Pre-filled syringe of aqueous solution of paracetamol and / or ibuprofen suitable for injectable administration

Abstract

The present invention relates to a pre-filled syringe (PFS) comprising a pharmaceutical composition of an aqueous solution for use in injectable administration, wherein the composition comprises a) paracetamol and / or b) ibuprofen in the form of either sodium salt or lysine, and comprises co-solvents, wherein the co-solvents are ethanol and / or glycerin and / or one or more cyclodextrins.

Description

[0001] Pre-filled syringe of aqueous solution of paracetamol and / or ibuprofen suitable for injectable administration

[0002] Description of the invention

[0003] The present invention relates to a pre-filled syringe (PFS) comprising a pharmaceutical composition of an aqueous solution for use in injectable administration, wherein the composition comprises a) paracetamol and / or b) ibuprofen in the form of either sodium salt or lysine, and comprises co-solvents, wherein the co-solvents are ethanol and / or glycerin and / or one or more cyclodextrins.

[0004] Pre-filled syringes provide greater patient safety by reducing the likelihood of accidental needle-stick injury, air aspiration, and exposure to unwanted contamination, e.g., microbial, that may occur when drawing medication from vials. Pre-filled syringes, in which the dosage has been pre-measured, can reduce dosing errors and improve patient compliance. Pre-filled syringes can also significantly reduce the need for manufacturers to overfill, unlike vials which are typically overfilled by 20-30% to account for potential losses. This is particularly important when the cost of manufacturing the product is high and the capacity for mass production is limited [Sagar Makwana, Biswajit Basu, Yogita Makasana, Abhay Dharamsi. Prefilled syringes: An innovation in parenteral packaging. Int. J. Pharm. Investig. 2011; 1(4): 200–206],

[0005] Paracetamol is the main active metabolite of phenacetin and acetanilide, with analgesic and antipyretic properties. Paracetamol has equivalent analgesic and antipyretic activity to that of aspirin, while exhibiting weak anti-inflammatory activity; therefore, its use in inflammatory rheumatic conditions is limited.

[0006] Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic, and antipyretic properties, indicated for the treatment of fever and pain, particularly when associated with inflammation [Irvine J., Afrose A., Islam N. Formulation and delivery strategies of ibuprofen: challenges and opportunities. Drug Dev Ind Pharm. 2018;44(2): 173–183], The combination of ibuprofen with paracetamolPCT / GR2O25 / OOor;23

[0007] is used to enhance analgesic efficacy, for example in musculoskeletal pain [Bettiol A., Marconi E., Vannacci A., Simonetti M., Magni A., Cricelli C., Lapi F. Effectiveness of ibuprofen plus paracetamol combination on persistence of acute musculoskeletal disorders in primary care patients. Int J Clin Pharm. 2021;43(4):1045–1054]. The low solubility of ibuprofen, which affects its dissolution and absorption and therefore its bioavailability, represents a significant challenge in the development of effective oral formulations of ibuprofen or ibuprofen-paracetamol combinations. Because of its properties, ibuprofen is widely used to combat symptoms of arthritis and / or rheumatoid arthritis. However, it has been associated with adverse cardiovascular effects, particularly in patients with rheumatoid arthritis [Eirik Ikdahl, Anne Kerola, Eli Sollerud, Anne Grete Semb. Cardiovascular Implications of Non-steroidal Anti¬ inflammatory Drugs: A Comprehensive Review, with Emphasis on Patients with Rheumatoid Arthritis. European Cardiology Review 2024;19:e27. https: / / doi.org / 10.15420 / ecr.2024.24].

[0008] Various injectable paracetamol solutions have been reported in prior art.

[0009] Document EP2389923B1 refers to paracetamol injection compositions for IV infusion with an optimal pH of 6 (ranging between 5.5 and 6.5), which contain at least one stabilizing-solubilizing substance for paracetamol in solution, selected from a group consisting of cyclodextrins, at least one stabilizing agent bearing a thiol functional group, and at least one stabilizing agent selected from a group consisting of thiamine salts, in an appropriate concentration capable of stabilizing and solubilizing paracetamol even at high temperatures.

