Process for preparation of compositions comprising acetaminophen and optionally one or more NSAIDs having low dissolved oxygen content and compositions obtained therefrom

Abstract

The present invention provides a process for preparing a composition having a low dissolved oxygen content comprising acetaminophen and optionally one or more NSAIDs wherein the composition has a dissolved oxygen of at most 1.0 ppm in a closed container, said process comprising flushing the mixing container at least once with water at a temperature of at least 80 DEG C, and the composition obtained therefrom, thereby heating the container and creating a hypoxic environment in the container; and dissolving the acetaminophen in water for injection in the flushed container, the water for injection having a temperature of at least 80 DEG C wherein one or more NSAIDs are optionally added before or after dissolving the acetaminophen. The method of the present invention can produce a stable, intravenously administered aqueous composition without the need to deoxidize the composition.

Description

[0001] This application is a divisional application of the invention patent with application number "201880035790.3", application date April 20, 2018, entitled "Method for preparing a composition having low dissolved oxygen content, comprising acetaminophen and optionally one or more NSAIDs, and the composition obtained therefrom". Technical Field

[0002] This invention relates to a method for preparing an intravenously administered aqueous composition comprising acetaminophen and optionally one or more nonsteroidal anti-inflammatory drugs, preferably ibuprofen. In a second aspect, the invention provides an intravenously administered aqueous composition comprising acetaminophen and optionally one or more NSAIDs, preferably ibuprofen. Background Technology

[0003] Acetaminophen, also known as paracetamol, is a known non-opioid, non-salicylic acid analgesic and antipyretic. Its chemical name is N-(4-hydroxyphenyl)acetamide. It can temporarily relieve mild pain and discomfort caused by burns or acid ingestion, as well as stomach upset associated with these symptoms.

[0004] Acetaminophen is known to be readily oxidized. Therefore, its stability in aqueous solution requires the removal of oxygen from the solution and / or the use of antioxidants. Another drawback is that oxidation products lead to the formation of colored compounds, making the aqueous solution unsuitable for therapeutic applications.

[0005] Current technological advancements include several methods for removing oxygen from aqueous solutions containing acetaminophen: US 6,992,218 discloses a method for preparing an aqueous solution containing acetaminophen with a dissolved oxygen content of less than 2 ppm. The method disclosed in US 6,992,218 involves 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. US 6,028,222 relates to a stable liquid formulation substantially composed of acetaminophen dispersed in an aqueous medium containing a buffer and at least one member of the group consisting of free radical scavengers and free radical antagonists, wherein the aqueous medium has been deoxygenated by bubbling with a water-insoluble inert gas. Furthermore, WO 2016 008 546 discloses a method for manufacturing an aqueous composition containing a combination of ibuprofen and paracetamol with a dissolved oxygen content of less than 2 ppm. The oxygen content is obtained by using an aqueous solvent at a temperature between 85°C and 99°C, through inert gas bubbling and / or the application of a vacuum.

[0006] However, methods for removing oxygen from aqueous solutions containing acetaminophen described in the prior art all involve a deoxygenation step in the aqueous solution. This deoxygenation step is known to be relatively complex, energy-intensive, and time-consuming.

[0007] In addition, it is known that acetaminophen in aqueous solution is also readily hydrolyzed to form p-aminophenol.

[0008] There is still a need for improved preparation methods for stable compositions containing low dissolved oxygen content.

[0009] The object of this invention is to provide a simple and direct method for manufacturing a stable acetaminophen solution 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.

[0010] Furthermore, the object of the present invention is to provide a combination product comprising acetaminophen and one or more NSAIDs (e.g., ibuprofen).

[0011] Combinations of acetaminophen and ibuprofen for intravenous administration are known. For example, US 2013 022 568 5 describes a composition comprising specific doses of acetaminophen and ibuprofen for providing pain and inflammation relief. The combination of these two active ingredients has been found to provide beneficial effects when administered to patients.

[0012] Ibuprofen is extremely poorly soluble in water and readily precipitates. As a result, it has been difficult to develop dosage forms such as oral or injectable compositions. One method to improve water solubility is to use water-soluble complexes and, for example, to prepare ibuprofen salts with sodium or amino acids.

[0013] However, there remains a need in the art to provide a stable solution of ibuprofen for intravenous use. Preferably, such a solution is a combination of acetaminophen and ibuprofen, whereby both active ingredients are retained in the solution and remain stable over time.

[0014] Therefore, another object of the present invention is to provide a method for preparing an intravenously applicable aqueous composition of acetaminophen and ibuprofen, which produces a stable intravenously applicable aqueous composition. Summary of the Invention

[0015] By providing a method for preparing an intravenously administered aqueous composition comprising acetaminophen and optionally one or more NSAIDs, preferably ibuprofen, without deoxygenating the composition, the present invention provides a solution to at least one of the aforementioned problems.

[0016] In a first aspect, the present invention provides a novel method for preparing an intravenously administered aqueous composition comprising acetaminophen and optionally one or more nonsteroidal anti-inflammatory drugs (NSAIDs).

[0017] Specifically, the present invention provides a method for preparing an intravenously administered aqueous composition comprising acetaminophen and optionally one or more nonsteroidal anti-inflammatory drugs (NSAIDs), wherein the dissolved oxygen in the final composition when in a closed container is at most 1.0 ppm, and wherein the method comprises the steps of: rinsing a mixing container with water, preferably with water for injection at a temperature of at least 80°C, more preferably at least 90°C or 80°C to 99°C, thereby heating the container and creating a hypoxic environment in the container; and dissolving acetaminophen in water for injection at a temperature of at least 80°C, more preferably at least 90°C or 80°C to 99°C. 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 addition of acetaminophen to the water for injection.

[0018] More specifically, in another preferred embodiment, the method of the present invention includes the following steps: - Rinse the mixing container with water, preferably water for injection at a temperature of at least 80°C, thereby heating the container and creating a low-oxygen environment in the container; - Introduce one or more excipients, preferably one or more isotonic agents and one or more pH adjusters, and optionally one or more NSAIDs into the mixing container; - Add water for injection at a temperature of 80-99°C, and mix the introduced excipient with water; - Acetaminophen is then dissolved in the mixture; and - Add one or more antioxidants and optionally one or more pH adjusters to the mixture to obtain the composition; wherein after the components of the composition are introduced into the container, the container is placed under nitrogen pressure.

[0019] The advantage of the method according to the invention is that deoxygenation of the composition is not required to prevent degradation of acetaminophen. The oxygen level in the container is reduced by rinsing it several times with hot water. This is achieved by evacuating the air from the container and thus removing oxygen through the steam generated during rinsing. By using heated water to prepare the formulation, the oxygen level will remain low. Re-oxidation of the formulation to unacceptable levels can be prevented by providing nitrogen pressure in the container each time the can is opened to introduce the ingredient.

