A composition and use thereof as a medicament

Abstract

The present invention provides a composition comprising acetylsalicylic acid, or a functional derivative thereof, and further comprising a first and a second excipient, wherein the first excipient is a non-aqueous solvent, and the second excipient is a non-5 aqueous carrier, wherein the composition is in liquid form and essentially water-free. Also provided is a composition comprising acetylsalicylic acid, or a functional derivative thereof, and further comprising at least two compounds of Formula (I), wherein: R1 is H or C1-2-alkyl, R2 is H or C1-2-alkyl, or R1 and R2 together with the atoms to which they are attached form a piperidyl heterocycle; R3 is C1-4-alkyl, and R4 is H or CH3. The present invention further provides a product comprising any one of the herein disclosed compositions, as well as a kit of parts comprising said product and a packaging. Additionally, the present invention is directed to the compositions for use as a medicament, for use in therapy by cutaneous administration, and / or for use in the treatment of skin irritation. Further provided is a method for the treatment of skin irritation in a human, comprising administering any one of the herein disclosed compositions to said human, as well as a method for manufacturing of the composition.

Description

[0001]A COMPOSITION AND USE THEREOF AS A MEDICAMENT Technical Field The present invention relates to the field of compositions comprisingacetylsalicylic acid. More particularly, the invention provides stabilised liquidcompositions comprising acetylsalicylic acid. Background There is a need in the art for over-the-counter pharmaceutical preparations thatprovide a quick pain-relieving effect on human skin and remove the pain by one singleapplication on the skin, without also providing a systemic effect on the body. Productsavailable today are often based on the local anaesthetic lidocaine or hydrocortisone, andusually only provide a soothing, cooling, or comforting effect, or enter the bloodstreamwhich may cause related adverse effects. Additionally, multiple applications on the skinare often needed due to recurring pain or irritation of the skin. Local anaesthetics are substances that induce reversible loss of sensation in a specific area of the body, allowing medical procedures to be performed without causing pain. Lidocaine belongs to a specific class of local anaesthetics known as amino amidelocal anaesthetics. It has a rapid onset and a relatively short duration of action. Othermembers of this class include bupivacaine, levobupivacaine, ropivacaine, mepivacaine,prilocaine, articaine, and etidocaine. Bupivacaine is known for its long duration ofaction. Levobupivacaine is the S-enantiomer of bupivacaine. Ropivacaine is similar tobupivacaine but with a safer cardiovascular profile. Mepivacaine has an intermediateduration of action. Prilocaine is another amino amide local anaesthetic with a rapidonset of action. Articaine is a relatively newer amino amide local anaesthetic, whichalso has a fast onset. Etidocaine is a long-acting amino amide local anaesthetic.Acetylsalicylic acid (ASA), also known as aspirin, is a medication with a historydating back to the use of willow bark in ancient times. Its primary known uses includepain relief, reduction of inflammation and fever, as well as cardiovascular protection.ASA is available in various forms and widely used as an over-the-counter medicationfor a range of conditions. Common forms include tablets of different types, powders,and suppositories. ASA can also be applied topically as a solution to address concernssuch as insect bites and muscle pain. However, ASA is susceptible to hydrolysis, aprocess that breaks it down into acetic acid and salicylic acid (SA), which has irritantpotential both when ingested and when applied on the skin. In aqueous environments,ASA can degrade almost entirely within a week. Various alternative liquid ASAformulations have been proposed, such as solutions in alcohols (see e.g., US5736126and WO0245687 A2) and solutions comprising a particulate water-adsorber such aszeolite (see WO0078354 A1). Nevertheless, there is a continued need in the art forliquid ASA compositions which remain stable upon storage for prolonged periods oftime. Summary One object of the present invention is to provide liquid compositions comprisingacetylsalicylic acid (ASA), which retain a significant amount of ASA for a significantamount of time, such as months or even years, thereby providing liquid ASAcompositions offering a reasonable period of use to consumers.More particularly, the present invention provides a composition comprisingacetylsalicylic acid, or a functional derivative thereof, and further comprising a first and a second excipient, wherein the first excipient is a non-aqueous solvent, and the second excipient is a non-aqueous carrier, wherein the composition is in liquid form and essentially water-free. Another object of the present invention is to provide a composition comprisingacetylsalicylic acid (ASA) and one or more compounds providing a prolonged pain-reducing effect. Accordingly, the present invention provides a composition comprisingacetylsalicylic acid, or a functional derivative thereof, and further comprising at leastone compounds of Formula (I), wherein: R1is H or C1-2-alkyl, R2is H or C1-2-alkyl, or R1and R2together with the atoms to which they are attached form a piperidyl heterocycle; R3is C1-4-alkyl, and R4is H or CH3. The present invention further provides a product comprising any one of theherein disclosed compositions, as well as a kit of parts comprising said product and a packaging. Additionally, the present invention is directed to the herein disclosedcompositions for use as a medicament. More particularly, the compositions are for usein therapy by cutaneous administration. Further, the compositions are for use in thetreatment of skin irritation. Further provided is a method for the treatment of skin irritation in a human,comprising administering any one of the herein disclosed compositions to said human.The present invention also provides a method for manufacturing of a composition, comprising: dissolving acetylsalicylic acid, or a functional derivative thereof, in a non- aqueous solvent having a dielectric constant of at least 10 at 25 °C, thereby obtaining a liquid solution of acetylsalicylic acid or the functional derivative thereof, mixing said liquid solution with at least one non-aqueous carrier,thereby obtaining the composition.Further features and advantages of the invention will become apparent from the following description of preferred embodiments of the invention, given by way ofexample only, which is made with reference to the accompanying drawings. It is notedthat the present invention relates to all possible combinations of features recited in theclaims. Brief Description of the Drawings Fig. 1 shows the stability of acetylsalicylic acid (ASA) in a composition furthercontaining dimethyl sulfoxide and castor oil, at room temperature and at 40 ºC.Fig. 2 depicts the stability of ASA in a composition further containing threeamino amide local anaesthetics, dimethyl sulfoxide, and castor oil, at room temperature (Fig.2A) and at 40 ºC (Fig.2B). Fig. 3 shows the stability of ASA in a composition further containing threeamino amide local anaesthetics, dimethyl sulfoxide, diethylene glycol monoethyl ether, and castor oil, at room temperature (Fig.3A) and at 40 ºC (Fig.3B). Fig. 4 is a graph showing the stability of ASA in a composition furthercontaining three amino amide local anaesthetics, ethanol, glycerol, and isopropanol, atroom temperature. Fig. 5 is a graph depicting the stability of ASA in a composition furthercontaining dimethyl sulfoxide, at room temperature.Fig. 6 shows the stability of ASA in a composition further containing ethylacetate and propylene glycol, at room temperature and at 40 ºC, at a ratio of 1:9 (Fig.6A) and at a ratio of 1:4 (Fig.6B) of ethyl acetate to propylene glycol. Detailed Description The present invention solves or at least mitigates the problems associated withpreviously known liquid compositions comprising acetylsalicylic acid, by providing acomposition comprising acetylsalicylic acid, or a functional derivative thereof, and further comprising a first and a second excipient, wherein the first excipient is a non- aqueous solvent, and the second excipient is a non-aqueous carrier, wherein the composition is in liquid form and essentially water-free. The present invention provides a stabilising effect on acetylsalicylic acid in a liquid composition upon storage, slowing down the rate of degradation of acetylsalicylic acid to salicylic acid. As shown in the experimental section herein, in acomposition consisting of acetylsalicylic acid, a non-aqueous solvent and a non-aqueous carrier in accordance with the present invention, about 90% of theacetylsalicylic acid was still present in the composition after 30 days of storage at 25°C, and about 80% of the acetylsalicylic acid was still present in the composition after60 days of storage at 25 °C, where 100% corresponds to the amount of acetylsalicylic acid present in the composition on the day of preparing the composition. In contrast, as also shown herein, in a composition consisting of acetylsalicylicacid and a non-aqueous solvent (no non-aqueous carrier present), only about 60% of the acetylsalicylic acid was still present in the composition after 30 days of storage at 25 °C. As further shown herein, acetylsalicylic acid was not stabilised in the presence of ethanol, but instead quickly degraded (half-life about 67 h), although the compositionalso comprised non-aqueous carriers fulfilling the requirements as defined herein.Ethanol would not be a suitable non-aqueous solvent for the purpose of stabilisingacetylsalicylic acid. Additionally, it is shown herein that acetylsalicylic acid wasquickly degraded (half-life of less than 50 h) in a composition containing a non-aqueoussolvent which does not fulfil the requirements as defined herein and a non-aqueouscarrier fulfilling the requirements as defined herein. The term “functional derivative” is used herein to denote a modified version oranalogue of a chemical compound that essentially retains the core biological orchemical activity of the original compound. Functional derivatives can take variousforms, including salts, esters, prodrugs, isomers, analogues, or other chemical modifications. The term “functional derivative of acetylsalicylic acid” is defined as aphysiologically tolerable, modified version of acetylsalicylic acid that retains the painrelieving and inflammation reducing activities of acetylsalicylic acid. Moreparticularly, a functional derivative of acetylsalicylic acid may be selected from aphysiologically tolerable prodrug (e.g., a glycol amide) or salt (e.g., a lysine salt) orester form of acetylsalicylic acid or an analogue thereof, e.g., a 4- or 5-substituted, forexample a 4- and / or 5-nitro and / or methoxy