Pharmaceutical composition containing ibuprofen
A combination of ibuprofen with cyclodextrins and amino acids like histidine addresses solubility and stability issues in ibuprofen-paracetamol formulations, enhancing solubility and absorption, and improving taste in oral forms.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- ツェティユリア
- Filing Date
- 2024-05-31
- Publication Date
- 2026-06-16
AI Technical Summary
Existing formulations of ibuprofen and paracetamol suffer from poor solubility, particularly in injectable forms, leading to dissolution and absorption issues, and there is a need for improved stability and solubility in both intravenous and oral administrations, especially with the use of cyclodextrin as a solubilizer.
A pharmaceutical composition comprising ibuprofen or its pharmaceutically acceptable derivatives, combined with solubilizers such as cyclodextrins and essential amino acids like histidine, to enhance solubility and stability, particularly in aqueous solutions for intravenous administration, and in oral forms like effervescent tablets or capsules.
The composition achieves enhanced solubility and stability, allowing for stable storage at high temperatures and improved absorption and onset of action, with improved taste in oral forms.
Smart Images
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Abstract
Description
Technical Field
[0001] The present invention relates to a pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable derivative thereof and one or more solubilizers, A) An aqueous solution for intravenous administration comprising ibuprofen, paracetamol, and preferably one or more cyclodextrins, either in the form of a sodium or lysine salt, or B) An aqueous solution for intravenous administration in which one or more solubilizers contain one or more essential amino acids and may contain one or more cyclodextrins, or C) A composition for oral administration comprising paracetamol and cyclodextrin, which is in any of the forms of i) a foaming tablet or granule, or ii) an oral suspension, syrup, or oral solution, or iii) a soft capsule in the form of a pharmaceutical composition.
Background Art
[0002] Ibuprofen is a nonsteroidal anti-inflammatory drug with anti-inflammatory, analgesic, and antipyretic properties, particularly indicated for the treatment of fever and pain 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 and paracetamol is used to enhance the analgesic effect, 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].
[0003] The poor solubility of ibuprofen causes dissolution problems in injectable forms, whether with or without paracetamol.
[0004] Reference CN101991540A relates to an ibuprofen injection containing ibuprofen as the main drug and pharmaceutically acceptable adjuvants, wherein the pharmaceutically acceptable adjuvants include cyclodextrin or a cyclodextrin derivative and a water-soluble excipient. The content is 0.5% to 20% by weight of ibuprofen, 10% to 60% of cyclodextrin or a cyclodextrin derivative, 1% to 40% of a water-soluble excipient, and the remainder is water. However, it does not mention the use of specific solubilizers such as basic amino acids, e.g., histidine or arginine.
[0005] Reference TW201617066A describes a method for preparing a combination product of ibuprofen and paracetamol, comprising the step of dissolving 2.8 to 3.2 mg of ibuprofen and 9.8 to 10.2 mg of paracetamol, expressed as per ml of the composition, in an aqueous solvent with a pH of 6.3 to 7.3, but does not mention the dissolution of even higher concentrations of ibuprofen, such as 100 mg / mL in this invention, in the presence of a solubilizer.
[0006] Reference EP2635269A1 relates to an intravenous composition containing ibuprofen and paracetamol in doses of a) approximately 125 mg to 175 mg of ibuprofen combined with approximately 475 mg to 525 mg of paracetamol, or b) approximately 275 mg to 325 mg of ibuprofen combined with approximately 975 mg to 1025 mg of paracetamol. The above amounts are dissolved in 100 mL of water. However, it does not describe the dissolution of even higher concentrations of ibuprofen, such as 100 mg / mL in this invention, in the presence of a solubilizer.
[0007] References EP2389923B1 and EP2277546B1 relate to injectable paracetamol compositions containing cyclodextrin as a stabilizer. However, they do not discuss the simultaneous dissolution of ibuprofen in addition to paracetamol.
[0008] Reference EP3169307B1 relates to a paracetamol and ibuprofen composition suitable for injection administration, wherein the composition has a pH of 6.3 to 7.3 and contains 2.8 to 3.2 mg of ibuprofen and 9.8 to 10.2 mg of paracetamol per ml of the composition. However, it does not mention solubilizers that may contribute to the dissolution of even higher concentrations of ibuprofen, such as 100 mg / mL in the present invention, through the presence of a solubilizer.