[0010] Document EP2277546B1 refers to paracetamol injection compositions for IV infusion with an optimal pH of 6 (ranging between 5.5 and 6.5), which contain at least one stabilizing and one solubilizing substance for paracetamol in a solution such as cyclodextrin, EDTA, or monothioglycerol (MTG), in an appropriate concentration capable of stabilizing and solubilizing paracetamol. Document CN101991540A refers to ibuprofen injection composition which comprises pharmaceutically acceptable auxiliary materials including cyclodextrins or cyclodextrin derivatives. Although, in said document there is no reference to other active substances, like paracetamol, nor any reference to pre-filled syringe.

[0011] Document US11213498B2 refers to aqueous composition for injection or infusion comprising ibuprofen and paracetamol. Although, in said document there is no mention of use of cyclodextrins or pre-filled syringe.

[0012] 0 The concept of pre-fiiied syringe is known in the state of art. For example, document W02018005937A1 describes an injection device comprising a pre-fiiled syringe which, although is not comprising the specific combination of active substances as described in the current invention.

[0013] 5 Despite the advancements described in the prior art, due to increasing quality and safety requirements, there remains a continuous need for further improvement of the dose accuracy of injectable aqueous solutions of active substances, improvement of the solubility and bioavailability of the active ingredient, enhancement of its stability, prevention of microbial growth, and facilitation of administration, especially in u emergency pain situations.

[0014] However, to date, the prior art has not disclosed pre-filled syringes (PFS) containing a pharmaceutical aqueous solution composition for injectable administration, wherein the composition comprises paracetamol and / or ibuprofen along with suitable co-5 solvents such as ethanol, glycerol, cyclodextrins, etc.

[0015] This newly proposed combination of container and formulation with these specific characteristics, as presented in the present invention, has all the advantages of the prior art and in fact demonstrates unexpectedly improved dose accuracy. More specifically, the present invention is defined by the following definitions:

[0016] Definition 1. A pre-filled syringe (PFS) comprising a pharmaceutical composition of an aqueous solution for injectable administration, said composition comprising (a) paracetamol and / or (b) ibuprofen in the form of either sodium salt or lysine, and containing co-solvents, wherein the co-solvents are ethanol and / or glycerol and / or one or more cyclodextrins.

[0017] Definition 2. A pre-filled syringe according to definition 1, preferably comprising hydroxyalkyl-p-cyclodextrins, more preferably 2-hydroxypropyl-p-cyclodextrin.

[0018] Definition 3. A pre-filled syringe according to any one of definitions 1 to 2, wherein the paracetamol content ranges from 1% to 30% weight / volume (g / ml), preferably from 5% to 20% g / ml, and more preferably 15% g / ml.

[0019] Definition 4. A pre-filled syringe according to any one of definitions 1 to 3, wherein the concentration of ibuprofen equivalent to free ibuprofen ranges from 0,1% to 80% weight / volume (g / ml), preferably from 0,3% to 50% g / ml, and more preferably 0,3% g / ml.

[0020] Definition 5. A pre-filled syringe according to any one of definitions 1 to 4 or combinations thereof, which is single-dose, siliconized, glass, sterile, having a capacity of 5 to 8 mL, preferably 5 mL, sealed with pre-sterilized plunger stoppers and containing 2 to 4,5 ml of injectable solution, preferably 4,2 mL, and which syringe is packaged in polyvinyl chloride and aluminum packaging.

[0021] Definition 6. A pre-filled syringe according to any one of definitions 1 to 5, wherein the ethanol concentration ranges from 0,001% to 0,1% g / ml, preferably 0,01% g / ml; the glycerol concentration ranges from 0,01% to 0,1% g / ml, preferably 0,049% g / ml; and the cyclodextrin concentration ranges from 0,2% g / ml to 19% g / ml, preferably from 0,2% g / ml to 6% g / ml, more preferably from 0,5% g / ml to 3% g / ml.

[0022] Definition 7. A pre-filled syringe according to any one of definitions 1 to 6, containing one or more additional active ingredients selected from (a) one or more local anesthetics, preferably lidocaine or a pharmaceutically acceptable salt thereof, and / or (b) one or more spasmolytic agents, preferably hyoscine or a pharmaceutically acceptable salt thereof.

