Pharmaceutical formulations: salts of 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one and treatment methods using the same
View Patent ↗Pharmaceutical formulations containing salts of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl]-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro [4.5]decan-2-one, represented by Formula I, are disclosed. Disclosed also are methods of treatment utilizing such dosage forms.
1. A pharmaceutical formulation comprising a_crystalline hydrochloride monohydrate salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl]-ethoxy}-methyl]-8-phenyl-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
Dose
Cmax*
(mg)
(ng/mL)
Tmax**
AUC***
T½ (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 θ, all values reflect an accuracy of ±0.2), lattice “d” spacing (in angstroms) and relative peak intensities(“RI”):
Diffraction angle (2θ ± 0.2)
RI
Lattice Spacing (Å ± 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 θ, all values reflect an accuracy of ±0.2) lattice “d” spacing (in angstroms) and relative peak intensities(“RI”):
Diffraction angle (2θ ± 0.2)
RI
Lattice Spacing (Å ± 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
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
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
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 θ, 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
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
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
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
Dose
Cmax*
(mg)
(ng/mL)
Tmax**
AUC***
T½ (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.