Pharmaceutical Compositions Having Improved Storage Stability

• US 20190275155A1
• Filed: 05/29/2019
• Published: 09/12/2019
• 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
• Granted Patent: US 10,639,376 B2
• Time in Patent Office: 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 minimizing in vitro degradation of a hydrolytically labile antipsychotic agent comprising adding to a composition comprising the antipsychotic agent and an aqueous vehicle (a) 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 non-ionic water insoluble and/or immiscible ester co-surfactant is provided in an amount sufficient to minimize in vitro degradation of the antipsychotic agent.

3. The method of claim 2, wherein the amount sufficient to minimize in vitro degradation is 0.25-0.45 weight percent of the total composition.

4. The method of claim 2, wherein the amount sufficient to minimize in vitro degradation is 0.3-0.4 weight percent of the total composition.

5. The method of claim 2, wherein the amount sufficient to minimize in vitro degradation does not exceed 0.5 weight percent of the total composition.

6. The method of claim 2, wherein the non-ionic water insoluble and/or immiscible ester co-surfactant is provided in an amount providing less than 50 parts per million of the hydrolyzed antipsychotic agent degradation product after the total composition stands for at least 24 months.

7. The method of claim 2, wherein the degradation is minimized at temperatures selected from any of 25°

C.-40°

C., over a time period selected from any of 1 month-24 months.

9. The methods of claim 1 or 8, wherein the composition is in a ready to use form.

10. The method of any of claims 1-9, 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.

11. The method of any of claims 1-10, 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.

12. The method of claim 10, wherein the sorbitan ester is sorbitan laurate.

13. The method of claim 11, wherein the polyoxyethylene derivative of a sorbitan ester is polysorbate 20.

14. The method of any of claims 1-13, wherein the antipsychotic agent is Compound A or Compound 1:

15. The method of any one of claims 1-14, wherein the hydrolysis product is one of the following compounds:

8. 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.

16. A pharmaceutical composition comprising:

(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.

17. The pharmaceutical composition of claim 16, 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.

18. The pharmaceutical composition of claim 16, 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.

19. The pharmaceutical composition of claim 16, 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 pharmaceutical composition of claim 18, wherein the sorbitan ester is sorbitan laurate.

21. The pharmaceutical composition of claim 19, wherein the polyoxyethylene derivative of a sorbitan ester is polysorbate 20.

22. The pharmaceutical composition of claim 16, wherein the antipsychotic agent is Compound A or Compound 1

23. The pharmaceutical composition of claim 22, wherein the hydrolysis product is of one or more of the following formulas:

24. The pharmaceutical composition of any of claims 16-23, wherein the majority of the antipsychotic agent is dissolved within the non-ionic water insoluble and/or immiscible ester co-surfactant.

25. The pharmaceutical composition of claim 24, 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.

26. The pharmaceutical composition of claim 25, wherein the sorbitan ester is sorbitan laurate.

27. A method for treating disorders of the central nervous system, comprising administering an effective amount of the composition of any one of claims 16-26 to an individual in need of such treatment.

28. A pharmaceutical composition comprising:

(a) 24-30 weight percent compound I;

29. A pharmaceutical composition comprising:

(a) about 26.6 weight percent compound I;