阅读说明：本技术 制备具有低溶解氧含量、包含对乙酰氨基酚和任选地一种或多种nsaid的组合物的方法以及由其获得的组合物 (Process for preparing a composition having a low dissolved oxygen content comprising paracetamol and optionally one or more NSAIDs and the composition obtained thereby ) 是由 T·雅各布森 于 2018-04-20 设计创作，主要内容包括：本发明提供一种用于制备包含对乙酰氨基酚和任选地一种或多种非甾体抗炎药(NSAID)的可静脉内施用的水性组合物的方法,其中在封闭容器中所述组合物的溶解氧最大为1.0ppm,所述方法包括用温度至少为80℃的水冲洗混合容器至少一次,从而加热容器并在所述容器中产生低氧环境；和在所述冲洗后的容器中,将对乙酰氨基酚溶解在注射用水中,所述注射用水的温度至少为80℃,其中在溶解对乙酰氨基酚之前或之后任选地加入一种或多种NSAID。(The present invention provides a process for preparing an intravenously administrable aqueous composition comprising paracetamol and optionally one or more non-steroidal anti-inflammatory drugs (NSAIDs), wherein the dissolved oxygen of the composition is at most 1.0ppm in a closed container, the process comprising rinsing the mixing container at least once with water having a temperature of at least 80 ℃, thereby heating the container and creating a hypoxic environment in said container; and dissolving acetaminophen in water for injection in the rinsed container, the water for injection having a temperature of at least 80 ℃, wherein one or more NSAIDs are optionally added before or after dissolving acetaminophen.)

1. A process for preparing an intravenously administrable aqueous composition comprising acetaminophen and optionally one or more non-steroidal anti-inflammatory drugs (NSAIDs), wherein the dissolved oxygen of the composition is at most 1.0ppm in a closed container, the process comprising rinsing the mixing container at least once with water having a temperature of at least 80 ℃, thereby heating the container and creating a low oxygen environment in the container; and dissolving acetaminophen in water for injection in the container after rinsing, the water for injection having a temperature of at least 80 ℃, wherein one or more NSAIDs are optionally added before or after dissolving acetaminophen.

2. The method of claim 1, comprising the steps of:

-flushing the mixing container at least once with water at least 80 ℃, thereby heating the container and creating a low oxygen environment in the container;

-introducing one or more excipients, preferably one or more isotonicity agents and one or more pH adjusting agents, and optionally one or more NSAIDs, into the mixing vessel;

-adding water for injection at a temperature of 80-99 ℃ and mixing the excipient introduced with water;

-subsequently dissolving paracetamol in the mixture; and

-adding one or more antioxidants, and optionally one or more pH adjusting agents, to said mixture, thereby obtaining said composition;

wherein after the ingredients of the composition are introduced into the container, the container is closed and placed under nitrogen pressure.

3. The method of claim 1 or 2, wherein the water for injection has a dissolved oxygen content of 0.5ppm or less at a temperature of at least 80 ℃.

4. The method of any one of the preceding claims, wherein the flushing of the mixing vessel is repeated.

5. The method of claim 4, wherein the flushing of the mixing vessel is repeated until the temperature of the mixing vessel is at least 80 ℃.

6. The method of claim 4 or 5, wherein the flushing of the mixing vessel is repeated until the temperature of the mixing vessel is at least 90 ℃.

7. The method of any one of claims 4 to 6, wherein the flushing of the mixing vessel is repeated until the oxygen content in the mixing vessel is less than 0.5 ppm.

8. A method according to any preceding claim, wherein the nitrogen pressure is applied by introducing nitrogen from the upper side of the vessel.

9. The method according to any one of the preceding claims, wherein the nitrogen pressure causes an overpressure in the mixing vessel of at least 0.1 bar.

10. The method according to any one of the preceding claims, wherein the nitrogen pressure causes an overpressure in the mixing vessel of at most 1.0 bar.

11. The method of any one of the preceding claims, wherein about 10mg of acetaminophen per ml of the composition is introduced into the mixing container.

12. The method of any one of the preceding claims, wherein about 2 to 4mg of one or more NSAIDs per ml of the composition is introduced into the mixing vessel.

13. The method of claim 2, wherein the one or more NSAIDs comprise ibuprofen.

14. The process of any preceding claim wherein a final volume of WFI is added to the composition after acetaminophen is introduced to the mixing vessel.

15. The method of any one of the preceding claims, wherein the one or more antioxidants is cysteine or acetylcysteine.

16. The method according to any of the preceding claims, wherein the one or more isotonicity agents are selected from the group of mannitol, sorbitol, inositol, glucose and glycerol.

17. The method of any preceding claim, wherein the dissolved oxygen content in the composition continuously increases during the manufacturing process.

18. The method of any preceding claim, wherein the pH of the composition prior to introducing the acetaminophen is 6.3-7.3.

19. The method of any preceding claim, wherein the pH of the composition is adjusted to 6.3-7.3 after the acetaminophen is introduced.

20. The method of claim 8 or 9, wherein the pH of the composition is adjusted by one or more pH adjusting agents.

21. The method according to any one of the preceding claims, wherein the one or more pH adjusting agents are selected from the group of hydrochloric acid and sodium hydroxide.

22. An intravenously administrable aqueous composition, characterized in that the composition comprises paracetamol, a dissolved oxygen content of at most 1.0ppm in a closed container, a pH value of 6.3 to 7.3, one or more antioxidants, one or more isotonicity agents and one or more pH adjusting agents.

23. The aqueous intravenously administrable composition according to claim 2, characterised in that the composition comprises 10mg/ml paracetamol.

24. An intravenously administrable aqueous composition according to claim 22 or 3, characterized in that the composition further comprises ibuprofen.

25. The aqueous intravenously administrable composition of claim 24, characterised in that the composition comprises 2-4mg ibuprofen per ml.