[0023] Definition 8. A pre-filled syringe according to any one of definitions 1 to 7, wherein the pH ranges from 5,0 to 8,0, preferably from 5,5 to 6,5 or 6, 3-7, 3 and wherein the composition further comprises pH adjusters selected from phosphate salts, metal hydroxides, citric acid and / or its salts, malic, acetic, sorbic, phosphoric, fumaric, lactic, gluconic, tartaric acids, or mixtures thereof, preferably disodium hydrogen phosphate dihydrate.

[0024] Definition 9. A pre-filled syringe according to any one of definitions 1 to 8, further comprising a chelating agent selected from EDTA, nitrilotriacetic acid, ethylenediamine-N, N'-dipropionic acid, ethylenediamine-tetra-(methylenephosphonic acid), 2,2'-(ethylenediamino)-dibutyric acid, bis(2-aminoet>hyl ether)-N, N, N'- ethyleneglycol, N '-tetraacetic acid and / or their salts, preferably EDTA, wherein the concentration of the chelating agent ranges from 0,001% to 0,2% g / ml, preferably from 0,005% to 0,1% g / ml, and more preferably 0,01% g / ml.

[0025] Definition 10. A pre-filled syringe according to any one of definitions 1 to 9, containing an antioxidant agent, preferably sodium metabisulfite, wherein the concentration of the antioxidant ranges from 0,01% to 0,5% g / ml, preferably from 0,05% to 0,2% g / ml, and more preferably 0,1% g / ml.

[0026] Definition 11. A pre-filled syringe according to any one of definitions 1 to 10, further comprising one or more derivatives bearing at least one thiol functional group, selected from thioglycerols, cysteine, acetylcysteine, thioglycolic acid and / or its salts, dithiothreitol, reduced glutathione, thiolactic acid and / or its salts, thiourea, and mercaptoethanesulfonic acid, preferably thioglycerol, and more preferably monothioglycerol, wherein the concentration of the derivative bearing at least one thiol group ranges from 0,001% to 0,2% g / ml.

[0027] Definition 12. A pre-filled syringe according to any one of definitions 1 to 11, further comprising one or more derivatives selected from thiamine salts, preferably thiamine hydrochloride, wherein the concentration of the thiamine salt ranges from 0,001% to 0,2% g / ml.

[0028] Definition 13. A pre-filled syringe according to any one of definitions 1 to 12, comprising i) paracetamol, preferably 15% g / ml, ii) ethanol, preferably 0,01% g / ml and / or glycerol, preferably 0,049% g / ml, and optionally iii) lidocaine, preferably 0,3% to 0,7% g / ml, more preferably 0,538% g / ml.

[0029] Definition 14. A pre-filled syringe according to any one of definitions 1 to 12, comprising i) ibuprofen, preferably 0,3% g / ml, ii) 2-hydroxypropyl-β-cyclodextrin, preferably 0,666% g / ml, and optionally iii) lidocaine, preferably 0,3% to 0,7% g / ml, more preferably 0,538% g / ml.

[0030] Definition 15. A pre-filled syringe according to any one of definitions 1 to 12, comprising i) paracetamol, preferably 15% g / ml, ii) ibuprofen, preferably 0,3% g / ml, iii) ethanol, preferably 0,01% g / ml and / or glycerol, preferably 0,049% g / ml and / or monothioglycerol, preferably 0,1% g / ml, as well as 2-hydroxypropyl-p-cyclodextrin, preferably 0,666% g / ml, and optionally iv) lidocaine, preferably 0,3% to 0,7% g / ml, more preferably 0,538% g / ml.

[0031] Definition 16. A pre-filled syringe according to any one of definitions 1 to 15, which is suitable for use in the treatment of (a) pain resulting from surgical procedures, particularly postoperative pain, or pain associated with neoplasms, (b) fever, for example due to Infections and / or neoplastic disease, (c) Inflammation, (d) symptoms of arthritis.

[0032] It was surprisingly found that pre-filled syringe (PFS) comprising a pharmaceutical composition of an aqueous solution for use in injectable administration, wherein the composition comprises paracetamol and / or ibuprofen, exhibit higher dose accuracy compared to the use of ampoules and subsequent syringe filling, which carries the risk of human error, e.g. incomplete filling, air introduction.

