Pharmaceutical composition comprising ibuprofen

Abstract

The present invention relates to a pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable derivative thereof and one or more solubilizers in the form: A) an aqueous solution for intravenous administration comprising a sodium salt or lysine salt of ibuprofen, acetaminophen and preferably one or more cyclodextrins; or B) an aqueous solution for intravenous administration wherein the one or more solubilizing agents are one or more essential amino acids and optionally one or more cyclodextrins; or C) a composition for oral administration comprising acetaminophen and cyclodextrin wherein the composition is in the form of i) an effervescent tablet or effervescent granule, or ii) an oral suspension or syrup or oral solution, or iii) a soft capsule.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480036893.7 (22) Application Date 2024.05.31 (30) Priority Data 20230100444 2023.06.02 GR 20230100623 2023.07.27 GR 20230100733 2023.09.13 GR (85) PCT International Application Entering National Phase Date 2025.12.02 (86) PCT International Application Application Data PCT / GR2024 / 000014 2024.05.31 (87) PCT International Application Publication Data WO2024 / 246565 EN 2024.12.05 (71) Applicant: Julia Zeti Address: Greece (72) Inventor: Julia Zeti (74) Patent Agency: Beijing Yinlong Intellectual Property Agency Co., Ltd. 11243 Patent Attorneys: Zhong Haisheng, Song Qinzhi (51) Int.Cl. A61K 9 / 08 (2006.01) A61K 9 / 16 (2006.01) A61K 31 / 192 (2006.01) A61K 31 / 167 (2006.01) A61K 47 / 18 (2017.01) A61K 47 / 40 (2006.01) A61K 9 / 46 (2006.01) A61K 9 / 20 (2006.01) A61K 9 / 48 (2006.01) A61K 9 / 10 (2006.01) A61K 9 / 00(2006.01) A61P 29 / 00(2006.01) (54) Invention Title Pharmaceutical Composition Containing Ibuprofen (57) Abstract This invention relates to pharmaceutical compositions comprising ibuprofen or a pharmaceutically acceptable derivative thereof and one or more solubilizers, said pharmaceutical compositions being in the following forms: A) an aqueous solution for intravenous administration comprising a sodium or lysine salt of ibuprofen, acetaminophen and preferably one or more cyclodextrins; or B) an aqueous solution for intravenous administration wherein said one or more solubilizers are one or more essential amino acids and optionally one or more cyclodextrins; or C) a composition for oral administration comprising acetaminophen and cyclodextrins, wherein said composition is in the following forms: i) effervescent tablets or effervescent granules, or ii) oral suspensions or syrups or oral solutions, or iii) soft capsules.Claims (2 pages), Description (9 pages), CN 121285367 A, 2026.01.06, CN 1 21 28 53 67 A. 1. A pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable derivative thereof and one or more solubilizers, said pharmaceutical composition being in the following forms: A) an aqueous solution for intravenous administration, comprising a sodium salt or lysine salt of ibuprofen, acetaminophen, and preferably one or more cyclodextrins; or B) an aqueous solution for intravenous administration, wherein said one or more solubilizers are one or more essential amino acids and optionally one or more cyclodextrins; or C) a composition for oral administration, comprising acetaminophen and cyclodextrin, wherein said composition is in the following forms: i) effervescent tablets or effervescent granules; or ii) oral suspensions, syrups, or oral solutions; or iii) soft capsules. 2. The pharmaceutical composition according to claim 1, wherein said ibuprofen is preferably in the form of a sodium salt. 3. The pharmaceutical composition according to any one of claims 1 to 2, wherein the amount of ibuprofen is from 1 mg to 1000 mg, preferably from 150 mg to 600 mg, or 200 mg to 500 mg, or 300 mg to 400 mg. 4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is present in the form of an aqueous solution A or B, and the equivalent concentration of free ibuprofen is from 1 mg / mL to 400 mg / mL, preferably from 2 mg / mL to 100 mg / mL, more preferably from 3 mg / mL to 50 mg / mL, and even more preferably from 3 mg / mL. 5. The pharmaceutical composition according to any one of claims 1 to 4, comprising acetaminophen, preferably, the ratio of ibuprofen to acetaminophen is 600 mg:1000 mg, or 500 mg:1000 mg, or 500 mg:500 mg, or 400 mg:1000 mg, or 400 mg:500 mg, or 300 mg:1000 mg, or 300 mg:500 mg, or 200 mg:1000 mg, or 200 mg:500 mg, or 200 mg:200 mg, or 200 mg:100 mg, or 150 mg:1000 mg, or 150 mg:500 mg, or 150 mg:200 mg, or 150 mg:100 mg. 6. The pharmaceutical composition according to any one of claims 1 to 5, wherein, when present in the form of aqueous solution A, the concentration of acetaminophen is 0.20% to 10% m / v, preferably 0.5% to 1.5% m / v.7. The pharmaceutical composition according to any one of claims 1 to 6, wherein, when present in the form of aqueous solution A or B, the composition comprises one or more cyclodextrins, preferably hydroxyalkyl-β-cyclodextrin, more preferably 2-hydroxypropyl-β-cyclodextrin, wherein the concentration of the cyclodextrin is from 0.2% to 19% m / v, preferably from 0.2% to 6% m / v, more preferably from 0.5% to 3% m / v. 8. The pharmaceutical composition according