Liquid pharmaceutical formulations of palonosetron

• US 8,729,094 B2
• Filed: 05/24/2013
• Issued: 05/20/2014
• Est. Priority Date: 01/30/2003
• Status: Expired due to Term

• Current Assignee: Helsinn Advanced Synthesis SA (Helsinn Healthcare SA), Helsinn Therapeutics (U.S.), Inc (Helsinn Healthcare SA), Helsinn Birex Pharmaceuticals Ltd. (Helsinn Holding SA)
• Original Assignee: Helsinn Healthcare SA, Roche Palo Alto LLC (Roche Holding AG)
• Inventors: Calderari, Giorgio, Bonadeo, Daniele, Cannella, Roberta, Macciocchi, Alberto, Miksztal, Andrew, Malefyt, Thomas, Lee, Kathleen M
• Primary Examiner(s): Gembeh, Shirley V
• Application Number:
  US13/902,132
• Publication Number:
  US 20130261150A1
• Time in Patent Office: 361 Days
• Field of Search: 514/296
• US Class Current: 514/296
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 47/00 Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: B65B 55/02 Sterilising, e.g. of complete packages
• CPC Class Codes: B65B 7/16 Closing semi-rigid or rigid containers or receptacles not deformed by, or not taking-up shape of, contents, e.g. boxes or cartons

Abstract

The present invention relates to shelf-stable liquid formulations of palonosetron for reducing chemotherapy and radiotherapy induced emesis with palonosetron. The formulations are particularly useful in the preparation of intravenous and oral liquid medicaments.

Claims

1. A method for reducing the likelihood of cancer chemotherapy-induced nausea and vomiting, comprising intravenously administering to a human in need thereof a pharmaceutical single-use, unit-dose formulation comprising a 5 mL sterile aqueous isotonic solution buffered at a pH of about 5.0±

0.5, said solution comprising;

about 0.05 mg/mL palonosetron hydrochloride based on the weight of its free base;

about 41.5 mg/mL mannitol;

about 0.5 mg/mL EDTA; and

a citrate buffer,

wherein said formulation is stable at 24 months when stored at room temperature, and

wherein said intravenous administration to said human occurs before the start of the cancer chemotherapy.

2. The method of claim 1, wherein said intravenous administration to said human occurs over a period of time of 10 to 60 seconds.

3. The method of claim 1, wherein said intravenous administration reduces the likelihood of acute nausea and vomiting in said human.

4. The method of claim 1, wherein said intravenous administration reduces the likelihood of delayed nausea and vomiting in said human.

5. A method for reducing the likelihood of cancer chemotherapy-induced nausea and vomiting, comprising intravenously administering to a human in need thereof a pharmaceutical single-use, unit-dose formulation comprising a 5 mL sterile aqueous isotonic solution buffered at a pH of about 5.0±

0.5, said solution comprising;

about 0.05 mg/mL palonosetron hydrochloride based on the weight of its free base;

from about 10 mg/mL to about 80 mg/mL mannitol; and

from about 0.3 mg/mL to about 0.7 mg/mL EDTA;

wherein said solution optionally comprises a citrate buffer,

wherein said formulation is stable at 24 months when stored at room temperature, and

wherein said intravenous administration to said human occurs before the start of the cancer chemotherapy.

6. The method of claim 5, wherein said intravenous administration to said human occurs over a period of time of 10 to 60 seconds.

7. The method of claim 5, wherein said intravenous administration reduces the likelihood of acute nausea and vomiting in said human.

8. The method of claim 5, wherein said intravenous administration reduces the likelihood of delayed nausea and vomiting in said human.

9. The method of claim 5, wherein said solution comprises from about 20 mg/mL to about 60 mg/mL mannitol.

10. The method of claim 9, wherein said solution comprises from about 40 mg/mL to about 45 mg/mL mannitol.

11. The method of claim 10, wherein said solution comprises about 41.5 mg/mL mannitol and about 0.5 mg/mL EDTA.

12. The method of claim 5, wherein said solution comprises a citrate buffer.

13. A method for reducing the likelihood of cancer chemotherapy-induced nausea and vomiting, comprising intravenously administering to a human in need thereof a pharmaceutical single-use, unit-dose formulation comprising a 5 mL sterile aqueous isotonic solution, said solution comprising:

about 0.05 mg/mL palonosetron hydrochloride based on the weight of its free base;

a tonicifying effective amount of mannitol; and

from about 0.3 mg/mL to about 0.7 mg/mL EDTA;

wherein said solution optionally comprises a citrate buffer and optionally has a pH of from about 5.0±

0.5,

wherein said formulation is stable at 24 months when stored at room temperature, and

wherein said intravenous administration to said human occurs before the start of the cancer chemotherapy.

14. The method of claim 13, wherein said intravenous administration to said human occurs over a period of time of 10 to 60 seconds.

15. The method of claim 13, wherein said intravenous administration reduces the likelihood of acute nausea and vomiting in said human.

16. The method of claim 13, wherein said intravenous administration reduces the likelihood of delayed nausea and vomiting in said human.

17. The method of claim 13, wherein said solution comprises a citrate buffer.

18. The method of claim 13, wherein said solution is buffered at a pH of about 5.0±

0.5.

19. The method of claim 13, wherein said solution comprises from about 10 mg/mL to about 80 mg/mL mannitol.

20. The method of claim 19, wherein said solution comprises from about 20 mg/mL to about 60 mg/mL mannitol.

21. The method of claim 20, wherein said solution comprises about 41.5 mg/mL mannitol and about 0.5 mg/mL EDTA.

22. A method for reducing the likelihood of cancer chemotherapy-induced nausea and vomiting, comprising intravenously administering to a human in need thereof a pharmaceutical single-use, unit-dose formulation comprising a 5 mL sterile aqueous isotonic solution buffered at a pH of about 5.0±

0.5, said solution comprising;

about 0.05 mg/mL palonosetron hydrochloride based on the weight of its free base; and

a tonicifying effective amount of mannitol;

wherein said solution optionally comprises one or a combination of a citrate buffer and a chelating agent,

wherein said formulation is stable at 24 months when stored at room temperature, and

wherein said intravenous administration to said human occurs before the start of the cancer chemotherapy.

23. The method of claim 22, wherein said intravenous administration to said human occurs over a period of time of 10 to 60 seconds.

24. The method of claim 22, wherein said intravenous administration reduces the likelihood of acute nausea and vomiting in said human.

25. The method of claim 22, wherein said intravenous administration reduces the likelihood of delayed nausea and vomiting in said human.

26. The method of claim 22, wherein said solution comprises a citrate buffer.

27. The method of claim 22, wherein said solution comprises a chelating agent.

28. The method of claim 27, wherein said chelating agent is EDTA.

29. The method of claim 28, wherein said solution comprises from about 0.3 mg/mL to about 0.7 mg/mL EDTA.

30. The method of claim 22, wherein said solution comprises from about 10 mg/mL to about 80 mg/mL mannitol.