[0033] It was also surprisingly found that pre-filled syringe (PFS) comprising a pharmaceutical composition of an aqueous solution for use in injectable administration, wherein the composition comprises paracetamol and / or ibuprofen, offer the advantage of being usable by the patient themselves, without the need for medical training in syringe filling and without the presence of medical or nursing personnel.

[0034] Furthermore, it was surprisingly found that pre-filled syringe (PFS) comprising a pharmaceutical composition of an aqueous solution for use in injectable administration, wherein the composition comprises paracetamol and / or ibuprofen, provide the advantage of immediate use in emergency pain situations, without time being lost in syringe preparation.

[0035] In addition, it was surprisingly found pre-filled syringe (PFS) comprising a pharmaceutical composition of an aqueous solution for use in injectable administration, wherein the composition comprises paracetamol and / or ibuprofen, offer the advantage of avoiding microbial contamination during the filling process of a conventional syringe.

[0036] It was also surprisingly found that pre-filled syringe (PFS) comprising a pharmaceutical composition of an aqueous solution for use in injectable administration, wherein the composition comprises paracetamol and / or ibuprofen, are much less prone to breaking than conventional glass ampoules, thus providing greater protection to the contained formulation. Moreover, it was surprisingly found that in pre-filled syringe (PFS) comprising a pharmaceutical composition of an aqueous solution for use in injectable administration, wherein the composition comprises paracetamol and / or ibuprofen, the contained formulation demonstrates increased stability and a longer shelf life.

[0037] Furthermore, it was surprisingly found that by adjusting the pH of the composition as described in the definitions above the solubility of the actives was significantly improved.

[0038] It was further found that pre-filled syringes (PFS) pre-filled syringe (PFS) comprising a pharmaceutical composition of an aqueous solution for use in injectable administration are particularly advantageous when the active ingredient is paracetamol and / or ibuprofen.

[0039] It was also found that the use of solvents as described in the preceding claims significantly improved the solubilization of the active ingredients and consequently their bioavailability.

[0040] It was surprisingly found that the aqueous solution composition of ibuprofen in the form of either sodium salt or lysine and paracetamol, using one or more solubilizing agents, preferably one or more cyclodextrins and ethanol, was stable even at high temperatures over a long period of time.

[0041] It was also surprisingly found that the aqueous solution composition of ibuprofen in the form of either sodium salt or lysine and paracetamol, using one or more solubilizing agents, preferably one or more cyclodextrins, exhibited even greater solubilization of ibuprofen and paracetamol. -9- PCT / GR2O25 / OOOO23

[0042] It was surprisingly found that when ibuprofen is used for the treatment of arthritis, the likelihood of cardiovascular complications is unexpectedly reduced, especially when used in combination with paracetamol.

[0043] Finally, it was surprisingly found that the more specific the subject matter of the above definitions, the more pronounced and significant the advantages of the present invention are.

[0044] The compositions of the present invention can be prepared using methods known in the prior art.

[0045] The present invention is described by the following indicative, non-limiting examples.

[0046] Example 1: In a preferred embodiment, the composition of the present invention contained in the pre-filled syringe comprises the following per ml.

[0047] Ingredient Amount per 1,0 ml Concentration Function

[0048]

[0049] AcHvP Paracetamol 150,000 mg 15,000 ingredient Lidocaine Active hydrochloride 5,376 mg 0,538j„gredient monohydrate

[0050] EDTA 0,100 mg 0,010ChJ^n9

[0051] 3agent _..,,.,nnAntioxidant Sodium metabisulfite 1,000 mg 0,100 agent

[0052] Disodium phosphate 1,050 mg 0,105 ggent"'^

[0053]

[0054] Ethanol 0,100 mL 0,010 Co-solvent Glycerol 0,490 ml 0,049 Co-solvent Water for injection q.s. to 1,000 ml q.s. to 1,000 mL Solvent Example 2: In a preferred embodiment, the composition of the present invention contains the following per 100 L

[0055] Ingredient Amount per 100 mL Function Sodium ibuprofen 331,97 mg Active ingredient 2-Hydroxypropyl-p-cydodextrin 666 mg Solubilizing agent EDTA 10 mg Chelating agent Stabilizer / thiol-containing Monothioglycerol 10 mg compound Thiamine hydrochloride 10 mg Stabilizing agent Sodium chloride 600 mg Tonicity-adjusting agent Disodium phosphate 35,6 mg Buffering agent Water for injection q.s< to 100 mL Solvent Final pH (adjusted with 1M HCl „

[0056]

[0057] or NaOH)

[0058] Example 3: In a preferred embodiment, the composition of the present invention contains the following per 100 ml.