[0020] In a second aspect, the present invention provides a stable, intravenously applicable aqueous composition. More specifically, the present invention provides an intravenously applicable aqueous composition comprising acetaminophen, a dissolved oxygen content of up to 1.0 ppm in a closed container, a pH of 6.3 to 7.3, one or more antioxidants, one or more isotonic agents, and one or more pH adjusters. Detailed Implementation

[0021] This invention relates to a method for preparing an intravenously administered aqueous composition comprising acetaminophen and optionally one or more NSAIDs, preferably ibuprofen, having a dissolved oxygen content of up to 1.0 ppm, preferably up to 0.50 ppm, in a closed container. In a second aspect, the invention provides an intravenously administered composition comprising acetaminophen and optionally one or more NSAIDs, preferably ibuprofen, having a dissolved oxygen content of up to 1.0 ppm in a closed container.

[0022] Clearly, the method can be used to prepare intravenously administered aqueous compositions containing only acetaminophen as the active pharmaceutical ingredient, or to prepare intravenously administered aqueous compositions containing both acetaminophen and one or more NSAIDs, preferably ibuprofen, as the active ingredient. By applying the method of the present invention, a stable solution suitable for intravenous injection is obtained.

[0023] Unless otherwise defined, all terms (including technical and scientific terms) used in disclosing this invention have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Further guidance, including terminology definitions, is provided to better understand the teachings of this invention.

[0024] As used in this document, the following terms have the following meanings: Unless the context clearly indicates otherwise, the terms “a,” “an,” and “the” as used herein refer to both the singular and plural pronouns. For example, “interval” refers to one or more intervals.

[0025] As used herein, “about” and “approximately” refer to measurable values ​​such as parameters, quantities, durations, etc., and are intended to cover a variation of + / - 5% or less, preferably + / - 3% or less, more preferably + / - 2% or less, even more preferably + / - 1% or less, and even more preferably + / - 0.1% or less, provided that such variation is suitable for implementation in the disclosed invention. However, it should be understood that the values ​​referred to by the modifiers “about” or “approximately” are themselves specifically disclosed.

[0026] As used herein, “comprise,” “comprising,” “comprises,” and “comprised of” are synonymous with “include,” “including,” “includes,” or “contain,” “containing,” and are inclusive or open-ended terms used to indicate the presence of subsequent objects (e.g., components) and do not exclude or deny the presence of other undescribed components, features, elements, components, or steps known in the art or disclosed herein.

[0027] The description of the endpoints to the numerical range includes all numbers and fractions contained within the range, as well as the listed endpoints.

[0028] Unless otherwise defined, in this document and throughout the specification, the terms “% by weight,” “percentage by weight,” “%wt” or “wt%” refer to the relative weight of the corresponding component based on the total weight of the formulation.

[0029] For the purposes of this invention, the term "aqueous" should be understood as a solution containing water.

[0030] For the purposes of this invention, the term "atmosphere" should be understood as the atmosphere of the space in which the mixing container is placed. For obvious reasons, the atmospheric pressure and air described in this specification are assumed to be similar to atmospheric conditions on Earth. Earth's atmosphere contains approximately 20.95% by volume, or 209,500 ppm, of oxygen.

[0031] In a first aspect, the present invention provides a method for preparing an aqueous composition for intravenous administration, the aqueous composition comprising acetaminophen and optionally one or more NSAIDs, having a dissolved oxygen content of up to 1.0 ppm, preferably up to 0.50 ppm, in a closed container.

[0032] The method of the present invention includes the following steps: rinsing a mixing container with water, preferably at a temperature of at least 80°C, more preferably at least 90°C, or between 80°C and 99°C, thereby heating the container and creating a hypoxic environment within it; and dissolving acetaminophen in the water for injection in the rinsed container, the water for injection being at a temperature of at least 80°C, more preferably at least 90°C, or between 80°C and 99°C. Optionally, the water for injection may already contain one or more excipients dissolved in the heated WFI present in the container when acetaminophen is added to the container. The one or more excipients may be, but are not limited to, isotonic agents, pH adjusters, 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 addition of acetaminophen to the water for injection.

[0033] In a preferred embodiment, the water used for rinsing the container and for further preparation of the composition is drawn from a loop, thereby heating the water to a preferred temperature, which allows the water to circulate continuously.

[0034] In particular, in a preferred embodiment, the method includes the following steps: - Rinse the mixing container with water, preferably water for injection (WFI) at at least 80°C, thereby heating the container and creating a low-oxygen environment in the container; - Introduce one or more excipients and optionally one or more NSAIDs (when intended to produce a combined product) into the mixing container, wherein the excipients are preferably one or more isotonic agents and one or more pH adjusters; - Add water for injection, wherein the water temperature is above 80°C, preferably above 85°C, more preferably above 90°C, more preferably above 95°C, preferably between 80°C and 99°C, or between 90°C and 99°C, and mix the introduced excipient and water; - Acetaminophen is then dissolved in the mixture; and - Add one or more antioxidants and optionally one or more pH adjusters to the mixture to obtain the composition; -In this case, after the components of the composition are introduced into the container, the container is sealed and placed under nitrogen pressure.

[0035] Compositions with a dissolved oxygen content of less than or equal to 1.0 ppm are beneficial in preventing the oxidation and degradation of acetaminophen.

[0036] Dissolved oxygen content can be measured using techniques known to the technician. Initial or residual dissolved oxygen content can be measured using an oxygen meter operating based on Clark's principle, providing an oxygen content value in mg / L. The scale is calibrated between zero (reduced solution) and the oxygen saturation of distilled water, taking into account the medium temperature and atmospheric pressure. The oxygen content is calculated using charts based on temperature and pressure.

[0037] More specifically, the method of the present invention provides a method for preparing a composition comprising acetaminophen and optionally one or more NSAIDs, preferably ibuprofen, having a dissolved oxygen content of up to 1.0 ppm, preferably up to 0.50 ppm, in a closed container.

[0038] As described above, the method according to the invention is particularly advantageous because it does not require deoxygenation of the formulation in any way. This contrasts sharply with most methods currently described in the art, which require an active step to evacuate or expel oxygen from the formulation (e.g., bubbling with an inert gas or using a vacuum, see, for example, US 6,992,218). By utilizing the method of the invention, a low-oxygen environment is created. Reoxygenation of the formulation during production is prevented by using nitrogen pressure in the container (preferably in the top space of the container).

[0039] In a preferred embodiment, pretreatment of the mixing container before introducing the ingredients comprises rinsing the mixing container several times with water at a temperature of 80-99°C, preferably 90-99°C, more preferably between 95°C and 99°C. In a preferred embodiment, the water is water for injection (WFI). In a more preferred embodiment, the WFI is provided by a loop that circulates the WFI at a constant temperature of 80-99°C, preferably 90-99°C, more preferably between 95°C and 99°C. The WFI, particularly at such high temperatures, contains less than 0.5 ppm, for example, about 0.20 ppm of dissolved oxygen. As mentioned, rinsing the mixing container before introducing the ingredients causes preheating of the mixing container. In a second aspect, steam is generated during the rinsing due to the high temperature of the WFI. The steam has a density lower than air and thus acts as a lifter. As a result, the generated steam expels air present in the top space of the mixing container, thereby reducing the oxygen content in the mixing container. In this way, pre-treating the mixing vessel before introducing the ingredients results in preheating of the mixing vessel and a reduction in the oxygen content within it.