26. The intravenously administrable aqueous composition according to any one of claims 22 to 5, characterized in that said composition is obtainable by the method according to any one of claims 1-1.

Technical Field

The present invention relates to a process for the preparation of an intravenously administrable aqueous composition comprising paracetamol and optionally one or more non-steroidal anti-inflammatory drugs, preferably ibuprofen. In a second aspect, the present invention provides an intravenously administrable aqueous composition comprising paracetamol and optionally one or more NSAIDs, preferably ibuprofen.

Background

Acetaminophen, also known as paracetamol, is a known non-opiate, non-salicylic acid analgesic and antipyretic drug. Its chemical name is N- (4-hydroxyphenyl) acetamide. It can temporarily relieve minor pain and distress caused by burns or acid intake, and the stomach discomfort associated with these symptoms.

Acetaminophen is known to be susceptible to oxidation. Thus, its stability in aqueous solution requires the removal of oxygen from the solution and/or the use of antioxidants. Another disadvantage is that the oxidation products lead to the formation of colored compounds, making aqueous solutions unsuitable for therapeutic applications.

The current state of the art includes several methods for removing oxygen from aqueous solutions containing paracetamol: US6,992,218 discloses a process for the preparation of an aqueous solution comprising paracetamol and having a dissolved oxygen content of less than 2 ppm. The method disclosed in US6,992,218 comprises deoxygenating the aqueous solution by bubbling with at least one inert gas and/or inducing a vacuum until the oxygen content is below 2 ppm. US6,028,222 relates to a stable liquid formulation consisting essentially of acetaminophen dispersed in an aqueous medium containing a buffer and at least one member of the group consisting of a radical scavenger and a radical antagonist, wherein the aqueous medium has been deoxygenated by bubbling a water-insoluble inert gas. Further, WO 2016008546 discloses a process for the manufacture of an aqueous composition comprising a combination of ibuprofen and paracetamol and having a dissolved oxygen content below 2 ppm. The oxygen content is obtained by bubbling an inert gas and/or applying a vacuum using an aqueous solvent at a temperature between 85 ℃ and 99 ℃.

However, the processes described in the state of the art for removing oxygen from paracetamol containing aqueous solutions all involve a deoxygenation step of the aqueous solution. The deoxygenation step is known to be relatively complex, energy consuming and time consuming.

In addition, it is known that paracetamol in aqueous solution is also susceptible to hydrolysis, thereby forming para-aminophenol.

There remains a need for improved methods of making stable compositions comprising low dissolved oxygen content.

It is an object of the present invention to provide a simple and straightforward method for making stable acetaminophen solutions suitable for intravenous use. Preferably, the method does not require deoxygenation of the formulation after preparation, resulting in a cost effective and straightforward production process.

Furthermore, it is an object of the present invention to provide a combination product comprising paracetamol and one or more NSAIDs (e.g. ibuprofen).

Combinations of paracetamol and ibuprofen for intravenous administration are known. For example, US 20130225685 describes a composition comprising specific doses of acetaminophen and ibuprofen for providing pain relief and inflammation relief. The combination of these two active ingredients was found to provide beneficial effects when administered to a patient.

Ibuprofen is very insoluble in water and precipitates easily. As a result, it has been difficult to develop dosage forms such as oral or injectable compositions. One way to increase the water solubility is to use water soluble complexes and prepare ibuprofen salts, for example with sodium or amino acids.

However, there remains a need in the art to provide a stable solution of ibuprofen that can be used for intravenous use. Preferably, this solution is a combination of acetaminophen and ibuprofen, whereby both active ingredients remain in solution and remain stable over time.

It is therefore also an object of the present invention to provide a process for the preparation of an intravenously administrable aqueous composition of acetaminophen and ibuprofen, which results in a stable intravenously administrable aqueous composition.

Disclosure of Invention

The present invention provides a solution to at least one of the problems mentioned above by providing a process for the preparation of an intravenously administrable aqueous composition comprising paracetamol and optionally one or more NSAIDs, preferably ibuprofen, without the need to deoxygenate the composition.

In a first aspect, the present invention provides a novel process for the preparation of an intravenously administrable aqueous composition according to claim 1.

In particular, the present invention provides a process for the preparation of an intravenously administrable aqueous composition comprising paracetamol and optionally one or more non-steroidal anti-inflammatory drugs (NSAIDs), wherein the final composition has a dissolved oxygen of at most 1.0ppm when in a closed container, and wherein the process comprises the steps of: flushing the mixing container with water, preferably water for injection at a temperature of at least 80 ℃, more preferably at least 90 ℃ or from 80 ℃ to 99 ℃, thereby heating the container and creating a hypoxic environment in said container; and dissolving acetaminophen in water for injection, the water for injection having a temperature of at least 80 ℃, more preferably at least 90 ℃ or from 80 ℃ to 99 ℃. The water for injection may optionally contain one or more excipients when acetaminophen is added. In another embodiment, one or more NSAIDs, such as ibuprofen, are added to the composition. The addition of the NSAID may be performed before or after the paracetamol is added to the water for injection.

More specifically, the process of the present invention comprises in another preferred embodiment the following steps:

-flushing the mixing container with water, preferably with water for injection at a temperature of at least 80 ℃, thereby heating the container and creating a low oxygen environment in said container;

-introducing one or more excipients, preferably one or more isotonicity agents and one or more pH adjusting agents, and optionally one or more NSAIDs, into the mixing vessel;

-adding water for injection at a temperature of 80-99 ℃ and mixing said introduced excipient with water;

-subsequently dissolving paracetamol in the mixture; and

-adding one or more antioxidants and optionally one or more pH adjusting agents to the mixture, thereby obtaining the composition; wherein after introducing the ingredients of the composition into the container, the container is placed under nitrogen pressure.

