Aqueous formulation with paracetamol and ibuprofen

Description

TECHNICAL FIELD

[0001] The present invention relates to compositions comprising ibuprofen and paracetamol obtained using the method of the present application, and to their use as a medicine especially for intravenous injection or infusion.

[0002] The invention is particularly useful for use in hospitals where it is desirable to have access to stable liquid pharmaceutical formulations combining ibuprofen with paracetamol for administration by injection, in particular for intravenous injection or infusion.INTRODUCTION

[0003] Ibuprofen is a known non-steroidal anti-inflammatory drug that possesses analgesic and antipyretic activities. Its chemical name is 2-(p-isobutylphenyl)propionic acid. It is indicated in the treatment for relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, mild to moderate pain and treatment of primary dysmenorrhea.

[0004] Ibuprofen is very poorly soluble in water. Consequently dosage forms such as oral or injectable liquids have been difficult to develop. An approach followed to improve water solubility has been the use of water-soluble complexes and the preparation of an ibuprofen salt such as sodium or with an amino acid.

[0005] Paracetamol, also known as acetaminophen, is a known non-opiate, non-salicylate analgesic and antipyretic drug. Its chemical name is N-(4-hydroxyphenyl)acetamide. It provides temporary relief of minor aches and pains with heartburn or acid ingestion and upset stomach associated with these symptoms.

[0006] It is known that paracetamol in aqueous solution is liable to undergo hydrolysis. The formation of p-aminophenol following hydrolysis of paracetamol which itself can degrade into quinoneimine is for instance described in the publication of J.E. Fairbrother, "Acetaminophen" in Analytical Profiles of Drug Substances, 1974, vol. 3, pages 1-109. The rate of degradation of paracetamol increases with increasing temperature and light. This rate is minimal at a pH in the region of 6 (K.T. Koshy et al., 1961, J. Pharm. Sci. 50, pages 116-118). Paracetamol is also known as being susceptible to oxidation. Its stability in aqueous solutions therefor requires the use of antioxidants and / or the removal of oxygen from the solution. This poses extra constrains on the development of a formulation for intravenous injection on account of the toxicity of some antioxidants and / or complexity to remove oxygen which dissolves easily in water. Depending on the technique used the removal of oxygen may require a considerable amount of time. Another disadvantage is that oxidation products lead to the formation of coloured compounds, making the aqueous solution unsuitable for therapeutic applications.

[0007] Document WO 2012 / 060719 A1 discloses a combination composition comprising ibuprofen and paracetamol, suitable for intravenous administration. The composition having ibuprofen and paracetamol in combination for delivering to a human at each dose: a) approximately 125mg to approximately 175mg ibuprofen in combination with approximately 475mg to approximately 525 mg paracetamol; or b) approximately 275mg to approximately 325mg ibuprofen in combination with approximately 975mg to approximately 1,025 mg paracetamol. The pH of said composition is adjusted to 5-6.

[0008] Use of ibuprofen alone is associated with a number of side effects such as rash, ringing in the ears, headaches, dizziness, drowsiness, abdominal pain, nausea, diarrhoea, constipation and heartburn. The side effects may lead to patient discomfort and may result in poor medication follow up. A known approach is the combination with other active principles complementary to ibuprofen, preferably allowing a lower dose of ibuprofen.

[0009] There is a demand in the field for products that combine ibuprofen and paracetamol, especially in a form suitable for intravenous injection.

[0010] The pH of existing formulations in the market of ibuprofen alone is about 7. Ibuprofen sodium formulations commonly have a pH ranging from 7.0 to 7.4 and are buffered. Ibuprofen lysate formulations have a pH ranging from 6.8 to 7.1. The pH of existing paracetamol formulations in the market is about 5.5 to 6.0. The pH of 7 avoids precipitation of ibuprofen and the pH of 5.5 to 6.0 is advantageous for paracetamol as hydrolytic degradation of paracetamol is minimal at this pH. At pH 7 degradation of paracetamol is significant and at pH 5.5 to 6.0 ibuprofen precipitates.

[0011] It is the aim of the present invention to provide a combination product of ibuprofen and paracetamol that solves at least one of the problems described above. In particular the invention aims to provide a combination product in aqueous form suitable for intravenous injection. It is a further object of the invention to provide a method for the preparation of the ibuprofen / paracetamol combination.SUMMARY OF THE INVENTION

[0012] The current invention provides a solution for at least one of the above mentioned problems by providing a composition combining ibuprofen and paracetamol with improved compatibility.

[0013] In a first aspect, the present invention provides an aqueous composition according to the claims.

[0014] Products according to an embodiment of the invention are characterized in that they provide a stable combination of ibuprofen and paracetamol at a physiologically acceptable pH.

[0015] In another aspect the present invention provides an aqueous composition according to the claims for use as a medicament or for use in the treatment of pain and / or inflammation; preferably for administration by intravenous injection or infusion.DETAILED DESCRIPTION OF THE INVENTION

[0016] Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the present invention.

[0017] As used herein, the following terms have the following meanings: "A", "an", and "the" as used herein refers to both singular and plural referents unless the context clearly dictates otherwise. By way of example, "a compartment" refers to one or more than one compartment. "Comprise," "comprising," and "comprises" and "comprised of" as used herein are synonymous with "include", "including", "includes" or "contain", "containing", "contains" and are inclusive or open-ended terms that specifies the presence of what follows e.g. component and do not exclude or preclude the presence of additional, non-recited components, features, element, members, steps, known in the art or disclosed therein.