[0040] The term "headspace of the mixing container" refers to the volume of the mixing container that is not occupied by the composition.

[0041] According to GMP requirements to avoid microbial growth, WFI should always be circulated at a temperature not lower than 75°C in the dispensing loop of the manufacturing plant. However, by circulating and using WFI at a temperature of 80-99°C, preferably 90-99°C, in the loop, the risk of microbial growth is further reduced. In a preferred method, WFI at a temperature of 80-99°C, preferably 90-99°C, and more preferably between 95°C and 99°C, from the same dispensing loop is used to rinse the mixing container and as a solvent for the aqueous composition.

[0042] In addition to its beneficial effect on the oxygen content in the container, preheating the mixing container before introducing the ingredients also prevents the WFI or composition (or intermediate mixture) from cooling during preparation in the mixing container. More specifically, preheating the container before introducing the ingredients allows the WFI or composition (or intermediate mixture) to remain at a higher temperature for a longer period. This is advantageous because higher temperatures increase the solubility of the ingredients in the aqueous solvent or composition (or intermediate mixture), and moreover, the aqueous composition dissolves less oxygen at higher temperatures, thus helping to maintain a low level of dissolved oxygen in the composition and its intermediate mixture.

[0043] In one embodiment, the mixing container is rinsed at least once with heated water (WFI). In a preferred embodiment, the mixing container is repeatedly rinsed with WFI at a temperature of 80-99°C, preferably 90-99°C, and more preferably 95-99°C. In a more preferred embodiment, the rinsing of the mixing container is repeated until the temperature of the mixing container reaches at least 80°C, more preferably at least 90°C. The container may be rinsed at least 2 times, more preferably at least 3 times, and even more preferably at least 4, 5, 6, 7 to 10 times.

[0044] The capacity of the mixing container can be as high as 250,000 liters. As a result, filling the mixing container can be time-consuming. However, in a preferred embodiment, the mixing container is rinsed with a volume of water smaller than its volume. In a more preferred embodiment, the container is rinsed with a volume of water equal to 3 to 20% of its volume. This significantly reduces the time and WFI consumption, thus allowing for a cheaper preparation process.

[0045] In another or further embodiment, the mixing container may be preheated electronically. However, simply preheating the mixing container before introducing the ingredients is insufficient to adequately reduce the oxygen content in the headspace of the mixing container. Therefore, it is preferable to combine electronic preheating of the mixing container with a pretreatment that results in a reduction of the oxygen content in the headspace of the mixing container before introducing the ingredients.

[0046] In the method according to the invention, after pretreatment, particularly rinsing the mixing container, the first or more components and / or WFI are introduced only into the mixing container to reduce the oxygen content in the mixing container and preheat the mixing container. In one embodiment, the oxygen content in the mixing container is reduced to less than 0.5 ppm before the components are introduced into the mixing container.

[0047] Preferably, the mixing container is preheated to a temperature of at least 80°C, and more preferably at least 90°C.

[0048] After adequate pretreatment of the mixing container, one or more excipients and optionally one or more NSAIDs, such as ibuprofen, are introduced into the mixing container. Water-soluble fiber (WFI) is added at a temperature of 80-99°C, preferably 90-99°C, and most preferably between 95°C and 99°C. The composition is then mixed, preferably until all introduced components are dissolved. Preferably, the one or more excipients comprise one or more isotonic agents and one or more pH adjusters.

[0049] Preferably, the total concentration of NSAID in the composition is 2 to 4 mg per milliliter of the composition, more preferably 3 to 4 mg per milliliter of the composition. More preferably, ibuprofen is present at a concentration of 2 to 4 mg per milliliter, more preferably 3 to 4 mg per milliliter.

[0050] For a dose of 3.0 mg ibuprofen / ml, use 3.85 mg ibuprofen sodium.

[0051] In a preferred embodiment, the one or more isotonic agents comprise mannitol. Preferably, the pH adjuster is hydrochloric acid, more preferably in an amount such that the pH of the composition is 6.3-7.3 after the addition of WFI.

[0052] While introducing water-based solvent (WFI) at a temperature of 80-99°C, preferably 90-99°C, and more preferably 95°C to 99°C, into the mixing vessel, the vessel is kept open to prevent overpressure buildup in the top space. Furthermore, the vapor generated during the addition of the aqueous solvent at high temperatures flows outwards, preventing atmospheric entry into the vessel. The aqueous solvent is introduced into the vessel at a stable rate to avoid turbulence, thereby preventing oxygen from dissolving in the WFI.

[0053] In a preferred embodiment, after the components of the composition are introduced into the container, the mixing container is placed under nitrogen pressure. In one embodiment, nitrogen pressure is applied to the mixing container, more specifically, to the top space of the mixing container, before the components introduced into the mixing container are mixed. Applying nitrogen pressure to the mixing container prevents the formulation from being reoxygenated in the container. As a result, the dissolution of oxygen in the final or intermediate composition or intermediate mixture thereof is avoided, which is particularly important during the mixing of the composition or intermediate mixture thereof. Preferably, the nitrogen pressure causes an overpressure of at least 0.1 bar, preferably a maximum of 1.0 bar, in the mixing container compared to atmospheric pressure. More preferably, the overpressure in the mixing container is at least 0.1 bar, preferably at most 0.5 bar, compared to atmospheric pressure. Obviously, the mixing container is sealed when nitrogen overpressure is applied to the top space of the mixing container. It is emphasized that the overpressure is applied to the top space of the mixing container by introducing nitrogen from the top side of the container, more preferably from the top side. In this way, nitrogen does not pass through the aqueous composition or intermediate mixture thereof, and the dissolution of oxygen into the composition or intermediate composition thereof is avoided.

[0054] Preferably, overpressure is applied to the headspace of the mixing vessel by introducing nitrogen gas. More preferably, overpressure is applied to the headspace of the mixing vessel by introducing filtered nitrogen gas. Preferably, the nitrogen gas is nitrogen gas filtered through a 0.22 μm filter.

[0055] After mixing the introduced excipients, if a combined product is formed, one or more NSAIDs, such as ibuprofen, are added together with the introduced WFI, the mixing container is opened, and acetaminophen is introduced into the mixing container. After the introduction of acetaminophen, the container should be sealed as soon as possible to prevent atmospheric entry, and the components should be mixed, preferably until all components are dissolved. When the mixing container is opened, the overpressure applied in the mixing container will cause nitrogen to flow outward in a directional manner; this flow prevents atmospheric entry. Preferably, acetaminophen is introduced within the time interval during which the overpressure in the headspace equalizes to atmospheric pressure.

[0056] In a preferred embodiment, after the introduction of acetaminophen and before mixing, overpressure is reapplied to the top space of the container by introducing nitrogen gas from the top side of the container. Preferably, the overpressure is 0.1 to 1.0 bar, and more preferably 0.1 to 0.5 bar.