to any one of claims 1 to 6, wherein, when present in the form of aqueous solution A or B, the composition comprises one or more cyclodextrins, preferably hydroxyalkyl-β-cyclodextrin, more preferably 2-hydroxypropyl-β-cyclodextrin, wherein the concentration of the cyclodextrin is from 10 mg / mL to 2000 mg / mL, preferably from 200 mg / mL to 1500 mg / mL, more preferably from 350 mg / mL to 750 mg / mL. 9. The pharmaceutical composition according to any one of claims 1 to 8, comprising one or more essential amino acids, preferably histidine or arginine, more preferably histidine, wherein when the composition is present in the form of aqueous solution A or B, the concentration of the essential amino acid is from 1 mg / L to 400 mg / L, preferably from 20 mg / L to 300 mg / L, more preferably from 50 mg / L to 200 mg / L, and even more preferably from 70 mg / L to 100 mg / L. 10. The pharmaceutical composition according to claim 9, wherein, when present in the form of aqueous solution A or B, the composition comprises one or more essential amino acids and one or more cyclodextrins, wherein the concentration of the essential amino acid is from 0.5 mg / L to 200 mg / L, preferably from 10 mg / L to 150 mg / L, more preferably from 25 mg / L to 100 mg / L, and even more preferably from 35 mg / L to 50 mg / L, and the concentration of the cyclodextrin is from 10 mg / L to 2000 mg / mL, preferably from 200 mg / L to 1500 mg / mL, and more preferably from 350 mg / L to 750 mg / mL. 11. The pharmaceutical composition according to any one of claims 1 to 10, wherein, when present in aqueous solution A or B, the composition further comprises a derivative having at least one thiol functional group, said derivative having at least one thiol functional group being selected from thioglycerol, cysteine, acetylcysteine, thioglycolic acid and / or its salts, dithiothreitol, reduced glutathione, thiolactic acid and / or its salts, and mercaptoethanesulfonic acid, preferably thioglycerol, particularly preferably monothiol glycerol, wherein the concentration of said derivative having at least one thiol functional group is 0.001% to 0.5% m / v, 1.5% to 3% m / v, or 2% to 2.5% m / v.12. The pharmaceutical composition according to any one of claims 1 to 11, wherein, when present in the form of aqueous solution A or B, the composition comprises a chelating agent selected from: EDTA, hypozinotriacetic acid, ethylenediamine-N,N'-dipropionic acid, ethylenediamine-tetra-(methylenephosphonic acid), 2,2'-(ethylenediamino)-dibutyric acid, bis(2-aminoethyl ether)-N,N,N'-ethylene glycol, N'-tetraacetic acid and / or salts thereof, preferably EDTA, wherein the concentration of the chelating agent is 0.001% to 0.5% m / v, 1.5% to 3% m / v, or 2% to 2.5% m / v. 13. The pharmaceutical composition according to any one of claims 1 to 12, wherein, when present in the form of aqueous solution A or B, the composition comprises one or more derivatives selected from thiamine salts, preferably thiamine hydrochloride, wherein the concentration of the thiamine salt is 0.001% m / v to 0.2% m / v. 14. The pharmaceutical composition according to any one of claims 1 to 13, wherein, when present in the form of aqueous solution A or B, the pH is 4 to 8, preferably 6 to 8, more preferably 7 to 8, for example, pH = 7.6, wherein the pH is adjusted by using a suitable alkalizing agent (preferably sodium carbonate) and / or by at least one acid and its ionized form, said acid being selected from citric acid, malic acid, acetic acid, sorbic acid, phosphoric acid, fumaric acid, lactic acid, gluconic acid, and tartaric acid, or mixtures thereof. 15. The pharmaceutical composition according to any one of claims 1 to 14, wherein, when present in the form of A or B, the composition further comprises one or more pharmaceutically acceptable excipients. 16. The pharmaceutical composition according to any one of claims 1 to 5, wherein, when present in the form C suitable for effervescent tablets or effervescent granules, the composition comprises one or more effervescent agents, preferably ascorbic acid, and / or anhydrous citric acid, and / or anhydrous sodium bicarbonate, and / or sodium bicarbonate, and / or sodium tartrate, and / or sodium bitartrate. 17. The pharmaceutical composition of claim 16, wherein, when present in form C, the composition further comprises one or more excipients, preferably one or more diluents, and / or one or more lubricants, and / or one or more binders, and / or one or more sweeteners, and / or one or more flavor enhancers.18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the pharmaceutical composition further comprises one or more active substances or pharmaceutically acceptable derivatives thereof other than ibuprofen or acetaminophen, such as other nonsteroidal anti-inflammatory drugs (e.g., acetylsalicylic acid), and / or opioids (e.g., codeine), and / or anticonvulsants (e.g., scopolamine), and / or antihistamines (e.g., chlorpheniramine, phenytoin), and / or mucolytics (e.g., acetylcysteine), and / or sympathomimetic drugs (e.g., pseudoephedrine), and / or vitamin C and / or caffeine. Claims 2 / 2 Page 3 CN 121285367 A Pharmaceutical Compositions Containing Ibuprofen Technical Field