[0018] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within that range, as well as the recited endpoints. All percentages are to be understood as percentage by weight and are abbreviated as "%wt", unless otherwise defined or unless a different meaning is obvious to the person skilled in the art from its use and in the context wherein it is used.

[0019] In a first aspect, the present invention provides an aqueous composition comprising ibuprofen and paracetamol in combination characterized in that it comprises a pH 6.3-7.3 and in that it is manufactured by a process comprising the steps of: a) providing an aqueous solvent of pH 6.0-8.0, preferably 6.2-7.5, more preferably 6.3-7.3, b) dissolving in said aqueous solvent ibuprofen and paracetamol, c) if required adjusting the pH to 6.3-7.3, d) thereby obtaining said aqueous composition comprising ibuprofen and paracetamol in combination and pH 6.3-7.3 wherein the composition further comprises a buffering agent.

[0020] With the term "aqueous" is meant, comprising water. Preferably the aqueous solvent is water and more preferably a saline solution.

[0021] Preferably, the ibuprofen and paracetamol are dissolved in the aqueous solvent under mechanical agitation e.g. stirring. Ibuprofen is preferably used in the form of ibuprofen sodium. The amount of ibuprofen in the combination product is 2.8 to 3.2 mg per ml of the composition; preferably the amount is 3.0 mg / ml. Preferably ibuprofen sodium is used. For an amount of 3.0 mg ibuprofen / ml 3.85 mg ibuprofen sodium is used.

[0022] The amount of paracetamol in the combination product is 9.8 to 10.2 mg; preferably 10.0 mg / ml.

[0023] The aqueous solvent to which the active ingredients are added is characterized by a pH of 6.0-8.0, preferably 6.2-7.5, preferably 6.3 to 7.3. In a more preferred embodiment, the aqueous solvent has a pH of 6.4-6.6. In a more preferred embodiment, the final composition has a pH of 6.4-6.6. With "final composition", the composition is meant that will be filled into receptacles and is stored. It was found advantageous to start at the low end of the pH range. The final product has a pH on storage that remains stable or may evolve within the specified range (6.3-7.3).

[0024] The pH range at the same time avoids the precipitation of ibuprofen and degradation of paracetamol.

[0025] The pH may be adjusted to a desired level prior to admixing using a pH adjuster such as NaOH or HCl.

[0026] The pH of the solution is buffered. Suitable buffering agents may include one or more of citric acid, sodium citrate, sodium phosphate, potassium citrate, and the like. Preferably the buffering agent is disodium phosphate.

[0027] In a preferred embodiment the aqueous solvent has a dissolved oxygen content below 2 ppm.

[0028] An oxygen content of maximum 2 ppm is a favourable level for avoiding degradation of paracetamol in the presence of ibuprofen, in the present method and compositions obtained thereof.

[0029] In a preferred embodiment the oxygen content of the aqueous solution is below 5 ppm, preferably below 2 ppm, more preferably below 1 ppm, even more preferably below 0.5 ppm, most preferably below 0.2 ppm.

[0030] The dissolved oxygen content can be measured by techniques known to a skilled person. The initial or residual dissolved oxygen content can be measured with the aid of an oxygen meter operating according to the Clark principle giving the value of the oxygen content in mg / l. The scale is calibrated between a point zero (reducing solution) and the content at oxygen saturation of distilled water, taking into account the temperature of the medium and the atmospheric pressure. The oxygen content is calculated using a chart as a function of the temperature and the pressure.

[0031] In a preferred embodiment of a process of the invention the reduced dissolved oxygen content is obtained using an aqueous solvent having a temperature, as from the outset, of between 65 °C and 99 °C, preferably between 80 °C and 98 °C. In an embodiment, the invention relates to a method as defined herein, wherein the aqueous solvent has, as from the outset, a temperature between 85 °C and 97°C or between 90°C and 95°C.

[0032] A preferred process comprises admixing of the active principles to the aqueous solvent that has a raised temperature. Advantageously, the aqueous solvent is not cooled prior to admixture of the active principle, which constitutes not only a gain in the preparation time of the formulation as there is no need to use heat exchangers to cool the aqueous solvent, but also permits to obtain a suitable oxygen concentration. Addition of the oxygen sensitive paracetamol and anti-oxidant to a medium with lowered oxygen content, as opposed to deoxygenation of the solution already containing these ingredients, has the advantage that the detrimental effects of oxygen are kept minimal. The anti-oxidant is not prematurely consumed as remains available to provide long term storage stability.

[0033] In another preferred embodiment of a process of the invention the reduced oxygen content is obtained by bubbling of an inert gas through said solvent. The gas that is bubbled into the solution to drive out oxygen may be nitrogen, argon or xenon. Preferred is nitrogen. Most preferred is nitrogen with low oxygen content.

[0034] In another embodiment of a process of the invention the reduced oxygen content is obtained using vacuum. Vacuum may be obtained using an appropriate vacuum pump such as a vane pump.

[0035] Techniques for reduction of the oxygen content in the formulation, such as the warm water, bubbling and / or vacuum method as described above, may be combined.

[0036] In a preferred embodiment, the solution before filling in a receptacle, is topped up with an inert gas, such as nitrogen, argon or xenon. Preferred is argon. The use of argon is advantageous as it is heavier than air and is believed to provide a protective layer on top of the solution.

[0037] In a preferred embodiment of a process of the invention, the pH of the aqueous solvent in step a) is 6.3 to 6.5. Starting the process at a pH of 6.4 ± 0.1 has the advantage that the resulting composition has a longer storage stability.

