Stable, highly pure L-cysteine compositions for injection and methods of use

• US 10,653,719 B1
• Filed: 01/27/2020
• Issued: 05/19/2020
• Est. Priority Date: 01/15/2019
• Status: Active Grant

• Current Assignee: Exela Pharma Sciences LLC (Exela Holdings Incorporated)
• Original Assignee: Exela Pharma Sciences LLC (Exela Holdings Incorporated)
• Inventors: Maloney, John, Koganti, Aruna, Koneru, Phanesh
• Primary Examiner(s): Packard, Benjamin J
• Application Number:
  US16/773,563
• Time in Patent Office: 113 Days
• CPC Class Codes: A23L 33/16 Inorganic salts, minerals or trace elements
• CPC Class Codes: A23L 33/17 Amino acids, peptides or proteins
• CPC Class Codes: A23L 33/175 Amino acids
• CPC Class Codes: A23V 2002/00 Food compositions, function of food ingredients or processes for food or foodstuffs
• CPC Class Codes: A23V 2250/052 Pyruvic acid
• CPC Class Codes: A23V 2250/0616 Cysteine
• CPC Class Codes: A23V 2250/1564 Aluminium
• CPC Class Codes: A61J 1/1412 Containers with closing means, e.g. caps
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/095 Sulfur, selenium, or tellurium compounds, e.g. thiols
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/191 having two or more hydroxy groups, e.g. gluconic acid
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/4172 Imidazole-alkanecarboxylic acids, e.g. histidine
• CPC Class Codes: A61K 33/00 Medicinal preparations containing inorganic active ingredients
• CPC Class Codes: A61K 33/06 Aluminium, calcium or magnesium; Compounds thereof , e.g. clay
• CPC Class Codes: A61K 33/241 Lead; Compounds thereof
• CPC Class Codes: A61K 33/28 Mercury; Compounds thereof
• CPC Class Codes: A61K 33/36 : Arsenic; Compounds thereof
• CPC Class Codes: A61K 47/02 : Inorganic compounds
• CPC Class Codes: A61K 47/12 : Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 9/0029 : Parenteral nutrition; Parenteral nutrition compositions as drug carriers
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals

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 O₂ 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.

Claims

1. A solution of L-cysteine comprising,

a pharmaceutically acceptable carrier,

about 50 mg/mL of L-cysteine hydrochloride monohydrate, or equivalent amount of a pharmaceutically acceptable L-cysteine or a salt or hydrate thereof,

less than about 150 ppb of aluminum,

a pH from about 1.0 to about 2.5, and

wherein the solution is substantially free of visually detectable particulate matter and suitable for use as an additive in a parenteral nutrition composition for administration to an individual.

2. The solution of claim 1, which comprises less than about 100 ppb of aluminum.

3. The solution of claim 1, which comprises less than about 50 ppb of aluminum.

4. The solution of claim 1, which comprises less than about 20 ppb of aluminum.

5. The solution of claim 1, which comprises less than about 10 ppb of aluminum.

6. The solution of claim 1, which comprises from about 1 ppb to about 150 ppb of aluminum.

7. The solution of claim 1, which has a dissolved oxygen content of less than 2 ppm.

8. The solution of claim 1, wherein the pH is about 1.8 and in which the solution is substantially free of cystine precipitates.

9. The solution of claim 1, wherein the solution is substantially free of visually detectable particulate matter when stored for 18 months at about 25°

C. and about 60% relative humidity.

10. The solution of claim 9, wherein the pharmaceutically acceptable carrier is aqueous.

11. The solution of claim 1, wherein the solution is essentially free of cystine precipitates.

12. A solution of L-cysteine comprising,

a pharmaceutically acceptable carrier,

about 50 mg/mL of L-cysteine hydrochloride monohydrate, or equivalent amount of a pharmaceutically acceptable L-cysteine or a salt or hydrate thereof,

less than about 150 ppb of aluminum, and

a pH from about 1.0 to about 2.5,

wherein the solution is substantially free of visually detectable particulate matter for at least 6 months from the time of manufacture of the solution and is suitable for use as an additive in a parenteral nutrition composition for administration to a neonate or infant.

13. The solution of claim 12, wherein the solution is substantially free of visually detectable particulate matter for at least 9 months from the time of manufacture of the solution.

14. The solution of claim 12, wherein the solution is substantially free of visually detectable particulate matter for at least 12 months from the time of manufacture of the solution.

15. The solution of claim 12, wherein the solution is substantially free of visually detectable particulate matter for at least 24 months from the time of manufacture of the solution.

16. The solution of claim 12, wherein the solution is essentially free of cystine precipitates.

17. A solution of L-cysteine comprising,

a pharmaceutically acceptable carrier,

about 50 mg/mL of L-cysteine hydrochloride monohydrate, or equivalent amount of a pharmaceutically acceptable L-cysteine or a salt or hydrate thereof, in a low oxygen environment,

less than about 150 ppb of aluminum, and

a pH from about 1.0 to about 2.5,

wherein the solution is substantially free of visually detectable particulate matter and is suitable for use as an additive in a parenteral nutrition composition for administration to a neonate or infant.

18. The solution of claim 17, wherein the solution is substantially free of visually detectable particulate matter for at least 6 months after the time of manufacture of the solution.

19. The solution of claim 17, wherein the solution is substantially free of visually detectable particulate matter for at least 9 months after the time of manufacture of the solution.

20. The solution of claim 17, wherein the solution is substantially free of visually detectable particulate matter for at least 12 months after the time of manufacture of the solution.

21. The solution of claim 17, wherein the solution is substantially free of visually detectable particulate matter for at least 24 months after the time of manufacture of the solution.

22. The solution of claim 17, wherein the solution has a dissolved oxygen content of less than about 5 ppm.

23. The solution of claim 17, wherein the solution has a dissolved oxygen content of less than about 2 ppm.

24. The solution of claim 17, wherein the solution has a dissolved oxygen content of less than about 1 ppm.

25. The solution of claim 17, wherein the solution has a dissolved oxygen content of about 0.4 ppm to about 3.8 ppm.

26. The solution of claim 17, wherein the solution is essentially free of cystine precipitates.

27. The solution of claim 18, wherein the solution is essentially free of cystine precipitates.