[0001] The present invention relates to pharmaceutical compositions comprising ibuprofen or a pharmaceutically acceptable derivative thereof and one or more solubilizers, said pharmaceutical compositions being in the following forms:

[0002] A) an aqueous solution for intravenous administration comprising a sodium salt or lysine salt of ibuprofen, acetaminophen, and preferably one or more cyclodextrins, or

[0003] B) an aqueous solution for intravenous administration, wherein said one or more solubilizers are one or more essential amino acids and optionally one or more cyclodextrins, or

[0004] C) a composition for oral administration comprising acetaminophen and cyclodextrin, wherein said composition is in the following forms: i) effervescent tablets or effervescent granules, or ii) oral suspensions or syrups or oral solutions, or iii) soft capsules. Background Art

[0005] Ibuprofen is a nonsteroidal anti-inflammatory drug with anti-inflammatory, analgesic and antipyretic properties, indicated for the treatment of fever and pain, especially when associated with inflammation (Irvine J., Afrose A., Islam N. Ibuprofen formulations and administration strategies: challenges and opportunities. Drug Dev Ind Pharm. 2018;44(2):173-183).The combination of ibuprofen and acetaminophen is used to enhance analgesic effects, as described, 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).

[0006] In injectable form, ibuprofen’s low solubility causes dissolution problems, whether or not it contains acetaminophen.

[0007] Document CN101991540A relates to an ibuprofen injection containing ibuprofen as the main drug and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients include cyclodextrin or cyclodextrin derivatives and water-soluble excipients. The content of ibuprofen is 0.5% to 20% by weight, cyclodextrin or cyclodextrin derivatives is 10% to 60%, water-soluble excipients are 1% to 40%, and the remainder is water. However, this document does not mention the use of specific solubilizers, such as basic amino acids, such as histidine or arginine.

[0008] Document TW201617066A relates to a method for preparing a combination product of ibuprofen and acetaminophen, comprising the step of dissolving 2.8 to 3.2 mg of ibuprofen and 9.8 to 10.2 mg of acetaminophen (per ml of the composition) in an aqueous solvent at pH 6.3-7.3, however, it does not relate to dissolving even higher concentrations of ibuprofen due to the presence of a solubilizer, such as the 100 mg / mL of the present invention.

[0009] Document EP2635269A1 refers to an intravenous injection composition comprising the following doses of ibuprofen and acetaminophen: a) a combination of about 125 mg to about 175 mg of ibuprofen and about 475 mg to about 525 mg of acetaminophen, or b) a combination of about 275 mg to about 325 mg of ibuprofen and about 975 mg to about 1025 mg of acetaminophen. The above amounts are dissolved in 100 mL of water. However, this document does not mention the dissolution of even higher concentrations of ibuprofen due to the presence of solubilizers, such as the 100 mg / mL of CN 121285367 A on page 1 / 9 of this specification.

[0010] Documents EP2389923B1 and EP2277546B1 relate to injectable acetaminophen compositions containing cyclodextrin as a stabilizer. However, these documents do not mention the simultaneous dissolution of ibuprofen other than acetaminophen.

[0011] Document EP3169307B1 relates to a composition of acetaminophen and ibuprofen suitable for injection, wherein the pH of the composition is 6.3 to 7.3, and the composition contains 2.8 to 3.2 mg of ibuprofen and 9.8 to 10.2 mg of acetaminophen per ml of the composition. However, this document does not mention a solubilizer, since the presence of a solubilizer may facilitate the dissolution of even higher concentrations of ibuprofen, such as the 100 mg / mL of the present invention.

[0012] Document EP3612157A1 relates to a composition comprising ibuprofen and acetaminophen suitable for injection, further comprising, in a closed container, a maximum dissolved oxygen concentration of 1.0 ppm, a pH of 6.3 to 7.3, one or more antioxidants, one or more isotonic agents, and one or more buffers, wherein the concentration of acetaminophen is 10 mg / mL and the concentration of ibuprofen is 2 to 4 mg / mL. However, this document does not mention a solubilizer, since the presence of a solubilizer may help dissolve even higher concentrations of ibuprofen, such as the 100 mg / mL of the present invention.

[0013] Furthermore, the low solubility of ibuprofen affects its dissolution and absorption, and thus its bioavailability, which is a major problem during the development of effective formulations for oral administration of the ibuprofen-acetaminophen combination.

[0014] Document EP2089013A1 relates to an analgesic and antipyretic composition for oral dosage, comprising ibuprofen and acetaminophen in a ratio of 5:19 to 81:95.