[0038] In a preferred embodiment, solutions prepared with a process of the invention, with pH of 6.4 + / - 0.1, have a storage stability of at least 6 months, preferably 12 months, more preferably 18 months, most preferably 18 months.

[0039] In another preferred embodiment, solutions prepared with a process of the invention, with pH of 6.3-6.6 at the time of preparation (t 0 ), have a storage stability of at least 6 months (t 6 ), preferably at least 8 months (t 8 ), more preferably at least 10 months (t 10 ), most preferably at least 12 months (t 12 ).

[0040] In a preferred embodiment of a process and composition of the invention, an anti-oxidant is added to the aqueous composition. Anti-oxidants for use in the invention are preferably selected from the list of a sulphite, or sulphite derivative, a thiolic substance such as, for example, cysteine, acetylcysteine, dithiothreitol or alpha-thioglycerol, thiomalic acid, thioglycerol, methionine; a hydroxylated substance such as ascorbic acid, iso-ascorbic acid, mannitol, sorbitol, an ethylenically unsaturated substance such as sorbic acid, undecylenic acid or fumaric acid or a hydroxy polycarboxylic acid, or a reducing sugar such as trehalulose, maltulose or isomaltulose. In a preferred embodiment the anti-oxidant is selected from a cysteine and acetyl cysteine. Cysteine is preferably cysteine hydrochloride. The acetyl cysteine or cysteine hydrochloride is preferably the monohydrate. By the term "(acetyl)cysteine" as used herein, is meant acetylcysteine and / or cysteine. Acetyl cysteine or cysteine as anti-oxidant suppresses the generation of unknown degradation products of paracetamol by oxidation. In spite of the risk that their use will provide yellow solutions, they are preferred as they can reduce the risk of paracetamol toxicity.

[0041] In case the warm water technique is used, the temperature of the composition is lowered to 40 °C or lower prior to addition of cysteine or acetyl cysteine. The cooling may be under mechanical agitation e.g. stirring. The anti-oxidant is added at a temperature of at most 40°C to avoid degradation of the acetyl cysteine or cysteine at higher temperatures. The aqueous solution comprising ibuprofen and paracetamol is then cooled to a temperature of at most 40 °C, preferably to 39 °C or 38°C, 37°C, 36°C or 35 °C, prior to the addition of acetyl cysteine or cysteine. Preferably the addition of cysteine or acetyl cysteine to said aqueous solvent does not change said pH outside of 6.3 and 7.3. In a preferred embodiment, the aqueous composition has a pH of 6.3 to 7.3 prior to and after addition of the anti-oxidant. Preferably the pH of the final product is around 6.6.

[0042] In a preferred embodiment of a process and composition of the invention the aqueous solvent further comprises an isotonic agent. Use of an isotonic agent has the advantage that an osmotic pressure is created in the region of that of physiological saline. The isotonic agent herein may be a polyol, a sugar, a linear or cyclic glucitol having from 2 to 10 carbon atoms selected from mannitol, sorbitol, inositol, glucose and glycerol. A preferred isotonic agent is mannitol.

[0043] The mass ratio (w / w) of the isotonic agent to paracetamol, for instance mannitol:paracetamol, is preferably 2 to 6:1, more preferably 3 to 5:1, most preferably around 4:1. Preferably the isotonic agent is added to the aqueous solution, preferably water, prior to the addition of ibuprofen and paracetamol.

[0044] In a preferred embodiment, the pH adjusters used in a method according to the invention, are sodium hydroxide-disodium phosphate salt and acetyl cysteine or cysteine.

[0045] The final pH of the formulation is from 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 a process of the invention the aqueous composition obtained has a pH around 6.6. Preferably the pH is 6.3 to 7.3 after a shelf-life of at least six months.

[0046] After the additions are complete, the reaction vessel is closed, and the air remaining in the upper side of the vessel is compressed by an inert gas such nitrogen, introduced from the upper side of the vessel. Preferably the pressure is at 1-1.5 bar. Following the introduction of inert gas, stirring ensues.

[0047] Preferably, the mass ratio (w / w) of cysteine hydrochloride to paracetamol is 0.010 to 0.040: 1, preferably 0.020 to 0.030: 1, preferably 0.025: 1.

[0048] Preferably, the mass ratio (w / w) of acetyl cysteine or cysteine hydrochloride to ibuprofen is 0.20 to 0.40:1, preferably 0.10 to 0.20:1, preferably 0.08:1.

[0049] For example, in a formulation and method as defined herein, (acetyl)cysteine hydrochloride may be present in the final formulation in an amount preferably between 0.015 % and 0.05 %, preferably around 0.025 % (w / v).

[0050] The solution obtained may be filtered, for example in a filtration unit.

[0051] As during compounding, oxygen contact or oxygen ingress into the aqueous solution during filling / packaging and / or storage is preferably avoided.

[0052] Preferably the containers, such as vials, for receipt of the paracetamol- ibuprofen solution are washed with warm water prior to filling. In particular, the containers may be washed with water for injection at a temperature of 75 °C - 100 °C. This water has a low dissolved oxygen content. It is particularly suitable to take up oxygen from the container and reduced its oxygen content.

[0053] In a subsequent step, the washed containers may be dried. Preferably drying is carried out with dry air. Dry air with low moisture content, again minimizes re-uptake of oxygen by the packaging and later on by the paracetamol-ibuprofen solution.