[0059] Ingredient Amount per 100 mL Function Sodium ibuprofen 331,97 mg Active ingredient Lidocaine hydrochlorideArtive |d[eni:monohydrate

[0060]

[0061] 2-Hydroxypropyl-p-cyclodextrin 666 mg Solubilizing agent EDTA 10 mg Chelating agent „.,, Stabilizer / thiol-containing Monothioglycerol 10 mg compound Thiamine hydrochloride 10 mg Stabilizing agent Sodium chloride 600 mg Tonicity-adjusting agent Disodium phosphate 35,6 mg Buffering agent Water for injection q.s. to 100 mL Solvent Final pH (adjusted with IM HCI „f r. ___

[0062]

[0063] or NaOH) -11- PCT / GR2O25 / OOOO23

[0064] Example 4: In a preferred embodiment, the composition of the present invention contained in the pre-filled syringe comprises the following per 100 mL Ingredient

[0065]

[0066] Amount per 1OO mL Function Sodium ibuprofen 331,97 mg Active ingredient Paracetamol 1000 mg Active ingredient 2-Hydroxypropyl-|3-cyclodextrin 666 mg Solubilizing agent EDTA 10 mg Chelating agent Stabilizer / thiol-containing Monothioglycerol 10 mg compound Sodium chloride 600 mg Tonicity-adjusting agent Disodium phosphate 35,6 mg Buffering agent Water for injection q.s. to 100 mL Solvent Final pH (adjusted with 1M HCl

[0067] or NaOH)

[0068] Example 5: In a preferred embodiment, the composition of the present invention contains the following per 100 mL.

[0069] Ingredient Amount per 100 mL Lysine ibuprofen 512,7 mg Paracetamol 1000 mg

[0070] 2-Hydroxypropyl-p-cyclodextrin 666 mg

[0071] EDTA 10 mg Monothioglycerol 10 mg

[0072] Sodium chloride 600 mg

[0073] Disodium phosphate 35.6 mg

[0074] Water for injection q.s. to 100 mL

[0075] Final pH (adjusted with 1M HCl or NaOH) 5,5-6,5

[0076] Example 6: In a preferred embodiment, the composition of the present invention contains the following per 100 mL

[0077] Ingredient Amount per 100 ml

[0078] Sodium ibuprofen 331,97 mg

[0079] Paracetamol 1000 mg

[0080] 2-Hydroxypropyl-p-cyclodextrin 666 mg

[0081]

[0082] Amount per 100 ml

[0083] EDTA 10 mg Monothioglycerol 10 mg

[0084] Thiamine hydrochloride 10 mg

[0085] Sodium chloride 600 mg

[0086] Disodium phosphate 35,6 mg

[0087] Water for injection q.s. to 100 mL

[0088] Final pH (IM HCI or NaOH) 5,5-6, 5

[0089] Example 7: In a preferred embodiment, the composition of the present invention contains the following per 1 ml.

[0090] _ Ingredient Amount per 1 mL Paracetamol Micronized 10,000 mg Ibuprofen Sodium Dihydrate 3,840 mg Hydroxypropylbetadex (Hydroxypropyl-B-Cyclodextrin) 6,660 mg Disodium EDTA 0,100 mg Monothioglycerol 0,100 mg Disodium Hydrogen Phosphate Dihydrate 0,356 mg Sodium chloride 5,100 mg Water for injection q.s. to 1,000 mL Final pH (IM HCI or NaOH) 6, 3-7, 3

[0091] Example 8: In a preferred embodiment, the composition of the present invention contains the following per 1 mL.