[0009] Reference EP3612157A1 relates to a composition containing ibuprofen and paracetamol suitable for injection administration, further comprising a maximum dissolved oxygen concentration of 1.0 ppm in a sealed container, pH 6.3-7.3, one or more antioxidants, one or more isotonic agents, and one or more buffering agents, wherein the paracetamol concentration is 10 mg / mL and the ibuprofen concentration is 2-4 mg / mL. However, it does not mention solubilizers that may contribute to the dissolution of even higher concentrations of ibuprofen, such as 100 mg / mL in the present invention, due to the presence of solubilizers.
[0010] Furthermore, the poor solubility of ibuprofen, which affects its dissolution, absorption, and ultimately its bioavailability, is a major problem in the development of effective oral formulations of the ibuprofen-paracetamol combination.
[0011] Reference EP2089013A1 relates to an analgesic and antipyretic composition for oral administration containing ibuprofen and paracetamol in a ratio of 5:19 to 81:95.
[0012] Reference CN102389423A relates to formulations of ibuprofen sodium in combination with other active substances, including the ibuprofen-paracetamol combination, which are formulated into oral forms such as tablets, dispersible tablets, extended-release tablets, capsules, granules, dry suspensions, suspendings, and other similar forms. The amount of ibuprofen is in the range of 12.5 to 1000 mg, preferably 50 to 500 mg, and the amount of paracetamol is in the range of 25 to 1000 mg, preferably 100 to 500 mg.
[0013] Reference WO2009083759A1 relates to an oral pharmaceutical suspension composition containing 40-80 mg / 5 mL of ibuprofen, 100-500 mg / 5 mL of paracetamol, and one or more pharmaceutically acceptable excipients.
[0014] Reference EP0109281A1 relates to a composition of flurbiprofen or ibuprofen or its derivatives, paracetamol, and a pharmaceutically acceptable carrier, which is formulated as a powder or liquid.
[0015] Reference CN103751158A relates to a pharmaceutical oral suspension composition containing 40-80 mg / 5 mL of ibuprofen, 100-500 mg / 5 mL of paracetamol, and one or more pharmaceutically acceptable excipients.
[0016] Reference EP1129709A2 relates to a foaming composition containing ibuprofen and cyclodextrin, but without paracetamol.
[0017] Reference CN100404025C relates to a foaming composition containing paracetamol and cyclodextrin, but without ibuprofen. [Overview of the project] [Problems that the invention aims to solve]
[0018] However, none of the above-mentioned literature on formulations for oral administration mentions the triple combination of ibuprofen, paracetamol, and cyclodextrin in the composition.
[0019] Despite the achievements already described in current technology, increasing quality and safety requirements necessitate further improvements in the stability of aqueous solutions of ibuprofen and paracetamol, either sodium salt or lysine salt, for IV administration, even at high temperatures and for extended periods without the need for storage in airtight bottles.
[0020] However, combinations of ibuprofen and paracetamol in the form of a sodium salt or lysine salt, and preferably cyclodextrin as a solubilizer, for the preparation of injectable solution compositions suitable for intravenous administration have not yet been reported in the current art.
[0021] In particular, when a person skilled in the art wants to improve the solubility starting from a product containing two active ingredients, paracetamol and ibuprofen, the person skilled in the art will start with ibuprofen, which is the more difficult to dissolve. The prior art describes the use of solubilizers for the least insoluble substance, i.e., paracetamol, such as cyclodextrin, but there is no technical information on how to improve the solubility of a pharmaceutical composition containing ibuprofen and paracetamol.
[0022] Despite the achievements already described in the prior art, due to the increasing requirements for quality and safety, there is a continuing need to further improve the stability of an aqueous solution of ibuprofen for use in IV infusions, even at high temperatures and without the need for long-term storage in a completely airtight bottle.
[0023] However, a combination of ibuprofen and histidine, which may contain cyclodextrin, for the preparation of a composition of an injectable ibuprofen solution suitable for intravenous administration has not yet been reported in the prior art.
[0024] Despite the achievements already described in the prior art, there is a continuing need for further improvement of pharmaceutical products of ibuprofen combined with paracetamol for oral administration, which emphasize pharmaceutical forms other than classical tablets in order to improve patient compliance by facilitating swallowing.
[0025] However, a combination of ibuprofen - paracetamol in an oral dosage form including a foamed form, by using a solubilizer, particularly cyclodextrin, in an appropriate amount to achieve sufficient dissolution and / or suspension of the active substance, has not yet been mentioned in the prior art.
Means for Solving the Problems
[0026] More specifically, the present invention is defined as follows.