The advantage of the process according to the invention is that no deoxygenation of the composition needs to take place in order to prevent degradation of the paracetamol. Due to the fact that the container in which the composition is prepared is flushed several times with hot water, the oxygen level in the container is reduced. This is achieved by evacuating air and thus oxygen from the container by the steam generated during the flushing. By using heated water to prepare the formulation, the oxygen level will remain low. By providing nitrogen pressure in the container each time the canister is opened to introduce ingredients, reoxidation of the formulation above unacceptable levels can be prevented.

In a second aspect, the present invention provides a stable intravenously administrable aqueous composition according to claim 22. More specifically, the present invention provides an intravenously administrable aqueous composition comprising acetaminophen, a maximum dissolved oxygen content of 1.0ppm in a closed container, a pH of 6.3 to 7.3, one or more antioxidants, one or more isotonicity agents, and one or more pH adjusting agents.

Detailed Description

The present invention relates to a process for the preparation of an intravenously administrable aqueous composition comprising paracetamol and optionally one or more NSAIDs, preferably ibuprofen, having a dissolved oxygen content of at most 1.0ppm, preferably at most 0.50ppm, in a closed container. In a second aspect, the present invention provides an intravenously administrable composition comprising paracetamol and optionally one or more NSAIDs, preferably ibuprofen, having a dissolved oxygen content of at most 1.0 in a closed container.

It is clear that the relevant process can be used for the preparation of an intravenously administrable aqueous composition comprising paracetamol as the active pharmaceutical ingredient alone or for the preparation of an intravenous aqueous composition comprising paracetamol and one or more NSAIDs, preferably ibuprofen, as active ingredients simultaneously. By applying the method of the invention, a stable solution suitable for intravenous injection is obtained.

Unless defined otherwise, all terms (including technical and scientific terms) used in disclosing the invention have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. By way of further guidance, definitions of terms are included to better understand the teachings of the present invention.

As used herein, the following terms have the following meanings:

as used herein, the terms "a", "an" and "the" refer to both singular and plural referents unless the context clearly dictates otherwise. For example, "interval" refers to one or more intervals.

As used herein, "about" and "approximately" refer to measurable values such as parameters, amounts, durations, and the like, intended to encompass variations of +/-5% or less, preferably +/-3% or less, more preferably +/-2% or less, even more preferably +/-1% or less, and yet more preferably +/-0.1% or less of the specified values, provided that the variations are suitable for practice in the disclosed invention. It should be understood, however, that the value to which the modifier "about" or "approximately" refers is also specifically disclosed per se.

As used herein, "comprising," "comprises," "comprising," and "comprising of" are synonymous with, "including," "includes," "including," "contains," or "containing," "containing," or "contains," and are inclusive or open-ended terms used to indicate the presence of a subsequent object (e.g., component) and not to exclude or deny the presence of other unrecited components, features, elements, components, steps known in the art or disclosed therein.

The recitation of endpoints to numerical ranges includes all numbers and fractions subsumed within that range as well as the recited endpoints.

Unless otherwise defined, the expressions "weight%", "weight percent", "% wt", or "wt%" refer to the relative weight of the respective components based on the total weight of the formulation, herein and throughout the specification.

For the purposes of the present invention, the term "aqueous" is understood to mean a solution comprising water.

For the purposes of the present invention, the term "atmosphere" is understood to be the atmosphere of the space in which the mixing vessel is placed. For obvious reasons, the atmospheric pressure and air in the description of the present invention are considered to be similar to the atmospheric conditions on earth. The atmosphere on earth contains about 20.95% by volume or 209,500ppm oxygen.

In a first aspect, the present invention provides a method of preparing an intravenously administrable aqueous composition comprising paracetamol and optionally one or more NSAIDs, having a dissolved oxygen content of at most 1.0ppm, preferably at most 0.50ppm, in a closed container.

The method of the invention comprises the following steps: flushing the mixing container with water, preferably water for injection at a temperature of at least 80 ℃, more preferably at least 90 ℃ or between 80 ℃ and 99 ℃, thereby heating the container and creating a hypoxic environment in said container; and dissolving acetaminophen in the water for injection in the rinsed container, the water for injection having a temperature of at least 80 ℃, more preferably at least 90 ℃ or between 80 ℃ and 99 ℃. The water for injection may optionally already contain one or more excipients that have been dissolved in the heated WFI present in the container upon addition of acetaminophen to the container. The one or more excipients may be, but are not limited to, isotonic agents, pH adjusting agents, antioxidants, stabilizers, preservatives, or any combination thereof. In another embodiment, one or more NSAIDs, such as ibuprofen, are added to the composition. The addition of the NSAID may be performed before or after the paracetamol is added to the water for injection.

In a preferred embodiment, the water used to flush the container and further prepare the composition will come from the circuit, whereby the water is heated to a preferred temperature, which continuously circulates the water.

In particular, in a preferred embodiment, the method comprises the steps of:

-flushing the mixing container with water, preferably with water for injection (WFI) at least 80 ℃, thereby heating the container and creating a low oxygen environment in said container;

-introducing one or more excipients, preferably one or more isotonic agents and one or more pH adjusting agents, and optionally one or more NSAIDs (when a combination product is intended to be produced) into the mixing vessel;

-adding water for injection, wherein said water temperature is higher than 80 ℃, preferably higher than 85 ℃, more preferably higher than 90 ℃, more preferably higher than 95 ℃, preferably between 80 ℃ and 99 ℃, or between 90 ℃ and 99 ℃, and mixing said introduced excipient and water;

-subsequently dissolving paracetamol in the mixture; and

-adding one or more antioxidants, and optionally one or more pH adjusting agents, to said mixture, thereby obtaining said composition;

-wherein after introducing the ingredients of the composition into the container, the container is closed and placed under nitrogen pressure.