[0015] Document CN102389423A relates to a formulation of ibuprofen sodium in combination with other active substances, comprising an ibuprofen-acetaminophen combination, which is formulated into an oral form, such as tablets, dispersible tablets, sustained-release tablets, capsules, granules, dry suspensions, suspensions and other similar dosage forms. The content of ibuprofen is 12.5 to 1000 mg, preferably 50 to 500 mg, and the content of acetaminophen is 25 to 1000 mg, preferably 100 to 500 mg.

[0016] Document WO2009083759A1 relates to an oral pharmaceutical suspension composition comprising 40-80 mg / 5 mL ibuprofen, 100-500 mg / 5 mL acetaminophen and one or more pharmaceutically acceptable excipients.

[0017] Document EP0109281A1 relates to a composition of flurbiprofen or ibuprofen or derivatives thereof, acetaminophen and a pharmaceutically acceptable carrier, formulated as a powder or liquid.

[0018] Document CN103751158A relates to an oral suspension composition comprising 40-80 mg / 5 mL ibuprofen, 100-500 mg / 5 mL acetaminophen, and one or more pharmaceutically acceptable excipients.

[0019] Document EP1129709A2 relates to an effervescent composition comprising ibuprofen and cyclodextrin, but excluding acetaminophen.

[0020] Document CN100404025C relates to an effervescent composition comprising acetaminophen and cyclodextrin, but excluding ibuprofen.

[0021] However, none of the above-mentioned documents concerning oral formulations mention a triple combination of ibuprofen, acetaminophen, and cyclodextrin in the composition.

[0022] Although the aforementioned achievements have been mentioned in the prior art, due to increased requirements for quality and safety, there is still a need to further improve the stability of aqueous solutions of ibuprofen (in the form of sodium salt or lysine salt) and acetaminophen for intravenous administration, ensuring long-term stability even at high temperatures without requiring storage in completely sealed bottles.

[0023] However, there is no prior art report on the combination of ibuprofen in the form of sodium salt or lysine salt with acetaminophen and preferably cyclodextrin as a solubilizer for preparing injectable solutions suitable for intravenous administration.

[0024] It is worth noting that if those skilled in the art wish to improve the solubility of products containing both acetaminophen and ibuprofen as active ingredients, they would start with ibuprofen, which is less soluble. Although the prior art mentions the use of solubilizers (e.g., cyclodextrin) for the least soluble (i.e., acetaminophen), there is no technical information on how to improve the solubility of pharmaceutical compositions containing ibuprofen and acetaminophen.

[0025] Although some achievements have been mentioned in the prior art, further improvements are needed in the stability of ibuprofen aqueous solutions for intravenous infusion, even at high temperatures, without requiring storage in completely sealed bottles, due to increasing demands for quality and safety.

[0026] However, compositions combining ibuprofen with histidine and optionally with cyclodextrin for the preparation of injectable ibuprofen solutions suitable for intravenous administration have not been reported in the prior art.

[0027] Despite the aforementioned achievements in the prior art, further improvements are needed in pharmaceutical products combining ibuprofen and acetaminophen for oral administration, emphasizing dosage forms other than classic tablets to improve patient compliance by promoting swallowing.

[0028] However, the prior art has not mentioned the use of appropriate amounts of solubilizers (especially cyclodextrin) in oral dosage forms (including effervescent formulations) of the ibuprofen-acetaminophen combination to achieve adequate dissolution and / or suspension of the active substances.

[0029] More specifically, the present invention is defined as follows:

[0030] Definition 1. A pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable derivative thereof and one or more solubilizers, said pharmaceutical composition being in the following forms:

[0031] A) an aqueous solution for intravenous administration comprising a sodium salt or lysine salt of ibuprofen, acetaminophen, and preferably one or more cyclodextrins, or

[0032] B) an aqueous solution for intravenous administration, wherein said one or more solubilizers are one or more essential amino acids and optionally one or more cyclodextrins, or

[0033] C) a composition for oral administration comprising acetaminophen and cyclodextrin, wherein said composition is in the following forms: i) effervescent tablets or effervescent granules, or ii) oral suspensions or syrups or oral solutions, or iii) soft capsules.

[0034] Definition 2. The pharmaceutical composition according to Definition 1, wherein said ibuprofen is preferably in the form of a sodium salt.

[0035] Definition 3. A pharmaceutical composition according to any one of Definitions 1 to 2, wherein the amount of ibuprofen is 1 mg to 1000 mg, preferably 150 mg to 600 mg, 200 mg to 500 mg, or 300 mg to 400 mg.

[0036] Definition 4. A pharmaceutical composition according to any one of Definitions 1 to 3, wherein, when present in the form of aqueous solution A or B, the concentration of equivalent free ibuprofen is 1 mg / mL to 400 mg / mL, preferably 2 to 100 mg / mL, more preferably 3 mg / mL to 50 mg / mL, and even more preferably 3 mg / mL.