acetylsalicylic acid. In one embodiment ofthe invention the functional derivative of acetylsalicylic is not salicylic acid. Herein, the term “non-aqueous” is intended to mean essentially water-free. Thisdefinition is true for non-aqueous solvents, non-aqueous carriers, and non-aqueouscompositions, as described herein. Herein, the term “essentially water-free” is intended to mean that a composition comprises less than 5%, such as less than 3%, such as less than 1%, such as less than 0.5% water when using standard industry techniques for detection of water. In some embodiments the composition comprises no detectable water when using standard industry techniques for detection of water. The non-aqueous solvent in some embodiments has a dielectric constant of atleast 10 at 25 °C, such as a dielectric constant of at least 12, 14, 16 or 18 at 25 °C, or a dielectric constant of from 10, 12, 14, 16, or 18 at 25 °C. Such solvents may be called polar solvents. Non-limiting examples of non-aqueous solvents having a dielectricconstant of at least 10 at 25 °C include dimethyl sulfoxide (DMSO) (dielectric constantof about 49 at 25 °C), formic acid (dielectric constant of about 51 at 25 °C), dimethylisosorbide (DMI) (dielectric constant of about 36.5 at 25 °C), dihydrolevoglucosenone,also known as Cyrene (dielectric constant of about 37.3 at 25 °C), and N,N-dimethylacetamide (NNDMA) (dielectric constant of about 37.8 at 25 °C).Without wishing to be bound by theory it is believed that polar solvents enhance the solubility of acetylsalicylic acid compared to non-polar solvents, and may further have a penetration enhancing effect when included in a composition for cutaneous administration. Despite fulfilling the criterion of having a dielectric constant of at least 10 at 25°C, ethanol is not a suitable non-aqueous solvent for the purpose of the presentinvention, i.e., the purpose of stabilising acetylsalicylic acid in liquid compositions.Accordingly, the present disclosure includes that the non-aqueous solvent may have adielectric constant of at least 10 at 25 °C, with the provision that the non-aqueoussolvent is not ethanol. Despite fulfilling the criterion of having a dielectric constant of at least 10 at 25 °C, methanol is not a suitable non-aqueous solvent for the purpose of the present invention, i.e., the purpose of stabilising acetylsalicylic acid in liquid compositions. Accordingly, the present disclosure includes that the non-aqueous solvent may have a dielectric constant of at least 10 at 25 °C, with the provision that the non-aqueous solvent is not methanol. Despite fulfilling the criterion of having a dielectric constant of at least 10 at 25 °C, isopropanol is not a particularly suitable non-aqueous solvent for the purpose of the present invention, i.e., the purpose of stabilising acetylsalicylic acid in liquid compositions. Accordingly, the present disclosure includes that the non-aqueous solvent may have a dielectric constant of at least 10 at 25 °C, with the provision that the non-aqueous solvent is not isopropanol. Consequently, the present disclosure includes that the non-aqueous solvent has a dielectric constant of at least 10 at 25 °C, with the provision that the non-aqueous solvent is not selected from methanol, ethanol, or isopropanol. The dielectric constant of a material may be measured for example byperforming the method described in https: / / www.britannica.com / science / dielectric-constant. In some embodiments the solvent is selected from a group of non-aqueoussolvents comprising dimethyl sulfoxide (DMSO), dimethyl isosorbide (DMI), N,N-dimethylacetamide (NNDMA), formic acid, dihydrolevoglucosenone, and cyclopentylmethyl ether (CPME), optionally with the provision that the non-aqueous solvent is notselected from methanol, ethanol, or isopropanol. In some embodiments the solvent is selected from a group of non-aqueoussolvents consisting of dimethyl sulfoxide (DMSO), dimethyl isosorbide (DMI), N,N-dimethylacetamide (NNDMA), formic acid, dihydrolevoglucosenone, and cyclopentylmethyl ether (CPME). In some embodiments the solvent is dimethyl sulfoxide (DMSO).In some embodiments the solvent is dimethyl isosorbide (DMI).In some embodiments the solvent is N,N-dimethylacetamide (NNDMA).In some embodiments the solvent is formic acid.In some embodiments the solvent is dihydrolevoglucosenone.In some embodiments the solvent is cyclopentyl methyl ether (CPME).The non-aqueous solvent may have a relative polarity of at least 0.3 relative toa value of 1 for water. According to non-limiting examples, the non-aqueous solventmay have a relative polarity of 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9, relative to a value of 1 for water. The relative polarity of a solvent may be obtained for example by first measuring a spectral shift in the UV-visible absorbance of a solvatochromatic due. The wavelength of absorbance by the dye is shifted as a function of a solvent polarity. The relative polarity of a given solvent can be calculated based on the wavelength shift compared with a polar (e.g., water) and a non-polar (e.g., tetramethylsilane, TMS)reference standard (see for example Reichardt C., Chem. Rev. 1994, 94, 8, 2319–2358).Despite fulfilling the criterion of having a relative polarity of at least 0.3(relative to a value of 1 for water), methanol, ethanol, and isopropanol are not suitablenon-aqueous solvents for the purpose of the present invention, i.e., the purpose of stabilising acetylsalicylic acid in liquid compositions. Accordingly, the presentdisclosure includes that the non-aqueous solvent may have a relative polarity of at least0.3, with the provision that the non-aqueous solvent is not selected from methanol,ethanol, or isopropanol. The non-aqueous solvent may be organic or non-organic. The non-aqueous solvent may be physiologically acceptable.The non-aqueous carrier may be described in terms of its octanol-water partition coefficient, which is a common way of expressing the lipophilicity of a compound.More particularly, the octanol-water partition coefficient represents the ratio ofconcentrations of a (not ionized) compound between two phases, one being a water-saturated octanolic phase and the other an octanol-saturated aqueous phase. Theoctanol-water partition coefficient is typically expressed in logarithm form and isindicated as log Kow or log P (https: / / www.sciencedirect.com / topics / chemistry / octanol-water-partition-coefficient). This parameter may for example be obtained by usingexperimental procedures, as known by persons skilled in the art. Positive values for logKow indicate some hydrophobic character, with larger values showing morehydrophobicity. A negative value for log Kow indicates some hydrophilic character.The non-aqueous carrier may have an octanol-water partition coefficient of from about -1.4, such as about -1.4, -1.2, -1.0, -0.8, -0.6, -0.4, -0.2, 0, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, or 8.0. Without wishing to be bound by theory it is believed that incorporating carrierswhich are non-aqueous and have a hydrophobic character results in improved stabilityof the acetylsalicylic acid since hydrolysis is reduced. Without wishing to be bound by theory it is believed that incorporating carriers which are non-aqueous and have a positive value for octanol-water partition coefficientresults in improved stability of the acetylsalicylic acid since hydrolysis is reduced. Herein, the term “about”, when used together with a specified value of theoctanol-water partition coefficient, may be replaced by “± l-5%” of the value asspecified. In relation to carriers having more hydrophilic character, the octanol-waterpartition coefficient in some embodiments is from about -1.4 to about 0. Non-limitingexamples of such non-aqueous carriers are diethylene glycol monoethyl ether (log Kow -0.54 to -0.47 approx.), polyethylene glycol (PEG) (log Kow -1.36 to -1 approx.),propylene glycol (log Kow -0.92 approx.), and 1-methoxy-2-propanol (log Kow -0.43approx.). In relation to carriers having slightly more hydrophobic character, the octanol-water partition coefficient in some embodiments is from about 0 to about 5. A non-limiting example of such non-aqueous carriers is benzyl alcohol (log Kow1 to 1.05 approx.). In relation to carriers having highly hydrophobic character, the octanol-waterpartition coefficient in some embodiments is from about 5.0, such as 5.0, 5.5, 6.0, 6.5,7.0, 7.5, or 8.0. Non-limiting examples of non-aqueous carriers having an octanol-waterpartition coefficient of from about 5.0 include oleic acid (log Kow 7.73), isopropylmyristate (log Kow7.71), and stearyl alcohol (log Kow7.4), and oils, such as mineral oil (log Kow 6). The carrier in some embodiments is selected from a group of non-aqueouscarriers comprising castor oil, mineral oil, coconut oil, palm oil, soyabean oil, canolaoil, olive oil, diethylene glycol monoethyl ether, polyethylene glycol (PEG), benzyl alcohol, propylene glycol, oleic acid, stearic acid, isopropyl myristate, isopropylpalmitate, stearyl alcohol, squalene, squalane, 1-methoxy-2-propanol, waxes, paraffins,and gums. The carrier in some embodiments is selected from a group of non-aqueouscarriers consisting of castor oil, mineral oil, coconut oil, palm oil, soyabean oil, canolaoil, olive oil, diethylene glycol monoethyl ether, polyethylene glycol (PEG), benzyl alcohol, propylene glycol, oleic acid, stearic acid, isopropyl myristate, isopropyl palmitate, stearyl alcohol, squalene, squalane, 1-methoxy-2-propanol, waxes, paraffins, and gums. Squalene is a polyunsaturated hydrocarbon having a chemical formula ofC30H50. Squalane is a saturated derivative of squalene and has a chemical formula ofC30H62. Non-limiting examples of waxes are beeswax, carnauba wax, candelilla wax, and rice bran wax. A non-limiting example of paraffins is soft paraffin, also known as white paraffin, or petroleum jelly (tradename Vaseline). Non-limiting examples of gums are guar gum, acacia gum, xanthan gum, and locust-bean gum. The carrier is a compound that helps to stabilise acetylsalicylic acid uponstorage of the liquid composition. The carrier has a storage-stabilising effect onacetylsalicylic acid. For example, the carrier in some embodiments provides a storage-stabilising effect on acetylsalicylic acid to the extent that at least 80%, such as 85%, or 90%, of the amount of acetylsalicylic acid present in the composition right after it hasbeen prepared, is still present in the composition after 30 days of storage at 25 °C. Inother words, the carrier in some embodiments provides a storage-stabilising effect onacetylsalicylic acid to the extent that at most 20%, such as 15%, or 10%, of the amountof acetylsalicylic acid is degraded after 30 days of storage at 25 °C. According toanother example, the carrier in some embodiments provides a storage-stabilising effecton acetylsalicylic acid to the extent that at least 70%, such as 75%, or 80%, of the amount of acetylsalicylic acid present in the composition right after it has beenprepared, is