Claims for Patent: 11,857,683

Summary for Patent: 11,857,683

Title:	Stabilization of phenobarbital sodium for injection
Abstract:	The present invention relates to a lyophilized pharmaceutical composition of hydrolytically unstable pharmaceutical compounds, such as phenobarbital or salts thereof. The present invention also relates to an aqueous solution for injection of phenobarbital or salts thereof that is reconstituted from the lyophilized pharmaceutical composition. The pharmaceutical compositions of the present disclosure have an ethanol content in the range from about 5000 ppm to about 70000 ppm. The composition of the present disclosure, in certain embodiments, is stable following two years of storage, wherein the total impurities do not exceed 0.5%. The pharmaceutical compositions of the present disclosure may be used for the treatment of neonatal seizures.
Inventor(s):	Malay Shah, Bhushan Borole, Ravi PATEL, Ajay Jaysingh Khopade
Assignee:	Sun Pharma Advanced Research Co Ltd
Application Number:	US17/715,491
Patent Claims:	1. A lyophilized pharmaceutical composition of phenobarbital or salts thereof having an ethanol content in the range from 12000 ppm to 50000 ppm, wherein an amount of total impurities in the lyophilized pharmaceutical composition does not exceed 0.2% following 36 months of storage at 20-25° C., wherein the lyophilized pharmaceutical composition is free of benzyl alcohol and propylene glycol. 2. The lyophilized pharmaceutical composition of claim 1, wherein the composition has an ethanol content in the range from about 12000 ppm to about 25000 ppm. 3. The lyophilized pharmaceutical composition of claim 1, wherein the phenobarbital or salts thereof is phenobarbital sodium. 4. The lyophilized pharmaceutical composition of claim 1, wherein the total impurities are selected from the group consisting of 2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, α-phenylbutyrylguanidine, 2-phenylbutyric acid and 5-methyl-5-phenylbarbituric acid. 5. A method for the treatment of neonatal seizure in newborn infants of 2 weeks of age or younger in need thereof, comprising administering the lyophilized pharmaceutical composition of claim 1. 6. The method of claim 5, wherein the method comprises reconstituting the lyophilized pharmaceutical composition immediately prior to the administration. 7. The method of claim 6, wherein the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution. 8. A lyophilized pharmaceutical composition comprising phenobarbital sodium having an ethanol content in the range from about 12000 ppm to about 25000 ppm, wherein an amount of total impurities in the lyophilized pharmaceutical composition does not exceed 0.2% following 36 months of storage at 20-25° C., and wherein the pharmaceutical composition is free of benzyl alcohol and propylene glycol. 9. A method for the treatment of neonatal seizure in newborn infants of 2 weeks of age or younger in need thereof, comprising administering the lyophilized pharmaceutical composition of claim 8. 10. The method of claim 9, wherein the method comprises reconstituting the lyophilized pharmaceutical composition immediately prior to the administration. 11. The method of claim 10, wherein the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution. 12. A pharmaceutical composition of phenobarbital or salts thereof made by a method comprising reconstituting a lyophilized pharmaceutical composition of the phenobarbital or salts thereof, wherein an amount of total impurities in the pharmaceutical composition does not exceed 0.2% following 12 hours of storage at 20-25° C. or 36 hours of storage at 2-8° C., and wherein the pharmaceutical composition has an ethanol content in a range from 12000 ppm to 50000 ppm. 13. The pharmaceutical composition of claim 12, wherein the ethanol content is in a range of from about 12000 ppm to about 25000 ppm. 14. The pharmaceutical composition of claim 12, wherein the phenobarbital or salts thereof is phenobarbital sodium. 15. The pharmaceutical composition of claim 12, wherein the total impurities are selected from the group consisting of 2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide, α-phenylbutyrylguanidine, 2-phenylbutyric acid and 5-methyl-5-phenylbarbituric acid. 16. The pharmaceutical composition of claim 12, wherein the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution. 17. The pharmaceutical composition of claim 12, wherein the phenobarbital or salts thereof is present in a concentration of 10-200 mg/ml. 18. The pharmaceutical composition of claim 12, wherein the composition is free of benzyl alcohol and propylene glycol. 19. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition has an osmolality below 500 mOsm/kg. 20. A method for the treatment of neonatal seizure in newborn infants of 2 weeks of age or younger in need thereof, comprising administering a pharmaceutical composition of claim 12. 21. A pharmaceutical composition of phenobarbital sodium having an ethanol content in the range from about 12000 ppm to about 25000 ppm, wherein the pharmaceutical composition is made by reconstituting the lyophilized pharmaceutical composition of phenobarbital sodium; wherein the amount of total impurities present following 12 hours of storage at 20-25° C. or following 36 hours of storage at 2-8° C. does not exceed 0.2%; wherein phenobarbital sodium is present in a concentration from 10-200 mg/ml; and wherein the pharmaceutical composition is free of benzyl alcohol and propylene glycol. 22. The pharmaceutical composition of claim 21, wherein the lyophilized pharmaceutical composition is reconstituted with water for injection, an aqueous saline or an aqueous dextrose solution. 23. A method for the treatment of neonatal seizure in newborn infants of 2 weeks of age or younger in need thereof, comprising administering a pharmaceutical composition of claim 21. 24. The lyophilized pharmaceutical composition of claim 1, wherein the lyophilized pharmaceutical composition comprises HCl. 25. A lyophilized pharmaceutical composition of phenobarbital or salts thereof having an ethanol content in the range from 12000 ppm to 50000 ppm, wherein an amount of total impurities in the lyophilized pharmaceutical composition does not exceed 0.2% following 36 months of storage at 20° C.-25° C., wherein, said lyophilized pharmaceutical composition upon reconstitution with water for injection or an aqueous saline or an aqueous dextrose solution provides a stable reconstituted composition up to 12 hours of storage at 20° C.-25° C. or 36 hours of storage at 2° C.-8° C.; wherein, an amount of total impurities in the reconstituted composition does not exceed 0.2% following 12 hours of storage at 20° C.-25° C. or 36 hours of storage at 2° C.-8° C.; wherein said lyophilized pharmaceutical composition and said reconstituted composition are free of benzyl alcohol and propylene glycol; optionally wherein said lyophilized pharmaceutical composition and said reconstituted composition comprise HCl; and wherein said reconstituted composition is suitable for the treatment of neonatal seizure in newborn infants of 2 weeks of age or younger in need thereof.