[0057] In a preferred embodiment, 9.8 to 10.2 mg, more preferably 10.0 mg / ml, of acetaminophen is introduced into the mixing container.

[0058] Advantageously, the aqueous mixture is not cooled before mixing one or more active ingredients. This not only benefits the preparation time of the formulation because a heat exchanger is not needed to cool the aqueous solvent, but also allows for a suitable oxygen concentration. In contrast to deoxygenation of solutions already containing these ingredients, the addition of oxygen-sensitive acetaminophen and antioxidants to a medium with reduced oxygen content has the advantage of minimizing the harmful effects of oxygen, preventing premature depletion of potentially present antioxidants, and providing long-term storage stability. Preferably, the temperature of the mixture is maintained at at least 80°C, more preferably at least 90°C, before mixing the active ingredients.

[0059] In a preferred embodiment, after introducing and mixing acetaminophen, WFI for the final volume of the composition is added, followed by mixing. More preferably, overpressure is applied after adding WFI for the final volume and before mixing.

[0060] The mixture containing acetaminophen and optionally one or more NSAIDs is then cooled. Preferably, the cooling process is accelerated by circulating cold water in a double-jacketed system of the mixing vessel.

[0061] In a preferred embodiment of the method according to the invention, one or more antioxidants are added to a cooled aqueous mixture. The antioxidants used in this invention are preferably selected from the following list: sulfites or sulfite derivatives, thiols (e.g., cysteine, acetylcysteine, dithiothreitol or α-thioglycerol, thiomalic acid, thioglycerol, methionine), hydroxylated substances (e.g., ascorbic acid, isoascorbic acid, mannitol, sorbitol), olefinic unsaturated substances (e.g., sorbic acid, undecanoic 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, a monohydrate form is used. The term "(acetyl)cysteine" as used herein refers to acetylcysteine ​​and / or cysteine. Acetylcysteine ​​or cysteine, as antioxidants, can inhibit the formation of inappropriate degradation products of acetaminophen through oxidation. Although their use may produce a yellow solution, they are preferred because they can reduce the risk of acetaminophen poisoning.

[0062] In a more preferred embodiment, the antioxidant is added at a temperature of up to 40°C to avoid degradation of acetylcysteine ​​or cysteine ​​at higher temperatures. Preferably, the mixture containing acetaminophen and optionally one or more NSAIDs is cooled to a temperature of up to 40°C, preferably to 39°C, 38°C, 37°C, 36°C, or 35°C, before the addition of acetylcysteine ​​or cysteine. Preferably, the addition of cysteine ​​or acetylcysteine ​​to the mixture does not change the pH of 6.3-7.3. In a preferred embodiment, the pH of the aqueous composition is 6.3 to 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, if the pH of the mixture before the introduction of one or more antioxidants is not within the above range, one or more pH adjusters may be introduced into the mixing vessel at the time of introduction of the one or more antioxidants.

[0063] In a preferred embodiment, overpressure is applied to the headspace of the mixing container each time it is opened, and before the composition or intermediate compositions thereof are mixed within the mixing container during the preparation process. This is advantageous because the overpressure equalizes with atmospheric pressure each time the mixing container is opened. Overpressure prevents atmospheric air from entering the headspace when the container is opened and minimizes the solubility of oxygen in the composition or intermediate compositions thereof during mixing. Obviously, as a result, one or more components must be introduced into the container as soon as possible after opening so that it can be sealed shortly after opening, allowing the container to be opened for only a limited period of time.

[0064] In a preferred embodiment, the pH of the mixture to which the pharmaceutically active ingredient acetaminophen and optionally one or more NSAIDs are added is 6.0-8.0, preferably 6.2-7.5, and more preferably 6.3-7.3. In a more preferred embodiment, the pH of the mixture is 6.4-6.6. In a preferred embodiment, the pH of the final composition is 6.4-6.6. The term "final composition" refers to the composition to be filled into a container (preferably a vial) and ready for use. It is 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 a specified range. This pH range simultaneously avoids the precipitation of ibuprofen and the degradation of acetaminophen.

[0065] Before mixing the active ingredients, the pH can be adjusted to the desired level using one or more pH adjusters. In a preferred embodiment, the pH of the mixture is 6.3 to 7.3 before the introduction of acetaminophen and optionally one or more NSAIDs, preferably ibuprofen. Preferably, the pH of the mixture is 6.3 to 7.3 after the introduction of acetaminophen and optionally one or more NSAIDs, preferably ibuprofen. Therefore, in a preferred embodiment, the intravenously administerable composition contains a pH adjuster. In a more preferred embodiment, the pH adjuster used in the method according to the invention is hydrochloric acid and sodium hydroxide.

[0066] The pH of the composition can be buffered. Suitable buffers may include one or more of citric acid, sodium citrate, sodium phosphate, potassium citrate, etc. Preferably, the buffer is disodium phosphate.

[0067] In a preferred embodiment of the method and composition of the present invention, the composition comprises one or more isotonic agents. The advantage of using one or more isotonic agents is that osmotic pressure is generated within the pressure range of physiological saline. The isotonic agents described herein can be polyols, sugars, straight-chain or cyclic glucose alcohols having 2 to 10 carbon atoms, selected from mannitol, sorbitol, inositol, glucose, and glycerol. Mannitol is a preferred isotonic agent.

[0068] More pharmaceutically acceptable excipients may be present. However, in a preferred embodiment, no other excipients are present.

[0069] The mass ratio (w / w) of one or more isotonic agents to acetaminophen, such as mannitol:acetaminophen, is preferably 2 to 6:1, more preferably 3 to 5:1, and most preferably about 4:1. Preferably, one or more isotonic agents are added to an aqueous solution, preferably to water, before the introduction of acetaminophen, and optionally before the introduction.

[0070] In a preferred embodiment, the pH adjuster used in the method according to the invention is sodium hydroxide-disodium phosphate and acetylcysteine ​​or cysteine. In a more preferred embodiment, the pH adjuster is hydrochloric acid and sodium hydroxide.

[0071] 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 method of the present invention, the obtained aqueous composition 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.

[0072] Preferably, the mass ratio (w / w) of cysteine ​​hydrochloride to acetaminophen in the final formulation is 0.010 to 0.040:1, more preferably 0.020 to 0.030:1, and even more preferably 0.025:1.

[0073] Preferably, the mass ratio (w / w) of acetylcysteine ​​or cysteine ​​hydrochloride to ibuprofen in the final formulation is 0.20 to 0.40:1, more preferably 0.10 to 0.20:1, and even more preferably 0.08:1.

[0074] For example, in the formulations and methods defined herein, (acetyl)cysteine ​​hydrochloride may be present in the final formulation in an amount preferably from 0.015% to 0.05%, preferably about 0.025% (w / v).

[0075] The resulting composition can be filtered, for example, in a filtration unit.

[0076] During mixing, it is preferable to avoid oxygen contact or oxygen entering the aqueous solution during filling / packaging and / or storage.