[0054] After drying the washed and / or dried containers may be rinsed with nitrogen. Preferably nitrogen low in oxygen is used.

[0055] Following the pre-treatment of the containers, said containers are filled with the ibuprofen / paracetamol solution.

[0056] The compounding procedure preferably provides an aqueous ibuprofen / paracetamol solution prior to filling / packaging with a dissolved oxygen content of below 2.0 ppm, more preferably below 1.0 ppm, even more preferably below 0.8 ppm, most preferably below 0.5 ppm; typically around 0.4 ppm.

[0057] In a preferred embodiment, a paracetamol-ibuprofen solution prepared according to a method of the invention has less than or equal to 0.8 ppm dissolved oxygen during filing.

[0058] Preferably the containers are sealed under vacuum; preferably said vacuum is between 450 mbar and around 1 bar.

[0059] The containers are then sealed, for instance by adding a stopper, sealing under vacuum and providing a crimping cap covering the stopper.

[0060] These bottles can subsequently be heat-sterilised, for instance for 15 minutes at 121 °C.

[0061] In a preferred embodiment, a method according to the invention further comprises in specified order the steps of: washing said containers with water for injection at a temperature of 75 °C - 100 °C, drying said washed containers with dried air, rinsing said washed containers with nitrogen, filling said nitrogen washed container with the ibuprofen / paracetamol aqueous solution, sealing said container under vacuum, preferably between 450 mbar and around 1 bar.

[0062] In a more preferred embodiment, said vacuum sealed product container comprises a stopper made of an elastic material covered by a crimping cap.

[0063] In a preferred embodiment said elastic material of the stopper is rubber, preferably a butyl rubber or halo butyl rubber. These rubber types have a low oxygen transmission coefficient. Preferably the stopper is sealed by an aluminium crimping caps. Preferably said vial is closed with a (halo)butyl rubber stopper, preferably bromobutyl rubber, and sealed by an aluminium caps.

[0064] Preferably the container used to obtain a product according to an embodiment of the invention is a vial; preferably a colourless type II glass Eur. Ph. 3.2.1 vial.

[0065] In a preferred embodiment according to the invention the closed product container has reduced pressure inside. Preferably the pressure is reduced to allow the addition of solvent for injection to the closed system, e.g. by means of penetrating the closure with a needle. Preferably the reduced pressure is between 450 mbar and around 1 bar.

[0066] In a preferred embodiment the container comprises a vial with a blow back inside of the flange. The blow back improves the fit of the stopper and avoids that the stopper pops out of the vial. The flange of the vial and the dimensions of the stopper are chosen in a way to guarantee a good fit of the stopper during stoppering and sealing. It is preferred to have a blow back with dimensions in size to provide sufficient sealing surface between the vial and the stopper in order to keep a vacuum in the vial as long as possible.

[0067] Preferably the container / closure system has a blow back; particularly when applying reduced pressure. In comparison to systems having no blow back, blow back systems are very tight and the risk of influx of air and thus oxidation can be reduced.

[0068] A formulation according to an embodiment of the invention can generally be prepared as follows. First, exact quantities of the formulation of isotonic agent (mannitol), ibuprofen sodium and hydrochloric acid in an amount to obtain a pH of 6.3 - 7.3 are added to a reaction vessel. Optionally one or more other water-miscible solvent(s), and / or surfactants may be present. Then, as solvent, water for injections is provided at a temperature of between 65°C and 98°C. The reaction vessel is closed and the air remaining in the upper side of the vessel is compressed by 0.22µm filtered nitrogen introduction from the upper side of the vessel. Then components are dissolved by stirring. After stirring is stopped the reaction vessel is quickly opened and paracetamol is quickly added. The procedure is at this point carried out without mixing to reduce the introduction of air. Then the reaction vessel is closed. Air is hardly soluble in water when it is at a temperature of more than 60°C.

[0069] Remaining air in the upper side of the vessel is compressed by 0.22 µm filtered nitrogen from the upper side, preferably at 1-1.5 bar, then stirring ensues. The solution is cooled to a temperature of at most 40°C. Once cooled, reaction vessel is quickly opened and exact quantities of sodium hydroxide and disodium phosphate of the formulation, for obtaining a pH 6.3 - 7.3, are quickly added and reaction vessel is closed. Remaining air in the upper side of the vessel is compressed by 0.22 µm filtered nitrogen from the upper side, preferably at 1-1.5 bar, stirring ensues. The reaction vessel is quickly opened and cysteine or acetyl cysteine is quickly added and the reaction vessel is again closed. The air remaining in the upper side of the vessel is compressed by 0.22 µm filtered nitrogen introduced from the upper side, preferably at 1-1.5 bar, then stirring ensues. The nitrogen used is filtered prior to its introduction with a 0.22 µm filter.

[0070] The present inventor has found that the indicated pH range unexpectedly allows the combination of ibuprofen and paracetamol in aqueous solution thereby at the same time reducing ibuprofen precipitation and paracetamol degradation.

[0071] Preferably the aqueous solvent comprises water and an isotonic agent. In a more preferred embodiment said isotonic agent is mannitol.

[0072] More pharmaceutically acceptable excipients may be present.

[0073] Preferably the aqueous solution has an osmolality of between 285-320 mosmoljl as determined by point depression according to USP 788.

[0074] In a preferred embodiment said 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 paracetamol / ibuprofen content as measured by HPLC in accordance with European Pharmacopeia 2.2.29 and USP 621.