[0037] Definition 5. A pharmaceutical composition according to any one of Definitions 1 to 4, comprising acetaminophen, preferably ibuprofen:acetaminophen in a ratio of 600 mg:1000 mg, or 500 mg:1000 mg, or 500 mg:500 mg, or 400 mg:1000 mg, or 400 mg:500 mg, or 300 mg:1000 mg, or 300 mg:500 mg, or 200 mg:1000 mg, or 200 mg:500 mg, or 200 mg:200 mg, or 200 mg:100 mg, or 150 mg:1000 mg, or 150 mg:500 mg, or 150 mg:200 mg, or 150 mg:100 mg.

[0038] Definition 6. The pharmaceutical composition according to any one of Definitions 1 to 5, wherein, when present in the form of aqueous solution A, the concentration of acetaminophen is 0.20% to 10% m / v, preferably 0.5% to 1.5% m / v.Instructions for Use, Page 3 / 9, CN 121285367 A

[0039] Definition 7. A pharmaceutical composition according to any one of Definitions 1 to 6, wherein, when present in the form of an aqueous solution A or B, the composition comprises one or more cyclodextrins, preferably hydroxyalkyl-β-cyclodextrin, more preferably 2-hydroxypropyl-β-cyclodextrin, wherein the concentration of the cyclodextrin is from 0.2% m / v to 19% m / v, preferably from 0.2% m / v to 6% m / v, more preferably from 0.5% m / v to 3% m / v.

[0040] Definition 8. A pharmaceutical composition according to any one of Definitions 1 to 6, wherein, when present in the form of an aqueous solution A or B, the composition comprises one or more cyclodextrins, preferably hydroxyalkyl-β-cyclodextrin, more preferably 2-hydroxypropyl-β-cyclodextrin, wherein the concentration of the cyclodextrin is from 10 mg / mL to 2000 mg / mL, preferably from 200 mg / mL to 1500 mg / mL, more preferably from 350 mg / mL to 750 mg / mL.

[0041] Definition 9. A pharmaceutical composition according to any one of Definitions 1 to 8, comprising one or more essential amino acids, preferably histidine or arginine, more preferably histidine, wherein, when the composition is present in the form of an aqueous solution A or B, the concentration of the essential amino acid is from 1 mg / L to 400 mg / L, preferably from 20 mg / L to 300 mg / L, more preferably from 50 mg / L to 200 mg / L, even more preferably from 70 mg / L to 100 mg / L.

[0042] Definition 10. A pharmaceutical composition according to Definition 9, wherein, when present in the form of an aqueous solution A or B, the composition comprises one or more essential amino acids and one or more cyclodextrins, wherein the concentration of the essential amino acid is from 0.5 mg / L to 200 mg / L, preferably from 10 mg / L to 150 mg / L, more preferably from 25 mg / L to 100 mg / L, and even more preferably from 35 mg / L to 50 mg / L, and the concentration of the cyclodextrin is from 10 mg / L to 2000 mg / mL, preferably from 200 mg / L to 1500 mg / mL, and more preferably from 350 mg / L to 750 mg / mL.

[0043] Definition 11. A pharmaceutical composition according to any one of Definitions 1 to 10, wherein, when present in the form of an aqueous solution A or B, the composition further comprises a derivative having at least one thiol functional group, the derivative being selected from thioglycerol, cysteine, acetylcysteine, mercaptoglycolic acid and / or its salts, dithiothreitol, reduced glutathione, thiolactic acid and / or its salts, and mercaptoethanesulfonic acid, preferably thioglycerol, particularly preferably monothioglycerol, wherein the concentration of the derivative having at least one thiol functional group is 0.001% to 0.5% m / v, 1.5% to 3% m / v, or 2% to 2.5% m / v.

[0044] Definition 12. A pharmaceutical composition according to any one of Definitions 1 to 11, wherein, when present in the form of an aqueous solution A or B, the composition comprises a chelating agent selected from: EDTA, hypozinotriacetic acid, ethylenediamine-N,N'-dipropionic acid, ethylenediamine-tetra-(methylene phosphate), 2,2'-(ethylenediamino)-dibutyl acid, bis(2-aminoethyl ether)-N,N,N'-ethylene glycol, N'-tetraacetic acid and / or salts thereof, preferably EDTA, wherein the concentration of the chelating agent is 0.001% to 0.5% m / v, 1.5% to 3% m / v or 2% to 2.5% m / v.

[0045] Definition 13. A pharmaceutical composition according to any one of Definitions 1 to 12, wherein, when present in the form of an aqueous solution A or B, the composition comprises one or more derivatives selected from thiamine salts, preferably thiamine hydrochloride, wherein the concentration of the thiamine salt is from 0.001% m / v to 0.2% m / v.

[0046] Definition 14. A pharmaceutical composition according to any one of Definitions 1 to 13, wherein, when present in the form of an aqueous solution A or B, the pH is from 4 to 8, preferably from 6 to 8, more preferably from 7 to 8, for example, pH = 7.6, wherein the pH is adjusted by using a suitable alkalizing agent (preferably sodium carbonate) and / or by at least one acid and its ionized form, wherein the acid is selected from citric acid, malic acid, acetic acid, sorbic acid, phosphoric acid, fumaric acid, lactic acid, gluconic acid and tartaric acid or mixtures thereof.

