Pharmaceutical compositions having improved storage stability

• US 10,342,877 B2
• Filed: 09/14/2017
• Issued: 07/09/2019
• Est. Priority Date: 09/19/2012
• Status: Active Grant

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Inventors: Perry, Jason M., Deaver, Daniel R., Hickey, Magali B., Remenar, Julius F., Vandiver, Jennifer, Palmieri, Jr., Michael J., Pan, Zhengzheng
• Primary Examiner(s): Ward, Paul V
• Application Number:
  US15/705,237
• Publication Number:
  US 20180000944A1
• Time in Patent Office: 663 Days
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• 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 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 215/227 only one oxygen atom which is attached in position 2

Abstract

The present invention relates to a pharmaceutical composition that provides long-term stability of a hydrolytically labile antipsychotic agent.

Claims

1. A method for the preparation of an aqueous pharmaceutical composition comprising a hydrolytically labile antipsychotic agent, wherein the method comprises adding to a composition comprising the antipsychotic agent and an aqueous vehicle (a) a stabilizing amount of a non-ionic water insoluble and/or immiscible ester co-surfactant and (b) a water miscible and/or soluble non-ionic surfactant.

2. The method of claim 1, wherein the composition is in a ready to use form.

3. The method of claim 1, wherein the non-ionic water insoluble and/or immiscible ester co-surfactant is a sorbitan ester of a carboxylic acid, wherein the carboxylic acid comprises 4-20 carbon atoms.

4. The method of claim 1, wherein the water miscible and/or soluble non-ionic surfactant is a polyoxyethylene derivative of a sorbitan ester of a carboxylic acid, wherein the carboxylic acid comprises 8-14 carbon atoms.

5. The method of claim 3, wherein the sorbitan ester is sorbitan laurate.

6. The method of claim 4, wherein the polyoxyethylene derivative of a sorbitan ester is polysorbate 20.

7. The method of claim 6, wherein the antipsychotic agent is Compound A or Compound 1:

8. The method of claim 7, wherein the hydrolysis product is one of the following compounds:

9. A method for treating disorders of the central nervous system, comprising administering an effective amount of a composition formed by the method of claim 1 to an individual in need of such treatment.

10. The method of claim 9, wherein the pharmaceutical composition comprises:

(a) a hydrolytically labile antipsychotic agent;

(b) a non-ionic water insoluble and/or immiscible ester co-surfactant;

(c) a water miscible and/or soluble non-ionic surfactant; and

(d) an aqueous vehicle;

wherein the pharmaceutical composition comprises less than 50 parts per million of the hydrolysis product of the antipsychotic agent after standing for at least 24 months.

11. The method of claim 10, wherein the pharmaceutical composition comprises less than 30 parts per million of the hydrolyzed antipsychotic agent degradation product after standing for at least 24 months.

12. The method of claim 10, wherein the non-ionic water insoluble and/or immiscible ester co-surfactant is a sorbitan ester of a carboxylic acid, wherein the carboxylic acid comprises 4-20 carbon atoms.

13. The method of claim 10, wherein the water miscible and/or soluble non-ionic surfactant is a polyoxyethylene derivative of a sorbitan ester of a carboxylic acid, wherein the carboxylic acid comprises 8-14 carbon atoms.

14. The method of claim 12, wherein the sorbitan ester is sorbitan laurate.

15. The method of claim 13, wherein the polyoxyethylene derivative of a sorbitan ester is polysorbate 20.

16. The method of claim 10, wherein the antipsychotic agent is Compound A or Compound 1

17. The method of claim 15, wherein the hydrolysis product is of one or more of the following formulas:

18. The method of claim 10, wherein the majority of the antipsychotic agent is dissolved within the non-ionic water insoluble and/or immiscible ester co-surfactant.

19. The method of claim 18, wherein the water miscible and/or soluble non-ionic surfactant is a polyoxyethylene derivative of a sorbitan ester of a carboxylic acid, wherein the carboxylic acid comprises 8-14 carbon atoms.

20. The method of claim 19, wherein the sorbitan ester is sorbitan laurate.

21. The method of claim 7, wherein the antipsychotic agent is Compound 1.

22. The method of claim 16, wherein the antipsychotic agent is Compound 1.

23. The method of claim 9, wherein the disorder of the central nervous system is schizophrenia.