Compositions having a dissolved oxygen content of less than or equal to 1.0ppm are advantageous in avoiding oxidation and degradation of acetaminophen.

The dissolved oxygen content can be measured by techniques known to the skilled person. The initial or residual dissolved oxygen content can be measured by means of an oxygen meter operating according to the clark principle, the values given for the oxygen content being given in mg/l. The scale is calibrated between zero (reducing solution) and the oxygen saturation content of distilled water, taking into account the medium temperature and the atmospheric pressure. The oxygen content was calculated from the temperature and pressure using a chart.

More specifically, the process of the present invention provides a process for the preparation of a composition comprising paracetamol and optionally one or more NSAIDs, preferably ibuprofen, having a dissolved oxygen content of at most 1.0ppm, preferably at most 0.50ppm, in a closed container.

As mentioned above, the method according to the invention is particularly advantageous because it does not require any means for deoxygenating the formulation. This is in sharp contrast to most methods currently described in the art, which all require an active step to evacuate oxygen or drive out of the formulation (e.g., bubbling with an inert gas or using a vacuum, see e.g., US6,992,218). By using the method of the present invention, a low oxygen environment is created. The formulation is prevented from being re-oxygenated during production by using nitrogen pressure in the container, preferably in the headspace of the container.

In a preferred embodiment, pre-treating the mixing vessel prior to introducing the ingredients comprises rinsing the mixing vessel with water at a temperature of 80-99 ℃, preferably at a temperature of 90-99 ℃, more preferably at a temperature between 95 ℃ and 99 ℃, preferably several times. In a preferred embodiment, the water is water for injection (WFI). In a more preferred embodiment, WFI is provided by a circuit that constantly circulates WFI at a temperature of 80-99 ℃, preferably 90-99 ℃, more preferably between 95 ℃ and 99 ℃. WFI, particularly at such elevated temperatures, contains a dissolved oxygen content of less than 0.5ppm, such as about 0.20 ppm. As mentioned, flushing the mixing vessel prior to introducing the ingredients causes preheating of the mixing vessel. In a second aspect, during the flushing, steam is generated due to the high temperature of the WFI. The steam comprises a lower density than air and thus acts as a lift gas. As a result, the generated steam pushes out the air present in the headspace of the mixing vessel, resulting in a reduction of the oxygen content in the mixing vessel. In this way, pre-treating the mixing vessel prior to introducing the ingredients results in pre-heating of the mixing vessel and a reduction in the oxygen content in the mixing vessel.

The term "headspace of the mixing vessel" refers to the volume of the mixing vessel not occupied by the composition.

In accordance with GMP requirements to avoid microbial growth, WFI should always be cycled in the dispensing loop of the manufacturing plant at temperatures not lower than 75 ℃. However, the risk of microbial growth is even further reduced by circulating in the loop and using WFI at a temperature of 80-99 ℃, preferably at a temperature of 90-99 ℃. In a preferred process, WFI at a temperature of 80-99 ℃, preferably 90-99 ℃, more preferably between 95 ℃ and 99 ℃ from the same dispensing loop is used to flush the mixing vessel and as solvent for the aqueous composition.

In addition to the beneficial effect on oxygen content in the vessel, preheating the mixing vessel prior to introducing the ingredients also prevents the WFI or composition (or intermediate mixture) from cooling during preparation in the mixing vessel. More particularly, preheating the vessel prior to introducing the ingredients may maintain the WFI or composition (or intermediate mixture thereof) at an elevated temperature for a longer period of time. This is advantageous because the high temperature of the aqueous solvent or composition (or intermediate mixture thereof) increases the solubility of the ingredients and, in addition, the aqueous composition at higher temperatures will dissolve less oxygen, thereby helping to keep the dissolved oxygen content in the composition and intermediate mixtures thereof at a low level.

In one embodiment, the mixing vessel is flushed at least once with heated WFI. In a preferred embodiment, the mixing vessel is repeatedly flushed with WFI at a temperature of 80 to 99 deg.C, preferably at a temperature of 90 to 99 deg.C, more preferably at a temperature of 95 to 99 deg.C. In a more preferred embodiment, the flushing of the mixing vessel is repeated until the temperature of the mixing vessel is at least 80 ℃, more preferably at least 90 ℃. The container may be rinsed at least 2 times, more preferably at least 3 times, more preferably at least 4 times, 5 times, 6 times, 7 to 10 times.

The mixing vessel may have a capacity of up to 250,000 litres. As a result, filling the mixing container can be time consuming. However, in a preferred embodiment, the flushing of the mixing vessel is performed with a volume of water that is smaller than the volume of the mixing vessel. In a more preferred embodiment, the flushing of the vessel is performed with a volume of water equal to 3 to 20% of the volume of the mixing vessel. Thus, the time and WFI consumption is greatly reduced. This then allows a cheaper manufacturing process.

In another or further embodiment, the mixing vessel may be electrically preheated. However, merely preheating the mixing vessel prior to introducing the ingredients is not sufficient to substantially reduce the oxygen content in the headspace of the mixing vessel. Thus, prior to introducing the ingredients into the mixing vessel, it is preferred to combine electronic preheating of the mixing vessel with pretreatment that results in a reduction in the oxygen content in the headspace of the mixing vessel.

In the process according to the invention, after pretreatment, in particular rinsing, of the mixing vessel, the first one or more ingredients and/or WFI are introduced only into the mixing vessel, so that the oxygen content in the mixing vessel is reduced and the mixing vessel is preheated. In one embodiment, the oxygen content in the mixing vessel is reduced to less than 0.5ppm prior to introducing the ingredients into the mixing vessel.

Preferably, the mixing vessel is preheated to a temperature of at least 80 ℃ and more preferably at least 90 ℃.

