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.

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..].

.Iadd.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..Iaddend.

.Iadd.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..Iaddend.

.Iadd.6. The stable injectable noradrenaline solution according to claim 4, wherein the solvent has an oxygen content equal to or lower than 100 ppb..Iaddend.

.Iadd.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..Iaddend.

.Iadd.8. The solution of claim 5 wherein said sterilizing comprises filtrating during step (c)..Iaddend.

.Iadd.9. The solution of claim 5, wherein the solvent has an oxygen content equal to or lower than 100 ppb..Iaddend.

.Iadd.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..Iaddend.

.Iadd.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..Iaddend.

.Iadd.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..Iaddend.

.Iadd.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..Iaddend.

.Iadd.14. The stable injectable noradrenaline solution according to claim 12, wherein the solvent has an oxygen content equal to or lower than 100 ppb..Iaddend.

.Iadd.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..Iaddend.

.Iadd.16. The solution of claim 13 wherein said sterilizing comprises filtrating during step (c)..Iaddend.

.Iadd.17. The solution of claim 13, wherein the solvent has an oxygen content equal to or lower than 100 ppb..Iaddend.

.Iadd.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..Iaddend.

.Iadd.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..Iaddend.

.Iadd.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..Iaddend.

.Iadd.21. The container of claim 20, wherein said sterilizing comprises filtrating during step (c)..Iaddend.

.Iadd.22. The container of claim 20, wherein the solution is preservative-free, antioxidant-free, and free of complexing agents..Iaddend.

.Iadd.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..Iaddend.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The Applicant has identified a process for producing noradrenaline injectable solutions, in particular at low concentrations, which are particularly stable in the absence of anti-oxidizing, preservative and/or complexing agents.

(2) According to certain aspects the invention thus relates to a process for the production of a noradrenaline injectable solution, in particular with a content of noradrenaline of 0.04 to 0.20 mg/ml comprising the following steps: a. dissolving noradrenaline and optionally an excipient in deoxygenated or degassed water to give a noradrenaline solution, b. adjusting the pH of the noradrenaline solution by adding an aqueous solution of hydrochloric acid to reach a pH from 3.2 to 3.6, c. filtrating the noradrenaline solution resulting from step b. in a current of inert gas, typically nitrogen, d. distributing the noradrenaline solution of step c. in a current of inert gas, typically nitrogen, e. sterilizing the noradrenaline solution obtained by step d.

(3) According to some embodiments of the invention, the dissolving step includes dissolving 0.04 to 0.20 mg of noradrenaline per ml of infusion water.

(4) Typically, the water used to prepare the solution is degassed or deaerated, distilled, sterile, pyrogen-free water for pharmaceutical use.

(5) According to some embodiments, the deoxygenated or degassed water is obtained by blowing or bubbling an inert gas current, typically based on nitrogen or a noble gas such as argon.

(6) In the process of the invention, any inert gas can be used, such as nitrogen, argon and mixtures thereof, to remove oxygen or air in one or more of the steps and to limit risks of oxidation of the noradrenaline contained in the injectable aqueous solution.

(7) Typically, in step a) noradrenaline and any optional excipients is dissolved in water for pharmaceutical sterile preparations, for example deaerated or degassed by bubbling or blowing an inert gas. Dissolution can be carried out within a suitable inert container, in which air or oxygen have been removed by passage of inert gas. During dissolution of the noradrenaline an inert gas can be blown into the container or tank of the solution, to remove any residual oxygen.

(8) According to some embodiments, upon completion of process step a) the noradrenaline injectable solution obtained has a residual oxygen content equal to or lower than 100 ppb.

(9) In process step b), the pH of the noradrenaline aqueous solution is finely adjusted within the selected range of 3.2 to 3.6, preferably within a pH range of 3.3 to 3.6, in particular until a value close to 3.4 is reached, for example, typically by adding 1N HCl, in order to further stabilize the solution, reducing noradrenaline degradation.

(10) The Applicant has indeed verified that pH values of the solution higher than 3.6 cause an increase of the formation of arterenone, while pH values lower than 3.2 have greater incidence in the appearance of d-noradrenaline.

(11) It was unexpectedly observed that, even a small variation or adjustment of the pH value of the noradrenaline injectable solution from 3.1 to 3.2, even more and especially from 3.1 to 3.3, causes a significant reduction or absence in the racemization of noradrenaline to d-noradrenaline and an increase to the therapeutic activity as well as stability of the injectable solution.

(12) Therefore, the specific conditions of the process of the invention minimize the formation of arterenone, the main degradation product of noradrenaline and enantiomer of d-noradrenaline, which features lower therapeutic activity.

(13) Step c) of filtration of the process is performed by passing the solution containing noradrenaline through a filter of the type for sterilization. Passage of the noradrenaline solution through the filter can be speeded up by blowing a current of inert gas which acts as a carrier.

(14) Suitable filters are those used in the pharmaceutical technology for preparation of sterile injectable solutions.