[0047] Definition 15. A pharmaceutical composition according to any one of Definitions 1 to 14, wherein, when present in the form of A or B, the composition further comprises one or more pharmaceutically acceptable excipients.

[0048] Definition 16. A pharmaceutical composition according to any one of Definitions 1 to 5, wherein, when present in form C suitable for effervescent tablets or effervescent granules, the composition comprises one or more effervescent agents, preferably ascorbic acid, and / or anhydrous citric acid, and / or anhydrous sodium bicarbonate, and / or sodium bicarbonate, and / or sodium tartrate, and / or sodium hydrogen tartrate. Specification 4 / 9 pages 7 CN 121285367 A

[0049] Definition 17. A pharmaceutical composition according to Definition 16, wherein, when present in form C, the composition further comprises one or more excipients, preferably one or more diluents, and / or one or more lubricants, and / or one or more binders, and / or one or more sweeteners, and / or one or more flavor enhancers.

[0050] Definition 18. A pharmaceutical composition according to any one of Definitions 1 to 17, wherein the pharmaceutical composition further comprises one or more active substances or pharmaceutically acceptable derivatives thereof other than ibuprofen or acetaminophen, such as other nonsteroidal anti-inflammatory drugs, such as acetylsalicylic acid, and / or opioids, such as codeine, and / or anticonvulsants, such as scopolamine, and / or antihistamines, such as chlorpheniramine, phenacetin, and / or mucolytics, such as acetylcysteine, and / or sympathomimetic agents, such as pseudoephedrine, and / or vitamin C, and / or caffeine.

[0051] Surprisingly, it has been found that compositions of ibuprofen and acetaminophen in the form of sodium salts or lysine salts, containing one or more solubilizers, preferably one or more cyclodextrins, are stable even at prolonged high temperatures.

[0052] Surprisingly, it has been found that compositions of ibuprofen and acetaminophen in the form of sodium or lysine salts, containing one or more solubilizers, preferably one or more cyclodextrins, exhibit a further increase in ibuprofen solubility.

[0053] This newly proposed composition of ibuprofen in the form of sodium or lysine salts with acetaminophen and preferably cyclodextrin exhibits all the advantages of the prior art and actually has a surprisingly improved stability, particularly improved solubility.

[0054] Surprisingly, compositions of ibuprofen aqueous solutions containing one or more solubilizers, particularly one or more basic amino acids and optionally one or more cyclodextrins, are stable even at prolonged high temperatures.

[0055] Surprisingly, compositions of ibuprofen aqueous solutions containing one or more solubilizers, particularly one or more basic amino acids and optionally one or more cyclodextrins, exhibit a further increase in ibuprofen solubilization.

[0056] The novel combination of ibuprofen with histidine and optionally with cyclodextrin of the present invention exhibits all the advantages of the prior art, with unexpectedly improved stability, especially improved solubility.

[0057] In addition to significantly improving the solubility of the active substances in the composition and avoiding their immediate precipitation, it is surprisingly found that, when present in oral dosage forms, the absorption of the active substances is improved on the one hand, and their onset of action is accelerated on the other hand.

[0058] It is also surprising that, when present in oral dosage forms, the ibuprofen, acetaminophen, and additional cyclodextrin composition of the present invention shows an unexpected improvement in unpleasant taste, which is produced not only by ibuprofen but also by the combination of ibuprofen and acetaminophen.

[0059] The novel ibuprofen-acetaminophen-cyclodextrin combination of the present invention solves all the aforementioned problems of the prior art and actually achieves unexpected and surprising results in terms of improved solubility.

[0060] Furthermore, it has been surprisingly found that the more the scope of the claims is limited, the more significant the effects and advantages of the invention become.

[0061] In particular, the effects and advantages of the invention are observed to be more significant when ibuprofen is combined with acetaminophen.

[0062] The expression "equivalent free ibuprofen" refers to the free form of ibuprofen, i.e., not in salt form (e.g., sodium form) or other complex form (e.g., complex with lysine).

[0063] The stable aqueous solution composition for intravenous infusion according to the invention may further contain an isotonic agent, preferably sodium chloride.

[0064] The stable aqueous solution formulation for intravenous infusion according to the invention can be sterilized by heating or by filtration.

[0065] The aqueous medium of the stable aqueous solution composition for intravenous infusion according to the invention can be deoxygenated by an inert gas (N2) insoluble in water.

[0066] The compositions of the present invention are administered intravenously and remain stable when stored at room temperature for more than 24 months, thereby saving refrigeration costs during transportation and storage and reducing patient discomfort during administration. Furthermore, the compositions remain stable when stored at high temperatures (e.g., 70°C) for more than 30 days.

[0067] The compositions of the present invention can be prepared in solution and stored in transparent glass containers, such as glass ampoules, vials, tubes, sealed glass vials, or stoppered glass vials, or bottles made of polymeric materials (e.g., polyethylene), or bags made of soft polyethylene, polyvinyl chloride, or polypropylene. The glass should preferably be transparent for ease of use.