[0077] Preferably, before filling, the container, preferably a vial, for a composition containing acetaminophen and optionally one or more NSAIDs, preferably ibuprofen, is washed with warm water. Specifically, the container can be washed with a water-based solution (WFI) at a temperature above 80°C, more preferably with a temperature between 80-99°C, and most preferably with a temperature between 90°C and 99°C. At such temperatures, the dissolved oxygen content of the WFI is low. This is particularly suitable for absorbing oxygen from the container and reducing its oxygen content.

[0078] In a subsequent step, the washed containers can be dried. Preferably, drying is carried out with dry air. Dry air with a low moisture content again minimizes oxygen reabsorption caused by packaging, and subsequently by oxygen reabsorption caused by compositions containing acetaminophen or compositions containing acetaminophen and one or more NSAIDs, preferably ibuprofen.

[0079] After drying, the washed and / or dried containers can be rinsed with nitrogen. Nitrogen with a low oxygen content is preferred.

[0080] After pretreatment of the container, the container is filled with a composition containing acetaminophen or a composition containing acetaminophen and one or more NSAIDs, preferably ibuprofen.

[0081] The mixing process preferably provides an aqueous composition containing acetaminophen or acetaminophen and one or more NSAIDs, preferably ibuprofen, having a dissolved oxygen content of less than 1.0 ppm, more preferably less than 0.5 ppm, and more preferably about 0.4 ppm before filling / packaging.

[0082] An intravenously administered aqueous composition comprising acetaminophen or acetaminophen and one or more NSAIDs, preferably ibuprofen, prepared according to the method of the present invention has a dissolved oxygen of less than or equal to 1.0 ppm, more preferably less than or equal to 0.5 ppm during filling.

[0083] Preferably, the container is sealed under vacuum; preferably, the vacuum is between 450 mbar and about 1 bar.

[0084] Then, for example, by adding a stopper, sealing under vacuum, and providing a crimp cap to cover the stopper, the container is sealed.

[0085] These bottles can then be heat-sterilized, for example, at 121°C for 15 minutes. Those skilled in the art will understand that other sterilization methods are also applicable.

[0086] In a preferred embodiment, the method according to the invention further includes the following steps in a specified order: The container was washed with WFI at a temperature of 80℃-100℃. Dry the washed container, preferably with dry air. The washed container is preferably rinsed with nitrogen gas. The nitrogen-washed container is filled with an aqueous composition containing acetaminophen or acetaminophen and one or more NSAIDs, preferably ibuprofen; The container is preferably sealed under vacuum between 450 mbar and approximately 1 bar.

[0087] In a more preferred embodiment, the vacuum-sealed product container includes a stopper made of an elastic material, the stopper being covered by a crimp cap.

[0088] In a preferred embodiment, the elastic material of the stopper is rubber, preferably butyl rubber or halogenated butyl rubber. These types of rubber have low oxygen permeability. Preferably, the stopper is sealed with an aluminum crimp cap. Preferably, the vial is sealed with a (halogenated) butyl rubber stopper, preferably bromobutyl rubber, and sealed with an aluminum cap.

[0089] Preferably, the container for obtaining the product according to one embodiment of the invention is a vial, preferably a colorless type II glass vial (Eur. Ph. 3.2.1).

[0090] In a preferred embodiment of the invention, the sealed product container has a reduced pressure. Preferably, the pressure is reduced to allow solvent for injection to be added to the sealed system, for example, by penetrating the seal with a needle. Preferably, the pressure reduction is between 450 mbar and about 1 bar.

[0091] In a preferred embodiment, the container includes a vial with backflush inside the flange. Backflush improves the fit of the stopper and prevents the stopper from popping out of the vial. The dimensions of the vial's flange and the stopper are chosen to ensure a good fit of the stopper during insertion and sealing. Preferably, the backflush is sized to provide sufficient sealing surface between the vial and the stopper to maintain the vacuum in the vial for as long as possible.

[0092] Preferably, the container / closure system has backflushing, especially when pressure is applied. Compared to systems without backflushing, backflushing systems are very tight and reduce the risk of air inflow, thus reducing the risk of oxidation.

[0093] Obviously, the same method can also be used to prepare intravenously administered compositions containing acetaminophen but without one or more NSAIDs, such as ibuprofen.

[0094] As described above, methods known in the art describe preparation methods that include deoxygenating the composition. It is known from the literature that this can be time-consuming. Furthermore, deoxygenating the composition indicates that the dissolved oxygen content of the composition is insufficient to prevent the oxidation of acetaminophen before deoxygenation; therefore, the antioxidant may be consumed prematurely, or some of the acetaminophen in the composition may be affected by the insufficient dissolved oxygen content before deoxygenation. In the method according to the invention, no time interval of insufficient oxygen content of acetaminophen was observed. More specifically, during the preparation method according to the invention, the dissolved oxygen content of the composition continuously increases.

[0095] Therefore, the present invention provides a more efficient and simpler method for preparing a composition comprising acetaminophen and optionally one or more NSAIDs, preferably ibuprofen.

[0096] In a second aspect, the present invention provides an intravenously administered aqueous composition comprising acetaminophen and optionally one or more nonsteroidal anti-inflammatory drugs (NSAIDs), preferably ibuprofen, having a dissolved oxygen content of up to 1.0 ppm, preferably up to 0.5 ppm, in a closed container.

[0097] An oxygen content of less than or equal to 1.0 ppm, preferably less than or equal to 0.5 ppm, is advantageous for avoiding the oxidation of acetaminophen, especially in the presence of NSAIDs, preferably ibuprofen.

[0098] It is known from the prior art that acetaminophen is readily oxidized, and that the oxidation products of acetaminophen lead to the formation of undesirable colored compounds. The compositions according to the invention contain a dissolved oxygen content of a maximum of 1.0 ppm, preferably a maximum of 0.5 ppm, thus exhibiting 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.

[0099] In a preferred embodiment, the composition according to the invention comprises 9.8 to 10.2 mg of acetaminophen, preferably 10 mg of acetaminophen.

[0100] 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 isotonic agents, and / or one or more pH adjusters.

[0101] In one embodiment, the one or more antioxidants are selected from the group consisting of acetylcysteine ​​or cysteine, such as cysteine ​​hydrochloride.

[0102] In one embodiment, the one or more isotonic agents are selected from the group consisting of mannitol, sorbitol, inositol, glucose, and glycerol.

[0103] In one embodiment, the one or more pH adjusters are selected from the group consisting of hydrochloric acid and sodium hydroxide.

[0104] Preferably, the aqueous composition according to the invention has a weight osmotic concentration between 285 and 320 mOsmol / L, as determined by the point reduction method according to USP 788.

[0105] Literature indicates that acetaminophen is readily hydrolyzed. The degradation rate of acetaminophen increases with increasing temperature and light. This rate is lowest at a pH of around 6.

[0106] In a preferred embodiment, the aqueous composition according to the invention has a pH of 6.3 to 7.3, preferably 6.4 to 6.9, more preferably 6.5 to 6.8, and most preferably about 6. In this way, the degradation rate of acetaminophen in the aqueous composition according to the invention is greatly reduced.