After sufficient pre-treatment of the mixing vessel, one or more excipients and optionally one or more NSAIDs such as ibuprofen are introduced into the mixing vessel, WFI at a temperature of 80-99 deg.C, preferably 90-99 deg.C, preferably between 95 deg.C and 99 deg.C, is added, and the composition is mixed, preferably until all the introduced ingredients are dissolved. Preferably, the one or more excipients include one or more isotonic agents and one or more pH adjusting agents.

Preferably, the total concentration of NSAID in the composition is from 2 to 4mg per ml of composition, more preferably from 3 to 4mg per ml of composition. More preferably, ibuprofen is present in a concentration of 2 to 4mg per ml, more preferably 3 to 4mg per ml.

For an amount of 3.0mg ibuprofen/ml, 3.85mg sodium ibuprofen is used.

In a preferred embodiment, the one or more isotonicity agents include mannitol. Preferably, the pH adjusting agent is hydrochloric acid, more preferably in an amount such that the pH of the composition after addition of WFI is from 6.3 to 7.3.

While introducing WFI at a temperature of 80-99 ℃, preferably 90-99 ℃, more preferably 95-99 ℃ into the mixing vessel, the vessel is opened to prevent an overpressure from building up in the headspace of the vessel. In addition, the steam generated in the process of adding the aqueous solvent at high temperature generates outward flow, and the atmosphere is prevented from entering the container. The aqueous solvent is introduced into the vessel at a steady rate to avoid turbulence and thus oxygen dissolution in the WFI.

In a preferred embodiment, after the ingredients of the composition are introduced into the vessel, the mixing vessel is placed under nitrogen pressure. In one embodiment, nitrogen pressure is applied to the mixing vessel, more specifically, to the headspace of the mixing vessel, prior to mixing the ingredients introduced into the mixing vessel. Application of nitrogen pressure to the mixing vessel prevents re-oxygenation of the formulation in the vessel. As a result, dissolution of oxygen in the final or intermediate composition or intermediate mixture thereof is avoided, which is particularly important during mixing of the composition or intermediate mixture thereof. Preferably, the nitrogen pressure causes an overpressure in the mixing vessel of at least 0.1 bar, preferably at most 1.0 bar, compared to atmospheric pressure. More preferably, the overpressure in the mixing vessel is at least 0.1 bar, preferably at most 0.5 bar, compared to atmospheric pressure. Obviously, the mixing vessel was closed while applying a nitrogen overpressure to the headspace of the mixing vessel. It is emphasized that the overpressure is applied to the headspace of the mixing vessel by introducing nitrogen from the upper side of the vessel, more preferably from the top side. In this way, nitrogen does not pass through the aqueous composition or its intermediate mixture and dissolution of oxygen into the composition or its intermediate composition is avoided.

Preferably, the overpressure is applied in the headspace of the mixing vessel by introducing nitrogen. More preferably, the overpressure is applied in the headspace of the mixing vessel by introducing filtered nitrogen gas. Preferably, the nitrogen is 0.22 μm filtered nitrogen.

After mixing the introduced excipients, if a combined product is produced, one or more NSAIDs, such as ibuprofen, are added with the WFI introduced, the mixing vessel is opened, and acetaminophen is introduced into the mixing vessel. After the acetaminophen is introduced, the container should be closed as soon as possible to avoid atmospheric ingress and the ingredients mixed, preferably until all ingredients are dissolved. When the mixing vessel is opened, the overpressure applied in the mixing vessel will result in a directed flow of nitrogen gas outwards; the flow prevents the ingress of atmospheric air. Preferably, the paracetamol is introduced during the time interval during which the overpressure in the headspace is equalised to atmospheric pressure.

In a preferred embodiment, after the introduction of the acetaminophen and before the mixing, the overpressure is reapplied to the headspace of the container by introducing nitrogen from the upper side of the container. Preferably, the overpressure is 0.1 to 1.0 bar, and more preferably 0.1 to 0.5 bar.

In a preferred embodiment paracetamol is introduced into the mixing vessel in an amount of 9.8 to 10.2mg, more preferably 10.0 mg/ml.

Advantageously, not cooling the aqueous mixture prior to mixing the active ingredient or ingredients not only benefits the preparation time of the formulation as no heat exchanger is required to cool the aqueous solvent, but also allows a suitable oxygen concentration to be obtained. In contrast to deoxygenation of solutions already containing these ingredients, the addition of oxygen-sensitive acetaminophen and antioxidants to media with reduced oxygen content has the advantage that the deleterious effects of oxygen are kept to a minimum and the potentially present antioxidants are not prematurely consumed and can be used to provide long-term storage stability. Preferably, the temperature of the mixture is preferably maintained at least at 80 ℃, more preferably at least at 90 ℃ prior to mixing the active ingredients.

In a preferred embodiment, after the acetaminophen is introduced and mixed, the final volume of WFI for the composition is added, followed by mixing of the mixture. More preferably, the overpressure is applied after the WFI is added for the final volume and before the mixture is mixed.

The mixture comprising paracetamol and optionally one or more NSAIDs is then cooled. Preferably, the cooling process is accelerated by circulating cold water in the double jacket of the mixing vessel.

In a preferred embodiment of the process according to the invention, one or more antioxidants are added to the cooled aqueous mixture. The antioxidants used in the present invention are preferably selected from the following list: sulphite or sulphite derivatives, thiol substances (e.g. cysteine, acetylcysteine, dithiothreitol or a-thioglycerol, thiomalic acid, thioglycerol, methionine), hydroxylated substances (e.g. ascorbic acid, erythorbic acid, mannitol, sorbitol), ethylenically unsaturated substances (e.g. sorbic acid, undecylenic acid or fumaric acid) or hydroxy polycarboxylic acids, or reducing sugars (e.g. trehalose, maltulose or isomaltulose). In a preferred embodiment, the antioxidant is selected from cysteine and acetylcysteine. Cysteine is preferably cysteine hydrochloride. Preferably, the monohydrate form is used. The term "(acetyl) cysteine" as used herein refers to acetylcysteine and/or cysteine. Acetylcysteine or cysteine as an antioxidant can inhibit the formation of undesirable degradation products of acetaminophen by oxidation. Although their use may result in yellow colored solutions, they are preferred because they reduce the risk of acetaminophen poisoning.

