Infusion dosage form of norepinephrine

Patent metadata

Field	Value
Publication number	US-11865089-B2
Application number	US-202117451292-A
Country	US
Kind code	B2
Filing date	Oct 18, 2021
Priority date	Aug 8, 2019
Publication date	Jan 9, 2024
Grant date	Jan 9, 2024

Abstract

The present invention provides a ready to use stable aqueous dosage form of norepinephrine comprising an aqueous solution of norepinephrine or its pharmaceutically acceptable salt, one or more sulfite antioxidants and an ion chelator. The present invention also provides an infusion container filled with an aqueous solution of norepinephrine or its pharmaceutically acceptable salt, wherein the said solution is stable for a prolonged period of time and can be terminally sterilized by autoclaving.

First claim

What is claimed is:

1. An aqueous ready to infuse stable parenteral dosage form consisting essentially of:
a. norepinephrine or its pharmaceutically acceptable salt at a concentration ranging from to 75 micrograms/ml of norepinephrine base;
b. at least one sulfite antioxidant; and
c. at least one ion chelator,

wherein, after subjected to terminal sterilization by autoclaving and stored at 40° C. and 25% relative humidity for 6 months, the dosage form contains no more than 0.2% by weight of each of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol, 1,2,3,4-tetrahydroisoquinoline-4,7,8-triol, and 3,4-dihydroxybenzaldehyde.

2. The ready to infuse dosage form of claim 1 , further comprising sodium chloride.

3. The ready to infuse dosage form of claim 1 , wherein the dosage form, after subjected to terminal sterilization by autoclaving and stored at 40° C. and 25% relative humidity for 6 months, contains a total impurities content of no more than 1.0% by weight.

4. The ready to infuse dosage form of claim 1 , wherein the dosage form, after subjected to terminal sterilization by autoclaving and stored at 25° C. and 40% relative humidity for 18 months, contains no more than 0.2% by weight of each of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol, 1,2,3,4-tetrahydroisoquinoline-4,7,8-triol, and 3,4-dihydroxybenzaldehyde.

5. The ready to infuse dosage form of claim 1 , wherein the dosage form, after subjected to terminal sterilization by autoclaving and stored at 25° C. and 40% relative humidity for 18 months, contains a total impurities content of no more than 1.0% by weight.

6. The ready to infuse dosage form of claim 1 , wherein the dosage form further comprises an osmogen.

7. The ready to infuse dosage form of claim 6 , wherein the osmogen is selected from one or more of sodium chloride, calcium chloride, magnesium chloride, potassium chloride, inorganic salts, urea, glycerin, glycerol, sucrose, xylitol, fructose, maltitol, mannose, inositol, trehalose, and mixtures thereof.

8. The ready to infuse dosage form of claim 1 , wherein the dosage form is free of sugar and sugar alcohol.

9. The ready to infuse dosage form of claim 1 , wherein the dosage form further comprises at least one pH adjusting agent.

10. The ready to infuse dosage form of claim 1 , wherein the sulfite antioxidant is selected from one or more of sodium sulfite, potassium metabisulfite, sodium bisulfite, and sodium metabisulfite.

11. The ready to infuse dosage form of claim 1 , wherein the dosage form further comprises an antioxidant selected from one or more of butylated hydroxyl anisole, ascorbic acid, sodium ascorbate, propyl gallate, vitamin E, and alpha-tocopherol.

12. The ready to infuse dosage form of claim 1 , wherein the ion chelator is selected from one or more of ethylenediaminetetraacetic acid (EDTA), edetic acid, disodium edetate dihydrate, disodium edetate, disodium EDTA, dipotassium edetate, dipotassium EDTA, edetate calcium disodium, edetate trisodium, pentasodium pentetate, diethylenetriamine, and pentaacetic acid.

13. The ready to infuse dosage form of claim 12 , wherein the ion chelator is disodium edetate.

14. The ready to infuse dosage form of claim 12 , wherein the ion chelator is EDTA or its salt and present at a concentration ranging from about 16 microgram/ml to about 64 microgram/ml.

15. The ready to infuse dosage form of claim 1 , wherein the ion chelator is present at a concentration ranging from about 4 to about 100 microgram/ml.

16. The ready to infuse dosage form of claim 1 , wherein norepinephrine or its pharmaceutically acceptable salt is present at a concentration ranging from about 16 to about 64 microgram/ml of norepinephrine base.

