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

• US 20070275051A1
• Filed: 04/04/2007
• Published: 11/29/2007
• Est. Priority Date: 04/05/2006
• Status: Active Grant

• Current Assignee: Opko Health, Inc.
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Qiu, Zhihui, Reyderman, Larisa
• Granted Patent: US 7,563,801 B2
• Time in Patent Office: Days
• US Class Current: 424/451
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/438 The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

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.

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-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

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 θ

, all values reflect an accuracy of ±

0.2), lattice “

d”

spacing (in angstroms) and relative peak intensities (“

RI”

);

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”

);

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 Stirrer with sinkers operated at 75 RPM

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

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

8. ) A method of treating and/or preventing nausea and or emesis in a mammal comprising administering to the mammal the formulation of claim 1.

9. ) A method of treating and/or preventing nausea and or emesis in a mammal comprising administering to the mammal the formulation of claim 2.

10. ) The formulation of claim 1 wherein said lactose is lactose monohydrate.

11. ) 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.

12. ) 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.

13. ) The formulation of claim 12, 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.

14. ) A capsule containing an amount of the formulation of claim 13 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

15. ) A capsule containing an amount of the formulation of claim 13 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

16. ) A capsule containing an amount of the formulation of claim 13 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

17. ) A method of providing anti-emesis treatment and/or anti-nausea treatment to a mammal in need thereof comprising administering to the mammal the formulation of claim 14.

18. ) A method of providing anti-emesis treatment and/or anti-nausea treatment to a mammal in need thereof comprising administering to the mammal the formulation of claim 15.

19. ) A method of providing anti-emesis treatment and/or anti-nausea treatment to a mammal in need thereof comprising administering to the mammal the formulation of claim 16.

20. ) The formulation of claim 13 having the following PK profile

21. ) The formulation of claim 1 further comprising a chemotherapeutic agent.

22. ) The formulation of claim 21 wherein the chemotherapeutic agent is temozolomide.

23. ) A method of providing therapy for delayed onset emesis and/or delayed onset nausea along with chemotherapy by contemporaneuously or simultaneously administering the formulation of claim 1 and a chemotherapeutic agent to a patient in need of chemotherapy.

24. ) A method of providing therapy for delayed onset emesis and/or delayed onset nausea along with chemotherapy by contemporaneuously or simultaneously administering the formulation of claim 13 and a chemotherapeutic agent to a patient in need of chemotherapy.

25. ) A method of providing therapy for delayed onset emesis and/or delayed onset nausea along with chemotherapy by contemporaneuously or simultaneously administering the formulation of claim 20 and a chemotherapeutic agent to a patient in need of chemotherapy.

26. ) The treatment method of claim 23 wherein the chemotherapeutic agent is temozolomide.

27. ) The treatment method of claim 24 wherein the chemotherapeutic agent is temozolomide.

28. ) The treatment method of claim 25 wherein the chemotherapeutic agent is temozolomide.

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