In a more preferred embodiment, the antioxidant is added at a temperature of up to 40 ℃ to avoid degradation of acetylcysteine or cysteine at higher temperatures. Preferably, the mixture comprising paracetamol and optionally one or more NSAIDs is cooled to a temperature of at most 40 ℃, preferably to 39 ℃ or 38 ℃, 37 ℃, 36 ℃ or 35 ℃ before the addition of acetylcysteine or cysteine. Preferably, the addition of cysteine or acetylcysteine to the mixture does not change the pH from 6.3 to 7.3. In a preferred embodiment, the pH of the aqueous composition is between 6.3 and 7.3 before and after the addition of the antioxidant. Preferably, the pH of the final product is about 6.6. In a preferred embodiment, when the pH of the mixture prior to the introduction of the one or more antioxidants is not within the above range, then one or more pH adjusting agents may be introduced into the mixing vessel at the time of introduction of the one or more antioxidants.

In a preferred embodiment, an overpressure is applied to the headspace of the mixing vessel each time the mixing vessel is opened, and before the composition or its intermediate composition is mixed in the mixing vessel during the preparation process. This is advantageous because the overpressure will equilibrate to atmospheric pressure each time the mixing container is opened. The overpressure avoids atmospheric ingress into the headspace upon opening of the container and minimizes dissolution of oxygen in the composition or an intermediate composition thereof during mixing. It is clear that as a result, one or more ingredients must be introduced into the container as soon as possible after opening the container, so that it can be closed shortly after opening the container, so that the container is opened for only a limited period of time.

In a preferred embodiment, the pH of the mixture to which the pharmaceutically active ingredient paracetamol and optionally one or more NSAIDs are added is from 6.0 to 8.0, preferably from 6.2 to 7.5, preferably from 6.3 to 7.3. In a more preferred embodiment, the pH of the mixture is from 6.4 to 6.6. In a preferred embodiment, the pH of the final composition is from 6.4 to 6.6. The term "final composition" refers to a composition to be filled into a container (preferably a vial) and ready for use. It was found to be advantageous to start from the lower end of the pH range. Preferably, the storage pH of the final product remains stable or can vary within specified ranges. This pH range avoids both precipitation of ibuprofen and degradation of acetaminophen.

One or more pH adjusting agents may be used to adjust the pH to a desired level prior to mixing the active ingredients. In a preferred embodiment, the pH of the mixture is 6.3 to 7.3 prior to the introduction of the acetaminophen and optionally one or more NSAIDs, preferably ibuprofen. Preferably, after the introduction of the acetaminophen and optionally one or more NSAIDs, preferably ibuprofen, the pH of the mixture is 6.3 to 7.3. Thus, in a preferred embodiment, the intravenously administrable composition comprises a pH adjusting agent. In a more preferred embodiment, the pH adjusting agents used in the process according to the invention are hydrochloric acid and sodium hydroxide.

The pH of the composition may be buffered. Suitable buffering agents may include one or more of citric acid, sodium citrate, sodium phosphate, potassium citrate, and the like. Preferably, the buffer is disodium phosphate.

In a preferred embodiment of the methods and compositions of the present invention, the compositions comprise one or more isotonic agents. The advantage of using one or more isotonic agents is that an osmotic pressure is created within the pressure range of the physiological saline. The isotonicity agent herein can be a polyol, sugar, straight or cyclic glucitol having 2 to 10 carbon atoms selected from mannitol, sorbitol, inositol, glucose, and glycerol. The preferred isotonicity agent is mannitol.

Further pharmaceutically acceptable excipients may be present. However, in a preferred embodiment, no other excipients are present.

The mass ratio (w/w) of the one or more isotonicity agents to acetaminophen, for example the mass ratio (w/w) of mannitol to acetaminophen is preferably 2 to 6:1, more preferably 3 to 5:1, most preferably about 4: 1. Preferably, one or more isotonic agents are added to the aqueous solution, preferably to the water, prior to the introduction of the acetaminophen, and optionally prior to the introduction.

In a preferred embodiment, the pH adjusting agents used in the process according to the invention are sodium hydroxide-disodium phosphate and acetylcysteine or cysteine. In a more preferred embodiment, the pH adjusting agents are hydrochloric acid and sodium hydroxide.

In a preferred embodiment, the final pH of the formulation is 6.3 to 7.3. Preferably, the final pH is 6.4 to 6.9, more preferably 6.5 to 6.8. In a preferred embodiment of the process of the invention, the aqueous composition obtained has a pH of about 6.6. After a shelf life of at least six months, the pH is preferably 6.3 to 7.3.

Preferably, the mass ratio (w/w) of cysteine hydrochloride to paracetamol in the final formulation is from 0.010 to 0.040:1, preferably from 0.020 to 0.030:1, preferably 0.025: 1.

Preferably, the mass ratio (w/w) of acetylcysteine or cysteine hydrochloride to ibuprofen in the final formulation is 0.20 to 0.40:1, preferably 0.10 to 0.20:1, preferably 0.08: 1.

For example, in the formulations and methods defined herein, (acetyl) cysteine hydrochloride may be present in the final formulation in an amount of preferably 0.015% to 0.05%, preferably about 0.025% (w/v).

The obtained composition may be filtered, for example, in a filtration unit.

Such as during mixing, oxygen contact or ingress of oxygen into the aqueous solution during filling/packaging and/or storage is preferably avoided.