[0027] Definition 1. A pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable derivative thereof and one or more solubilizing agents, wherein: A) An aqueous solution for intravenous administration comprising ibuprofen in the form of either the sodium or lysine salt, paracetamol, and preferably one or more cyclodextrins, or B) An aqueous solution for intravenous administration in which one or more solubilizing agents comprise one or more essential amino acids and may comprise one or more cyclodextrins, or C) A composition for oral administration comprising paracetamol and cyclodextrin, which is in the form of either i) a effervescent tablet or effervescent granule or ii) an oral suspension or syrup or oral solution or iii) a soft capsule. A pharmaceutical composition characterized by being in the form of any of the above.
[0028] Definition 2. The pharmaceutical composition according to Definition 1, characterized in that ibuprofen is preferably in the form of the sodium salt.
[0029] Definition 3. The pharmaceutical composition according to any one of Definitions 1 to 2, characterized in that the amount of ibuprofen ranges from 1 to 1000 mg, preferably from 150 to 600 mg, or from 200 to 500 mg, or from 300 to 400 mg.
[0030] Definition 4. In the form of the aqueous solution A or B, the concentration of free ibuprofen equivalents ranges from 1 to 400 mg / mL, preferably from 2 to 100 mg / mL, more preferably from 3 to 50 mg / mL, and even more preferably 3 mg / mL. The pharmaceutical composition according to any one of Definitions 1 to 3 is characterized by this.
[0031] Definition 5. A pharmaceutical composition according to any one of Definitions 1 to 4, characterized by containing paracetamol preferably in the ratio of ibuprofen:paracetamol of 600 mg:1000 mg, 500 mg:1000 mg, 500 mg:500 mg, 400 mg:1000 mg, 400 mg:500 mg, 300 mg:1000 mg, 300 mg:500 mg, 200 mg:100 mg, 200 mg:500 mg, 200 mg:200 mg, 200 mg:100 mg, 150 mg:1000 mg, 150 mg:500 mg, 150 mg:200 mg, or 150 mg:100 mg.
[0032] Definition 6. A pharmaceutical composition according to any one of Definitions 1 to 5, characterized in that, in the form of aqueous solution A, the concentration of paracetamol is in the range of 0.20% to 10% m / v, preferably 0.5% to 1.5% m / v.
[0033] Definition 7. In the case of aqueous solution formulation A or B, the composition comprises one or more cyclodextrins, preferably hydroxyalkyl-β-cyclodextrin, more preferably 2-hydroxypropyl-β-cyclodextrin, and the concentration of the cyclodextrins is in the range of 0.2% m / v to 19% m / v, preferably 0.2% m / v to 6% m / v, more preferably 0.5% m / v to 3% m / v, as described in any of Definitions 1 to 6.
[0034] Definition 8. In the case of aqueous solution A or B, the composition comprises one or more cyclodextrins, preferably hydroxyalkyl-β-cyclodextrin, more preferably 2-hydroxypropyl-β-cyclodextrin, and the concentration of the cyclodextrins is in the range of 10 to 2000 mg / mL, preferably 200 to 1500 mg / mL, more preferably 350 to 750 mg / mL, as described in any of Definitions 1 to 6.
[0035] Definition 9. A pharmaceutical composition according to any one of Definitions 1 to 8, characterized in that it comprises one or more essential amino acids, preferably histidine or arginine, more preferably histidine, and when the composition is in the form of aqueous solution A or B, the concentration of the essential amino acid is in the range of 1 to 400 mg / L, preferably 20 to 300 mg / L, more preferably 50 to 200 mg / L, and even more preferably 70 to 100 mg / L.
[0036] Definition 10. In the case of aqueous solution A or B, the composition is characterized in that it contains one or more essential amino acids, the concentration of the essential amino acids is in the range of 0.5 to 200 mg / L, preferably 10 to 150 mg / L, more preferably 25 to 100 mg / L, and even more preferably 35 to 50 mg / L, and contains one or more cyclodextrins, the concentration of the cyclodextrins is in the range of 10 to 2000 mg / mL, preferably 200 to 1500 mg / mL, and more preferably 350 to 750 mg / mL.
[0037] Definition 11. In the case of aqueous solution A or B, the composition further comprises a derivative having at least one thiol functional group, selected from thioglycerol, cysteine, acetylcysteine, thioglycolic acid and / or salts thereof, dithiothreitol, reduced glutathione, thiolactic acid and / or salts thereof, and mercaptoethanesulfonic acid, preferably thioglycerol, particularly preferably monothioglycerol, wherein the concentration of the derivative having at least one thiol functional group is in the range of 0.001% to 0.5% m / v, 1.5% to 3% m / v, or 2% to 2.5% m / v, as described in any of Definitions 1 to 10.