still present in the composition after 60 days of storage at 25 °C. In otherwords, the carrier in some embodiments provides a storage-stabilising effect onacetylsalicylic acid to the extent that at most 30%, such as 25%, or 20%, of the amount of acetylsalicylic acid is degraded after 60 days of storage at 25 °C. The non-aqueous carrier in some embodiments is organic or non-organic.The non-aqueous carrier in some embodiments is physiologically acceptable. It is to be understood that in the context of compositions for use aspharmaceutical preparations, the solvents and carriers used, as well as the resultingcompositions, must be physiologically acceptable.The term “physiologically acceptable” is used in its conventional meaning inthe field of pharmaceutical preparations, i.e., a substance or composition which doesnot disturb or harm the normal biological functions of an individual who uses thesubstance or composition, or is exposed to it, in accordance with the user instructions.For example, in the context of compositions which are intended for cutaneous administration, this means that the solvents, carriers and compositions must not cause harm to the body when being applied on the skin. Further, it is to be understood that a physiologically acceptable compositionincludes, but is not limited to, being immunologically acceptable, meaning it does notdisturb or harm the body’s natural immune response, when being administered according to the user instructions. The solvent(s) forming part of the herein disclosed compositions in someembodiments is selected from solvents which are suitable for cutaneous administration.Similarly, the carrier(s) forming part of the herein disclosed compositions insome embodiments is selected from carriers which are suitable for cutaneousadministration. The term “cutaneous administration” is used in its conventional meaning in this field, i.e., administration to the skin. In particular, the cutaneous administration is usedfor local treatment, i.e., not for systemic treatment, affecting the whole body.The composition in some embodiments is in any cutaneously applicableadministration form which does not require rubbing of the affected skin, e.g., solutions, emulsions, dispersions, liposomal compositions, sprays, etc. It is preferable to select solvents and carriers which are environmentallyacceptable, i.e., solvents and carriers which, if released into the environment, would not do harm to the environment and / or living organisms.The solvent(s) forming part of the herein disclosed compositions are in someembodiments present in an amount ranging from about 5% – 30%, such as from about7% - 25%, such as from 10% – 20%.The carrier(s) forming part of the herein disclosed compositions are in someembodiments present in an amount ranging from about 50% - 95%, such as from about60% - 90%, such as from 70% – 80%.In one embodiment a composition comprising acetylsalicylic acid, a first and a second excipient, is a composition comprising: (i) acetylsalicylic acid,(ii) dimethyl sulfoxide, and(iii) castor oil.The concentration of acetylsalicylic acid of said composition in someembodiments is from about 0.25 mg / ml to about 150 mg / ml, such as from about 1mg / ml to about 100 mg / ml, such as from about 20 mg / ml to about 80mg / ml, such asfrom about 40 mg / ml to about 60mg / ml, or from about 0.25 mg / ml to about 20 mg / ml,such as from about 1 mg / ml to about 15 mg / ml, such as from about 6 to about 12 mg / ml, such as from about 8 to about 10 mg / ml. In said composition, the castor in some embodiments is in an amount rangingfrom about 50% - 95% v / v, such as from about 60% - 90% v / v, such as from 70% –80% v / v. In said composition, the dimethyl sulfoxide in some embodiments is in anamount ranging from about 5% – 30% v / v, such as from about 7% - 25% v / v, such asfrom 10% – 20% v / v.In one embodiment a composition comprising acetylsalicylic acid, a first and asecond excipient, is a composition comprising: (i) acetylsalicylic acid in a concentration ranging from about 0.25 mg / ml toabout 150 mg / ml, such as from about 1 mg / ml to about 100 mg / ml, such as from about 20 mg / ml to about 80mg / ml, such as from about 40 mg / ml to about 60mg / ml,(ii) dimethyl sulfoxide in an amount ranging from about 5% – 30% v / v, suchas from about 7% - 25% v / v, such as from 10% – 20% v / v, and(iii) castor oil in an amount ranging from about 50% - 95% v / v, such as fromabout 60% - 90% v / v, such as from 70% – 80% v / v.In one embodiment a composition comprising acetylsalicylic acid, a first and asecond excipient, is a composition comprising: (i) acetylsalicylic acid in a concentration ranging from about 0.25 mg / ml toabout 150 mg / ml, such as from about 1 mg / ml to about 100 mg / ml, such as from about 20 mg / ml to about 80mg / ml, such as from about 40 mg / ml to about 60mg / ml, (ii) dimethyl sulfoxide in an amount ranging from about 20% – 30% v / v,and (iii) castor oil in an amount ranging from about 70% – 80% v / v.In a still further embodiment a composition comprising acetylsalicylic acid, afirst and a second excipient, is a composition comprising: (i) acetylsalicylic acid in a concentration ranging from about 30 mg / ml toabout 100 mg / ml, (ii) dimethyl sulfoxide in an amount ranging from about 5% – 30% v / v, suchas from about 7% - 25% v / v, such as from 10% – 20% v / v, and(iii) castor oil in an amount ranging from about 70% – 95 % v / v.In a still further embodiment a composition comprising acetylsalicylic acid, afirst and a second excipient, is a composition comprising: (i) acetylsalicylic acid in a concentration ranging from about 30 mg / ml toabout 100 mg / ml, (ii) dimethyl sulfoxide in an amount ranging from about 5% – 30% v / v, and(iii) castor oil in an amount ranging from about 70% - 95% v / v, such as fromabout 75% - 90% v / v.In a still further embodiment a composition comprising acetylsalicylic acid, afirst and a second excipient, is a composition comprising:(i) acetylsalicylic acid in a concentration ranging from about 30 mg / ml toabout 100 mg / ml, (ii) dimethyl sulfoxide in an amount ranging from about 5% – 10% v / v, and(iii) castor oil in an amount ranging from about 90% – 95% v / v.Herein, the term “about”, when used together with a specified amount orconcentration, may be replaced by “± l-5%” of the amount or concentration as specified.The composition comprising acetylsalicylic acid, a first and a second excipient may further comprise a third excipient, which is a non-aqueous carrier. The third excipient, when present, is a different compound than the second excipient. However, just like the second excipient, the third excipient is a non-aqueous carrier which may be described in terms of its octanol-water partition coefficient. Alldetailed information above in relation to the octanol-water partition coefficient of thesecond excipient is relevant also in relation to the third excipient. The third excipient in some embodiments is a physiologically acceptable non-aqueous carrier. The third excipient in some embodiments is selected from a group ofphysiologically acceptable non-aqueous carriers comprising castor oil, mineral oil,coconut oil, palm oil, soyabean oil, canola oil, olive oil, diethylene glycol monoethylether, polyethylene glycol (PEG), benzyl alcohol, propylene glycol, oleic acid, stearic acid, isopropyl myristate, isopropyl palmitate, stearyl alcohol, squalene, squalane, 1- methoxy-2-propanol, waxes, paraffins, and gums. The third excipient in some embodiments is selected from a group ofphysiologically acceptable non-aqueous carriers consisting of castor oil, mineral oil,coconut oil, palm oil, soyabean oil, canola oil, olive oil, diethylene glycol monoethylether, polyethylene glycol (PEG), benzyl alcohol, propylene glycol, oleic acid, stearic acid, isopropyl myristate, isopropyl palmitate, stearyl alcohol, squalene, squalane, 1- methoxy-2-propanol, waxes, paraffins, and gums. The non-limiting examples of waxes, paraffins, and gums mentioned furtherabove in relation to the second excipient are relevant also in relation to the third excipient. The composition comprising acetylsalicylic acid, a first and a second excipient,and optionally a third excipient, in some embodiments further comprises at least onecompound of Formula (I), wherein: R1is H or C1-2-alkyl, R2is H or C1-2-alkyl, or R1and R2together with the atoms to which they are attached form a piperidyl heterocycle; R3is C1-4-alkyl, and R4is H or CH3. Acompound of Formula (I) in some embodiments is present in the compositionin the form of a single enantiomer or a racemate, having a chiral centre as shown byasterisk below: The at least one compound of Formula (I) in some embodiments is selected fromlidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine, etidocaine, and levobupivacaine. The compounds of Formula (I) belong to a group of local anaesthetics. More particularly, the compounds of Formula (I) belong to a group of amino amide local anaesthetics. In other words, the composition comprising acetylsalicylic acid, a first and asecond excipient, and optionally a third excipient, in some embodiments furthercomprises at least one compound selected from a group of amino amide localanaesthetics. The compound selected from the group of amino amide local anaesthetics insome embodiments is lidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine,etidocaine, or levobupivacaine. Another non-limiting example of an amino amide localanaesthetic is articaine. The concentration of the amino amide local anaesthetic, such as the compoundof Formula (I), in some embodiments is from about 1 mg / ml to about 60 mg / ml, suchas from about 10 mg / ml to about 50 mg / ml, such as from about 20 mg / ml to about 40 mg / ml, or a concentration of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg / ml. Herein, as mentioned above, the term “about”, when used together with aspecified amount or concentration, may be replaced by “± l-5%” of the amount orconcentration as specified. The composition may alternatively comprise a combination of at least two compounds selected from the group of amino amide local anaesthetics, such as at leasttwo compounds of Formula (I) in combination with an amino amide local anaestheticcompound not covered by Formula (I). It is particularly advantageous to select a first compound and a second compound from the group of amino amide local anaesthetics,such as at least two compounds of Formula (I) in combination with an amino amidelocal anaesthetic compound not covered by Formula (I), wherein the first compound and the second compound provide different onset and duration of action, respectively.The first compound in some embodiments is selected from a group of compoundshaving a relatively fast onset of action and a relatively short duration of action, and thesecond compound in some embodiments is selected from a group of compounds havingan intermediate to late onset of action and / or a longer duration of action, compared tothe first