Claims for Patent: 10,478,453

Summary for Patent: 10,478,453

Title:	Stable, highly pure L-cysteine compositions for injection and methods of use
Abstract:	The subject matter described herein is directed to stable L-cysteine compositions for injection, comprising: L-cysteine or a pharmaceutically acceptable salt thereof and/or hydrate thereof in an amount from about 10 mg/mL to about 100 mg/mL; Aluminum in an amount from about 1.0 parts per billion (ppb) to about 250 ppb; cystine in an amount from about 0.01 wt % to about 2 wt % relative to L-cysteine; pyruvic acid in an amount from about 0.01 wt % to about 2 wt % relative to L-cysteine; a pharmaceutically acceptable carrier, comprising water; headspace O.sub.2 that is less than 1.0%; dissolved oxygen present in the carrier in an amount from about 0.01 parts per million (ppm) to about 1 ppm, wherein the composition is enclosed in a single-use container having a volume of from 10 mL to 100 mL. Also described are compositions for a total parenteral nutrition regimen and methods for their use.
Inventor(s):	Maloney; John (Salisbury, NC), Koganti; Aruna (Lenoir, NC), Koneru; Phanesh (Waxhaw, NC)
Assignee:	Exela Pharma Sciences, LLC (Lenoir, NC)
Application Number:	16/248,460
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,478,453
Patent Claims:	1. A stable L-cysteine composition for parenteral administration, comprising: L-cysteine or a pharmaceutically acceptable salt thereof and/or hydrate thereof in an amount from about 10 mg/mL to about 100 mg/mL; Aluminum (Al) in an amount from about 1.0 parts per billion (ppb) to about 250 ppb; L-cystine in an amount from about 0.001 wt % to about 2.0 wt % relative to L-cysteine; pyruvic acid in an amount from about 0.001 wt % to about 2.0 wt % relative to L-cysteine; a pharmaceutically acceptable carrier, comprising water; headspace oxygen that is from about 0.5% v/v to 4.0% v/v from the time of manufacture to about 1 month from manufacture when stored at room temperature; dissolved oxygen present in the carrier in an amount from about 0.1 parts per million (ppm) to about 5 ppm from the time of manufacture to about 1 month from manufacture when stored at room temperature, wherein the composition is enclosed in a single-use container having a volume of from about 10 mL to about 100 mL. 2. The composition of claim 1, wherein the composition is essentially free of an antioxidant. 3. The composition of claim 1, wherein said Aluminum is present in an amount from about 1.0 ppb to about 200 ppb. 4. The composition of claim 1, wherein said Aluminum is present in an amount from about 1.0 ppb to about 150 ppb. 5. The composition of claim 1, wherein said Aluminum is present in an amount from about 1.0 ppb to about 100 ppb. 6. The composition of claim 1, wherein said Aluminum is present in an amount from about 1.0 ppb to about 50 ppb. 7. The composition of claim 1, wherein said Aluminum is present in an amount from about 1.0 ppb to about 20 ppb. 8. The composition of claim 1, wherein the composition comprises, from about 1.0 ppb to about 100 ppb of Aluminum from the container, from about 1.0 ppb to about 100 ppb of Aluminum from a cap of the container, from about 1.0 ppb to about 100 ppm of Aluminum from the L-cysteine, and from about 1.0 ppb to about 20 ppb of Aluminum from the water, wherein the total amount of Aluminum is from about 4.0 ppb to about 250 ppb. 9. The composition of claim 1, wherein said L-cysteine or a pharmaceutically acceptable salt thereof and/or hydrate thereof is present in an amount from about 20 mg/mL to about 70 mg/mL. 10. The composition of claim 1, wherein said L-cysteine or a pharmaceutically acceptable salt thereof and/or hydrate thereof is present in an amount from about 30 mg/mL to about 70 mg/mL. 11. The composition of claim 1, wherein said L-cysteine or a pharmaceutically acceptable salt thereof and/or hydrate thereof is present in an amount of about 37.5 mg/mL. 12. The composition of claim 1, wherein said headspace oxygen is from about 2.0% v/v to about 4.0% v/v. 13. The composition of claim 1, wherein said headspace oxygen is from about 3.0% v/v to about 4.0% v/v. 14. The composition of claim 1, further comprising one or more heavy metals selected from the group consisting of Lead, Nickel, Arsenic and Mercury. 