJ), Reyderman; Larisa (Watchung, NJ)
Assignee: OPKO Health, Inc. (Miami, FL)
Application Number:12/487,263
Patent Claims: 1. A method of treating nausea and/or emesis in a mammal comprising administering to the mammal a pharmaceutical formulation comprising a crystalline salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl]-ethoxy}-methyl]-8-ph- enyl-1,7-diazaspiro[4,5]decan-2-one, and a pharmaceutically acceptable excipient.

2. The method of claim 1 wherein said crystalline monohydrate salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl]-ethoxy}-methyl]-8-ph- enyl-1,7-diazaspiro[4,5]decan-2-one in said formulation has an X-ray powder diffraction spectrum containing the following characteristic peaks expressed in terms of diffraction angle (in 2.theta., all values reflect an accuracy of .+-.0.2) of 16.1, 18.4, 21.6, and 23.5, and said formulation is prepared by a process comprising: (a) preparing a granulate by the process comprising: (i) dry blending said crystalline hydrochloride monohydrate salt of formula I, lactose monohydrate, croscarmellose sodium and pregelatinized starch to provide a homogeneous powder blend; (ii) granulating the homogeneous powder blend provided in Step (i) with purified water until a granulate containing less than about 32 wt. % water is provided: (iii) wet milling the granulate provided in step (ii) through 5-10 mesh screen sieve; and (iv) drying the wet, milled granulate produced in Step (iii) in a fluid bed dryer; and (b) blending the granulate prepared in Step "a" with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate to form a homogeneous mixture.

3. The method of claim 1 wherein said formulation, when administered to a human at strengths of 5, 10, 25, 50, 100 or 200 mgs of the crystalline hydrochloride monohydrate salt of the active ingredient (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl]-ethoxy}-methyl]-8-ph- enyl-1,7-diazaspiro[4,5]decan-2-one, has a pK profile of: TABLE-US-00014 Dose Cmax (mg) (ng/mL) Tmax AUC T1/2 (hours) 5 27.3 2 931 not calc. 10 52.7 2.5 1820 not calc 25 119 2.5 17200 183 50 276 3 33600 171 100 475 2 74400 181 200 944 4 148000 169.

4. The method of claim 2 wherein said formulation, when administered to a human at strengths of 5, 10, 25, 50, 100 or 200 mgs of the crystalline hydrochloride monohydrate salt of the active ingredient (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl]-ethoxy}-methyl]-8-ph- enyl-1,7-diazaspiro[4,5]decan-2-one, has a pK profile of: TABLE-US-00015 Dose Cmax (mg) (ng/mL) Tmax AUC T1/2 (hours) 5 27.3 2 931 not calc. 10 52.7 2.5 1820 not calc 25 119 2.5 17200 183 50 276 3 33600 171 100 475 2 74400 181 200 944 4 148000 169.

5. The method of claim 1 wherein said formulation is incorporated into an oral dosage form and provides the following dissolution profile in a dissolution medium: TABLE-US-00016 Time Average % of active initially (min.) present released Range of % active released 5 69% 64%-74% 15 88% 83%-94% 30 94% 90%-100% 45 97% 93%-102% 60 98% 94%-103%.

6. The method of claim 1 wherein said formulation is incorporated into an oral dosage form and provides the following dissolution profile in a dissolution medium: TABLE-US-00017 Time Average % of active initially Range of % active (min.) present released released 5 87% 82%-91% 15 95% 91%-98% 30 98% 94%-100% 45 98% 95%-101% 60 99% 96%-100%.

7. The method of claim 1 wherein said formulation is incorporated into an oral dosage form and provides the following dissolution profile in a dissolution medium: TABLE-US-00018 Time Average % of active initially Range of % active (min.) Present released released 5 88% 74%-96% 15 97% 91%-101% 30 99% 94%-102% 45 100% 95%-102% 60 100% 96%-103%.

8. A method of providing therapy for delayed onset emesis and/or delayed onset nausea along with chemotherapy by administering a combination comprising a pharmaceutical formulation comprising a crystalline salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl]-ethoxy}-methyl]-8-ph- enyl-1,7-diazaspiro[4,5]decan-2-one and a chemotherapeutic agent to a patient in need of chemotherapy.

9. The method of claim 8 wherein said formulation is administered contemporaneously or simultaneously with the chemotherapeutic agent to the patient in need of chemotherapy, thereby providing therapy for delayed onset emesis and/or delayed onset nausea along with chemotherapy.

10. The treatment method of claim 4 wherein said formulation is administered contemporaneously or simultaneously with a chemotherapeutic agent to a patient in need of chemotherapy, thereby providing therapy for delayed onset emesis and/or delayed onset nausea along with chemotherapy.

