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Claims for Patent: 7,563,801

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Claims for Patent: 7,563,801

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: Schering Corporation (Kenilworth, NJ)
Application Number:11/732,663
Patent Claims: 1. 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, lactose, microcrystalline cellulose, croscarmellose sodium, pregelatinized starch, and magnesium stearate.

2. The formulation of claim 1 having the following PK profile 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 *Mean maximum plasma concentration following single administration. **Median time of maximum plasma concentration from administration. ***Integrated concentration over the period 0 to 72 hours post administration.

3. The formulation of claim 1 wherein the hydrochloride monohydrate salt has an X-ray Powder Diffraction Pattern containing the following characteristic peaks expressed in terms of diffraction angle (in 2 0 .theta., all values reflect an accuracy of .+-.0.2), lattice "d" spacing (in angstroms) and relative peak intensities("RI"): TABLE-US-00015 Diffraction angle (2.theta. .+-. 0.2) RI Lattice Spacing (.ANG. .+-. 0.04) 16.1 Medium 5.49 18.4 Medium 4.83 21.6 Strong 4.11 23.5 Weak 3.78.

4. The formulation of claim 2 wherein the hydrochloride monohydrate salt has an X-ray Powder Diffraction Pattern containing the following characteristic peaks expressed in terms of diffraction angle (in 2 .theta., all values reflect an accuracy of .+-.0.2) lattice "d" spacing (in angstroms) and relative peak intensities("RI"): TABLE-US-00016 Diffraction angle (2.theta. .+-. 0.2) RI Lattice Spacing (.ANG. .+-. 0.04) 16.1 Medium 5.49 18.4 Medium 4.83 21.6 Strong 4.11 23.5 Weak 3.78.

5. A capsule containing an amount of the formulation of claim 1 providing a 2.5 mg dose of the hydrochloride monohydrate which provides the following dissolution profile in 900 mL of dissolution medium comprising 0.25% sodium lauryl sulfate solution buffered with 0.05 M sodium acetate at pH 4.5 determined using a USP 2 Apparatus Paddle TABLE-US-00017 Time Average % of active (min.) initially 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. A capsule containing an amount of the formulation of claim 1 providing a 10.0 mg dose of the hydrochloride monohydrate which provides the following dissolution profile in 900 mL of dissolution medium comprising 0.25% sodium lauryl sulfate solution buffered with 0.05 M sodium acetate at pH 4.5 determined using a USP 2 Apparatus Paddle Stirrer with sinkers operated at 75 RPM TABLE-US-00018 Time Average % of active Range of % active (min.) initially present released released 5 87% 82%-91% 15 95% 91%-98% 30 98% 94%-100% 45 98% 95%-101% 60 99% 96%-100%.

7. A capsule containing an amount of the formulation of claim 1 providing a 50.0 mg dose of the hydrochloride monohydrate which provides the following dissolution profile in 900 mL of dissolution medium comprising 0.25% sodium lauryl sulfate solution buffered with 0.05 M sodium acetate at pH 4.5 determined using a USP 2 Apparatus Paddle Stirrer with sinkers operated at 75 RPM TABLE-US-00019 Average % of active Range of % active Time (min.) initially present released released 5 88% 74%-96% 15 97% 91%-101% 30 99% 94%-102% 45 100% 95%-102% 60 100% 96%-103%.

8. The formulation of claim 1 wherein said lactose is lactose monohydrate.

9. A capsule filled with a granulate prepared in accordance with claim 1 which is characterized by having a Q-45 of not less than 75% when tested as a six tablet average under S-1 conditions.

10. A pharmaceutical formulation according to claim 1 prepared by the process comprising: (a) preparing a granulate by the process comprising: (i) dry blending 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 "a" with purified water until a granulate containing less than about 32 wt.% water is provided; (iii) wet milling the granulate provided in step "b" through an 8 to 10 mesh screen sieve; and (iv)drying the wet, milled granulate produced in Step "c"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 powdered formulation.

11. The formulation of claim 10, wherein the crystalline hydrochloride monohydrate salt used in Step "a" 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.

12. A capsule containing an amount of the formulation of claim 11 providing a 2.5 mg dose of the hydrochloride monohydrate which provides the following dissolution profile in 900 mL of dissolution medium comprising 0.25% sodium lauryl sulfate solution buffered with 0.05 M sodium acetate at pH 4.5 determined using a USP 2 Apparatus Paddle Stirrer with sinkers operated at 75 RPM TABLE-US-00020 Time Average % of active Range of % active (min.) initially present released released 5 69% 64%-74% 15 88% 83%-94% 30 94% 90%-100% 45 97% 93%-102% 60 98% 94%-103%.

13. A capsule containing an amount of the formulation of claim 11 providing a 10.0 mg dose of the hydrochloride monohydrate which provides the following dissolution profile in 900 mL of dissolution medium comprising 0.25% sodium lauryl sulfate solution buffered with 0.05 M sodium acetate at pH 4.5 determined using a USP 2 Apparatus Paddle Stirrer with sinkers operated at 75 RPM TABLE-US-00021 Time Average % of active Range of % active (min.) initially present released released 5 87% 82%-91% 15 95% 91%-98% 30 98% 94%-100% 45 98% 95%-101% 60 99% 96%-100%.

14. A capsule containing an amount of the formulation of claim 11 providing a 50.0 mg dose of the hydrochloride monohydrate which provides the following dissolution profile in 900 mL of dissolution medium comprising 0.25% sodium lauryl sulfate solution buffered with 0.05 M sodium acetate at pH 4.5 determined using a USP 2 Apparatus Paddle Stirrer with sinkers operated at 75 RPM TABLE-US-00022 Average % of active Range of % Time (min.) initially present released active released 5 88% 74%-96% 15 97% 91%-101% 30 99% 94%-102% 45 100% 95%-102% 60 100% 96%-103%.

15. The formulation of claim 11 having the following PK profile TABLE-US-00023 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 *Mean maximum plasma concentration following single administration. **Median time of maximum plasma concentration from administration. ***Integrated concentration over the period 0 to 72 hours post administration.

16. The formulation of claim 1 further comprising a chemotherapeutic agent.

17. The formulation of claim 16 wherein the chemotherapeutic agent is temozolomide.

18. The combination of the formulation of claim 1 and other therapeutic agents.
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