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WO2025114578A1 - Composition et son utilisation comme médicament - Google Patents

Composition et son utilisation comme médicament Download PDF

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Publication number
WO2025114578A1
WO2025114578A1 PCT/EP2024/084182 EP2024084182W WO2025114578A1 WO 2025114578 A1 WO2025114578 A1 WO 2025114578A1 EP 2024084182 W EP2024084182 W EP 2024084182W WO 2025114578 A1 WO2025114578 A1 WO 2025114578A1
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Prior art keywords
composition
acetylsalicylic acid
optionally
concentration
oil
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Pending
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PCT/EP2024/084182
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English (en)
Inventor
Moustapha Mohamed Moustapha HASSAN
Ying Zhao
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Auxesis Pharma Holding Publ AB
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Auxesis Pharma Holding Publ AB
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Publication of WO2025114578A1 publication Critical patent/WO2025114578A1/fr
Pending legal-status Critical Current
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

Definitions

  • a COMPOSITION AND USE THEREOF AS A MEDICAMENT Technical Field T he present invention relates to the field of compositions comprising acetylsalicylic acid. More particularly, the invention provides stabilised liquid compositions comprising acetylsalicylic acid.
  • Background T here is a need in the art for over-the-counter pharmaceutical preparations that provide a quick pain-relieving effect on human skin and remove the pain by one single application on the skin, without also providing a systemic effect on the body.
  • Products available today are often based on the local anaesthetic lidocaine or hydrocortisone, and usually only provide a soothing, cooling, or comforting effect, or enter the bloodstream which may cause related adverse effects.
  • Lidocaine belongs to a specific class of local anaesthetics known as amino amide local anaesthetics. It has a rapid onset and a relatively short duration of action. Other members of this class include bupivacaine, levobupivacaine, ropivacaine, mepivacaine, prilocaine, articaine, and etidocaine. Bupivacaine is known for its long duration of action.
  • Levobupivacaine is the S-enantiomer of bupivacaine.
  • Ropivacaine is similar to bupivacaine but with a safer cardiovascular profile.
  • Mepivacaine has an intermediate duration of action.
  • Prilocaine is another amino amide local anaesthetic with a rapid onset of action.
  • Articaine is a relatively newer amino amide local anaesthetic, which also 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 history dating back to the use of willow bark in ancient times. Its primary known uses include pain 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 medication for 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 concerns such as insect bites and muscle pain. However, ASA is susceptible to hydrolysis, a process that breaks it down into acetic acid and salicylic acid (SA), which has irritant potential both when ingested and when applied on the skin. In aqueous environments, ASA can degrade almost entirely within a week.
  • SA salicylic acid
  • Various alternative liquid ASA formulations have been proposed, such as solutions in alcohols (see e.g., US5736126 and WO0245687 A2) and solutions comprising a particulate water-adsorber such as zeolite (see WO0078354 A1). Nevertheless, there is a continued need in the art for liquid ASA compositions which remain stable upon storage for prolonged periods of time.
  • Summary O ne object of the present invention is to provide liquid compositions comprising acetylsalicylic acid (ASA), which retain a significant amount of ASA for a significant amount of time, such as months or even years, thereby providing liquid ASA compositions offering a reasonable period of use to consumers.
  • ASA acetylsalicylic acid
  • 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-aqueous carrier, wherein the composition is in liquid form and essentially water-free.
  • Another object of the present invention is to provide a composition comprising acetylsalicylic acid (ASA) and one or more compounds providing a prolonged pain- reducing effect.
  • ASA acetylsalicylic acid
  • the present invention provides a composition comprising acetylsalicylic acid, or a functional derivative thereof, and further comprising at least one compounds of Formula (I), wherein: R 1 is H or C 1-2 -alkyl, R 2 is H or C 1-2 -alkyl, or R 1 and R 2 together with the atoms to which they are attached form a piperidyl heterocycle; R 3 is C 1-4 -alkyl, and R 4 is H or CH3.
  • T he 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.
  • the present invention is directed to the herein disclosed compositions for use as a medicament.
  • compositions are for use in therapy by cutaneous administration. Further, the compositions are for use in the treatment of skin irritation.
  • F urther 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.
  • F ig. 1 shows the stability of acetylsalicylic acid (ASA) in a composition further containing dimethyl sulfoxide and castor oil, at room temperature and at 40 oC.
  • Fig. 2 depicts the stability of ASA in a composition further containing three amino amide local anaesthetics, dimethyl sulfoxide, and castor oil, at room temperature (Fig.2A) and at 40 oC (Fig.2B).