[0068] The amount of cyclodextrin can be on the same order of magnitude as reported in CN101991540A, the entire contents of which are incorporated herein by reference. For example, the amount of cyclodextrin can be from 100 to 600 mg per dose, such as 120, 200, 300, 400, or 500 mg per dose.

[0069] The compositions of the present invention can be prepared by methods known in the prior art. Detailed Description

[0070] The present invention is further illustrated by the following indicative but non-limiting examples.

[0071] Example 1: In a preferred embodiment, each 100 mL of the composition of the present invention contains the following components:

[0072]

[0073] Suitable for intravenous injection

[0074] Example 2: In a preferred embodiment, each 100 mL of the composition of the present invention contains the following components:

[0075] Specification 6 / 9 pages 9 CN 121285367 A

[0076] Suitable for intravenous injection

[0077] Example 3: In a preferred embodiment, each 100 mL of the composition of the present invention contains the following components:

[0078]

[0079] Suitable for intravenous injection

[0080] Example 4: In a preferred embodiment, each mL of the composition of the present invention contains the following components:

[0081]

[0082] Suitable for intravenous injection

[0083] Example 5: In a preferred embodiment, each mL of the composition of the present invention contains the following components:

[0084]

[0085] Suitable for intravenous injection

[0086] Example 6: In a preferred embodiment, each mL of the composition of the present invention comprises the following components:

[0087] Specification 7 / 9 pages 10 CN 121285367 A

[0088] Suitable for intravenous injection

[0089] Example 7: In a preferred embodiment, each mL of the composition of the present invention comprises the following components:

[0090]

[0091] Suitable for intravenous injection for infusion

[0092] Example 8: In an embodiment, each effervescent tablet of the composition of the present invention comprises the following components:

[0093]

[0094] The composition of Example 1 is formulated into an effervescent tablet.

[0095] Example 9: In an embodiment, each sachet of the composition of the present invention comprises the following components:

[0096]

[0097] The composition of Example 1 is formulated into an effervescent granule.

[0098] Example 10: In this embodiment, each 5 mL dose of the composition of the present invention comprises the following components:

[0099]

[0100] The composition of Example 1 was formulated into a syrup.

[0101] The compositions of Examples 1-10 of the present invention exhibit all the advantages of the present invention described above, such as solubility, improved taste (in the case of oral administration of Examples 8-10), improved absorption, and faster onset of action.

[0102] Furthermore, the compositions of Examples 1-3 and 5-10 described above were prepared without the addition of cyclodextrin, and it was found that the solubility was significantly lower, while the active substance precipitated almost immediately.

[0099]

[0100]

Claims

1. A pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable derivative thereof and one or more solubilizers, said pharmaceutical composition being in the form of: A) an aqueous solution for intravenous administration comprising a sodium or lysine salt of ibuprofen, paracetamol and preferably one or more cyclodextrins, or B) a composition for oral administration comprising a sodium or lysine salt of ibuprofen and paracetamol, wherein said composition is in the form of: i) a tablet or a capsule, or ii) a suspension or a syrup or a solution for oral administration, or iii) a soft capsule, or C) a composition for oral administration comprising paracetamol and a cyclodextrin, wherein said composition is in the form of: i) an effervescent tablet or an effervescent granule, or ii) a suspension or a syrup or a solution for oral administration, or iii) a soft capsule. The one or more solubilizers are one or more essential amino acids and optionally one or more cyclodextrins, or B) aqueous solutions for intravenous administration which have The ibuprofen is preferably in the form of a sodium salt. The amount of ibuprofen is 1 mg to 1000 mg, preferably 150 mg to 600 mg, or 200 mg to 500 mg, or 300 mg to 400 mg.

2. The pharmaceutical composition according to claim 1, wherein, The pharmaceutical composition is present in the form of an aqueous solution A or B, the equivalent concentration of free ibuprofen being 1 mg / mL to 400 mg / mL, preferably 2 mg / mL to 100 mg / mL, more preferably 3 mg / mL to 50 mg / mL, even more preferably 3 mg / mL.

