Claims for Patent: RE49443

Summary for Patent: RE49443

Title:	Process for producing a stable low concentration, injectable solution of noradrenaline
Abstract:	In a first aspect, the present invention relates to a process for producing a stable, injectable solution with low content of noradrenaline, which includes dissolving noradrenaline and optionally an excipient in deoxygenated or degassed water, filtrating the resulting noradrenaline solution in a nitrogen current, distributing the solution in a nitrogen current, and sterilization, preferably hot. The invention further provides a stable, injectable solution with low content of noradrenaline, substantially free of anti-oxidizing and preservative agents, as well as uses thereof in the medical and pharmaceutical fields.
Inventor(s):	Augusto Mitidieri, Elisabetta Donati, Nicola Caronzolo
Assignee:	Sintetica SA
Application Number:	US17/006,838
Patent Claims:	1. A stable injectable noradrenaline solution comprising noradrenaline, a solvent, an excipient, and hydrochloric acid, wherein the amount of noradrenaline is from 0.04 to 0.2 mg/ml, the solvent is degassed or deaerated water, the excipient is NaCl, and the pH of the solution is in the range of from 3.3 to 3.6, and wherein the solution is free of preservatives and anti-oxidizing agents. 2. The stable injectable noradrenaline solution according to claim 1, obtained by a process comprising: a. dissolving noradrenaline and the excipient in deoxygenated or degassed water, to obtain a concentration of noradrenaline from 0.04 to 0.20 mg/ml, b. adjusting the pH of the resulting solution by adding hydrochloric acid until a value in the range from 3.3 to 3.6 is achieved, c. filtrating the resulting noradrenaline solution in an inert gas current, d. distributing the noradrenaline solution in an inert gas current, and e. sterilizing the noradrenaline solution. 3. The stable injectable noradrenaline solution according to claim 1, having an oxygen content is equal to or lower than 100 ppb. 4. A stable injectable noradrenaline solution comprising noradrenaline or a pharmaceutically acceptable salt thereof, a solvent, an excipient, and hydrochloric acid, wherein the concentration of noradrenaline or pharmaceutically acceptable salt thereof based on the weight of noradrenaline base is from 0.04 to 0.2 mg/ml, the solvent consists of degassed or deaerated water, the excipient is NaCl, and the pH of the solution is in the range of from 3.3 to 3.6, and wherein the solution is free of preservatives and anti-oxidizing agents and complexing agents. 5. The stable injectable noradrenaline solution according to claim 1, in one or more sealed containers, obtained by a process comprising: a) dissolving noradrenaline or pharmaceutically acceptable salt thereof and the excipient in deoxygenated or degassed water, to obtain a concentration of noradrenaline or pharmaceutically acceptable salt thereof based on the weight of the noradrenaline base of from 0.04 to 0.2 mg/ml, b) adjusting the pH of the resulting solution by adding hydrochloric acid until a value in the range of from 3.3 to 3.6 is achieved, c) filtrating the resulting noradrenaline solution in an inert gas current, d) distributing the noradrenaline solution in an inert gas current into said one or more containers, and e) sterilizing the noradrenaline solution, wherein said sterilizing comprises filtrating, optionally by step (c), or heat sterilizing. 6. The stable injectable noradrenaline solution according to claim 1, wherein the solvent has an oxygen content equal to or lower than 100 ppb. 7. The solution of claim 4, wherein the concentration of noradrenaline or pharmaceutically acceptable salt thereof based on the weight of noradrenaline base is from 0.04 to 0.12 mg/ml. 8. The solution of claim 4, wherein, after six months storage at 25° C., the solution comprises: a) <0.2% arterenone; b) <0.5% impurities other than arterenone; and c) <10% d-noradrenaline; based on the weight of the noradrenaline base. 9. The solution of claim 5 wherein said sterilizing comprises filtrating. 10. The solution of claim 5, wherein the concentration of noradrenaline or pharmaceutically acceptable salt thereof based on the weight of noradrenaline base is from 0.04 to 0.12 mg/ml. 11. The solution of claim 5, wherein, after six months storage at 25° C., the solution comprises: a) <0.2% arterenone; b) <0.5% impurities other than arterenone; and c) <10% d-noradrenaline; based on the weight of the noradrenaline base. 12. A stable injectable noradrenaline solution comprising noradrenaline or a pharmaceutically acceptable salt thereof, a solvent, an excipient, and hydrochloric acid, wherein the concentration of noradrenaline or pharmaceutically acceptable salt thereof based on the weight of noradrenaline base is about 0.04 mg/ml, the solvent consists of degassed or deaerated water, the excipient is NaCl, and the pH of the solution is in the range of from 3.3 to 3.6, and wherein the solution is free of preservatives and anti-oxidizing agents and complexing agents. 