[0038] Definition 12. In the case of aqueous solution A or B, the composition comprises a chelating agent selected from EDTA, nitrilotriacetic acid, ethylenediamine-N,N'-dipropionic acid, ethylenediamine-tetra-(methylenephosphate)), 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 in the range of 0.001% to 0.5% m / v, 1.5% to 3% m / v, or 2% to 2.5% m / v, as described in any of Definitions 1 to 11.
[0039] Definition 13. In the case of aqueous solution formulation A or B, the composition comprises one or more derivatives selected from thiamine salts, preferably thiamine hydrochloride salts, and the concentration of the thiamine salt is in the range of 0.001% m / v to 0.2% m / v, as described in any of Definitions 1 to 12.
[0040] Definition 14. A pharmaceutical composition according to any one of Definitions 1 to 13, characterized in that, in the form of aqueous solution A or B, the pH is between 4 and 8, preferably 6 and 8, more preferably 7 and 8, for example, pH = 7.6, and 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 a mixture thereof.
[0041] Definition 15. In the form of A or B, the pharmaceutical composition according to any one of Definitions 1 to 14, characterized in that the composition further comprises one or more pharmaceutically acceptable excipients.
[0042] Definition 16. In the case of form C suitable for effervescent tablets or effervescent granules, the pharmaceutical composition according to any one of Definitions 1 to 5, characterized in that 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 ditartrate.
[0043] In the form of Definition 17.C, the pharmaceutical composition according to Definition 16, characterized in that 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.
[0044] Definition 18. A pharmaceutical composition according to any one of Definitions 1 to 17, further comprising one or more active substances other than ibuprofen or paracetamol or pharmaceutically acceptable derivatives thereof, other nonsteroidal anti-inflammatory drugs such as acetylsalicylic acid, and / or opioids such as codeine, and / or anticonvulsants such as hyostine, and / or antihistamines such as chlorpheniramine or orphenadrine, and / or mucolytics such as acetylcysteine, and / or sympathomimetic agents such as pseudoephedrine, and / or vitamin C, and / or caffeine. [Modes for carrying out the invention]
[0045] Surprisingly, compositions of aqueous solutions of ibuprofen in either sodium salt or lysine salt form and paracetamol, comprising one or more solubilizers, preferably one or more cyclodextrins, were found to be stable for extended periods even at high temperatures.
[0046] Surprisingly, compositions of aqueous solutions of ibuprofen and paracetamol in either sodium or lysine salt form, comprising one or more solubilizers, preferably one or more cyclodextrins, were found to exhibit a further increase in ibuprofen solubilization.
[0047] The newly proposed combination of ibuprofen in either sodium or lysine salt form, paracetamol, and preferably cyclodextrin exhibits all the advantages of the prior art, and actually results in an unexpected improvement in stability, particularly in solubility.
[0048] Surprisingly, compositions of ibuprofen aqueous solutions containing one or more basic amino acids and possibly one or more cyclodextrins as solubilizers were found to be stable for extended periods even at high temperatures.
[0049] Surprisingly, compositions of ibuprofen aqueous solutions containing one or more solubilizers, particularly one or more basic amino acids and possibly one or more cyclodextrins, were found to exhibit an even greater increase in ibuprofen solubilization.
[0050] The newly proposed combination of ibuprofen and histidine, which may contain cyclodextrin, exhibits all the advantages of the prior art, along with an unexpected improvement in stability, particularly in solubility.
[0051] In addition to a powerful improvement in the solubility and non-immediate precipitation of the active substance in the composition in oral administration form, it was surprisingly found that the absorption of the active substance was improved on the one hand, and the onset of their action was accelerated on the other hand.
[0052] Surprisingly, it was also found that the ibuprofen, paracetamol, and cyclodextrin composition of the present invention, in its oral administration form, exhibits an unexpected improvement in the unpleasant taste resulting not only from ibuprofen alone, but also from the combination of ibuprofen and paracetamol.
[0053] The newly proposed combination of ibuprofen-paracetamol and cyclodextrin in this invention solves all of the above-mentioned problems of the existing technology and, in fact, yields unexpectedly surprising results in terms of improved solubility.