(15) In step d), the noradrenaline solution is distributed in suitable containers such vials or ampoules depyrogenated preferably in the presence of inert gas, typically nitrogen, in order to minimize the volume of residual oxygen in the head of the sealed bottle and to prevent oxidative effects that may affect the stability of the solution itself.

(16) Carrying out both steps c) and d), respectively for filtration and filling in nitrogen current, fulfils the main purpose of keeping the values of residual oxygen in the noradrenaline injectable solution to very low levels or oxygen free.

(17) In some embodiments, at the end of step d), the noradrenaline injectable solution obtained has a residual oxygen content equal to or lower than 100 ppb.

(18) The diluted noradrenaline solution sterilization step may be accomplished by heating, typically at temperatures above 100° C., for a time suitable for sterilization, for example equal to or greater than 15 minutes.

(19) Surprisingly, the noradrenaline injectable solution at low concentration was stable after sterilization for 15 minutes at 121° C.

(20) The inventors have found that the substantial absence of air or oxygen and the correction of the pH of the solution to a value in the range of 3.2 to 3.6, in particular close to 3.4 units, increases the stability of the noradrenaline solution, allowing storage at room temperature for long periods of time, up to 6 months.

(21) According to some aspects of the invention, the steps of the process of manufacture are carried out in sterile environments in order to avoid bacterial contamination of the noradrenaline solution.

(22) According to a further aspect the present invention provides a noradrenaline injectable solution stable and substantially free of preservatives and/or anti-oxidizing agents, optionally containing an excipient, in which the concentration of noradrenaline is in the range of 0.04 to 0.2 mg/ml and pH is 3.2 to 3.6.

(23) In some embodiments the noradrenaline stable injectable solution is substantially free of preservatives and/or anti-oxidizing agents and the noradrenaline concentration is between 0.04 and 0.2 mg/ml, and pH is between 3.2 and 3.6, preferably between 3.3 and 3.6.

(24) Within the scope of the invention, by the term “substantially free of preservatives and/or anti-oxidizing agents” is meant that preservatives and/or antioxidant agents, if present, are present as impurities, typically in an amount less than 0.005% by weight, as determined by HPLC-MS.

(25) In some embodiments the noradrenaline injectable solution is free of anti-oxidizing and/or preservative agents.

(26) Typically, the stable, injectable solution is a water-based solution and may be obtained by a process according to any one of the embodiments previously described.

(27) According to some embodiments, the injectable solution of the invention contains an excipient, typically NaCl, in particular at a concentration in the range of 8.2 to 8.6 mg/ml, for example equal to 8.4 mg/ml.

(28) The injectable solution of the invention has a particularly low content of oxygen dissolved in the solvent water, typically less than 100 ppb.

(29) According to some embodiments, the stable noradrenaline injectable solution of the invention contains less than 0.05% by weight of arterenone. According to these and other embodiments of the invention, the stable noradrenaline injectable solution of the invention has an acidic pH selected in the range of 3.2 to 3.6, preferably of 3.3 to 3.6, and may have a content of enantiomer d-noradrenaline equal to or less than 5% by weight, with respect to the total weight of active principle (noradrenaline in one of its active forms) present in the solution.

(30) In some embodiments, the injectable solution of the invention has a pH value from 3.3 to 3.6 and a content of enantiomer d-noradrenaline equal to or less than 2% by weight or 1% by weight with respect to the total weight of noradrenaline present in the solution.

(31) According to some embodiments, the noradrenaline contained in the injectable solution is in the form of a pharmaceutically acceptable salt, for example, bitartrate.

(32) The noradrenaline injectable solution has a surprising stability, even at high temperatures. The inventors have conducted studies on the stability at 40° C. with the noradrenaline injectable solutions, and have found that, in these conditions of temperature, stability lasts at least 3 months.

(33) With the present invention the inventors have achieved some significant advantages including a surprising increase of stability in injectable solutions with a concentration of 0.04 to 0.2 mg/ml and surprisingly low levels of impurities with a pH of 3.2-3.6, in particular of 3.3 to 3.6, which determine a significant increase in the product safety profile.

(34) In addition, the low concentration noradrenaline solution is surprisingly stable at room temperature for at least 6 months.

(35) Typically, the low concentration noradrenaline injectable solutions of the invention are filled into sterile containers such as vials or ampoules in a modified atmosphere, for example in the presence of an inert gas containing basically nitrogen and/or argon.

(36) According to a further aspect, the present invention relates to a pharmaceutical composition comprising noradrenaline in a quantity of 0.04 to 0.2 mg/ml obtained by a process according to any one of the embodiments previously described, and a pharmaceutically acceptable carrier and/or excipient.

(37) Pharmaceutically acceptable carriers and excipients include substances commonly used in the production techniques of pharmaceutical and medical devices.

(38) The present invention claims the priority of the Italian patent application MI2014A000306 of 27 Feb. 2014, the content of which is entirely incorporated herein by reference.

(39) The present invention is described below, with reference to the following examples, which are provided for illustrative purposes only and should not be understood as limiting the present invention.

