Pharmaceutical composition of a tachykinin receptor antagonist

• US 20040214746A1
• Filed: 12/09/2002
• Published: 10/28/2004
• Est. Priority Date: 12/10/2001
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Shelukar, Suhas D., Liversidge, Elaine, Bosch, H. William, Thompson, Karen C.
• Granted Patent: US 8,258,132 B2
• Time in Patent Office: Days
• US Class Current: 514/1
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention is directed to novel pharmaceutical compositions of the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine. The pharmaceutical compositions of this invention useful in the treatment or prevention of disorders such as psychiatric disorders including depression and anxiety, inflammatory diseases and emesis.

Claims

1. A nanoparticulate composition comprising the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine, or a pharmaceutically acceptable salt thereof, the compound having adsorbed on the surface thereof at least one surface stabilizer in an amount sufficient to maintain an effective average particle size of less than about 1000 nm.

2. The composition of claim 1 wherein the nanoparticles have an effective average particle size of less than about 400 nm.

3. The composition of claim 2 wherein the nanoparticles have an effective average particle size of less than about 250 nm.

4. The composition of claim 1 wherein the surface stabilizer is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose-super low viscosity, hydroxypropyl cellulose-low viscosity, polyvinylpyrrolidone, block copolymers of ethylene oxide and propylene oxide, dioctyl sodium sulfosuccinate and sodium lauryl sulfate.

5. The composition of claim 3 wherein the surface stabilizer is hydroxypropyl cellulose-super low viscosity or sodium lauryl sulfate.

6. A pharmaceutical composition comprising the nanoparticulate composition of claim 1 and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising the nanoparticulate composition of claim 1 which has been spray dried or spray coated on a solid support.

8. The pharmaceutical composition of claim 7 wherein the solid support is selected from microcrystalline cellulose spheres, sugar-starch spheres and lactose spheres.

15. A method for antagonizing the effect of substance P at its receptor site or for the blockade of neurokinin-1 receptors in a patient which comprises the administration to the patient of the composition of claim 1 in an amount that is effective for antagonizing the effect of substance P at its receptor site in the patient.

16. A method for treating depression in a patient in need thereof which comprises administering to the patient an effective amount of the composition of claim 1.

17. A method for treating or preventing anxiety in a patient in need thereof which comprises administering to the patient an effective amount of the composition of claim 1.

18. A method for treating or preventing emesis in a patient in need thereof which comprises administering to the patient an effective amount of the composition of claim 1.

9. A pharmaceutical composition comprising the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine having a particle size of less than about 400 nm, a surface stabilizer, a redispersing agent and a solid support.

10. The pharmaceutical composition of claim 9 comprising about 5-60% by weight of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine having a particle size of less than about 1000 nm;

about 1-20% by weight of a surface stabilizer;

about 0-50% by weight of a redispersing agent;

about 0-90% by weight of a solid support; and

about 0-5% by weight of a lubricant.

11. The pharmaceutical composition of claim 10 comprising about 25-50% by weight of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine having a particle size of less than about 1000 nm;

about 5-15% by weight of a surface stabilizer;

about 0-50% by weight of a redispersing agent;

about 10-50% by weight of a solid support; and

about 0-5% by weight of a lubricant.

12. A pharmaceutical composition comprising about 5-60% by weight of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine having a particle size of less than about 1000 nm;

about 1-20% by weight of hydroxypropyl cellulose;

about 10-50% by weight of sucrose;

about 5-80% by weight of microcrystalline cellulose; and

about 0-5% by weight of sodium lauryl sulfate.

13. The pharmaceutical composition of claim 12 comprising about 10-50% by weight of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine having a particle size of less than about 1000 nm;

about 2-15% by weight of hydroxypropyl cellulose;

about 10-50% by weight of sucrose;

about 5-60% by weight of microcrystalline cellulose; and

about 0-2% by weight of sodium lauryl sulfate.

14. The pharmaceutical composition of claim 13 comprising about 30-45% by weight of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl-morpholine;

about 5-10% by weight of hydroxypropyl cellulose;

about 30-45% by weight of sucrose;

about 15-20% by weight of microcrystalline cellulose; and

about 0-0.5% by weight of sodium lauryl sulfate.