Preferably, prior to filling, the container, preferably a vial, for the composition comprising paracetamol and optionally one or more NSAIDs, preferably ibuprofen is washed with warm water. Specifically, the vessel may be washed with WFI at a temperature above 80 deg.C, more preferably with WFI at a temperature between 80 and 99 deg.C, and most preferably with WFI at a temperature between 90 deg.C and 99 deg.C. The dissolved oxygen content of WFI at such temperatures is low. Particularly suitable for absorbing oxygen from a container and reducing its oxygen content.

In a subsequent step, the washed container may be dried. Preferably, the drying is carried out with dry air. The dry air with low moisture content again minimizes oxygen resorption by the package and subsequently by the composition comprising paracetamol or by the composition comprising paracetamol and one or more NSAIDs, preferably ibuprofen.

After drying, the washed and/or dried container may be flushed with nitrogen. Preferably, nitrogen with a low oxygen content is used.

After pre-treating the container, the container is filled with a composition comprising paracetamol or a composition comprising paracetamol and one or more NSAIDs, preferably ibuprofen.

The mixing procedure preferably provides an aqueous composition comprising paracetamol or paracetamol and one or more NSAIDs, preferably ibuprofen, having a dissolved oxygen content of less than 1.0ppm, preferably less than 0.5ppm, more preferably about 0.4ppm prior to filling/packaging.

The intravenously administrable aqueous composition comprising paracetamol or paracetamol and one or more NSAIDs, preferably ibuprofen, prepared according to the process of the invention has less than or equal to 1.0ppm, more preferably less than or equal to 0.5ppm dissolved oxygen during filling.

Preferably, the container is sealed under vacuum; preferably, the vacuum is between 450 mbar and about 1 bar.

The container is then sealed, for example by applying a plug, sealing under vacuum and providing a crimp cap covering the plug.

The bottles may then be heat sterilized, for example at 121 ℃ for 15 minutes. Those skilled in the art will appreciate that other sterilization methods are equally applicable.

In a preferred embodiment, the method according to the invention further comprises the following steps in the order specified:

-washing the vessel with WFI at a temperature of 80 ℃ to 100 ℃,

-drying the washed container, preferably with dry air,

flushing the washed container, preferably with nitrogen,

-filling the nitrogen washed container with an aqueous composition comprising paracetamol or paracetamol and one or more NSAIDs, preferably ibuprofen;

-sealing the container under vacuum, preferably between 450 mbar and about 1 bar.

In a more preferred embodiment, the vacuum-sealed product container comprises a stopper made of an elastic material, which is covered by a crimp cap.

In a preferred embodiment, said elastic material of the stopper is a rubber, preferably a butyl rubber or a halogenated butyl rubber. These rubber types have a low oxygen transmission coefficient. Preferably, the plug is sealed by an aluminium crimp cap. Preferably, the vial is closed with a (halo) butyl rubber stopper, preferably bromobutyl rubber, and sealed with an aluminum cap.

Preferably, the container used to obtain the product according to one embodiment of the invention is a vial, preferably a colourless type II glass eur.ph.3.2.1 vial.

In a preferred embodiment according to the invention, the closed product container has a reduced pressure inside. Preferably, the pressure is reduced to allow the solvent for injection to be added to the closed system, for example by penetrating the closure with a needle. Preferably, the reduced pressure is between 450 mbar and about 1 bar.

In a preferred embodiment, the container comprises a vial having blowback inside the flange. Blowback improves stopper fit and prevents the stopper from popping out of the vial. The dimensions of the flange and stopper of the vial are selected to ensure good fitting of the stopper during stopper plugging and sealing. It is preferred to have a blowback of a size to provide a sufficient sealing surface between the vial and the stopper to maintain the vacuum in the vial for as long as possible.

Preferably, the container/closure system has blow back, in particular when applying reduced pressure. The blow-back system is very compact compared to systems without blow-back and can reduce the risk of air inflow and thus the risk of oxidation.

It will be apparent that the related methods may also be used to prepare an intravenously administrable composition comprising paracetamol without one or more NSAIDs, for example ibuprofen.

As noted above, methods known in the art describe methods of preparation that include deoxygenating the composition. As is known from the literature, this can be time consuming. In addition, deoxygenation of the composition indicates that the dissolved oxygen content of the composition prior to deoxygenation is insufficient to prevent oxidation of the acetaminophen, and thus, the antioxidant may be prematurely consumed, or some of the acetaminophen in the composition may be affected by insufficient dissolved oxygen content prior to deoxygenation of the composition. In the process according to the invention, no time intervals in which the oxygen content of paracetamol is insufficient are observed. More specifically, during the preparation process according to the invention, the dissolved oxygen content of the composition increases continuously.

Thus, the present invention provides a more efficient and simpler process for the preparation of a composition comprising paracetamol and optionally one or more NSAIDs, preferably ibuprofen.

In a second aspect, the present invention provides an intravenously administrable aqueous composition comprising paracetamol and optionally one or more non-steroidal anti-inflammatory drugs (NSAIDs), preferably ibuprofen, having a dissolved oxygen content in a closed container of at most 1.0ppm, preferably at most 0.5 ppm.

An oxygen content of less than or equal to 1.0ppm, preferably less than or equal to 0.5ppm, is advantageous for avoiding oxidation of paracetamol, particularly in the presence of an NSAID, preferably ibuprofen.

It is known from the prior art that acetaminophen is susceptible to oxidation and that the oxidation products of acetaminophen lead to the formation of undesirable colored compounds. The composition according to the invention comprises a dissolved oxygen content of at most 1.0ppm, preferably at most 0.5ppm, and thus shows a reduced oxidation rate of acetaminophen. As a result, the compositions according to the invention have long durability and storage capacity and contain very low concentrations of undesirable acetaminophen oxidation products.

In a preferred embodiment, the composition according to the invention comprises 9.8 to 10.2mg of paracetamol, preferably 10mg of paracetamol.

