Claims for Patent: RE49422

Summary for Patent: RE49422

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:	US17/006,840
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, e. sterilizing the noradrenaline solution. 3. The stable injectable noradrenaline solution according to claim 1, 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 less than or equal 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 4, 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 less than or equal 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 during step (c), or heat sterilizing. 6. The stable injectable noradrenaline solution according to claim 4, wherein the solvent has an oxygen content equal to or lower than 100 ppb. 7. 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. 8. The solution of claim 5 wherein said sterilizing comprises filtrating during step (c). 9. The solution of claim 5, wherein the solvent has an oxygen content equal to or lower than 100 ppb. 10. 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. 11. The solution of claim 6, 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 bitartrate based on the weight of noradrenaline base is less than or equal 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. 13. The stable injectable noradrenaline solution according to claim 12, in one or more sealed containers, obtained by a process comprising: a) dissolving noradrenaline bitartrate and the excipient in deoxygenated or degassed water, to obtain a solution having a concentration of noradrenaline bitartrate based on the weight of the noradrenaline base of less than or equal 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 during step (c), or heat sterilizing. 14. The stable injectable noradrenaline solution according to claim 12, wherein the solvent has an oxygen content equal to or lower than 100 ppb. 15. 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. 16. The solution of claim 13 wherein said sterilizing comprises filtrating during step (c). 17. The solution of claim 13, wherein the solvent has an oxygen content equal to or lower than 100 ppb. 18. 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. 19. The solution of claim 14, 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. A container of a low concentration injectable noradrenaline bitartrate solution, having a noradrenaline bitartrate concentration less than 1 mg/ml based on the weight of noradrenaline base, produced by a method comprising the following steps in the substantial absence of air or oxygen: a) dissolving noradrenaline bitartrate in deoxygenated or degassed water to make a solution comprising less than 1 mg/ml noradrenaline bitartrate based on the weight of the noradrenaline base; b) adjusting the pH of the solution by adding hydrochloric acid until a value of from 3.3 to 3.6 is achieved; c) filtrating the solution in an inert gas current d) distributing the solution into said one or more containers in a current of an inert gas; and e) sterilizing the solution; wherein: i) said sterilizing comprises filtrating, optionally during step (c), or heat sterilizing; ii) after six months storage at 25° C., the solution comprises: <0.2% arterenone, <0.5% impurities other than arterenone; and <10% d-noradrenaline, based on the weight of the noradrenaline base; and iii) the solution is free of preservatives and anti-oxidizing agents. 21. The container of claim 20, wherein said sterilizing comprises filtrating during step (c). 22. The container of claim 20, wherein the solution is preservative-free, antioxidant-free, and free of complexing agents. 23. The container of claim 20, wherein the solution comprises less than or equal to 0.2 mg/ml noradrenaline bitartrate based on the weight of the noradrenaline base.