[0092] Ingredient Amount per 1 mL Paracetamol Micronized 10,000 mg Ibuprofen Sodium Dihydrate 3,840 mg Lidocaine hydrochloride monohydrate 5,376 mg Hydroxypropylbetadex (Hydroxypropyl-B-Cyclodextrin) 6,660 mg

[0093] Disodium EDTA 0,100 mg Ingredient Amount per 1 ml Monothioglycerol 0,100 mg

[0094] Disodium Hydrogen Phosphate Dihydrate 0,356 mg

[0095] Sodium chloride 5,100 mg

[0096] Water for injection q.s. to 1,000 mL Final pH (1M HCl or NaOH) 6,3-7,3

[0097] *3,840 mg ibuprofen sodium dihydrate corresponds 3,000 mg ibuprofen

[0098] Example 9: In a preferred embodiment, the composition of the present invention contained in the pre-filled syringe comprises the following per 100 mL.

[0099] Ingredient Amount per 100 mL Function Paracetamol 1000 mg Active ingredient 2-Hydroxypropyl-p-cyclodextrin 666 mg Solubilizing agent EDTA 10 mg Chelating agent.....,, Stabilizer / thiol-containing Monothioglycerol 10 mg compound Sodium chloride 600 mg Tonicity-adjusting agent Disodium phosphate 35,6 mg Buffering agent Water for injection q.s. to 100 mL Solvent Final pH (adjusted with 1M HCl

[0100] or NaOH)

[0101]

[0102] Example 10: In a preferred embodiment, the composition of the present invention contains the following per 100 mL.

[0103] Ingredient Amount per 100 mL Paracetamol 1000 mg

[0104] 2-Hydroxypropyl-β-cyclodextrin 666 mg

[0105] EDTA 10 mg

[0106] Monothioglycerol 10 mg

[0107] Thiamine hydrochloride 10 mg -14- PCT / GR2O25 / OOOO23

[0108] Ingredient Amount

[0109]

[0110] 100 mL

[0111] Sodium chloride 600 mg

[0112] Disodium phosphate 35,6 mg

[0113] Water for injection q.s. to 100 ml Final pH (IM HCI or NaOH) 5, 5-6, 5

[0114] The compositions of the above examples are contained in clean, pre-sterilized, collapsible, glass pre-filled syringes USP Type I, with a capacity of 5 mL, sealed with pre-sterilized plunger stoppers. The syringes are packaged in polyvinyl chloride (PVC)- aluminum blisters and further packed in cardboard boxes.

[0115] The compositions of the above examples exhibit all the advantages of the present invention.

Claims

-15- PCT / GR2O25 / OOOO23Claims1. A pre-filled syringe (PFS) comprising a pharmaceutical composition of an aqueous solution for use in injectable administration, wherein the composition comprises a) paracetamol and / or b) ibuprofen in the form of either sodium salt or lysine, and comprises co-solvents, wherein the co-solvents are ethanol and / or glycerin and / or one or more cyclodextrins.

2. A pre-filled syringe according to claim 1, which preferably comprises hydroxyalkyl-p-cyclodextrins, more preferably 2-hydroxypropyl-p-cyclodextrin,3. A pre-filled syringe according to any of claims 1 to 2, wherein the content of paracetamol is from 1% to 30% weight / volume (g / ml), preferably from 5% to 20% g / ml, more preferably 15% g / ml.

4. A pre-filled syringe according to any of claims 1 to 3, wherein the concentration of ibuprofen equivalent to free ibuprofen equivalent to free ibuprofen ranges from 0,1% to 80% weight / volume (g / ml), preferably from 0,3% to 50% g / ml, and more preferably 0,3% g / ml.

5. A pre-filled syringe according to any of claims 1 to 4 or combinations thereof, which is single-dose, siliconized, glass, sterilized, with a capacity of 5 to 8 ml, preferably 5 mL, sealed with pre-sterilized plunger stoppers, and containing 2 to 4,5 mL of injectable solution, preferably 4,2 mL, and which is packaged in a polyvinyl chloride (PVC)-aluminum package.

6. A pre-filled syringe according to any of claims 1 to 5, wherein the ethanol content ranges from 0,001% to 0,1% g / ml, preferably 0,01% g / ml; the glycerin content ranges from 0,01% to 0,1% g / ml, preferably 0,049% g / ml; and the cyclodextrin concentrationranges from 0,2% to 19% g / ml, preferably from 0,2% to 6% g / ml, more preferably from 0,5% to 3% g / ml.