[0054] Furthermore, surprisingly, it was found that the more limited the scope of the patent claims, the stronger the effects and advantages of the present invention become.
[0055] In particular, it was observed that the effects and advantages of the present invention were enhanced when ibuprofen was combined with paracetamol.
[0056] The expression "free ibuprofen equivalent" means the free form of ibuprofen, i.e., not its salt form, such as sodium, nor its complex with other substances, such as lysine.
[0057] The stable aqueous solution composition for use in intravenous infusion according to the present invention may further contain an isotonic agent, preferably sodium chloride.
[0058] The stable aqueous solution formulation for use in intravenous infusion according to the present invention can be sterilized by heat or filtration.
[0059] The aqueous medium of the stable aqueous solution composition for use in intravenous infusion according to the present invention may be deoxygenated with a water-insoluble inert gas (N2).
[0060] The composition of the present invention is stable when administered intravenously and stored at room temperature for 24 months or more, saving on refrigeration costs during transport and storage, and alleviating discomfort in patients during administration. Furthermore, the composition may even be stable when stored at high temperatures, for example, 70°C, for 30 days or more.
[0061] The compositions of the present invention may be prepared as solutions and stored in transparent glass containers, such as glass ampoules, vials, cartridges, glass sealed vials, or stoppered glass vials, or in bottles made of polymer materials such as polyethylene, or in bags made of flexible polyethylene, polyvinyl chloride, or polypropylene. The glass should preferably be transparent for ease of use.
[0062] The amount of cyclodextrin may be similar to that reported in CN101991540A, the full details of which are incorporated into the description of this invention. For example, the amount of cyclodextrin may be 100 to 600 mg per dose, for example, 120, 200, 300, 400, or 500 mg per dose.
[0063] The compositions of the present invention can be prepared by methods already known in the current art.
[0064] The present invention is further illustrated by the following explanatory but non-limiting embodiments.
[0065] Example 1: In a preferred embodiment, the composition of the present invention comprises the following per 100 mL.
[0066] [Table 1] Suitable for intravenous injection.
[0067] Example 2: In a preferred embodiment, the composition of the present invention comprises the following per 100 mL.
[0068] [Table 2] Suitable for intravenous injection.
[0069] Example 3: In a preferred embodiment, the composition of the present invention comprises the following per 100 mL.
[0070] [Table 3] Suitable for intravenous injection.
[0071] Example 4: In a preferred embodiment, the composition of the present invention contains the following per mL:
[0072] [Table 4] Suitable for intravenous injection.
[0073] Example 5: In a preferred embodiment, the composition of the present invention contains the following per mL:
[0074] [Table 5] Suitable for intravenous injection.
[0075] Example 6: In a preferred embodiment, the composition of the present invention comprises the following per mL:
[0076] [Table 6] Suitable for intravenous injection.
[0077] Example 7: In a preferred embodiment, the composition of the present invention comprises the following per mL:
[0078] [Table 7] It is suitable for intravenous injection via drip infusion.
[0079] Example 8: In one embodiment, the composition of the present invention comprises the following per effervescent tablet.
[0080] [Table 8] The composition of Example 1 is formulated into effervescent tablets.
[0081] Example 9: In one embodiment, the composition of the present invention comprises the following per sachet:
[0082] [Table 9] The composition of Example 1 is formulated into effervescent granules.
[0083] Example 10: In one embodiment, the composition of the present invention comprises the following per 5 mL dose.
[0084] [Table 10] The composition of Example 1 is formulated into a syrup.
[0085] The compositions of Examples 1 to 10 exhibit all the advantages of the present invention described above, such as improved solubility, improved taste (in the case of oral administration Examples 8 to 10), improved absorption, and faster onset of action.
[0086] In addition, the inventors prepared the compositions of Examples 1-3 and 5-10 in the absence of cyclodextrin and observed significantly lower solubility, along with almost immediate precipitation of the active substance.
Claims
1. A pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable derivative thereof and one or more solubilizing agents, A) An aqueous solution for intravenous administration containing either sodium or lysine salt ibuprofen, paracetamol, and preferably one or more cyclodextrins, or B) An aqueous solution for use in intravenous administration, in which one or more solubilizers contain one or more essential amino acids and may contain one or more cyclodextrins, or C) A composition for oral administration comprising paracetamol and cyclodextrin, which is in the form of i) an effervescent tablet or effervescent granule, ii) an oral suspension, syrup or oral solution, or iii) a soft capsule. A pharmaceutical composition characterized by being in the form of a pharmaceutical composition.