Preferably, the composition according to the invention comprises one or more pharmaceutically acceptable excipients. More preferably, the composition according to the invention comprises one or more antioxidants, one or more isotonicity agents and/or one or more pH adjusting agents.

In one embodiment, the one or more antioxidants are selected from the group of acetylcysteine or cysteine, e.g. cysteine hydrochloride.

In one embodiment, the one or more isotonic agents are selected from the group of mannitol, sorbitol, inositol, glucose and glycerol.

In one embodiment, the one or more pH adjusting agents are selected from the group of hydrochloric acid and sodium hydroxide.

Preferably, the aqueous composition according to the invention has an osmolality of between 285-320mOsmol/l as determined by the point reduction method according to USP 788.

It is known from the literature that acetaminophen is susceptible to hydrolysis. The degradation rate of acetaminophen increases with increasing temperature and light. This rate is minimal at pH around 6.

In a preferred embodiment, the pH of the aqueous composition according to the invention is from 6.3 to 7.3, preferably the pH is from 6.4 to 6.9, more preferably from 6.5 to 6.8, and most preferably the pH of the composition is about 6. In this way, the degradation rate of paracetamol in the aqueous composition according to the invention is greatly reduced.

In one embodiment, the composition according to the invention may further comprise one or more NSAIDs, preferably ibuprofen. In a preferred embodiment, the composition comprises 2 to 4mg, more preferably 3 to 4mg ibuprofen per ml of said composition and preferably 3mg ibuprofen per ml of said composition.

The ibuprofen is preferably introduced in the form of sodium ibuprofen.

In a preferred embodiment, the composition has a storage stability of at least 6 months, preferably at least 9 months, more preferably at least 12 months, most preferably 24 months, based on the acetaminophen content and acetaminophen/ibuprofen content measured by HPLC according to the european pharmacopoeia 2.2.29 and USP 621.

In a preferred embodiment, the amount of (acetyl) cysteine in the composition is at least 80%, preferably at least 85%, most preferably at least 90% of the initial addition amount at the completion of the preparation of the composition.

In a preferred embodiment, the (acetyl) cysteine hydrochloride is present in an amount of at least 40%, preferably at least 50%, preferably at least 75% of the initial addition during the shelf life of the composition. Low consumption of (acetyl) cysteine indicates little exposure to oxygen during storage.

In a preferred embodiment, the aqueous composition according to the invention is obtainable by the process according to the invention. In a most preferred embodiment, the aqueous composition according to the invention is obtainable by the process according to the invention.

In another embodiment, the composition is for use as a medicament. Of particular importance for its applicability in the pharmaceutical and medical fields is the pH of the composition.

In a more preferred embodiment, the composition is for use in the treatment of pain and/or inflammation.

In a preferred embodiment, the pH thereof makes the composition particularly suitable for administration by intravenous injection. In a most preferred embodiment, the composition is for administration by intravenous injection.

The composition thus obtained can be dispensed into ready-to-use hermetically-sealed or sealed bags, pouches or bottles.

Preferably, the composition is produced by a method as described above. More specifically, the composition is described by the following method:

a formulation according to one embodiment of the invention may generally be prepared as follows. The mixing vessel is pre-treated prior to introduction of the one or more components such that the vessel is pre-heated and the oxygen content of the headspace of the mixing vessel is reduced. Preferably, the pre-treatment comprises flushing the mixing vessel several times with a WFI having a temperature of 80-99 ℃, preferably with a WFI having a temperature of 90-99 ℃ until the temperature of the mixing vessel is at least 80 ℃, preferably at least 90 ℃. After pre-treating the container, the container is opened and one or more excipients and optionally one or more NSAIDs are introduced into the container. Then, WFI at a temperature of 80-99 deg.C, preferably 90-99 deg.C, is added and the vessel is closed. Prior to mixing the composition, nitrogen gas was introduced from the upper part of the mixing vessel to apply an overpressure to the headspace of the mixing vessel. Preferably, the one or more excipients include one or more isotonic agents, one or more pH adjusting agents and buffering agents. After stopping the mixing of the composition, the container was opened, acetaminophen was introduced into the composition, the container was closed, and a nitrogen overpressure was applied to the headspace of the mixing container prior to mixing the composition. Preferably, the temperature of the composition is maintained at least at 80 ℃, more preferably at least at 90 ℃ prior to mixing the active ingredients. After introducing the acetaminophen and mixing the composition, the composition is cooled, preferably to less than 40 ℃. On cooling the container was opened, sodium phosphate dibasic dihydrate to reach a pH of 6.3-7.3 and sodium hydroxide were added to the composition, the container was closed, and an overpressure of nitrogen was applied before mixing the composition. The vessel was then opened, cysteine hydrochloride was introduced, the vessel was closed, and a nitrogen overpressure was applied before mixing the composition. The composition is filtered and the filtered composition is filled into a container.

Advantageously, the introduction of the ingredients is performed as quickly as possible to avoid atmospheric air entering the headspace of the mixing vessel.

The present inventors have found that the indicated process allows the preparation of paracetamol, and optionally a combination of paracetamol and one or more NSAIDs, preferably ibuprofen, in an aqueous composition in a less complex, more cost effective and more time efficient manner and thereby simultaneously reduces the degradation of paracetamol, preferably ibuprofen.

It is clear that the method according to the invention can be carried out with and without the introduction of one or more NSAIDs.

The invention is described in more detail in the following examples, which are given as non-limiting illustrations. In these examples, the temperature is room temperature or expressed in degrees celsius and the pressure is atmospheric pressure. Water and all reagents used were injection grade.

Furthermore, all the embodiments form an integral part of the invention, including any feature described of an embodiment which also forms an integral part of the invention, which any feature appears to be novel with respect to any prior art, in the form of a general feature rather than a specific feature of an embodiment.