Infusion dosage form of norepinephrine

Patent metadata

Field	Value
Publication number	US-11197838-B2
Application number	US-202016989027-A
Country	US
Kind code	B2
Filing date	Aug 10, 2020
Priority date	Aug 8, 2019
Publication date	Dec 14, 2021
Grant date	Dec 14, 2021

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

The invention claimed is:

1. A ready to infuse stable parenteral dosage form consisting essentially of:
a. norepinephrine or its pharmaceutically acceptable salt at a concentration ranging from 10 to 75 micrograms/ml of norepinephrine base;
b. at least one sulfite antioxidant;
c. at least one ion chelator; and
d. sodium chloride,

wherein the dosage form is an aqueous solution and was terminally sterilized by autoclaving;
wherein the content of total impurities of norepinephrine in the sterilized solution, after storage at 40° C./25% RH for 6 months, is not more than 1% by weight of norepinephrine; and
wherein the dosage form, when stored at room temperature, is stable for a period of at least 18 months.

2. The ready to infuse dosage form of claim 1 , wherein the dosage form further comprises at least one osmogen.

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

4. The ready to infuse dosage form of claim 2 , 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, and trehalose.

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

6. 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.

7. 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.

8. 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 EDTA, di-potassium edetate, dipotassium EDTA, edetate calcium disodium, edetate trisodium, pentasodium pentetate, diethylenetriamine, and pentaacetic acid.

9. 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.

10. 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.

11. 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.

12. The ready to infuse dosage form of claim 8 , wherein the ion chelator is disodium edetate.

13. The ready to infuse dosage form of claim 8 , 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.

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

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

16. The ready to infuse dosage form of claim 15 , wherein the dosage form is further packaged in a secondary packaging.

17. The ready to infuse dosage form of claim 16 , wherein the secondary packaging comprises an aluminium pouch.

18. The ready to infuse dosage form of claim 16 , wherein a space between the infusion container and the secondary packaging is occupied with an oxygen scavenger or an inert gas.

19. The ready to infuse dosage form of claim 15 , wherein the infusion container is made up of a material selected from plastic; polyolefin polymers; polyethylene; polypropylene; cyclo olefin polymers; cyclo olefin copolymers; polypropylene based polyolefin polymers; polycarbonates; modified polyolefinpolyethylene polymers; styrene-polyolefin based polymers; and block co-polymers thereof.

20. A method for controlling blood pressure in an acute hypotensive state selected from the group consisting of pheochromocytomectomy, sympathectomy, poliomyelitis, spinal anesthesia, myocardial infarction, septicemia, blood transfusion, and a drug reaction, wherein the method comprises administering a ready to infuse dosage form of claim 1 .

21. An infusion container filled with a ready to infuse stable aqueous solution of norepinephrine, the solution consisting essentially of:
norepinephrine bitartrate at a concentration equivalent to about 10 microgram/ml to about 75 microgram/ml of norepinephrine base,
sodium metabisulfite at least one sulfite antioxidant at a concentration ranging from about 3 microgram/ml to about 15 microgram/ml,
disodium edetate at a concentration ranging from about 4 microgram/ml to about 100 microgram/ml,
butylated hydroxyanisole at a concentration ranging from about 0.1 microgram/ml to about 0.4 microgram/ml, and
sodium chloride,

wherein (i) the solution filled in the infusion container was terminally sterilized by autoclaving, and (ii) the solution has a pH of 3 to 4.5.

22. The infusion container of claim 21 , wherein the solution, when subjected to autoclaving at about 121° C. for 15 minutes and stored at 40° C. and 25% relative humidity for 6 months, contains no more than 0.2% by weight of 3,4-dihydroxybenzaldehyde.

23. The infusion container of claim 21 , wherein the solution filled in the infusion container was terminally sterilized by autoclaving at 121° C. for 15 minutes.

24. The ready to infuse dosage form of claim 1 , wherein the dosage form, when subjected to autoclaving at about 121° C. for 15 minutes, contains no more than 0.2% by weight of 3,4-dihydroxybenzaldehyde.

25. The ready to infuse dosage form of claim 1 , wherein the dosage form was terminally sterilized by autoclaving at 121° C. for 15 minutes.

Assignees

• Sun Pharmaceutical Ind Ltd

Inventors

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

Classifications

• A61K47/02

  Inorganic compounds · CPC title

• A61K47/183

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

• 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

• 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