[0075] In a preferred embodiment, the (acetyl)cysteine amount in the composition at the completion of its preparation is at least 80%, preferably at least 85%, most preferably at least 90%, of the initial amount added.

[0076] In a preferred embodiment, the (acetyl)cysteine hydrochloride content is at least 40% of the initial amount added, preferably at least 50%, preferably at least 75%, during the shelf-life of the ibuprofen / paracetamol solution. A low consumption of (acetyl)cysteine is indicative of a low exposure to oxygen during the period of storage.

[0077] In a further embodiment said composition is for use as a medicament. Especially important for its suitability in the pharmaceutical and medical field is the pH of the composition.

[0078] In a more preferred embodiment said composition is for use in the treatment of pain and / or of inflammation.

[0079] Its pH makes the composition particularly suitable for administration by intravenous injection. In a most preferred embodiment said composition is for administration by intravenous injection.

[0080] The solutions thus obtained may be distributed into ready-to-use hermetically stoppered or sealed, bags, pouches or bottles.

[0081] The invention is described in greater detail in the examples below, which are given as non-limiting illustrations. In these examples, the temperature is room temperature or is expressed in degrees Celsius, and the pressure is atmospheric pressure. The water and all the reagents used are of injectable grade.

[0082] Moreover, all the examples form an integral part of the invention, as does any characteristic of the description including the examples, which appears to be novel with respect to any prior art, in the form of a general characteristic rather than of a particular characteristic of the example.EXAMPLES

[0083] In the following, examples are intended to further clarify the present invention, and are nowhere intended to limit the scope of the present invention.1. Preparation of liquid pharmaceutical formulations according to the present invention

[0084] Formulations were prepared by admixing isotonic agent (mannitol) ibuprofen, hydrochloric acid, water for injections, paracetamol and acetyl cysteine or cysteine, and pH is at 6.3 - 7.3 by hydrochloric acid, sodium hydroxide and disodium phosphate. The preparation of the composition was followed by filtration and filling of glass vials or bottles. The filtration of the solution took place at a temperature below 40°C. These receptacles were sterilized for 15 minutes at 121°C.

[0085] The relevant manufacturing steps are performed quickly and without any unnecessary interruption in order to avoid incorporation of air in the compounding vessel and to keep the solution at the required temperatures i.e. between 65°C and 98°C for the admixing steps before acetyl cysteine or cysteine are added; and below 40°C for the acetyl cysteine or cysteine addition part.

[0086] The air inside the reaction vessel was compressed from the upper side of the vessel by 0.22 µm filtered nitrogen pressure. The nitrogen pressure applied on the solution in the compounding vessel pushes the solution through the filter.

[0087] Finally, the filled vials were sterilized at 121 °C for 15 minutes. Table 1: Formulation 1Name of ingredientUnit formula 100 mlFormula per 1 mlIbuprofen sodiumEquivalent to 300 mg ibuprofenEquivalent to 3 mg ibuprofenParacetamol1.0 g10 mgMannitol3.2850 g32.850 mgHydrochloric acidto pH = 6.6to pH = 6.6Cysteine hydrochloride monohydrate25.0 mg0.25 mgDi sodium phosphate dihydrate13.0 mg0.13 mgSodium hydroxideto pH = 6.6to pH = 6.6Water For Injectionq.s. ad 100.0 mlq.s. ad 1.0 mlNitrogen Low Oxygenq.s.q.s. 2. Preparation of an alternative liquid pharmaceutical formulation according to the present invention

[0088] An alternative formulation was prepared according to the method described under Example 1. Table 2: Formulation 2Name of ingredientUnit formula 100 mlFormula per 1 mlIbuprofen sodiumEquivalent to 300 mg ibuprofenEquivalent to 3 mg ibuprofenParacetamol1.0 g10 mgMannitol3.2850 g32.850 mgHydrochloric acid 1M / Sodium hydroxide 1Mto pH = 6.4to pH = 6.4Cysteine hydrochloride monohydrate25.0 mg0.25 mgDi sodium phosphate dihydrate15.0 mg0.15 mgWater For Injectionq.s. ad 100.0 mlq.s. ad 1.0 mlNitrogen Low Oxygenq.s.q.s. 3. Storage stability data

[0089] An ibuprofen / paracetamol combination product was prepared as follows: To a mixing tank were added mannitol, ibuprofen, hydrochloric acid 0.1N for obtaining a pH of 6.3 to 7.3 and water for injections (WFI) at a temperature above 75 °C. The quantity of hydrochloric acid to be added was calculated in advance and is such that the desired pH is maintained 6.3 - 7.3. The mixing vessel was closed and the air remaining in the upper side of the vessel was compressed by 0.22 µm filtered nitrogen introduced from the upper side, at 1-1.5 bar, followed by stirring.

[0090] The mixing vessel was quickly opened and paracetamol was quickly added without stirring. The mixing vessel was closed and the remaining air in the upper side of the vessel was compressed by 0.22 µm filtered nitrogen introduced from the upper side of the vessel, at 1-1.5 bar, followed by stirring.

[0091] The solution was cooled to a temperature below 40°C. The temperature reached, the mixing vessel was quickly opened and sodium hydroxide 0.1 N and disodium phosphate were quickly added without stirring. Mixing vessel was closed and the air remaining in the upper side of the vessel was compressed by 0.22 µm filtered nitrogen introduced from the upper side of the vessel, at 1-1.5 bar, followed by stirring.