11. The treatment method of claim 8 wherein the chemotherapeutic agent is temozolomide.

12. The treatment method of claim 9 wherein the chemotherapeutic agent is temozolomide.

13. The treatment method of claim 10 wherein the chemotherapeutic agent is temozolomide.

14. The method according to claim 8 further comprising administration of a corticosteroid and/or a 5HT3 receptor antagonist.

15. The method according to claim 14 wherein the corticosteroid is selected from dexamethasone and the 5HT3 antagonist is selected from the group consisting of ondansetron, granisetron, palonosetron, dolasetron or tropisetron.

16. The method of claim 1 wherein the salt is a hydrochloride salt.

17. The method according to claim 16 wherein the salt is a monohydrate hydrochloride.

18. The method according to claim 1 wherein the pharmaceutically acceptable excipient is selected from at least one of the group consisting of lactose, microcrystalline cellulose, croscarmellose sodium, pregelatinized starch, and magnesium stearate.

19. The method of claim 1 wherein the formulation is a granular formulation.

20. The method of claim 1 wherein the amount of active ingredient ranges from 5-200 mg per dosage form.

21. The method of claim 1 wherein the dosage form contains 200 mg of the salt of claim 1.

22. A method of providing therapy to a patient in need of treatment thereof for delayed onset emesis and/or delayed onset nausea along with chemotherapy by administering a combination comprising a pharmaceutical formulation comprising a crystalline hydrochloride monohydrate salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl]-ethoxy}-methyl]-8-ph- enyl-1,7-diazaspiro[4,5]decan-2-one, a corticosteroid and/or a 5HT3 receptor antagonist and a chemotherapeutic agent to a patient in need of chemotherapy and treatment for CINE.

23. The method according to claim 22 wherein the dosage strength of the crystalline hydrochloride monohydrate salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl]-ethoxy}-methyl]-8-ph- enyl-1,7-diazaspiro[4,5]decan-2-one is 5 to 200 mgs.

24. The method according to claim 23 wherein the pK profile of said 5-200 mg crystalline hydrochloride salt in a patient in need of treatment thereof under single dose rising rate study conditions is: Cmax (ng/mL) 27.3 to 944 ng/mL: Tmax 2-4 hrs: AUC 931 to 148000 ng/hr/mL and Half Life T1/2 (hours) 169-183 hrs.

25. The method according to claim 22 wherein, following day 1 administration, said patient has a Cmax of greater than about 254 ng/mL; a Tmax of about 3 hours and an AUC of greater than about 3400 ng hr/mL for 0-72 hours post administration.

26. A method of providing therapy to a patient in need of treatment thereof for delayed onset emesis and/or delayed onset nausea comprising administration of an oral dosage form comprising 5-200 mgs of the crystalline hydrochloride monohydrate salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl]-ethoxy}-methyl]-8-ph- enyl-1,7-diazaspiro[4,5]decan-2-one.

27. The method according to claim 26 wherein the oral dosage form is a tablet.

28. The method according to claim 27 wherein the tablet comprises 200 mgs of the crystalline hydrochloride monohydrate salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl]-ethoxy}-methyl]-8-ph- enyl-1,7-diazaspiro[4,5]decan-2-one.

29. The method according to claim 26 wherein individual AUC values (area under the curve from 0-72 hours post administration) in ng hr/mL ranges from 1,950 to 24,000 ng hr/mL.

30. The method according to claim 29 wherein, for a dose of 200 mgs, the individual AUC values range from 70,000 ng hr/mL to 240,000 ng hr/mL.

31. The method according to claim 26 wherein the median AUC for a dosage strength of 5-200 mgs of the crystalline monohydrate hydrochloride ranges from 931 to 148,000 ng hr/mL.

32. The method according to claim 26 wherein the median AUC for a dosage strength of 200 mgs of the crystalline monohydrate hydrochloride is between 50,000 and 250,000 ng hr/mL.

33. The method according to claim 9, wherein the formulation is administered contemporaneously with the chemotherapeutic agent.

34. The method according to claim 33, wherein the formulation is administered contemporaneously with the chemotherapeutic agent such that the formulation is administered before administration of the chemotherapeutic agent.

35. The method according to claim 33, wherein the formulation is administered contemporaneously with the chemotherapeutic agent such that the formulation is administered during administration of the chemotherapeutic agent.

36. The method according to claim 33, wherein the formulation is administered contemporaneously with the chemotherapeutic agent such that the formulation is administered after administration of the chemotherapeutic agent.
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