compound. Non-limiting examples of a compound having a relatively fast onsetof action are lidocaine and prilocaine. A non-limiting example of a compound havingan intermediate onset of action is mepivacaine. Non-limiting examples of compoundshaving a late onset of action and / or longer duration of action are bupivacaine, levobupivacaine, ropivacaine, and etidocaine.Another non-limiting example of an amino amide local anaesthetic which has afast onset of action is articaine.A non-limiting example of a suitable combination of two compounds selectedfrom the group of amino amide local anaesthetics is a combination of lidocaine andbupivacaine. Another non-limiting example of a suitable combination of twocompounds of Formula (I) is lidocaine in combination with ropivacaine. Yet anothernon-limiting example of a suitable combination of two compounds of Formula (I) islidocaine in combination with levobupivacaine.The composition in some embodiments comprises at least three compoundsselected from the group of amino amide local anaesthetics, such as three compounds ofFormula (I), or one compound of Formula (I) in combination with two amino amidelocal anaesthetic compounds not covered by Formula (I), or two compounds of Formula(I) in combination with one amino amide local anaesthetic compound not covered byFormula (I). The first compound in some embodiments is selected from a group ofcompounds having a relatively fast onset of action and a relatively short duration ofaction, and the second and third compound may be selected from a group of compoundshaving an intermediate to late onset of action and / or a longer duration of action, compared to the first compound. A non-limiting example of a suitable combination of three compounds selectedfrom the group of amino amide local anaesthetics is a combination of lidocaine,bupivacaine, and ropivacaine. Another non-limiting example of a suitable combinationof three compounds from the group of amino amide local anaesthetics is lidocaine incombination with levobupivacaine and ropivacaine.The concentration of each of the amino amide local anaesthetics in thecomposition in some embodiments is from about 1 mg / ml to about 60 mg / ml, such asfrom about 10 mg / ml to about 50 mg / ml, such as from about 20 mg / ml to about 40 mg / ml, or a concentration of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg / ml. Afurther object of the present invention is to provide a composition comprisingacetylsalicylic acid (ASA) and at least two compounds providing a prolonged pain-reducing effect. Accordingly, the present invention provides a composition comprising acetylsalicylic acid, or a functional derivative thereof, and further comprising at least two compounds of Formula (I), wherein: R1is H or C1-2-alkyl, R2is H or C1-2-alkyl, or R1and R2together with the atoms to which they are attached form a piperidyl heterocycle; R3is C1-4-alkyl, and R4is H or CH3. Said composition in some embodiments is in liquid form. A composition maybe described as “in liquid form” if it is flowable or pourable when the composition is atroom temperature. In some embodiments the composition has a viscosity of less than about 8cP at 25ºC. In some embodiments the composition is in liquid form when it has a viscosity of less than about 8cP at 25ºC. Said composition in some embodiments is essentially water-free. The term“essentially water-free” has been defined further above. The compound of Formula (I) may be present in said composition in the formof a single enantiomer or a racemate, having a chiral centre as shown by asterisk below: The at least one compound of Formula (I) in some embodiments is selected fromlidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine, etidocaine, and levobupivacaine. The compounds of Formula (I) belong to a group of local anaesthetics. More particularly, the compounds of Formula (I) belong to a group of amino amide local anaesthetics. In other words, said composition comprising acetylsalicylic acid in someembodiments further comprises at least two compounds selected from a group of aminoamide local anaesthetics. The at least two compounds selected from the group of amino amide localanaesthetics in some embodiments is selected from lidocaine, bupivacaine, ropivacaine,mepivacaine, prilocaine, etidocaine, or levobupivacaine. Another non-limiting exampleof an amino amide local anaesthetic is articaine. The concentration of each of the amino amide local anaesthetics in thecomposition in some embodiments is from about 1 mg / ml to about 60 mg / ml, such asfrom about 10 mg / ml to about 50 mg / ml, such as from about 20 mg / ml to about 40 mg / ml, or a concentration of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg / ml. Said composition in some embodiments comprises at least two compoundsselected from the group of amino amide local anaesthetics, such as at least two compounds of Formula (I), or one compound of Formula (I) in combination with an amino amide local anaesthetic compound not covered by Formula (I), wherein the first compound and the second compound provide different onset and duration of action,respectively. The first compound in some embodiments is selected from a group ofcompounds having a relatively fast onset of action and a relatively short duration ofaction, and the second compound in some embodiments is selected from a group ofcompounds having an intermediate to late onset of action and / or a longer duration of action, compared to the first compound. Non-limiting examples of a compound having a relatively fast onset of action are lidocaine and prilocaine. A non-limiting example of a compound having an intermediate onset of action is mepivacaine. Non-limiting examples of compounds having a late onset of action and / or longer duration of action are bupivacaine, levobupivacaine, ropivacaine, and etidocaine. Another non-limiting example of an amino amide local anaesthetic which has a fast onset of action is articaine. A non-limiting example of a suitable combination of two compounds selected from the group of amino amide local anaesthetics is a combination of lidocaine and bupivacaine. Another non-limiting example of a suitable combination of two compounds of Formula (I) is lidocaine in combination with ropivacaine. Yet another non-limiting example of a suitable combination of two compounds of Formula (I) is lidocaine in combination with levobupivacaine. Said composition in some embodiments comprises at least three compoundsselected from the group of amino amide local anaesthetics, such as three compounds of Formula (I), or one compound of Formula (I) in combination with two amino amide local anaesthetic compounds not covered by Formula (I), or two compounds of Formula (I) in combination with one amino amide local anaesthetic compound not covered byFormula (I). The first compound in some embodiments is selected from a group ofcompounds having a relatively fast onset of action and a relatively short duration ofaction, and the second and third compound in some embodiments is selected from agroup of compounds having an intermediate to late onset of action and / or a longer duration of action, compared to the first compound. Anon-limiting example of a suitable combination of three compounds, selectedfrom the group of amino amide local anaesthetics, is a combination of lidocaine,bupivacaine, and ropivacaine. Another non-limiting example of a suitable combinationof three compounds from the group of amino amide local anaesthetics is lidocaine incombination with levobupivacaine and ropivacaine. The above-described composition comprising acetylsalicylic acid and one ormore compounds selected from a group of amino amide local anaesthetics, such as oneor more compounds of Formula (I), in some embodiments further comprises a first anda second excipient, wherein the first excipient is a non-aqueous solvent, and the second excipient is a non-aqueous carrier, wherein the composition is in liquid form and essentially water-free.A non-aqueous solvent has been defined, described, and exemplified furtherabove in relation to the first composition disclosed. The same definition, description,and examples of the non-aqueous solvent are applicable to the non-aqueous solvent of this second composition. Anon-aqueous carrier has been defined, described, and exemplified furtherabove in relation to the first composition disclosed. The same definition, description,and examples of the non-aqueous carrier are applicable to the non-aqueous carrier ofthis second composition. Said composition in some embodiments further comprises a third excipient,which is a non-aqueous carrier. The third excipient, when present, is a differentcompound than the second excipient, but otherwise the same definition, description,and examples of the second excipient, being a non-aqueous carrier, are applicable to the third excipient, being a non-aqueous carrier. Any one of the herein disclosed compositions in some embodiments furthercomprises one or more excipients selected from a group of penetration enhancers, i.e.,skin penetration enhancers or skin permeation enhancers, such as an anionic surfactant, a cationic surfactant, a zwitterionic surfactant, a non-ionic surfactant, a fatty acid, a fatty ester, and a fatty amine. The amount or concentration of a penetration enhancer, present in any one ofthe herein disclosed compositions, may suitably be much lower than the amount orconcentration of the non-aqueous solvent, and / or the amount or concentration of the non-aqueous carrier. As a non-limiting example, the amount or concentration of penetration enhancer may be about 1-5% of the amount or concentration of the non- aqueous solvent. A non-limiting example of a fatty acid is oleic acid. Oleic acid can act as a non- aqueous carrier and as a penetration enhancer. Another non-limiting example of a fattyacid is stearic acid. Stearic acid can act as a non-aqueous carrier and as a penetrationenhancer. It is to be understood that if a compound included in the composition ascarrier also acts as a penetration enhancer, there is no need to add more of the samecompound to the composition to achieve its effect as penetration enhancer. Other non-limiting examples of penetration enhancers include glycols, glycerol, isopropanol, polyethylene glycol (PEG), ceramides, ethyl alcohol, Azone (laurocapram), and pyrrolidones (e.g., 2-pyrrolidone). Any one of the herein disclosed compositions in some embodiments is in theform of (i) a liquid under an inert atmosphere, or (ii) a nanoformulation. An inert atmosphere in some embodiments is provided by an inert gas, such asnitrogen, helium, or argon. In one embodiment the inert gas is nitrogen.In this context, the term “nanoformulation” is intended to mean a formulationcontaining nanoparticles, i.e., particles with dimensions in the nanometre range. A non-limiting example of a nanoformulation, which is suitable for any one of the presentlydisclosed compositions, is a liposomal emulsion.Any one of the herein disclosed compositions in some embodiments comprisesacetylsalicylic