17. The ready to infuse dosage form of claim 1 , wherein the sulfite antioxidant is present at a concentration ranging from about 3 to about 15 microgram/ml.

18. The ready to infuse dosage form of claim 1 , wherein the pH of the aqueous solution is in the range of 3.0 to 4.5.

19. The ready to infuse dosage form of claim 1 , wherein the dosage form is filled in an infusion container.

20. The ready to infuse dosage form of claim 1 , wherein the dosage form is filled in a flexible plastic infusion container.

21. The ready to infuse dosage form of claim 19 , wherein the dosage form is further packaged in a secondary packaging.

22. The ready to infuse dosage form of claim 21 , wherein the secondary packaging comprises an aluminium pouch.

23. The ready to infuse dosage form of claim 21 , wherein a space between the infusion container and the secondary packaging is occupied with an oxygen scavenger or an inert gas.

24. The ready to infuse dosage form of claim 19 , wherein the infusion container is made up of a material selected from a plastic; polyolefin polymers; polyethylene; polypropylene; cyclo olefin polymers; cyclo olefin copolymers; polypropylene based polyolefin polymers; polycarbonates; modified polyolefin-polyethylene polymers; styrene-polyolefin based polymers; and block co-polymers thereof.

25. A method for controlling blood pressure in an acute hypotensive state, the method comprising administering an aqueous ready to infuse stable parenteral dosage form to a patient in need thereof, the ready to infuse dosage form consisting essentially of:
a. norepinephrine or its pharmaceutically acceptable salt at a concentration ranging from to 75 micrograms/ml of norepinephrine base;
b. at least one sulfite antioxidant; and
c. at least one ion chelator,

wherein, after subjected to terminal sterilization by autoclaving and stored at 40° C. and 25% relative humidity for 6 months, the dosage form contains no more than 0.2% by weight of each of 1,2,3,4-tetrahydroisoquinoline-4,6,7-triol, 1,2,3,4-tetrahydroisoquinoline-4,7,8-triol, and 3,4-dihydroxybenzaldehyde.

26. The method of claim 25 , wherein the acute hypotensive state is selected from the group consisting of pheochromocytomectomy, sympathectomy, poliomyelitis, spinal anesthesia, myocardial infarction, septicemia, blood transfusion, and a drug reaction.

27. An infusion bag for parenteral administration of an aqueous solution consisting of:
(A) an aqueous ready to infuse parenteral solution consisting essentially of:
i. 10-75 micrograms/mL norepinephrine or its pharmaceutically acceptable salt;
ii. 9000 micrograms/mL sodium chloride;
iii. 3.2 micrograms/mL sodium metabisulfite;
iv. 16 micrograms/mL disodium edetate;
v. 0.1 micrograms/mL butylated hydroxyanisole; and
vi. optionally, sodium hydroxide or hydrochloric acid; and

(B) an inert gas which has displaced air in the infusion bag.

28. The infusion bag of claim 27 , wherein the aqueous ready to infuse parenteral solution comprises 16 micrograms/ml of norepinephrine or its pharmaceutically acceptable salt.

29. The infusion bag of claim 27 , wherein the aqueous ready to infuse parenteral solution comprises 32 micrograms/ml of norepinephrine or its pharmaceutically acceptable salt.

30. The infusion bag of claim 27 , wherein the aqueous ready to infuse parenteral solution comprises 64 micrograms/ml of norepinephrine or its pharmaceutically acceptable salt.

31. The infusion bag of claim 27 , wherein the pharmaceutically acceptable salt of norepinephrine is norepinephrine bitartrate.

32. The infusion bag of claim 27 , wherein the pH of the aqueo

Assignees

• Sun Pharmaceutical Ind Ltd

Inventors

• Kumar Samarth
• Soni Maheshkumar Parasmal
• SRIVASTAVA Praveen Kumar
• Kane Prashant
• Bhowmick Subhas Balaram

Classifications

• A61K31/137 Primary

  Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone} · CPC title

• A61K9/08 Primary

  Solutions {(composition of solutions A61K47/00)} · CPC title

• A61K47/02

  Inorganic compounds · CPC title

• A61K47/183

  Amino acids, e.g. glycine, EDTA or aspartame · CPC title

• A61K9/0019

  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 title