[0092] The quantities of sodium hydroxide and disodium phosphate to be added were calculated in advance and are such that the desired pH is maintained at 6.3 - 7.3 after the addition of cysteine.

[0093] The mixing vessel was quickly opened and acetyl cysteine or cysteine was quickly added without stirring. The mixing vessel was closed and the air remaining in the upper side of the vessel was compressed by 0.22 µm filtered nitrogen introduced from the upper side of the vessel, at 1-1.5 bar, followed by stirring.

[0094] Samples were stored and analysed after set time-intervals. The results for the solutions of pH 6.6 stored at a temperature of 25 + / - 2 °C at a relative humidity of 40 + / - 5% are summarized in Table 8. Those of pH 7.0 stored at a temperature of 25 + / - 2 °C at a relative humidity of 40 + / - 5% are provided in Table 9. Further results from a storage stability test on samples prepared as previously described, are provided in Table 10. These samples were kept at a temperature of 25 + / - 2 °C and a relative humidity of 40 + / - 5%. Those of pH 6.4 stored at a temperature of 25 + / - 2 °C at a relative humidity of 60 + / - 5% are provided in Table 11.

[0095] A series of analysis was performed on the sample. The appearance of a solution was determined by visual inspection according to USP 641, pH values were determined using potentiometry using USP 791, coloration was determined following Eur. Ph 2.2.2 point depression USP 785, sub visible particles were assessed using a light obscuration particle count method USP 788, cysteine.HCl* H 2 O, ibuprofen and acetaminophen were identified using liquid chromatography USP 621. Acetaminophen content was determined by HPLC, Eur. Ph. 2.2.29, 0049. Ibuprofen content and amount of cysteine HCl*H 2 O are 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.

[0096] From the data in both tables it can be seen that a clear liquid solution is provided. The physical appearance is obtained even after twelve months of storage and more. The cysteine content remains high and essentially stable over time. Impurity levels are very low for both paracetamol and ibuprofen, in spite of the pH considered disadvantages for the active principles when present alone.

[0097] The storage stability test results indicate that a product shelf-life of two years is feasible. It can be concluded that the invention provides stable ibuprofen / paracetamol combination products of pH 6.3 - 7.3.4. Compatibility

[0098] To test the compatibility of ibuprofen and paracetamol in combination, the following experiment was performed.

[0099] The pH 8.80 of a solution of 3.85 mg / ml of sodium ibuprofen 2H 2 O, equivalent to 3 mg / ml of ibuprofen, in water is gradually decreased and the absence or presence of precipitation is observed as an indication of solubility / compatibility. The results are noted down and summarized in Table 3. Precipitation of ibuprofen is observed once pH is at 5.75. The Ibuprofen solutions were stored for 1 month at 25 °C. They were again observed for signs of precipitation. The results are summarized in Table 4. Ibuprofen solutions at pH 6 showed precipitation, whereas in solutions of ibuprofen at pH 6.2, precipitation was absent. Table 3: Dissolution of sodium ibuprofen 2H 2 O alone in water (not according to the claimed invention)pH3455.55.866.26.46.66.877.5DissolvedNoNoNoNoYesYesYesYesYesYesYesYes Table 4: Dissolution of sodium ibuprofen 2H 2 O in water after 1 month storage at 25°C (not according to the claimed invention) pH5.866.26.46.66.877.5DissolutionNoNoYesYesYesYesYesYes

[0100] In a further experiment the dissolution of sodium ibuprofen 2H 2 O was studied in combination with paracetamol at a concentration of 10 mg paracetamol per liter. The results at varying pH are summarized in Table 5. The results after one month of storage at 25 °C are provided in Table 6. Composition at pH 6.2 is not according to the claimed invention. Table 5: Dissolution of sodium ibuprofen 2H 2 O in the formulation 3 mg / ml Paracetamol 10 mg / ml IbuprofenpH6.26.36.46.67DissolvedYesYesYesYesYes Table 6: Dissolution of sodium ibuprofen 2H 2 O in the formulation Paracetamol - Ibuprofen - 1 month pH6.26.36.46.67DissolutionNoYesYesYesYes Table 7: Dissolution of sodium ibuprofen 2H 2 O in the formulation Paracetamol - Ibuprofen - 6 months, 25 °C pH6.36.46.67DissolutionYesYesYesYes

[0101] The amount of paracetamol was studied at varies points in time and for different pH's. Data showed that minimal degradation of paracetamol occurred at the pH range 6.3-7.3.