acid or the functional derivative thereof at a concentration of from about 0.25 mg / ml to about 150 mg / ml, such as from about 1 mg / ml to about 100 mg / ml, such as from about 20 mg / ml to about 80mg / ml, such as from about 40 mg / ml to about 60mg / ml, or from about 0.25 mg / ml to about 20 mg / ml, such as from about 1 mg / ml to about 15 mg / ml, such as from about 6 to about 12 mg / ml, such as from about 8 to about 10 mg / ml, or at a concentration of about 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg / ml. In one embodiment a composition comprising acetylsalicylic acid, at least onecompound of Formula (I), a first excipient, a second excipient, and a third excipient, is a composition comprising: (i) acetylsalicylic acid,(ii) lidocaine,(iii) optionally ropivacaine or bupivacaine,(iv) dimethyl sulfoxide or dimethyl isosorbide,(v) castor oil and / or palm oil, and(vi) oleic acid. In said composition, the concentration of acetylsalicylic acid in someembodiments is from about 0.25 mg / ml to about 150 mg / ml, such as from about 1mg / ml to about 100 mg / ml, such as from about 20 mg / ml to about 80mg / ml, such as from about 40 mg / ml to about 60mg / ml, or from about 0.25 mg / ml to about 20 mg / ml, such as from about 1 mg / ml to about 15 mg / ml, such as from about 6 to about 12 mg / ml, such as from about 8 to about 10 mg / ml. In said composition, the concentration of lidocaine in some embodiments isfrom about 1 mg / ml to about 60 mg / ml, such as from about 10 mg / ml to about 50 mg / ml, such as from about 20 mg / ml to about 40 mg / ml, or a concentration of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg / ml. In said composition, the concentration of ropivacaine, if present, in someembodiments is from about 1 mg / ml to about 60 mg / ml, such as from about 10 mg / mlto about 50 mg / ml, such as from about 20 mg / ml to about 40 mg / ml, or a concentration of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg / ml. In said composition, the concentration of bupivacaine, if present, in someembodiments is from about 1 mg / ml to about 60 mg / ml, such as from about 10 mg / mlto about 50 mg / ml, such as from about 20 mg / ml to about 40 mg / ml, or a concentration of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg / ml. In said composition, the castor oil and / or palm oil in some embodiments is inan amount ranging from about 50% - 95% v / v, such as from about 60% - 90% v / v, suchas from 70% – 80% v / v.In said composition, the dimethyl sulfoxide or dimethyl isosorbide in someembodiments is in an amount ranging from about 5% – 30% v / v, such as from about7% - 25% v / v, such as from 10% – 20% v / v.One embodiment of a composition comprising acetylsalicylic acid, at least onecompound of Formula (I), a first excipient, and a second excipient, is a composition comprising: (i) acetylsalicylic acid in a concentration ranging from about 30 mg / ml toabout 100 mg / ml, (ii) lidocaine,(iii) optionally ropivacaine or bupivacaine,(iv) dimethyl sulfoxide, or dimethyl isosorbide, in an amount ranging fromabout 5% - 30% v / v, and(v) castor oil and / or palm oil in an amount ranging from about 70% - 95%v / v. In said composition, the concentration of lidocaine in some embodiments is from about 1 mg / ml to about 60 mg / ml, such as from about 10 mg / ml to about 50 mg / ml, such as from about 20 mg / ml to about 40 mg / ml, or a concentration of about 1, 5, 10,15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg / ml.In said composition, the concentration of ropivacaine, if present, in some embodiments is from about 1 mg / ml to about 60 mg / ml, such as from about 10 mg / ml to about 50 mg / ml, such as from about 20 mg / ml to about 40 mg / ml, or a concentration of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg / ml. In said composition, the concentration of bupivacaine, if present, in some embodiments is from about 1 mg / ml to about 60 mg / ml, such as from about 10 mg / ml to about 50 mg / ml, such as from about 20 mg / ml to about 40 mg / ml, or a concentration of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg / ml. Afurther embodiment of a composition comprising acetylsalicylic acid, at leastone compound of Formula (I), a first excipient, a second excipient, and a third excipient, is a composition comprising: (i) acetylsalicylic acid,(ii) lidocaine,(ii) dimethyl sulfoxide, or dimethyl isosorbide, in an amount ranging fromabout 5% - 30% v / v, and(iv) castor oil and / or palm oil in an amount ranging from about 50% - 95%v / v. In said composition, the concentration of acetylsalicylic acid in some embodiments is from about 0.25 mg / ml to about 150 mg / ml, such as from about 1 mg / ml to about 100 mg / ml, such as from about 20 mg / ml to about 80mg / ml, such as from about 40 mg / ml to about 60mg / ml, or from about 0.25 mg / ml to about 20 mg / ml, such as from about 1 mg / ml to about 15 mg / ml, such as from about 6 to about 12 mg / ml, such as from about 8 to about 10 mg / ml. In said composition, the concentration of lidocaine in some embodiments is from about 1 mg / ml to about 60 mg / ml, such as from about 10 mg / ml to about 50 mg / ml, such as from about 20 mg / ml to about 40 mg / ml, or a concentration of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg / ml. Afurther embodiment of a composition comprising acetylsalicylic acid, at leastone compound of Formula (I), a first excipient, a second excipient, and a third excipient, is a composition comprising: (i) acetylsalicylic acid in an amount ranging from 30 mg / ml – 100mg / ml,(ii) lidocaine in an amount ranging from 1 mg / ml – 60 mg / ml,(ii) dimethyl sulfoxide in an amount ranging from about 5% - 30% v / v, and(iv) castor oil in an amount ranging from about 50% - 95% v / v.In said composition, the concentration of acetylsalicylic acid in some embodiments is from about 40 mg / ml to about 60mg / ml. In said composition, the concentration of lidocaine in some embodiments is from about 10 mg / ml to about 50 mg / ml, such as from about 20 mg / ml to about 40 mg / ml, or a concentration of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg / ml. In said composition, the castor oil in some embodiments is in an amount rangingfrom about 60% - 90% v / v, such as from 70% – 80% v / v.In said composition, the dimethyl sulfoxide in some embodiments is in anamount ranging from about 7% - 25% v / v, such as from 10% – 20% v / v.Another embodiment of a composition comprising acetylsalicylic acid, at leasttwo compounds of Formula (I), a first excipient, a second excipient, and a third excipient, is a composition comprising: (i) acetylsalicylic acid,(ii) lidocaine,(iii) ropivacaine,(iv) dimethyl isosorbide,(v) 1-methoxy-2-propanol or white soft paraffin, and(vi) propylene glycol.In said composition, the concentration of acetylsalicylic acid in someembodiments is from about 0.25 mg / ml to about 150 mg / ml, such as from about 1mg / ml to about 100 mg / ml, such as from about 20 mg / ml to about 80mg / ml, such as from about 40 mg / ml to about 60mg / ml, or form about 0.25 mg / ml to about 20 mg / ml, such as from about 1 mg / ml to about 15 mg / ml, such as from about 6 to about 12 mg / ml, such as from about 8 to about 10 mg / ml. In said composition, the concentration of lidocaine in some embodiments is from about 1 mg / ml to about 60 mg / ml, such as from about 10 mg / ml to about 50 mg / ml, such as from about 20 mg / ml to about 40 mg / ml, or a concentration of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg / ml. In said composition, the concentration of ropivacaine in some embodiments is from about 1 mg / ml to about 60 mg / ml, such as from about 10 mg / ml to about 50 mg / ml, such as from about 20 mg / ml to about 40 mg / ml, or a concentration of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg / ml. In said composition, the dimethyl isosorbide in some embodiments is in anamount ranging from about 5% – 30% v / v, such as from about 7% - 25% v / v, such asfrom 10% – 20% v / v.Yet another embodiment of a composition comprising acetylsalicylic acid, atleast two compounds of Formula (I), a first excipient, a second excipient, and a third excipient, is a composition comprising: (i) acetylsalicylic acid,(ii) lidocaine,(iii) ropivacaine,(iv) N,N-dimethylacetamide,(v) glycerol, and(vi) propylene glycol. In said composition, the concentration of acetylsalicylic acid in someembodiments is from about 0.25 mg / ml to about 150 mg / ml, such as from about 1mg / ml to about 100 mg / ml, such as from about 20 mg / ml to about 80mg / ml, such as from about 40 mg / ml to about 60mg / ml, or from about 0.25 mg / ml to about 20 mg / ml, such as from about 1 mg / ml to about 15 mg / ml, such as from about 6 to about 12 mg / ml, such as from about 8 to about 10 mg / ml. In said composition, the concentration of lidocaine in some embodiments is from about 1 mg / ml to about 60 mg / ml, such as from about 10 mg / ml to about 50 mg / ml, such as from about 20 mg / ml to about 40 mg / ml, or a concentration of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg / ml. In said composition, the concentration of ropivacaine in some embodiments is from about 1 mg / ml to about 60 mg / ml, such as from about 10 mg / ml to about 50 mg / ml, such as from about 20 mg / ml to about 40 mg / ml, or a concentration of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg / ml. The present invention further provides a product comprising any one of the herein disclosed compositions. The composition may be integrated in an article or delivery system. Non-limiting examples of articles or delivery systems include a roll-on product, a spray, a foam, a stick, a capsule, a salve, an ointment, and a balm. The article or delivery system may be a woven or non-woven article or delivery system. A non-limiting example of a woven or non-woven article or delivery system is a wet wipe. Another non-limiting example of a woven or non-woven article or delivery system is a patch, a band-Aid, or a plaster, such as an adhesive plaster. Further provided is a kit of parts, comprising the above-disclosed product and a packaging. The product may be contained in the packaging under an inert atmosphere. Theinert atmosphere may be provided by an inert gas, such as nitrogen, helium, or argon.A currently preferred, non-limiting example of an inert gas is nitrogen. Any one of the herein disclosed compositions may be for use as a medicament. More particularly, any one of the compositions for use as a medicament may be for use by cutaneous administration on human skin. Any one of the herein disclosed compositions may be for use in therapy by cutaneous administration. Any one of the herein disclosed compositions may be for use in the treatmentof skin irritation in a human.The term “skin irritation” is intended to include, but not to be limited to,irritation manifesting itself in the form of inflammation, pain, and / or itching of the skin.Accordingly, the herein disclosed compositions may