7. A pre-filled syringe according to any of claims 1 to 6, further comprising one or more additional active ingredients selected from a) one or more local anesthetics, preferably lidocaine or a pharmaceutically acceptable salt thereof, and / or b) one or more antispasmodics, preferably hyoscine or a pharmaceutically acceptable salt thereof.

8. A pre-filled syringe according to any of claims 1 to 7, wherein the pH ranges from 5,0 to 8,0, preferably from 5,5 to 6,5 or 6, 3-7, 3, and wherein the composition further comprises pH regulators selected from phosphate salts, metal hydroxides, citric acid and / or salts thereof, malic acid, acetic acid, sorbic acid, phosphoric acid, fumaric acid, lactic acid, gluconic acid, tartaric acid, or mixtures thereof, preferably disodium hydrogen phosphate.

9. A pre-filled syringe according to any of claims 1 to 8, which additionally comprises a chelating agent selected from EDTA, nitrilotriacetic acid, ethylenediamine-N, N'- dipropionic acid, ethylenediamine-tetra-(methylene phosphoric acid), 2,2'-(ethylenediamino)-dibutyric acid, bis(2-aminoethyl ether)-N, N, N'-ethyleneglycol, N,N'- tetraacetic acid and / or salts thereof, preferably EDTA, wherein the chelating agent is present at 0,001% to 0,2% g / ml, preferably 0,005% to 0,1% g / ml, more preferably 0,01% g / ml.

10. A pre-filled syringe according to any of claims 1 to 9, further comprising an antioxidant, preferably sodium metabisulfite, wherein the antioxidant is present at 0,01% to 0,5% g / ml, preferably 0,05% to 0,2% g / ml, more preferably 0,1% g / ml.

11. A pre-filled syringe according to any of claims 1 to 10, further comprising one or more derivatives bearing at least one thiol functional group, selected from thioglycerols, cysteine, acetylcysteine, thiogiycolic acid and / or salts thereof, dithiothreitol, reduced glutathione, thiolactic acid and / or salts thereof, thiourea, and-17- PCT / GR2O25 / OOOO23mercaptoethanesulfonic acid. preferably thioglycerol, more preferably monothioglycerol, wherein the concentration of the thiol-bearing derivative ranges from 0,001% to 0,2% g / ml.

12. A pre-filled syringe according to any of claims 1 to 11, further comprising one or more derivatives selected from thiamine salts, preferably thiamine hydrochloride, wherein the concentration of the thiamine salt ranges from 0,001% to 0,2% g / ml.

13. A pre-filled syringe according to any of claims 1 to 12, comprising i) paracetamol, preferably 15% g / ml, ii) ethanol, preferably 0,01% g / ml, and / or glycerin, preferably 0,049% g / ml, and optionally iii) lidocaine, preferably 0,3% to 0,7% g / ml, more preferably 0,538% g / ml.

14. A pre-filled syringe according to any of claims 1 to 12, comprising i) ibuprofen, preferably 0,3% g / ml, ii) 2-hydroxypropyl-p-cyclodextrin, preferably 0,666% g / ml, and optionally iii) lidocaine, preferably 0,3% to 0,7% g / ml, more preferably 0,538% g / ml.

15. A pre-filled syringe according to any of claims 1 to 12, comprising i) paracetamol, preferably 15% g / mi, ii) ibuprofen, preferably 0,3% g / ml, iii) ethanol, preferably 0,01% g / ml, and / or glycerin, preferably 0,049% g / ml and / or monothioglycerol, preferably 0,1% g / ml, as well as 2-hydroxypropyl-β-cyclodextrin, preferably 0,666% g / ml, and optionally iv) lidocaine, preferably 0,3% to 0,7% g / ml, more preferably 0,538% g / ml.

16. A pre-filled syringe according to any of claims 1 to 15, suitable for use in the treatment of a) pain from surgical procedures, particularly postoperative conditions or neoplasms, b) fever, for example due to infections and / or neoplasms, c) inflammation, and d) arthritis symptoms.

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