[0107] 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 4 mg, more preferably 3 to 4 mg of ibuprofen per ml of the composition, and most preferably 3 mg of ibuprofen per ml of the composition.

[0108] Ibuprofen is preferably introduced in the form of ibuprofen sodium.

[0109] In a preferred embodiment, based on the acetaminophen content and acetaminophen / ibuprofen content measured by HPLC according to European Pharmacopoeia 2.2.29 and USP 621, the composition has a storage stability of at least 6 months, preferably at least 9 months, more preferably at least 12 months, and most preferably 24 months.

[0110] In a preferred embodiment, when the composition is prepared, the amount of (acetyl)cysteine ​​in the composition is at least 80% of the initial addition amount, preferably at least 85%, and most preferably at least 90%.

[0111] In a preferred embodiment, the content of (acetyl)cysteine ​​hydrochloride is at least 40%, preferably at least 50%, and most preferably at least 75% of the initial addition amount during the shelf life of the composition. The low consumption of (acetyl)cysteine ​​indicates minimal exposure to oxygen during storage.

[0112] In a preferred embodiment, the aqueous composition according to the invention can be obtained by the method according to the invention. In a most preferred embodiment, the aqueous composition according to the invention can be obtained by the method according to the invention.

[0113] In another embodiment, the composition is used as a medicine. The pH of the composition is particularly important for its suitability in the pharmaceutical and medical fields.

[0114] In a more preferred embodiment, the composition is used to treat pain and / or inflammation.

[0115] In a preferred embodiment, the pH of the composition makes it particularly suitable for intravenous administration. In a most preferred embodiment, the composition is intended for intravenous administration.

[0116] The resulting composition can be dispensed into ready-to-use airtight or sealed bags, pouches, or bottles.

[0117] Preferably, the composition is produced by the method described above. More specifically, the composition is described by the following method: The formulation according to one embodiment of the invention can generally be prepared as follows. Before introducing one or more ingredients, the mixing container is pretreated to preheat the container and reduce the oxygen content in the headspace of the mixing container. Preferably, the pretreatment includes rinsing the mixing container several times with a water-soluble fiber (WFI) at a temperature of 80-99°C, preferably 90-99°C, until the temperature of the mixing container is at least 80°C, preferably at least 90°C. After pretreatment of 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°C, preferably 90-99°C, is added, and the container is sealed. Before mixing the composition, nitrogen gas is introduced from the top of the mixing container to apply overpressure to the headspace of the mixing container. Preferably, the one or more excipients include one or more isotonic agents, one or more pH adjusters, and buffers. After stopping the mixing of the composition, the container is opened, acetaminophen is introduced into the composition, the container is sealed, and nitrogen overpressure is applied to the headspace of the mixing container before mixing the composition. Preferably, the temperature of the composition is maintained at at least 80°C, more preferably at least 90°C, before mixing the active ingredients. After introducing acetaminophen and mixing the composition, the composition is cooled, preferably to below 40°C. While cooling, the container is opened, and disodium hydrogen phosphate dihydrate and sodium hydroxide, reaching a pH of 6.3-7.3, are added to the composition. The container is then sealed, and nitrogen overpressure is applied before mixing the composition. The container is then opened, cysteine ​​hydrochloride is introduced, the container is sealed, and nitrogen overpressure is applied before mixing the composition. The composition is filtered, and the filtered composition is filled into the container.

[0118] Advantageously, the introduction of the ingredients is performed as quickly as possible to prevent atmospheric air from entering the top space of the mixing container.

[0119] The inventors have discovered that the indicated method allows for the preparation of acetaminophen in aqueous compositions, and optionally a combination of acetaminophen and one or more NSAIDs, preferably ibuprofen, in a less complex, more cost-effective, and more time-efficient manner, thereby simultaneously reducing the degradation of acetaminophen, preferably ibuprofen.

[0120] Obviously, the method according to the invention can be performed with or without the introduction of one or more NSAIDs.

[0121] The invention is described in more detail in the following examples, which are given as non-limiting illustrations. In these examples, temperature is room temperature or expressed in degrees Celsius, and pressure is atmospheric pressure. Water and all reagents used are injection grade.

[0122] Furthermore, all embodiments form part of the invention, including any features described in the embodiments, which are novel relative to any prior art and take the form of general features rather than specific features of the embodiments.

[0123] Example In the following examples, the invention is intended to be further illustrated, but is not intended to limit the scope of the invention.

[0124] According to one embodiment of the present invention, preparation of an intravenously administered composition comprising acetaminophen Step 1: Weigh the recombinant components More specifically, under Class C laminar flow conditions, the acetaminophen active pharmaceutical ingredient and excipients were weighed separately. Each component was dispensed into appropriately designated double-layered plastic bags, and the weight was double-checked.

[0125] Step 2: Mixing the composition The addition of ingredients should be carried out as soon as possible.

[0126] Open an empty mixing vessel and flush it several times with heated water-soluble fiber (WFI) at a temperature of at least 90°C without cooling. The heated WFI contains 0.24 ppm of dissolved oxygen. During the flushing with heated WFI, the vessel is preheated to 90°C, generating steam in the headspace of the mixing vessel. This steam causes overpressure, which forces air and oxygen from the headspace of the mixing vessel. As a result, the oxygen content in the headspace of the mixing vessel is significantly reduced.

[0127] Mannitol and 1M hydrochloric acid for batch formulation at pH 6.3-7.3 are introduced into a pretreated container, and 95% of the final required volume of WFI at a temperature of at least 90°C is added. The container is sealed, and nitrogen is introduced from the top of the container to bring it under overpressure (preferably between 0.1 and 1 bar), and the composition is mixed until all components are completely dissolved.

[0128] After mixing, open the container, introduce acetaminophen, close the container, and apply overpressure to the top space of the mixing container again by introducing nitrogen gas filtered through 0.22 µm from the top side of the container. Then mix until all components are completely dissolved.

[0129] After mixing the composition, open the container and add the required WFI volume of the composition to the loop at a temperature of at least 90°C. Close the container and bring it under overpressure by introducing nitrogen gas from the top of the mixing container before mixing.

[0130] Under mixing conditions, the formulation is cooled to 38°C by circulating water in the double-jacketed container.

[0131] Open the container and introduce the dehydrated disodium hydrogen phosphate and sodium hydroxide for the batch formulation of pH 6.3-7.3 into the container. Seal the container and place it under nitrogen overpressure from the top of the container. Then mix the mixture until the components are completely dissolved.

[0132] After mixing, open the container, introduce cysteine ​​hydrochloride monohydrate, close the container, and bring it under overpressure by introducing nitrogen gas from the top of the container. Then mix until the components are completely dissolved.

[0133] The mixing of the composition is complete.

[0134] Maximum duration of mixing of the composition (processing time): 4 hours.

[0135] Step 3: Clean the empty vial and stopper to remove pyrogens, filter the composition into the vial, and seal it tightly. Close and seal (press) the vial.