2. The pharmaceutical composition according to claim 1, characterized in that ibuprofen is preferably in the form of a sodium salt.
3. The pharmaceutical composition according to any one of claims 1 to 2, characterized in that the amount of ibuprofen is in the range of 1 to 1000 mg, preferably 150 to 600 mg, 200 to 500 mg, or 300 to 400 mg.
4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that, in the form of aqueous solution A or B, the concentration of free ibuprofen equivalents is in the range of 1 to 400 mg / mL, preferably 2 to 100 mg / mL, more preferably 3 to 50 mg / mL, and even more preferably 3 mg / mL.
5. A pharmaceutical composition according to any one of claims 1 to 4, characterized in that it preferably contains paracetamol in the ratio of ibuprofen:paracetamol 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.
6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that, in the form of aqueous solution A, the concentration of paracetamol is in the range of 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, characterized in that, 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, and the concentration of the cyclodextrins is in the range of 0.2% m / v to 19% m / v, preferably 0.2% m / v to 6% m / v, more preferably 0.5% m / v to 3% m / v.
8. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that, 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, and the concentration of the cyclodextrins is in the range of 10 to 2000 mg / mL, preferably 200 to 1500 mg / mL, more preferably 350 to 750 mg / mL.
9. A 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 in the form of aqueous solution A or B, the concentration of the essential amino acid is in the range of 1 to 400 mg / L, preferably 20 to 300 mg / L, more preferably 50 to 200 mg / L, and even more preferably 70 to 100 mg / L.
10. The pharmaceutical composition according to claim 9, characterized in that, in the form of aqueous solution A or B, the composition contains one or more essential amino acids, the concentration of the essential amino acids is in the range of 0.5 to 200 mg / L, preferably 10 to 150 mg / L, more preferably 25 to 100 mg / L, and even more preferably 35 to 50 mg / L, and also contains one or more cyclodextrins, the concentration of the cyclodextrins is 10 to 2000 mg / mL, preferably 200 to 1500 mg / mL, and more preferably 350 to 750 mg / mL.
11. In the case of aqueous solution A or B, the composition further comprises a derivative having at least one thiol functional group, selected from thioglycerol, cysteine, acetylcysteine, thioglycolic acid and / or salts thereof, dithiothreitol, reduced glutathione, thiolactic acid and / or salts thereof, and mercaptoethanesulfonic acid, preferably thioglycerol, particularly preferably monothioglycerol, characterized in that the concentration of the derivative having at least one thiol functional group is in the range of 0.001% to 0.5% m / v, 1.5% to 3% m / v, or 2% to 2.5% m / v, as described in any one of claims 1 to 10.
12. In the case of aqueous solution A or B, the composition comprises a chelating agent selected from EDTA, nitrilotriacetic acid, ethylenediamine-N,N'-dipropionic acid, ethylenediamine-tetra-(methylenephosphate)), 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 in the range of 0.001% to 0.5% m / v, 1.5% to 3% m / v, or 2% to 2.5% m / v, as described in any one of claims 1 to 11.
13. In the case of an aqueous solution A or B, the composition comprises one or more derivatives selected from thiamine salts, preferably thiamine hydrochloride salts, wherein the concentration of the thiamine salt is in the range of 0.001% m / v to 0.2% m / v, as described in any one of claims 1 to 12.
14. The pharmaceutical composition according to any one of claims 1 to 13, characterized in that, in the form of aqueous solution A or B, the pH is between 4 and 8, preferably 6 to 8, more preferably 7 to 8, for example pH = 7.6, and 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 a mixture thereof.
15. In the case of form A or B, the pharmaceutical composition according to any one of claims 1 to 14, characterized in that the composition further comprises one or more pharmaceutically acceptable excipients.
16. In the case of form C, which is suitable for effervescent tablets or effervescent granules, the pharmaceutical composition according to any one of claims 1 to 5 is characterized in that 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 ditartrate.
17. In the case of form C, the pharmaceutical composition according to 16 is characterized in that 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, further comprising one or more active substances other than ibuprofen or paracetamol or pharmaceutically acceptable derivatives thereof, other nonsteroidal anti-inflammatory drugs such as acetylsalicylic acid, and / or opioids such as codeine, and / or anticonvulsants such as hyostine, and / or antihistamines such as chlorpheniramine and orphenadrine, and / or mucolytics such as acetylcysteine, and / or sympathomimetic agents such as pseudoephedrine, and / or vitamin C, and / or caffeine.