15. A total parenteral nutrition composition for parenteral administration, comprising an admixture of: about 0.5 mL to about 10 mL an L-cysteine composition comprising: L-cysteine or a pharmaceutically acceptable salt thereof and/or hydrate thereof in an amount from about 10 mg/mL to about 100 mg/mL; Aluminum (Al) in an amount from about 10 ppb to about 80 ppb; L-cystine in an amount from about 0.0.1 wt % to about 2.0 wt % relative to L-cysteine; pyruvic acid in an amount from about 0.0.1 wt % to about 2.0 wt % relative to L-cysteine; a pharmaceutically acceptable carrier, comprising water; headspace oxygen that is from about 0.5% v/v to 4.0% v/v from the time of manufacture to about 1 month from manufacture when stored at room temperature; dissolved oxygen present in the carrier in an amount from about 0.1 parts per million (ppm) to about 5 ppm from the time of manufacture to about 1 month from manufacture when stored at room temperature, and, about 1 gram to 200 grams of an amino acid composition comprising: one or more amino acids selected from the group consisting of leucine, isoleucine, lysine, valine, phenylalanine, histidine, threonine, methionine, tryptophan, alanine, arginine, glycine, proline, serine, and tyrosine. 16. The composition of claim 15, where said L-cysteine composition and said amino acid composition are present in the admixture at a ratio of from about 1:50 to 1:1000. 17. The composition of claim 15, comprising: L-cysteine or a pharmaceutically acceptable salt thereof and/or hydrate thereof in an amount from about 10 mg/mL to about 100 mg/mL; From about 10 mg/g amino acid to about 80 mg/g of one or more amino acids selected from the group consisting of leucine, isoleucine, lysine, valine, phenylalanine, histidine, threonine, methionine, tryptophan, alanine, arginine, glycine, proline, serine, and tyrosine; and Aluminum (Al) in an amount from about 10 parts per billion (ppb) to about 80 ppb. 18. The composition of claim 17, wherein said L-cysteine is present at about 30 mg/g to about 50 mg/g of total amino acid content. 19. The composition of claim 17, wherein said L-cysteine is present at about 40 mg/g of total amino acid content. 20. The composition of claim 15, having a volume of about 100 mL to about 1000 mL for infusion within about 24 hours to about 48 hours of admixture. 21. A method of preparing the composition of claim 1, comprising: Stirring Water for Injection, USP (WFI) in a vessel at a temperature of NMT about 60.degree. C.; Contacting the stirring WFI with Argon until the dissolved oxygen is NMT 1 ppm; Allowing the vessel to cool to a temperature of NMT 30.degree. C.; Contacting under the Argon the WFI with L-Cysteine Hydrochloride, Monohydrate, USP (L-Cysteine) for NLT about 15 mins; Continuing the mixing under Argon until the dissolved oxygen is NMT 1 ppm; Adjusting the pH to about 1.8 with concentrated Hydrochloric Acid, NF and/or 5.0 N Sodium Hydroxide, NF; Mixing for a minimum of about 10 minutes; Capping the vessel under Argon and allowing to stand; Filling said mixture into containers of use; Reducing head space oxygen in said containers of use; and Sealing said containers of use, wherein the dissolved oxygen in said containers of use is about 0.1 ppm to about 5 ppm. 22. A method of preparing a reduced Aluminum composition for a total parenteral nutrition regimen comprising L-cysteine, the method comprising: mixing a composition comprising L-cysteine or a pharmaceutically acceptable salt thereof and/or hydrate thereof comprising: Aluminum in an amount from about 1.0 parts per billion (ppb) to about 250 ppb; L-cystine in an amount from about 0.001 wt % to about 2.0 wt % relative to L-cysteine; and pyruvic acid in an amount from about 0.001 wt % to about 2.0 wt % relative to L-cysteine; with a composition comprising one or more amino acids selected from the group consisting of: leucine, isoleucine, lysine, valine, phenylalanine, histidine, threonine, methionine, tryptophan, alanine, arginine, glycine, proline, serine, and tyrosine; and a pharmaceutically acceptable carrier, comprising water, to form a composition for infusion having a volume of about 100 mL to about 1000 mL, wherein the Aluminum provided in said parenteral nutrition regimen is from about 1-2 to about 4-5 micrograms/kg/day.