[0102] From the above it is concluded that the combination of ibuprofen and paracetamol is stable with a pH range of 6.3 - 7.3. Table 8: storage stability date 3 mg / ml ibuprofen 10 mg / ml paracetamol with cysteine (pH 6.6, 25 + / - 2 °C, 40 + / - 5% relative humidity)Analysis Specification 1 month2 months3 months6 months9 months12 months15 months18 months24 monthsAppearance of solutionClear liquidclear liquidclear liquidclear liquidclear liquidclear liquidclear liquidclear liquidclear liquidclear liquidpH valueTo be determined6,666,666,696,706,756,726,796,816,83Coloration≤ Y6< Y6< Y6< Y6< Y6< Y6< Y6< Y6< Y6< Y6Sub visible particles≥ 10 µm ≤ 6000 p / vial31581020388590525824895N.R.1790888≥ 25 µm: ≤ 600 p / vial50520384765N.R.4017IdentificationCysteine HCl*H 2 OSame retention time as standardCompliesCompliesCompliesCompliesCompliesCompliesCompliesCompliesCompliesIbuprofenCompliesCompliesCompliesCompliesCompliesCompliesCompliesCompliesCompliesAcetaminophenCompliesCompliesCompliesCompliesCompliesCompliesCompliesCompliesCompliesAcetaminophen content (HPLC)95-105%10410410410199101103104103Ibuprofen content (HPLC)95-105%104104103102103100102103103Cysteine HCl*H 2 O (HPLC)Min 60%89%86%87%90%87%85%90%72%84%Impurities AcetaminophenImpurity K (4-aminophenol)<0,05%0,020,020,010,010,030,030,030,040,03Impurity F (4-nitrophenol)<0,05%0,000,000,000,000,000,000,000,000,00Any other impurity<0,10%0,010,010,010,010,020,030,020,030,01Total impurities<0,2%0,00,00,00,00,00,10,00,10,0Impurities IbuprofenImpurity A<0,1%0,00,00,00,00,00,00,000,000,00Impurity B<0,2%0,00,00,00,00,00,00,000,000,00Any other impurity<0,10%0,000,000,000,000,000,000,0000,0000,000Total impurities<0,2%0,00,00,00,00,00,00,000,000,00 Table 9: storage stability data - 3 mg / ml ibuprofen and 10 mg / ml paracetamol with cysteine (pH 7.0, 25 + / - 2 °C, 40 + / - 5% relative humidity) Analysis Specification Method and Method No.1 month 2 months 3 months 6 months Appearance of solutionClear liquidVisual inspection.USP<641>clear liquidclear liquidclear liquidclear liquidpH valueTo be determinedPotentiometry.USP<791>7,026,997,007,00Coloration≤ Y6Eur.Ph 2.2.2< Y6< Y6< Y6< Y6Sub visible particles≥ 10 µm: ≤ 6000 p / vialLight obscuration particle342528101142795≥ 25 µm:≤ 600 p / vialcount method.USP<788>371035Deliverable volumes> 100mlVolume measurement.USP<698>N.R.N.R.N.R.103 Identification Cysteine HCl*H 2 OSame retention timeLiquid chromatography.CompliesCompliesCompliesCompliesIbuprofenas standardUSP<621>CompliesCompliesCompliesCompliesAcetaminophenCompliesCompliesCompliesCompliesAcetaminophen content by HPLC95-105%Eur.Ph 2.2.29; 004997989795Ibuprofen content by HPLC95-105%Liquid chromatography.991009997,00Cysteine HCl*H 2 O by HPLCMin 60%USP<621>75%72%77%83% Acetaminophen Imourity K (4-aminophenol)<0,05%Eur.Ph 2.2.29; 00490,020,020,020,03Imourity F (4-nitrophenol)<0,05%0,000,000,000,00Any other impurity<0,10%0,010,010,010,01Total impurities<0,2%0,20,20,10,2 Ibuprofen Imouritv A<0,1%Eur.Ph 2.2.290,00,00,00,0Impurity B<0,2%0,00,00,00,0Any other imouritv<0,10%0,000,000,000,00Total impurities<0,2%0,00,00,00,0 Table 10: storage stability test - 3 mg / ml ibuprofen and 10 mg / ml paracetamol with cysteine (pH 6.6, 25 + / - 2 °C, 40 + / - 5% relative humidity) Analysis Specification Method and Method No. 1 mont h 2 mont hs 3 mont hs 6 mont hs Appearance of solutionClear liquidVisual inspection. USP<641>Comp liesCompli esCompli esCompli espH valueTo be determinedPotentiometry. USP<791>6,966,957,027,00Coloration≤ Y6Eur.Ph 2.2.2< Y6< Y6< Y6< Y6Sub visible particles≥ 10 µm:≤ 6000 p / vialLight obscuration particle3250169029922407≥ 25 µm:≤ 600 p / vialcount method. USP<788>330315Deliverable volumes> 100mlVolume measurement. USP<698>N.R.N. R.N.R.102Identification Cysteine HCl*H 2 OSame retention timeLiquid chromatographyComp liesCompli esCompli esCompli esIbuprofenas standardUSP<621>Comp liesCompli esCompli esCompli esAcetaminophenComp liesCompli esCompli esCompli esAcetaminophen content by HPLC95-105%Eur.Ph 2.2.29; 0049103103103100Ibuprofen content by HPLC95-105%Liquid chromatography104104104102Cysteine HCl*H 2 0 by HPLCMin 60%USP<621>90859091Acetaminophen Impurity K (4-aminophenol)<0,05%Eur.Ph 2.2.29; 00490,020,020,020,02Impurity F (4-nitrophenol)<0,05%0,000,000,000,00Any other impurity<0,10%0,000,000,020,03Total impurities<0,2%0,00,00,00,0Ibuprofen Impurity A<0,1%Eur.Ph 2.2.290,00,00,00,0Impurity B<0,2%0,00,00,00,0Any other impurity<0,10%0,000,000,000,00Total impurities<0,2%0,00,00,00,0 Table 11: storage stability test - 3 mg / ml ibuprofen and 10 mg / ml paracetamol with cysteine (pH 6.4, 25+ / -2 °C, 60 + / -5% relative humidity) Analysis Specification Method and Method No. Rele ase 1 mont h 3 mont hs 6 mont hs 9 mont hs 12 mon ths Appearance of solutionClear liquidVisual inspection.USP<6 31>, Ph.Eur.2.2.1clear liquidclear liquidclear liquidclear liquidclear liquidclear liqui dpH6,3 - 7,3Potentiometry.US P<791> Eur.Ph 2.2.3; Eur.Ph 2.9.176,46,66,86,96,96,9Coloration≤ Y6Eur.Ph 2.2.2< Y6< Y5< Y5< Y5< Y5< Y5Particulate matter≥ 10 µm:≤ 6000 p / vialLight obscuration particle count USP<788> Ph.Eur.2.9.1923311083229148N. R.394≥ 25 µm:≤ 600 p / vial43232N. R.2 IdentificationIbuprofenSame retention time as standard as standardUSP<621> Ph.Eur.2.2.29Comp liesComp liesComp! iesComp liesComp liesCom pliesAcetaminophenComp liesComp liesComp! iesComp liesComp liesCom pliesCysteineComp liesComp liesComp! iesComp liesComp liesCom pliesAcetaminophen content (HPLC)95,0-105,0%Eur.Ph 2.2.29; 0049102,0 %100,4 %101,9 %100,7 %101,4 %99,9 %Ibuprofen content (HPLC)95,0-105,0%Liquid chromatography USP<621> In house-Ph.Eur.2.2.2998,0 %99,7 %99,6 %98,7 %98,0 %100, 2%Cysteine hydrochloride monohydrate (HPLC)80 - 105% at release Min 40% at s.h.Liquid chromatography USP<621> In house-Ph.Eur.2.2.2984%86%84%78,0 %77,2 %80,6 % Impurities AcetaminophenImpurity K (4-aminophenol)≤ 0,05%Eur.Ph 2.2.29; 00490,0200,0210,0200,0250,0280,03 0Impurity F (4-nitrophenol)≤ 0,05%0,0000,0000,0000,0000,0000,00 0Any other impurity≤ 0,10%0,0170,0130,0190,0100,0170,01 1Total impurities≤ 0,2%0,0370,0350,0390,0350,0450, 04 1 Impurities IbuprofenImpurity A≤ 0,1%Eur.Ph 2.2.290,00,00,00,00,00,0Impurity B≤ 0,2%0,00,00,00,00,00,0Any other impurity≤ 0,10%0,000,000,000,000,000,00Total impurities≤ 0,2%0,00,00,00,00,00,0