13. The stable injectable noradrenaline solution according to claim 12, in one or more sealed containers, obtained by a process comprising: a) dissolving noradrenaline or a pharmaceutically acceptable salt thereof in deoxygenated or degassed water, to obtain a solution having a concentration of noradrenaline or pharmaceutically acceptable salt thereof based on the weight of the noradrenaline base of about 0.04 mg/ml, b) adjusting the pH of the solution by adding hydrochloric acid until a value in the range of from 3.3 to 3.6 is achieved, c) filtrating the solution in an inert gas current, d) distributing the solution in an inert gas current into said one or more containers, and e) sterilizing the solution, wherein said sterilizing comprises filtrating, optionally by step (c), or heat sterilizing. 14. The solution of claim 12, wherein, after six months storage at 25° C., the solution comprises: a) <0.2% arterenone; b) <0.5% impurities other than arterenone; and c) <10% d-noradrenaline; based on the weight of the noradrenaline base. 15. The solution of claim 13, wherein said sterilizing comprises filtrating. 16. The solution of claim 13, wherein, after six months storage at 25° C., the solution comprises: a) <0.2% arterenone; b) <0.5% impurities other than arterenone; and c) <10% d-noradrenaline; based on the weight of the noradrenaline base. 17. A stable injectable noradrenaline solution comprising noradrenaline bitartrate, a solvent, an excipient, and hydrochloric acid, wherein the concentration of noradrenaline bitartrate based on the weight of noradrenaline base is from 0.04 to 0.2 mg/ml, the solvent consists of degassed or deaerated water, the excipient is NaCl, the pH of the solution is in the range of from 3.3 to 3.6, and the solution is free of preservatives and anti-oxidizing agents. 18. The stable injectable noradrenaline solution according to claim 17, in one or more sealed containers, obtained by a process comprising: a) dissolving noradrenaline bitartrate in deoxygenated or degassed water, to obtain a solution having a concentration of noradrenaline bitartrate based on the weight of the noradrenaline base of from 0.04 to 0.2 mg/ml, b) adjusting the pH of the solution by adding hydrochloric acid until a value in the range of from 3.3 to 3.6 is achieved, c) filtrating the solution in an inert gas current, d) distributing the solution in an inert gas current into said one or more containers, and e) sterilizing the solution, wherein said sterilizing comprises filtrating, optionally by step (c), or heat sterilizing. 19. The solution of claim 17, wherein, after six months storage at 25° C., the solution comprises: a) <0.2% arterenone; b) <0.5% impurities other than arterenone; and c) <10% d-noradrenaline; based on the weight of the noradrenaline base. 20. The solution of claim 18, wherein said sterilizing comprises filtrating. 21. The solution of claim 18, wherein, after six months storage at 25° C., the solution comprises: a) <0.2% arterenone; b) <0.5% impurities other than arterenone; and c) <10% d-noradrenaline; based on the weight of the noradrenaline base. 22. A stable injectable noradrenaline solution comprising noradrenaline bitartrate, a solvent, an excipient, and hydrochloric acid, wherein the concentration of noradrenaline bitartrate based on the weight of noradrenaline base is about 0.04 mg/ml, the solvent consists of degassed or deaerated water, the excipient is NaCl, the pH of the solution is in the range of from 3.3 to 3.6, and the solution is free of preservatives and anti-oxidizing agents. 23. The stable injectable noradrenaline solution according to claim 22, in one or more sealed containers, obtained by a process comprising: a) dissolving noradrenaline bitartrate in deoxygenated or degassed water, to obtain a solution having a concentration of noradrenaline bitartrate based on the weight of the noradrenaline base of about 0.04 mg/ml, b) adjusting the pH of the solution by adding hydrochloric acid until a value in the range of from 3.3 to 3.6 is achieved, c) filtrating the solution in an inert gas current, d) distributing the solution in an inert gas current into said one or more containers, and e) sterilizing the solution, wherein said sterilizing comprises filtrating, optionally by step (c), or heat sterilizing. 24. The solution of claim 22, wherein, after six months storage at 25° C., the solution comprises: a) <0.2% arterenone; b) <0.5% impurities other than arterenone; and c) <10% d-noradrenaline; based on the weight of the noradrenaline base. 25. The solution of claim 23, wherein said sterilizing comprises filtrating.