3. The pharmaceutical composition according to any one of claims 1 to 2, wherein, 5. The pharmaceutical composition according to any one of claims 1 to 4, comprising paracetamol, preferably the ratio ibuprofen:paracetamol is 600 mg:1000 mg, or 500 mg:1000 mg, or 500 mg:500 mg, or 400 mg:1000 mg, or 400 mg:500 mg, or 300 mg:1000 mg, or 300 mg:500 mg, or 200 mg:1000 mg, or 200 mg:500 mg, or 200 mg:200 mg, or 200 mg:100 mg, or 150 mg:1000 mg, or 150 mg:500 mg, or 150 mg:200 mg, or 150 mg:100 mg.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein, When present in the form of an aqueous solution A, the concentration of paracetamol is 0.20% to 10% m / v, preferably 0.5% to 1.5% m / v. When present in the form of an aqueous solution A or B, the composition comprises one or more cyclodextrins, preferably a hydroxyalkyl- -cyclodextrin, more preferably a 2-hydroxypropyl- -cyclodextrin, wherein the concentration of the cyclodextrin is 0.2% to 19% m / v, preferably 0.2% to 6% m / v, more preferably 0.5% to 3% m / v.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein, When present in the form of an aqueous solution A or B, the composition comprises one or more cyclodextrins, preferably a hydroxyalkyl- -cyclodextrin, more preferably a 2-hydroxypropyl- -cyclodextrin, wherein the concentration of the cyclodextrin is 10 mg / mL to 2000 mg / mL, preferably 200 mg / mL to 1500 mg / mL, more preferably 350 mg / mL to 750 mg / mL.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein, ​ 8. The pharmaceutical composition according to any one of claims 1 to 6, wherein, ​ 9. The pharmaceutical composition according to any one of claims 1 to 8, comprising one or more essential amino acids, preferably histidine or arginine, more preferably histidine, wherein, When the composition is present in the form of an aqueous solution A or B, the concentration of the essential amino acids is 1 mg / L to 400 mg / L, preferably 20 mg / L to 300 mg / L, more preferably 50 mg / L to 200 mg / L, even more preferably 70 mg / L to 100 mg / L.

10. The pharmaceutical composition of claim 9, wherein, When present in the form of an aqueous solution A or B, the composition comprises one or more essential amino acids and one or more cyclodextrins, wherein the concentration of the essential amino acids is 0.5 mg / L to 200 mg / L, preferably 10 mg / L to 150 mg / L, more preferably 25 mg / L to 100 mg / L, even more preferably 35 mg / L to 50 mg / L, and the concentration of the cyclodextrins is 10 mg / L to 2000 mg / mL, preferably 200 mg / L to 1500 mg / mL, more preferably 350 mg / L to 750 mg / mL.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein, When present in the form of an aqueous solution A or B, the composition additionally comprises a derivative with at least one thiol function selected from the group consisting of thioglycerol, cysteine, acetylcysteine, mercaptoacetic acid and / or salts thereof, dithiothreitol, reduced glutathione, thiolactic acid and / or salts thereof and mercaptoethanesulfonic acid, preferably thioglycerol, in particular monothioglycerol, wherein the concentration of the derivative with at least one thiol function is 0.001 % to 0.5 % m / v, 1.5 % to 3 % m / v or 2 % to 2.5 % m / v.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein, When present in the form of an aqueous solution A or B, the composition comprises a chelating agent selected from the group consisting of EDTA, nitrilotriacetic acid, ethylenediamine-N,N'-dipropionic acid, ethylenediamine-tetra-(methylene phosphonic acid), 2,2'(ethylenediamino)-dibutyric acid, bis(2-aminoethylether)-N,N,N'ethyleneglycol, N'-tetraacetic acid and / or salts thereof, preferably EDTA, wherein the concentration of the chelating agent is 0.001 % to 0.5 % m / v, 1.5 % to 3 % m / v or 2 % to 2.5 % m / v.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein, When present in the form of an aqueous solution A or B, the composition comprises one or more derivatives selected from the group consisting of thiamine salts, preferably thiamine hydrochloride, wherein the concentration of the thiamine salt is 0.001 % m / v to 0.2 % m / v.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein, When present in the form of an aqueous solution A or B, the pH is 4 to 8, preferably 6 to 8, more preferably 7 to 8, for example pH = 7.6, the pH being adjusted by using a suitable basifying agent, preferably sodium carbonate, and / or by at least one acid and its ionized form, the acid being selected from the group consisting of citric acid, malic acid, acetic acid, sorbic acid, phosphoric acid, fumaric acid, lactic acid, gluconic acid and tartaric acid or mixtures thereof.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein, When present in the form of A or B, the composition additionally comprises one or more pharmaceutically acceptable excipients.

16. The pharmaceutical composition according to any one of claims 1 to 5, wherein, When present in the form of C suitable for effervescent tablets or effervescent granules, the composition comprises one or more effervescent agents, preferably ascorbic acid, and / or anhydrous citric acid, and / or anhydrous sodium bicarbonate, and / or sodium bicarbonate, and / or sodium tartrate, and / or sodium hydrogen tartrate.

17. The pharmaceutical composition of claim 16, wherein, When present in the form of C, the composition additionally comprises one or more excipients, preferably one or more diluents, and / or one or more lubricants, and / or one or more binders, and / or one or more sweeteners, and / or one or more taste enhancers.

18. The pharmaceutical composition according to any one of claims 1 to 17, additionally comprising one or more active substances other than ibuprofen or acetaminophen or a pharmaceutically acceptable derivative thereof, such as other non-steroidal anti-inflammatory drugs (e.g. acetylsalicylic acid), and / or opioids (e.g. codeine), and / or anticonvulsants (e.g. hyoscine), and / or antihistamines (e.g. chlorphenamine, orphenadrine), and / or mucolytics (e.g. acetylcysteine), and / or sympathomimetics (e.g. pseudoephedrine), and / or vitamin C and / or caffeine.