[0136] These operations are performed online: - After mixing the composition in the mixing container, open the valve connecting the mixing container to the filter and the valve connecting the filter to the intermediate container. Filter the composition using a 0.22 μm filter.

[0137] -At the same time, the vials are continuously cleaned and depyrogenated.

[0138] - Clean the plug, remove the pyrogens, and finally rinse with the WFI provided by the supplier.

[0139] Once filling begins, the composition flows from the mixing container through the entire 0.22 µm filter to the intermediate container on the filling machine. The composition is then removed from the intermediate container via the filling machine to fill the vials.

[0140] - Fill the vial with the composition as follows: Rinse the empty vial with nitrogen. Fill the vial with the composition. Purge the air from the top of the vial with nitrogen. Seal the vial with a stopper under vacuum. If filling stops for more than one minute, discard all filled vials that are not sealed with stoppers.

[0141] - The sealed vials on the filling machine are driven in a Class C conveyor to a sealing machine located in front of the sealing chamber, where they are sealed with aluminum caps.

[0142] The dissolved oxygen content of the composition in the filled vial is less than 0.5 ppm.

[0143] Clean the empty vial to remove pyrogens, filter the composition into the vial, and plug (close) and seal (crush) the vial for a maximum duration (processing time): 10 hours.

[0144] Step 4: Terminal sterilization The composition filled in vials is sterilized in an autoclave.

[0145] Step 5: Visual inspection The 100% sterilized vials are visually inspected using automated machines.

[0146] Step 6: Carton Printing The batch number and expiration date are printed on the cardboard boxes by an automatic printer.

[0147] Step 7: Labeling and Final Packaging The batch number and expiration date are printed on the labels of the small bottles using automated machines. The small bottles are then labeled and packaged in cartons.

[0148] The relevant manufacturing steps are performed quickly without any unnecessary interruptions to reduce air incorporation in the mixing vessel and maintain the composition at the desired temperature, i.e., between 65°C and 98°C in the mixing step prior to the addition of acetylcysteine ​​or cysteine; and below or at 38°C in the addition of acetylcysteine ​​or cysteine.

[0149] Air in the top space of the mixing container is compressed from the top of the container by nitrogen pressure filtered through a 0.22 µm filter. The nitrogen pressure applied to the composition in the mixing container pushes the composition through the filter.

[0150] Table 1: Formulation 1 Preparation of an alternative liquid pharmaceutical formulation comprising both acetaminophen and ibuprofen according to one embodiment of the present invention The alternative formulation was prepared according to the method described in Example 1. In this method, a formulation comprising both acetaminophen and ibuprofen was prepared. Therefore, dehydrated ibuprofen sodium was added simultaneously with mannitol and hydrochloric acid. In contrast to the detailed examples provided above, the dissolved oxygen content in the following examples was measured to one decimal place. As a result, the error range was greater than that in Example 1.

[0151] Total component analysis prior to filtration showed a dissolved oxygen content of 0.2 ppm, while the dissolved oxygen content in the first filled vial after filtration was 0.4 ppm. Therefore, an increase in dissolved oxygen content was observed.

[0152] Table 2: Formulation 2 The importance of rinsing The formulation was prepared almost entirely according to the method described in claim 1. The only difference between the preparation method and that in Example 1 is the number of consecutive rinsing steps during the pretreatment of the headspace of the mixing container. More specifically, the container was rinsed only twice with WFI at a temperature not lower than 90°C in the loop without cooling. The dissolved oxygen content of the rinse water was 0.24 ppm. After rinsing, the temperature of the container was only 56°C.

[0153] The preparation method was carried out exactly as described in Example 1.

[0154] Compared to the 0.34 ppm oxygen in Example 1, the dissolved oxygen content of the composition was 0.56 ppm after introducing and mixing mannitol, sodium dihydrate, 1M hydrochloric acid (to obtain pH 6.3-7.3) and 95% WFI volume into the batch formulation.

[0155] After introducing acetaminophen and WFI to reach the final volume, the dissolved oxygen content of the composition was 0.49 ppm, and the temperature was only 73°C.

[0156] At the end of the mixing process, the dissolved oxygen content of the composition was 0.50 ppm, and after the composition was filtered and filled into vials (including stoppering and sealing), the dissolved oxygen content of the composition was 0.52 ppm.

[0157] Storage stability data The preparation of the ibuprofen / acetaminophen combination product is as follows: An empty mixing container was flushed at least three times with WFI at the circuit temperature of 97.8°C without cooling. As a result, air inside the container was forced out due to overpressure caused by the generated steam, and the container was heated to a temperature of 92.3°C. The dissolved oxygen content of the WFI used to flush the container was 0.24 ppm.

[0158] Mannitol, ibuprofen, 0.1N hydrochloric acid (to obtain a pH of 6.3 to 7.3), and WFI (water-soluble fiber) at a temperature of 97.8°C and a dissolved oxygen content of 0.24 ppm are added to a rinsed, preheated, and empty mixing vessel. The amount of hydrochloric acid to be added is calculated beforehand to maintain the desired pH between 6.3 and 7.3. The mixing vessel is sealed, and any remaining air in the top space of the vessel is compressed by introducing 1.2–1.5 bar of nitrogen from the top, followed by stirring. At this point, the oxygen content of the composition in this preparation method is 0.35 ppm.

[0159] Quickly open the mixing container and rapidly add acetaminophen without stirring. Seal the container and compress the residual air in the top space of the container with 1.2–1.5 bar of nitrogen introduced from the top side of the container, then stir. The dissolved oxygen content of the composition is 0.36 ppm.

[0160] Cool the composition to below 40°C. Once the temperature is reached, quickly open the mixing container and rapidly add 0.1N sodium hydroxide and disodium hydrogen phosphate without stirring. Seal the mixing container and compress any remaining air in the top space of the container by introducing 1.2-1.5 bar of nitrogen gas from the top side of the container, then stir. The dissolved oxygen content of the composition is 0.36 ppm.

[0161] The amounts of sodium hydroxide and disodium hydrogen phosphate to be added are calculated in advance to maintain the desired pH value of 6.3-7.3 after the addition of cysteine.

[0162] Quickly open the mixing container and rapidly add acetylcysteine ​​or cysteine ​​without stirring. Seal the mixing container and compress any remaining air in the top space of the container with filtered nitrogen gas at 1.2–1.5 bar introduced from the top, then stir. At this point, the dissolved oxygen content of the composition is 0.36 ppm.

[0163] Samples were stored and analyzed at set time intervals. Table 8 summarizes the results for the pH 6.6 composition stored at 25 ± 2 °C and 40 ± 5% relative humidity. Table 9 provides the pH 7.0 composition stored at 25 ± 2 °C and 40 ± 5% relative humidity. Table 10 provides additional results for the storage stability tests of samples prepared as previously described. These samples were maintained at 25 ± 2 °C and 40 ± 5% relative humidity. Table 11 provides the pH 6.4 composition stored at 25 ± 2 °C and 60 ± 5% relative humidity.