Example 1

(40) 4 diluted solutions of noradrenaline at different concentration were studied: diluted solution containing 0.04 mg/ml (2 mg/50 ml) of noradrenaline, diluted solution containing 0.06 mg/ml (3 mg/50 ml) of noradrenaline, diluted solution containing 0.12 mg/ml (6 mg/50 ml) of noradrenaline, diluted solution containing 0.20 mg/ml (10 mg/50 ml) of noradrenaline,

(41) The noradrenaline solutions were prepared using water deoxygenated by nitrification (residual oxygen <100 ppb).

(42) The noradrenaline solutions were obtained with a process which involved the following schematic steps: a) dissolving the active principle and the excipients in water deoxygenated by degassing in a nitrogen current b) filtrating the solution in a nitrogen current c) distribution of the solution in a nitrogen current, d) sterilizing the vials at 121° C. for 15 minutes.

(43) After loading the blender, the water for injections was degassed by boiling and then cooled to 25° C. Sodium chloride and noradrenaline bitartrate were added in this order. The solution was kept under stirring, maintaining a constant blowing of nitrogen, for 10 minutes. After 10 minutes, the pH value of the solution was measured and corrected with 1N hydrochloric acid, until it reached the value of 3.4 units, in any case within the range of 3.2-3.6.

(44) TABLE-US-00001 2 mg/50 ml 3 mg/50 ml 6 mg/50 ml 10 mg/50 ml pH 3.4 3.5 3.4 3.5

(45) The solution was filtered under nitrogen pressure in a nitrogen current and distributed in clear glass 50 ml bottles. The bottles were then subjected to terminal sterilization in autoclave under overkill conditions (121° C. for 15 minutes).

(46) Tests carried out on the vials after sterilization gave the following results:

(47) TABLE-US-00002 2 mg/50 ml 3 mg/50 ml 6 mg/50 ml 10 mg/50 ml Color and In In In In transparency conformity conformity conformity conformity pH of the 3.4 3.5 3.4 3.5 solution Titer of 99.3% 99.2%  98.8%  98.7% Noradrenaline (HPLC) Titer of Not detected Not detected Not detected <0.05% Arterenone (HPLC) Titer of Not detected Not detected <0.05% <0.05% impurities (HPLC)

Example 2

(48) Stability of Diluted Noradrenaline Solutions

(49) Stability: 4 batches with concentration of noradrenaline respectively of 0.04 mg/ml, 0.06 mg/ml, 0.12 mg/ml, 0.20 mg/ml were placed at 25° C. and 40° C.

(50) After 6 months at 25° C. and 3 months at 40° C., the solutions were unchanged from a physico-chemical point of view.

(51) The titer of noradrenaline remains above 90%. Arterenone impurity was always below 0.2% and the total of other impurities was less than 0.5%. The enantiomer concentration remains always lower than 10%.

Example 3

(52) Low Concentration Noradrenaline Injectable Solutions

(53) TABLE-US-00003 Noradrenaline 0.04 mg/ml Pro 1 ml Pro 50 ml Noradrenaline Bitartrate 0.08* mg 4.00* mg Sodium Chloride 8.4 mg 420.0 mg Hydrochloric acid q.s. ad q.s. ad pH 3.3-3.6 pH 3.3-3.6 Water for injections ad 1 ml ad 50 ml *Corresponding respectively to 0.04 mg and 2.00 mg of noradrenaline base

Example 4

(54) Low Concentration Noradrenaline Injectable Solutions

(55) TABLE-US-00004 Noradrenaline 0.06 mg/ml Pro 1 ml Pro 50 ml Noradrenaline Bitartrate 0.12* mg 6.00* mg Sodium Chloride 8.4 mg 420.0 mg Hydrochloric acid q.s. ad q.s. ad pH 3.2-3.6 pH 3.2-3.6 Water for injections ad 1 ml ad 50 ml *Corresponding respectively to 0.06 mg and 3.00 mg of noradrenaline base

Example 5

(56) Low Concentration Noradrenaline Injectable Solutions

(57) TABLE-US-00005 Noradrenaline 0.12 mg/ml Pro 1 ml Pro 50 ml Noradrenaline Bitartrate 0.24* mg 12.00* mg Sodium Chloride 8.4 mg 420.0 mg Hydrochloric acid q.s. ad q.s. ad pH 3.2-3.6 pH 3.2-3.6 Water for injections ad 1 ml ad 50 ml *Corresponding respectively to 0.12 mg and 6.00 mg of noradrenaline base

Example 6

(58) Low Concentration Noradrenaline Injectable Solutions

(59) TABLE-US-00006 Noradrenaline 0.2 mg/ml Pro 1 ml Pro 50 ml Noradrenaline Bitartrate 0.40* mg 20.0* mg Sodium Chloride 8.4 mg 420.0 Hydrochloric acid q.s. ad q.s. ad pH 3.3-3.6 pH 3.3-3.6 Water for injections ad 1 ml ad 50 ml *Corresponding respectively to 0.20 mg and 10.0 mg of noradrenaline base