be used as an anti-inflammatory, analgesic (i.e., painkilling, or pain-relieving), and / or antipruritic (i.e.,anti-itching, or itch-relieving) agent.The skin irritation may be caused by a poisonous plant, a poisonous animal, aninsect bite, an insect sting, a scratch, a dermatological disorder, such as eczema or cold sores, or a burn, such as sunburn. Non-limiting examples of poisonous plants are stinging nettle, poison ivy,Australian stinging tree, and poison hemlock. Non-limiting examples of poisonous animals are stinging jellyfish, scorpion,poisonous spider, and poisonous insect. The compositions may be for use in the treatment of skin irritation by cutaneousadministration, in particular by administration locally at the site of skin irritation. The skin irritation to be treated may be located in the epidermis.To treat skin irritation in a human, any one of the herein disclosed compositionsmay be administered in one single application or in multiple applications, depending onthe cause of the skin irritation and / or the severity of the skin irritation. For example, causes which normally generate skin irritation for 1-2 days ifuntreated, such as certain poisonous plants and poisonous animals, may require a higher number of applications than causes which normally generate skin irritation for less than a day, such as a scratch or a mild eczema. In general, a composition comprising acetylsalicylic acid but not comprisingany amino amide local anaesthetic may require a higher number of applications than acomposition comprising both acetylsalicylic acid and one or more amino amide local anaesthetics, since acetylsalicylic acid has a shorter duration of action than most amino amide local anaesthetics. The present invention further provides a method for the treatment of skin irritation in a human, comprising administering any one of the herein disclosed compositions to said human. In particular, the composition may be administered locally at the site of skin irritation. More particularly, the composition may be administered cutaneously. The present invention also provides a method for manufacturing of a composition, comprising: dissolving acetylsalicylic acid, or a functional derivative thereof, in a non- aqueous solvent having a dielectric constant of at least 10 at 25 °C, thereby obtaining a liquid solution of acetylsalicylic acid or the functional derivative thereof, mixing said liquid solution with at least one non-aqueous carrier,thereby obtaining the composition.The thus obtained composition may be in liquid form. The thus obtained composition may be essentially water-free. The definition, description, and examples of the non-aqueous solvents provided further above, in relation to the herein disclosed compositions, are applicable also to the non-aqueous solvent used in the method for manufacture. The definition, description, and examples of the non-aqueous carriers provided further above, in relation to the herein disclosed compositions, are applicable also to the non-aqueous carrier used in the method for manufacture.The herein disclosed method for manufacturing of a composition maycomprise: dissolving acetylsalicylic acid, or a functional derivative thereof, in a non- aqueous solvent having a dielectric constant of at least 10 at 25 °C, optionally wherein the non-aqueous solvent is selected from a group of physiologically acceptable non-aqueous solvents comprising dimethyl sulfoxide(DMSO), dimethyl isosorbide (DMI), N,N-dimethylacetamide (NNDMA), formicacid, dihydrolevoglucosenone, and cyclopentyl methyl ether (CPME), optionally with the provision that the non-aqueous solvent is not selected from methanol, ethanol, or isopropanol,thereby obtaining a liquid solution comprising acetylsalicylic acid, or the functionalderivative thereof, mixing said liquid solution with at least one non-aqueous carrier, optionally wherein the at least one non-aqueous carrier is selected from a group of physiologically acceptable non-aqueous carriers comprising castor oil, mineral oil,coconut oil, palm oil, soyabean oil, canola oil, olive oil, diethylene glycol monoethylether, polyethylene glycol (PEG), benzyl alcohol, propylene glycol, oleic acid, stearic acid, isopropyl myristate, isopropyl palmitate, stearyl alcohol, squalene, squalane, 1- methoxy-2-propanol, waxes, paraffins, and gums, thereby obtaining a composition. Said composition may optionally be mixed with one or more excipientsselected from a group of penetration enhancers. The penetration enhancer may be selected from an anionic surfactant, a cationic surfactant, a zwitterionic surfactant, a non-ionic surfactant, a fatty acid, afatty ester, or a fatty amine. The definition, description and examples of penetrationenhancers given further above in relation to the herein disclosed compositions are relevant also in relation to the method for manufacturing of a composition. The method for manufacture may further comprise dissolving at least one compound of Formula (I), (I) wherein: R1is H or C1-2-alkyl, R2is H or C1-2-alkyl, or R1and R2together with the atoms to which they are attached form a piperidyl heterocycle; R3is C1-4-alkyl, and R4is H or CH3, in a non-aqueous solvent having a dielectric constant of at least 10 at 25 °C, optionally wherein the non-aqueous solvent is selected from a group of physiologically acceptable non-aqueous solvents comprising dimethyl sulfoxide(DMSO), dimethyl isosorbide (DMI), N,N-dimethylacetamide (NNDMA), formicacid, dihydrolevoglucosenone, and cyclopentyl methyl ether (CPME), optionally with the provision that the non-aqueous solvent is not selected from methanol, ethanol, or isopropanol,thereby obtaining a liquid solution comprising the compound of Formula (I),mixing said liquid solution with the liquid solution comprising acetylsalicylic acid or the functional derivative thereof, thereby obtaining a liquid solution comprising acetylsalicylic acid, or the functional derivative thereof, and the compound of Formula (I), mixing said liquid solution with the at least one non-aqueous carrier, thereby obtaining the composition. The method for manufacture may further comprise dissolving acetylsalicylic acid and at least one compound of Formula (I), (I) wherein: R1is H or C1-2-alkyl, R2is H or C1-2-alkyl, or R1and R2together with the atoms to which they are attached form a piperidyl heterocycle; R3is C1-4-alkyl, and R4is H or CH3, in a non-aqueous solvent having a dielectric constant of at least 10 at 25 °C, optionally wherein the non-aqueous solvent is selected from a group of physiologically acceptable non-aqueous solvents comprising dimethyl sulfoxide(DMSO), dimethyl isosorbide (DMI), N,N-dimethylacetamide (NNDMA), formicacid, dihydrolevoglucosenone, and cyclopentyl methyl ether (CPME),optionally with the provision that the non-aqueous solvent is not selected from methanol, ethanol, or isopropanol, thereby obtaining a liquid solution comprising acetylsalicylic acid, or the functional derivative thereof, and the compound of Formula (I), mixing said liquid solution with the at least one non-aqueous carrier, thereby obtaining the composition. The at least one compound of Formula (I) may be selected from lidocaine,bupivacaine, ropivacaine, mepivacaine, prilocaine, etidocaine, and levobupivacaine. As described further above, lidocaine, bupivacaine, ropivacaine, mepivacaine,prilocaine, etidocaine, and levobupivacaine all belong to a group of amino amide localanaesthetics. Accordingly, the method for manufacturing of the composition mayalternatively comprise dissolving at least one compound selected from a group ofamino amide local anaesthetics, thereby obtaining a liquid solution comprising the at least one amino amide local anaesthetic, mixing said liquid solution with the liquid solution comprising acetylsalicylic acid or the functional derivative thereof, thereby obtaining a liquid solution comprising acetylsalicylic acid, or the functional derivative thereof, and the at least one amino amide local anaesthetic, mixing said liquid solution with the at least one non-aqueous carrier, thereby obtaining the composition. If two or more non-aqueous carrier is used in the method for manufacturing of a composition, the two or more non-aqueous carriers may be mixed before mixing the resulting carrier mixture with the liquid solution comprising acetylsalicylic acid, or a functional derivative thereof, and optionally further comprising at least one compound of Formula (I) or an amino amide local anaesthetic. The concentration of acetylsalicylic acid, in the composition manufactured by said method, may be from about 0.25 mg / ml to about 150 mg / ml, such as from about 1 mg / ml to about 100 mg / ml, such as from about 20 mg / ml to about 80mg / ml, such as from about 40 mg / ml to about 60mg / ml, or from about 0.25 mg / ml to about 20 mg / ml, such as from about 1 mg / ml to about 15 mg / ml, such as from about 6 to about 12 mg / ml, such as from about 8 to about 10 mg / ml. If present in the composition manufactured by said method, the concentration of the amino amide local anaesthetic, such as the compound of Formula (I), may be from about 1 mg / ml to about 60 mg / ml, such as from about 10 mg / ml to about 50 mg / ml, such as from about 20 mg / ml to about 40 mg / ml, or a concentration of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg / ml. Herein, use of the verb “to comprise” and its conjugations does not exclude thepresence of elements or steps other than those stated. Further, the article “a” or “an”preceding an element does not exclude the presence of a plurality of such elements. EXPERIMENTAL SECTIONExample 1: ASA formulated with solvent DMSO and carrier castor oil0.1 g acetylsalicylic acid (ASA) was dissolved in 10 ml dimethyl sulfoxide(DMSO) to prepare a liquid solution of acetylsalicylic acid at a concentration of 10mg / ml of acetylsalicylic acid. The liquid solution of acetylsalicylic acid was then mixedwith 90 ml castor oil to prepare a composition in the form of an ointment, suitable forcutaneous application. The ointment was stored in a sealed, coloured glass bottle atroom temperature and at 40°C, respectively. 100 µl samples were collected at differenttime points post preparation. 50-time dilutions in acetonitrile were subjected to High-Performance Liquid Chromatography (HPLC) analysis. Stability of acetylsalicylic acidin the composition is shown in Fig. 1. More particularly, Fig. 1 shows the amount ofacetylsalicylic acid (ASA) in the ointment, at multiple time points after preparation, atroom temperature (RT), and at 40 °C, respectively. Data is represented as the percentageof the amount of ASA at day 0 right after preparation (Mean ± SD, n=3).Example 2: ASA and local anaesthetics formulated with solvent DMSO andcarrier castor oil 0.4 g acetylsalicylic acid (ASA) was dissolved in 10 ml dimethyl sulfoxide(DMSO) to prepare a liquid solution of acetylsalicylic acid at a concentration of 40mg / ml of acetylsalicylic acid. Similarly, 0.4 g lidocaine, 0.4 g ropivacaine and 0.4 gbupivacaine were each dissolved in 10 ml dimethyl sulfoxide (DMSO) to prepare aliquid solution of lidocaine, ropivacaine and bupivacaine, respectively, at aconcentration of 40 mg / ml of each. The thus prepared four different types of liquidsolution were then mixed at a ratio of 1:1:1:1, to prepare a mixed liquid solutioncontaining acetylsalicylic acid, lidocaine, ropivacaine and bupivacaine at aconcentration of 10 mg / ml of each. Subsequently, 10 ml of the thus prepared mixedliquid solution was mixed with 90 ml castor oil to prepare a composition in the form ofan ointment, suitable for cutaneous application. The ointment was stored in a sealed,coloured glass bottle at room temperature and at 40°C, respectively. 