[0164] A series of analyses were performed on the samples. The appearance of the composition was determined by visual inspection according to USP 641; the pH was determined using potentiometric analysis according to USP 791; the coloration was determined according to the Eur. Ph 2.2.2 point reduction method (USP 785); sub-visible particles were assessed using the light-masking particle counting method (USP 788); and cysteine ​​(HCl*H2O), ibuprofen, and acetaminophen were identified using liquid chromatography (USP 621). The acetaminophen content was determined by HPLC and Eur. Ph 2.2.29, 0049. The ibuprofen content and the amount of cysteine ​​(HCl*H2O) were determined by liquid chromatography (USP 621). Acetaminophen impurities were determined using Eur. Ph 2.2.29, 0049. Ibuprofen impurities were determined using Eur. Ph 2.2.29.

[0165] The data from the two tables show that a clear liquid composition is provided. The physical appearance is maintained even after storage for twelve months or longer. Cysteine ​​content remains high and essentially stable over time. Impurity levels of acetaminophen and ibuprofen are very low, although the pH is considered unfavorable to the active ingredients when present alone.

[0166] Storage stability tests showed that a two-year shelf life for the product is feasible. It can be concluded that this invention provides a stable ibuprofen / acetaminophen combination product with a pH of 6.3-7.3.

[0167] Compatibility The following experiments were conducted to test the compatibility of ibuprofen and acetaminophen in combination.

[0168] The pH of the composition of 3.85 mg / ml ibuprofen sodium 2H2O (equivalent to 3 mg / ml ibuprofen) in water was gradually decreased from 8.80, and no precipitation or precipitation was observed, indicating solubility / compatibility. The results were recorded and summarized in Table 3. Once the pH reached 5.75, ibuprofen precipitation was observed. The ibuprofen compositions were stored at 25°C for 1 month. Precipitation was observed again. The results are summarized in Table 4. Ibuprofen compositions at pH 6 showed precipitation, while those at pH 6.2 did not.

[0169] Table 3: Solubility of ibuprofen sodium 2H2O in water alone Table 4: Solubility of ibuprofen sodium 2H2O in water after 1 month of storage at 25℃ In another experiment, the solubility of ibuprofen sodium 2H2O combined with acetaminophen was investigated at a concentration of 10 mg / L. Results at different pH values ​​are summarized in Table 5. Table 6 provides results after one month of storage at 25°C.

[0170] Table 5: Solubility of ibuprofen sodium in 2H2O in formulations of 3 mg / ml acetaminophen and 10 mg / ml ibuprofen Table 6: Solubility of Ibuprofen Sodium in Acetaminophen-Ibuprofen Formulation (2H2O) - 1 Month Table 7: Solubility of ibuprofen sodium 2H2O in acetaminophen-ibuprofen formulation - 6 months, 25℃ The amount of acetaminophen was investigated at different time points and pH values. Data showed that acetaminophen degradation was minimal in the pH range of 6.3–7.3.

[0171] From the above, we can conclude that the combination of ibuprofen and acetaminophen is stable in the pH range of 6.3-7.3.

[0172] Table 8: Storage stability data - 3 mg / ml ibuprofen and 10 mg / ml acetaminophen containing cysteine ​​(pH 6.6, 25 + / - 2℃, 40 + / - 5% relative humidity) Table 9: Storage stability data - 3 mg / ml ibuprofen and 10 mg / ml acetaminophen containing cysteine ​​(pH 7.0, 25 + / - 2℃, 40 + / - 5% relative humidity) Table 10: Storage stability test - 3 mg / ml ibuprofen and 10 mg / ml acetaminophen containing cysteine ​​(pH 6.6, 25 + / - 2℃, 40 + / - 5% relative humidity) Table 11: Storage stability test - 3 mg / ml ibuprofen and 10 mg / ml acetaminophen containing cysteine ​​(pH 6.4, 25+ / -2℃, 60+ / -5% relative humidity)

Claims

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

2. The method according to claim 1, comprising the following steps: - Rinse the mixing container at least once with water at at least 80°C to heat the container and create a low-oxygen environment within it; - Introduce one or more excipients, preferably one or more isotonic agents and one or more pH adjusters, and optionally one or more NSAIDs into the mixing container; - Add water for injection at a temperature of 80-99°C, and mix the introduced excipient with water; - Acetaminophen is then dissolved in the mixture; and - Add one or more antioxidants and optionally one or more pH adjusters to the mixture to obtain the composition; After the components of the composition are introduced into the container, the container is sealed and placed under nitrogen pressure. In particular, one or more NSAIDs include ibuprofen.

3. The method according to claim 1 or 2, wherein the dissolved oxygen content of the water for injection at a temperature of at least 80°C is 0.5 ppm or less; and / or, the dissolved oxygen content in the composition continuously increases during the preparation process.

4. The method according to any one of the preceding claims, wherein the rinsing of the mixing container is repeated; in particular, the rinsing of the mixing container is repeated until the temperature of the mixing container is at least 80°C, preferably at least 90°C; in particular, the rinsing of the mixing container is repeated until the oxygen content in the mixing container is less than 0.5 ppm.

5. The method according to any one of the preceding claims, wherein the nitrogen pressure is applied by introducing nitrogen from the upper side of the container; in particular, the nitrogen pressure causes an overpressure of at least 0.1 bar in the mixing container; in particular, the nitrogen pressure causes an overpressure of up to 1.0 bar in the mixing container.

6. The method according to any one of the preceding claims, wherein about 10 mg of acetaminophen per ml of the composition is introduced into the mixing container; and / or, wherein about 2 to 4 mg of one or more NSAIDs per ml of the composition is introduced into the mixing container; and / or, wherein after introducing acetaminophen into the mixing container, a final volume of WFI is added to the composition.

7. The method according to any one of the preceding claims, wherein the one or more antioxidants are cysteine ​​or acetylcysteine; and / or, the one or more isotonic agents are selected from the group consisting of mannitol, sorbitol, inositol, glucose and glycerol.

8. The method according to any one of the preceding claims, wherein the pH of the composition is 6.3-7.3 before the introduction of acetaminophen; and / or wherein the pH of the composition is adjusted to 6.3-7.3 after the introduction of acetaminophen; in particular, the pH of the composition is adjusted by one or more pH adjusters; in particular, the one or more pH adjusters are selected from the group consisting of hydrochloric acid and sodium hydroxide.

9. An aqueous composition for intravenous administration, characterized in that... The composition comprises acetaminophen, a dissolved oxygen content of up to 1.0 ppm in a closed container, a pH of 6.3 to 7.3, one or more antioxidants, one or more isotonic agents, and one or more pH adjusters; preferably, the composition comprises 10 mg / ml acetaminophen; in particular, the composition also comprises ibuprofen; preferably, the composition contains 2-4 mg of ibuprofen per milliliter.

10. The intravenously applicable aqueous composition according to claim 9, characterized in that... The composition can be obtained by the method according to any one of claims 1-8.

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