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 container of a low concentration, preservative free, anti-oxidant-free, injectable noradrenaline bitartrate solution made by a process 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 having a noradrenaline bitartrate concentration less than 1 mg/ml based on the weight of 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 said sterilizing comprises filtrating or heat sterilizing. .Iaddend.

.Iadd.5. The container of claim 4, wherein: a) the solution is preservative-free, antioxidant-free, and free of complexing agents; b) after six months storage at 25° C., the solution comprises based on the weight of the noradrenaline base: i) <0.2% arterenone; ii) <0.5% impurities other than arterenone; and iii) <10% d-noradrenaline; c) the solution comprises less than 0.2 mg/ml noradrenaline bitartrate based on the weight of the weight of noradrenaline base; and d) the deoxygenated or degassed water comprises less than 100 ppb oxygen. .Iaddend.

.Iadd.6. The container of claim 4, wherein: a) after six months storage at 25° C., the solution comprises based on the weight of the noradrenaline base: i) <0.2% arterenone; ii) <0.5% impurities other than arterenone; and iii) <10% d-noradrenaline; b) the solution comprises less than 0.2 mg/ml noradrenaline bitartrate based on the weight of the weight of noradrenaline base; and c) the deoxygenated or degassed water comprises less than 100 ppb oxygen; and d) said sterilizing comprises filtrating during step (c). .Iaddend.

Description

Example 1

(1) 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,

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

(3) 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.

(4) 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.

(5) 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

(6) 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).

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

(8) 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

(9) Stability of Diluted Noradrenaline Solutions

(10) 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.

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

(12) 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

(13) Low Concentration Noradrenaline Injectable Solutions

(14) 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

(15) Low Concentration Noradrenaline Injectable Solutions

(16) 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

(17) Low Concentration Noradrenaline Injectable Solutions

(18) 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

(19) Low Concentration Noradrenaline Injectable Solutions

(20) 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