100 µl sampleswere collected at different time points post preparation.50-time dilutions in acetonitrilewere subjected to HPLC analysis. Stability of acetylsalicylic acid in the composition isshown in Fig. 2. More particularly, Fig. 2A shows the amount of acetylsalicylic acid(ASA) in the ointment, at multiple time points after preparation, at room temperature(RT). Fig. 2B shows the amount of acetylsalicylic acid (ASA) in the ointment, atmultiple time points after preparation, at 40°C. Data is represented as the percentage ofthe amount of ASA at day 0 right after preparation (Mean ± SD, n=3). The stability oflidocaine, ropivacaine, and bupivacaine in the composition was excellent, the amountof each being above 90% at 30 days and above 85% at 57 days post preparation (datanot shown).Example 3: ASA and local anaesthetics formulated with solvent DMSO andcarriers diethylene glycol monoethyl ether and castor oil 0.4 g acetylsalicylic acid (ASA) was dissolved in 10 ml dimethyl sulfoxide(DMSO) to prepare a liquid solution of acetylsalicylic acid at a concentration of 40mg / ml of acetylsalicylic acid. Similarly, 0.4 g lidocaine, 0.4 g ropivacaine and 0.4 gbupivacaine were each dissolved in 10 ml dimethyl sulfoxide (DMSO) to prepare aliquid solution of lidocaine, ropivacaine and bupivacaine, respectively, at aconcentration of 40 mg / ml of each. The thus prepared four different types of liquidsolution were then mixed at a ratio of 1:1:1:1, to prepare a mixed liquid solutioncontaining acetylsalicylic acid, lidocaine, ropivacaine and bupivacaine at aconcentration of 10 mg / ml of each. Subsequently, 10 ml of the thus prepared mixedliquid solution was mixed with 10 ml diethylene glycol monoethyl ether and 80 mlcastor oil to prepare a composition in the form of an ointment, suitable for cutaneousapplication. The ointment was stored in a sealed, coloured glass bottle at roomtemperature and at 40 °C, respectively. 100 µl samples were collected at different timepoints post preparation. 50-time dilutions in acetonitrile were subjected to HPLCanalysis. Stability of acetylsalicylic acid in the composition is shown in Fig. 3. Moreparticularly, Fig. 3A shows the amount of acetylsalicylic acid (ASA) in the ointment,at multiple time points after preparation, at room temperature (RT). Fig. 3B shows theamount of acetylsalicylic acid (ASA) in the ointment, at multiple time points after preparation, at 40°C. Data is represented as the percentage of the amount of ASA at day 0 right after preparation (Mean ± SD, n=3).Example 4: Solvent ethanol – comparative exampleFor comparison, each of acetylsalicylic acid, lidocaine, ropivacaine, andbupivacaine, was dissolved separately in ethanol (conc. 99.5%), and the resulting fourliquid solutions were combined into one liquid solution.9 ml of said liquid solution was mixed with 0.5 ml glycerol and 0.5 ml isopropanol (conc. 99.9%). The resultingcomposition was stored in a sealed, coloured glass bottle at room temperature. 100 µlsamples were collected at different time points post preparation. 50-time dilutions inacetonitrile were subjected to HPLC analysis. Stability of acetylsalicylic acid in thecomposition is shown in Fig. 4. The half-life of acetylsalicylic acid was only 67.06hours when using ethanol as the solvent. Thus, it is shown that ethanol is not a suitablesolvent for stabilising acetylsalicylic acid.Example 5: Solvent DMSO, no carrier – comparative exampleFor comparison, 25 mg acetylsalicylic acid was dissolved in 1 ml DMSO. The resulting liquid solution was not mixed with any non-aqueous carrier but was stored in a sealed, coloured glass bottle at room temperature. 100 µl samples were collected atdifferent time points post preparation. 50-time dilutions in acetonitrile were subjectedto HPLC analysis. Stability of acetylsalicylic acid in the composition is shown in Fig.5. At 30 days post preparation, about 60% of the original amount of acetylsalicylic acid remained in the liquid solution. Accordingly, the acetylsalicylic acid degraded morequickly in DMSO (a non-aqueous solvent which fulfils the requirements as definedherein) alone, than when formulated in a mixture of DMSO and one or more non-aqueous carriers fulfilling the requirements as defined herein (see Examples 1-3).Example 6: Solvent ethyl acetate – comparative exampleFor comparison, acetylsalicylic acid (ASA) was dissolved in ethyl acetate andthe resulting liquid solution was mixed with propylene glycol at a ratio of: (a) 1:9 of ethyl acetate to propylene glycol, and (b) 1:4 of ethyl acetate to propylene glycol, respectively.The two compositions were stored in sealed, coloured glass bottles at room temperature,and at 40 °C, respectively. 100 µl samples were collected at different time points postpreparation. 50-time dilutions in acetonitrile were subjected to HPLC analysis. Stabilityof acetylsalicylic acid in the two compositions is shown in Fig. 6. More particularly,the amount of ASA in the composition containing 10% ethyl acetate and 90% propyleneglycol at two time points after preparation, at room temperature (RT) and at 40 °C, isshown in Fig.6A, while the amount of ASA in the composition containing 20% ethylacetate and 80% propylene glycol at two time points after preparation, at roomtemperature (RT) and at 40 °C, is shown in Fig. 6B. In conclusion, the half-life of acetylsalicylic acid was less than 50 hours when dissolving it in ethyl acetate (dielectric constant <10, relative polarity <0.3, i.e., a solvent which does not fulfil the requirements of non-aqueous solvents as defined herein), although the composition also contained a high percentage of propylene glycol, which is a non-aqueous carrier fulfilling the requirements as defined herein. Example 7 Compositions comprising acetylsalicylic acid and two amino amide localanaesthetics are prepared as in Examples 2-3 above, with the following variations (a)-(g) of components:(a) Acetylsalicylic acid 10 mgLidocaine 10 mgRopivacaine 10 mg Dimethyl sulfoxide (DMSO) 1 mlCastor oil 9 mlOleic acid 1 mgOleic acid, which is in solid form at room temperature, is either dissolved in the non- aqueous solvent used (here, DMSO), or is heated until in liquid form, after which it is added to the liquid mixture. (b) Acetylsalicylic acid 10 mgLidocaine 10 mgRopivacaine 10 mg Dimethyl sulfoxide (DMSO) 1 mlCastor oil 5 mlPalm oil 4 mlOleic acid 1 mg(c) Acetylsalicylic acid 10 mgLidocaine 10 mgBupivacaine 10 mgDimethyl sulfoxide (DMSO) 1 mlCastor oil 9 mlOleic acid 1 mg(d) Acetylsalicylic acid 10 mgLidocaine 10 mgRopivacaine 10 mg Dimethyl isosorbide (DMI) 1 mlCastor oil 9 mlOleic acid 1 mg Acetylsalicylic acid 10 mgLidocaine 10 mgRopivacaine 10 mg Dimethyl isosorbide (DMI) 1 ml1-methoxy-2-propanol 8 mlPropylene glycol 1 ml (f) Acetylsalicylic acid 10 mgLidocaine 10 mgRopivacaine 10 mg Dimethyl isosorbide (DMI) 1 mlWhite soft paraffin 8 mlPropylene glycol 1 ml(g) Acetylsalicylic acid 10 mgLidocaine 10 mgRopivacaine 10 mg N,N-dimethylacetamide (NNDMA) 1 mlGlycerol 5 mlPropylene glycol 4 mlExample 8: ASA and local anaesthetics formulated with solvent DMSO and fourdifferent oils0.4 g acetylsalicylic acid (ASA) was dissolved in 10 ml dimethyl sulfoxide(DMSO) to prepare a liquid solution of acetylsalicylic acid at a concentration of 40mg / ml of acetylsalicylic acid. Similarly, 0.4 g lidocaine, 0.4 g ropivacaine and 0.4 gbupivacaine were each dissolved in 10 ml dimethyl sulfoxide (DMSO) to prepare aliquid solution of lidocaine, ropivacaine and bupivacaine, respectively, at aconcentration of 40 mg / ml of each. The thus prepared four different types of liquidsolution were then mixed at a ratio of 1:1:1:1, to prepare a mixed liquid solutioncontaining acetylsalicylic acid, lidocaine, ropivacaine and bupivacaine at aconcentration of 10 mg / ml of each. Subsequently, 10 ml of the thus prepared mixedliquid solution was mixed with the following oils to prepare a composition in the formof an ointment, suitable for cutaneous application:10% DMSO + 90% Castor oil 20% DMSO + 80% Castor oil 10% DMSO + 45% Castor oil + 45% Soybean oil 20% DMSO + 40% Castor oil + 40% Soybean oil The ointment was stored in a sealed, coloured glass bottle at room temperature and at40 °C, respectively. 100 µl samples were collected at different time points postpreparation. 50-time dilutions in acetonitrile were subjected to HPLC analysis. Stabilityof acetylsalicylic acid in the composition is shown in Table 1 below:Room Temp Half Life ASA 40ºC half life ASA10% DMSO + 90% Castor oil 271 days 103 days20% DMSO + 80% Castor oil 250 days 73 days10% DMSO + 45% Castor oil580 days 47 days+ 45% Soybean oil 20% DMSO + 40% Castor oil176 days 39 days+ 40% Soybean oil Ropivacaine, bupivacaine and lidocaine showed higher stability in DMSO / Castor oil compared with DMSO / Castor oil / soybean oil with half-lives of 600, 1689 and > 1500 days at 40oC in (DMSO / Castor oil) for Bup, Rup and Lido, respectively, Half-lives of 257, 302 and 575 days at 40oC in (DMSO / Castor oil / Soybean oil) for Bup, Rop and Lido respectively.The formulation containing 10% DMSO + 90% Castor oil was further tested at +4ºCunder otherwise the same experimental conditions as described above and it was found that the ASA had a half-life of 305 days at +4ºC, whilst the half-lives for Lidocaine and Bupivacaine were found to be over 600 days at +4ºC. The above embodiments are to be understood as illustrative examples of the invention. Further embodiments of the invention are envisaged. For example, it isforeseen that other combinations of the excipients as disclosed herein may be as usefulas the specific combinations described above. It is to be understood that any featuredescribed in relation to any one embodiment may be used alone, or in combination with other features described, and may also be used in combination with one or more features of any other of the embodiments, or any combination of any other of the embodiments. Furthermore, equivalents and modifications not described above may also be employed without departing from the scope of the invention, which is defined in the accompanying claims. REFERENCES US5736126 WO0245687 A2WO0078354 A1https: / / www.britannica.com / science / dielectric-constantReichardt C., Chem. Rev. 1994, 94, 8, 2319–2358https: / / www.sciencedirect.com / topics / chemistry / octanol-water-partition-coefficient