Claims

1. An aqueous composition comprising ibuprofen and paracetamol in combination characterized in that it comprises a pH 6.3-7.3 and in that it is manufactured by a process comprising the steps of: a) providing an aqueous solvent of pH 6.0-8.0, preferably 6.2-7.5, more preferably 6.3-7.3, b) dissolving in said aqueous solvent ibuprofen and paracetamol, c) if required adjusting the pH to 6.3-7.3, d) thereby obtaining said aqueous composition comprising ibuprofen and paracetamol in combination and pH 6.3-7.3 wherein the composition further comprises a buffering agent.

2. The aqueous composition according to claim 1 is characterized in that the buffering agent includes one or more of citric acid, sodium citrate, sodium phosphate, and potassium citrate; preferably the buffering agent is disodium phosphate.

3. The aqueous composition according to claim 1 or 2 is characterized in that said aqueous solvent has a dissolved oxygen content below 2 ppm, and / or in that said composition has a dissolved oxygen content below 2 ppm.

4. The aqueous composition according to claim 3 is characterized in that the process further comprises providing an aqueous solvent having a temperature ranging from 85 to 99°C and / or bubbling an inert gas through said solvent and / or using vacuum to reduce the oxygen content.

5. The aqueous composition according to any one of claims 1 to 4 is characterized in that the pH of the aqueous solvent in step a) is 6.3 to 6.5.

6. The aqueous composition according to any one of claims 1 to 5 is characterized in that the composition comprises 2.8-3.2 mg ibuprofen and 9.8-10.2 mg paracetamol per ml of said composition.

7. The aqueous composition according to any one of claims 1 to 6 is characterized in that ibuprofen provided in step b) is in the form of ibuprofen sodium.

8. The aqueous composition according to any one of claims 1 to 7 is characterized in that the composition comprises an anti-oxidant; preferably said anti-oxidant is cysteine or acetyl cysteine.

9. The aqueous composition according to claim 8 is characterized in that the process further comprises providing an aqueous solvent having a temperature ranging from 85 to 90°C and cooling the aqueous composition to 40 °C or lower prior to addition of cysteine or acetyl cysteine.

10. The aqueous composition according to claim 8 or 9 is characterized in that the anti-oxidant is cysteine or acetyl cysteine; wherein cysteine is cysteine hydrochloride; and in that the mass ratio (w / w) of acetyl cysteine or cysteine hydrochloride to ibuprofen is 0.20 to 0.40:1.

11. The aqueous composition according to any one of claims 1 to 10 is characterized in that the aqueous solvent comprises an isotonic agent, preferably the isotonic agent is selected from a polyol, a sugar, a linear or cyclic glucitol having from 2 to 10 carbon atoms selected from mannitol, sorbitol, inositol, glucose and glycerol.

12. The aqueous composition according to claim 11 is characterized in that the isotonic agent is mannitol; with preference, mass ratio (w / w) of the mannitol to paracetamol is 2 to 6:1.

13. The aqueous composition according to claim 11 or 12 is characterized in that the isotonic agent is added to the aqueous solvent prior to the addition of ibuprofen and paracetamol.

14. The aqueous composition according to any one of claims 1 to 13, for use as a medicament or for use in the treatment of pain and / or inflammation; preferably for administration by intravenous injection or infusion.