Claims

CLAIMS1. A composition comprising acetylsalicylic acid, or a functional derivativethereof, and further comprising a first and a second excipient, wherein the first excipient is a non-aqueous solvent, and the second excipient is a non-aqueous carrier, wherein the composition is in liquid form and essentially water-free.

2. The composition according to claim 1, wherein the non-aqueous solvent has adielectric constant of at least 10 at 25 °C, optionally wherein the non-aqueous solvent is selected from a group of physiologically acceptable non-aqueous solvents comprising dimethyl sulfoxide(DMSO), dimethyl isosorbide (DMI), N,N-dimethylacetamide (NNDMA), formicacid, dihydrolevoglucosenone, and cyclopentyl methyl ether (CPME), optionally with the provision that the non-aqueous solvent is not selected from methanol, ethanol, or isopropanol.

3. The composition according to claim 1 or 2, wherein the non-aqueous carrier isa physiologically acceptable non-aqueous carrier, optionally wherein the non-aqueous carrier is selected from a group of physiologically acceptable non-aqueous carriers comprising castor oil, mineral oil, coconut oil, palmoil, soyabean oil, canola oil, olive oil, diethylene glycol monoethyl ether,polyethylene glycol (PEG), benzyl alcohol, propylene glycol, oleic acid, stearic acid, isopropyl myristate, isopropyl palmitate, stearyl alcohol, squalene, squalane, 1- methoxy-2-propanol, waxes, paraffins, and gums.

4. The composition according to any one of claims 1-3, further comprising a third excipient which is a non-aqueous carrier, optionally wherein the third excipient is selected from a group of physiologically acceptable non-aqueous carriers comprising castor oil, mineral oil, coconut oil, palmoil, soyabean oil, canola oil, olive oil, diethylene glycol monoethyl ether,polyethylene glycol (PEG), benzyl alcohol, propylene glycol, oleic acid, stearic acid, isopropyl myristate, isopropyl palmitate, stearyl alcohol, squalene, squalane, 1- methoxy-2-propanol, waxes, paraffins, and gums.

5. The composition according to any one of claims 1-4, comprising:(i) acetylsalicylic acid,(ii) dimethyl sulfoxide, and(iii) castor oil,optionally wherein the concentration of acetylsalicylic acid is from about 0.25 mg / ml to about 150 mg / ml, such as from about 1 mg / ml to about 100 mg / ml, such as from about 20 mg / ml to about 80mg / ml, such as from about 40 mg / ml to about 60mg / ml.

6. The composition according to any one of claims 1-5, further comprising one or more excipients selected from a group of penetration enhancers, such as an anionic surfactant, a cationic surfactant, a zwitterionic surfactant, a non-ionic surfactant, a fatty acid, a fatty ester, and a fatty amine.

7. The composition according to any one of claims 1-6, further comprising atleast one compound of Formula (I),wherein: R1is H or C1-2-alkyl, R2is H or C1-2-alkyl, or R1and R2together with the atoms to which they are attached form a piperidyl heterocycle; R3is C1-4-alkyl, and R4is H or CH3, optionally wherein the at least one compound of Formula (I) is selected from lidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine, etidocaine, and levobupivacaine.

8. A composition comprising acetylsalicylic acid, or a functional derivativethereof, and further comprising at least two compounds of Formula (I),(I) wherein: R1is H or C1-2-alkyl, R2is H or C1-2-alkyl, or R1and R2together with the atoms to which they are attached form a piperidyl heterocycle; R3is C1-4-alkyl, and R4is H or CH3, optionally wherein the at least two compounds of Formula (I) are selected from lidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine, etidocaine, and levobupivacaine, optionally wherein the composition is in liquid form and essentially water-free.

9. The composition according to any one of claims 1-8, wherein the compositionis in the form of: (i) a liquid under an inert atmosphere, or (ii) a nanoformulation, optionally a liposomal emulsion.

10. The composition according to any one of claims 1-9, comprising theacetylsalicylic acid or the functional derivative thereof at a concentration of from 0.25 mg / ml to about 150 mg / ml, such as from about 1 mg / ml to about 100 mg / ml, such as from about 20 mg / ml to about 80mg / ml, such as from about 40 mg / ml to about 60mg / ml.

11. The composition according to any one of claims 1-10, comprising:(i) acetylsalicylic acid,(ii) lidocaine,(iii) optionally ropivacaine or bupivacaine,(iv) dimethyl sulfoxide or dimethyl isosorbide,(v) castor oil and / or palm oil, and(vi) oleic acid,optionally wherein: the concentration of acetylsalicylic acid is from about 0.25 mg / ml to about 150 mg / ml, such as from about 1 mg / ml to about 100 mg / ml, such as from about 20 mg / ml to about 80mg / ml, such as from about 40 mg / ml to about 60mg / ml, the concentration of lidocaine is from about 1 mg / ml to about 60 mg / ml, the concentration of ropivacaine, when present, is from about 1 mg / ml to about60 mg / ml, and / or the concentration of bupivacaine, when present, is from about 1 mg / ml toabout 60 mg / ml.

12. The composition according to any one of claims 1-10, comprising: (i) acetylsalicylic acid,(ii) lidocaine,(iii) ropivacaine,(iv) dimethyl isosorbide,(v) 1-methoxy-2-propanol or white soft paraffin, and(vi) propylene glycol,optionally wherein: the concentration of acetylsalicylic acid is from about 0.25 mg / ml to about 150 mg / ml, such as from about 1 mg / ml to about 100 mg / ml, such as from about 20 mg / ml to about 80mg / ml, such as from about 40 mg / ml to about 60mg / ml, the concentration of lidocaine is from about 1 mg / ml to about 60 mg / ml, and / or the concentration of ropivacaine is from about 1 mg / ml to about 60 mg / ml.

13. The composition according to any one of claims 1-10, comprising:(i) acetylsalicylic acid,(ii) lidocaine,(iii) ropivacaine,(iv) N,N-dimethylacetamide,(v) glycerol, and(vi) propylene glycol,optionally wherein: the concentration of acetylsalicylic acid is from about 0.25 mg / ml to about 150 mg / ml, such as from about 1 mg / ml to about 100 mg / ml, such as from about 20 mg / ml to about 80mg / ml, such as from about 40 mg / ml to about 60mg / ml, the concentration of lidocaine is from about 1 mg / ml to about 60 mg / ml, and / or the concentration of ropivacaine is from about 1 mg / ml to about 60 mg / ml.

14. A product comprising the composition according to any one of claims 1-13,optionally wherein the composition is integrated in an article or delivery system, such as a woven or non-woven article or delivery system, a roll-on product, a spray, a foam, a stick, a capsule, a salve, an ointment, or a balm, optionally wherein the woven or non-woven article or delivery system is a wet wipe.

15. A kit of parts comprising the product according to claim 14 and a packaging, wherein the product is contained in the packaging under an inert atmosphere, optionally wherein the inert atmosphere is provided by an inert gas, such as nitrogen, helium, or argon.

16. The composition according to any one of claims 1-13 for use as a medicament.

17. The composition for use according to claim 16, wherein the composition is for use by cutaneous administration on human skin.

18. The composition according to any one of claims 1-13 for use in therapy bycutaneous administration.

19. The composition according to any one of claims 1-13 for use in the treatmentof skin irritation in a human, optionally wherein the skin irritation is caused by a poisonous plant, a poisonous animal, an insect bite, an insect sting, a burn, a scratch, or a dermatological disorder, such as eczema or cold sores, optionally wherein the composition is administered locally at the site of skin irritation.

20. A method for the treatment of skin irritation in a human, comprising administering the composition according to any one of claims 1-13 to said human,optionally locally at the site of skin irritation, optionally wherein the composition is administered cutaneously.

21. A method for manufacturing of a composition, comprising:dissolving acetylsalicylic acid, or a functional derivative thereof, in a non- aqueous solvent having a dielectric constant of at least 10 at 25 °C, optionally wherein the non-aqueous solvent is selected from a group of physiologically acceptable non-aqueous solvents comprising dimethyl sulfoxide(DMSO), dimethyl isosorbide (DMI), N,N-dimethylacetamide (NNDMA), formicacid, dihydrolevoglucosenone, and cyclopentyl methyl ether (CPME), optionally with the provision that the non-aqueous solvent is not selected from methanol, ethanol, or isopropanol, thereby obtaining a liquid solution comprising acetylsalicylic acid or the functional derivative thereof, mixing said liquid solution with at least one non-aqueous carrier, optionally wherein the at least one non-aqueous carrier is selected from a group of physiologically acceptable non-aqueous carriers comprising castor oil, mineral oil,coconut oil, palm oil, soyabean oil, canola oil, olive oil, diethylene glycol monoethylether, polyethylene glycol (PEG), benzyl alcohol, propylene glycol, oleic acid, stearic acid, isopropyl myristate, isopropyl palmitate, stearyl alcohol, squalene, squalane, 1- methoxy-2-propanol, waxes, paraffins, and gums, thereby obtaining a composition, optionally mixing said composition with one or more excipients selected from a group of penetration enhancers, optionally wherein the penetration enhancer is selected from an anionic surfactant, a cationic surfactant, a zwitterionic surfactant, a non-ionic surfactant, a fatty acid, a fatty ester, or a fatty amine.

22. The method according to claim 21, comprising dissolving acetylsalicylic acidand at least one compound of Formula (I),(I) wherein: R1is H or C1-2-alkyl, R2is H or C1-2-alkyl, or R1and R2together with the atoms to which they are attached form a piperidyl heterocycle; R3is C1-4-alkyl, and R4is H or CH3,in the non-aqueous solvent having a dielectric constant of at least 10 at 25 °C, mixingsaid liquid solution with the at least one non-aqueous carrier, thereby obtaining the composition.

Images