  • Fig.2A shows the stability of ASA in a composition further containing three amino 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 three amino amide local anaesthetics, dimethyl sulfoxide, diethylene glycol monoethyl ether, and castor oil, at room temperature (Fig.3A) and at 40 oC (Fig.3B).
  • F ig. 4 is a graph showing the stability of ASA in a composition further containing three amino amide local anaesthetics, ethanol, glycerol, and isopropanol, at room temperature.
  • F ig. 5 is a graph depicting the stability of ASA in a composition further containing dimethyl sulfoxide, at room temperature.
  • FIG. 6 shows the stability of ASA in a composition further containing ethyl acetate 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.
  • the present invention solves or at least mitigates the problems associated with previously known liquid compositions comprising acetylsalicylic acid, by providing 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-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.
  • acetylsalicylic acid was not stabilised in the presence of ethanol, but instead quickly degraded (half-life about 67 h), although the composition also comprised non-aqueous carriers fulfilling the requirements as defined herein. Ethanol would not be a suitable non-aqueous solvent for the purpose of stabilising acetylsalicylic acid.
  • acetylsalicylic acid was quickly degraded (half-life of less than 50 h) in a composition containing a non-aqueous solvent which does not fulfil the requirements as defined herein and a non-aqueous carrier fulfilling the requirements as defined herein.
  • the term “functional derivative” is used herein to denote a modified version or analogue of a chemical compound that essentially retains the core biological or chemical activity of the original compound. Functional derivatives can take various forms, including salts, esters, prodrugs, isomers, analogues, or other chemical modifications.
  • T he term “functional derivative of acetylsalicylic acid” is defined as a physiologically tolerable, modified version of acetylsalicylic acid that retains the pain relieving and inflammation reducing activities of acetylsalicylic acid.
  • a functional derivative of acetylsalicylic acid may be selected from a physiologically tolerable prodrug (e.g., a glycol amide) or salt (e.g., a lysine salt) or ester form of acetylsalicylic acid or an analogue thereof, e.g., a 4- or 5-substituted, for example a 4- and/or 5-nitro and/or methoxy acetylsalicylic acid.
  • the functional derivative of acetylsalicylic is not salicylic acid. H erein, the term “non-aqueous” is intended to mean essentially water-free.
  • non-aqueous solvents non-aqueous carriers, and non-aqueous compositions, as described 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.
  • the composition comprises no detectable water when using standard industry techniques for detection of water.
  • T he non-aqueous solvent in some embodiments has a dielectric constant of at least 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 dielectric constant of at least 10 at 25 °C include dimethyl sulfoxide (DMSO) (dielectric constant of about 49 at 25 °C), formic acid (dielectric constant of about 51 at 25 °C), dimethyl isosorbide (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).
  • DMSO dimethyl sulfoxide
  • DMI dimethyl isosorbide
  • NBDMA N,N- dimethylacetamide
  • 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.
  • ethanol 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.
  • 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 ethanol.
  • 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.
  • 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.
  • 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.
  • 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 by performing the method described in https://www.britannica.com/science/dielectric- constant.
  • the solvent is selected from a group of non-aqueous solvents comprising dimethyl sulfoxide (DMSO), dimethyl isosorbide (DMI), N,N- dimethylacetamide (NNDMA), formic acid, dihydrolevoglucosenone, and cyclopentyl methyl ether (CPME), optionally with the provision that the non-aqueous solvent is not selected from methanol, ethanol, or isopropanol.
  • DMSO dimethyl sulfoxide
  • DMI dimethyl isosorbide
  • NNDMA N,N- dimethylacetamide
  • CPME cyclopentyl methyl ether
  • the solvent is selected from a group of non-aqueous solvents consisting of dimethyl sulfoxide (DMSO), dimethyl isosorbide (DMI), N,N- dimethylacetamide (NNDMA), formic acid, dihydrolevoglucosenone, and cyclopentyl methyl ether (CPME).
  • DMSO dimethyl sulfoxide
  • DI dimethyl isosorbide
  • NDMA N,N-dimethylacetamide
  • the solvent is formic acid.
  • the solvent is dihydrolevoglucosenone.
  • the solvent is cyclopentyl methyl ether (CPME).
  • the non-aqueous solvent may have a relative polarity of at least 0.3 relative to a value of 1 for water.
  • the non-aqueous solvent may 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).
  • a polar e.g., water
  • a non-polar e.g., tetramethylsilane, TMS
  • methanol, ethanol, and isopropanol are not suitable non-aqueous solvents for the purpose of the present invention, i.e., the purpose of stabilising acetylsalicylic acid in liquid compositions.
  • the present disclosure includes that the non-aqueous solvent may have a relative polarity of at least 0.3, 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. T he 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.
  • the octanol-water partition coefficient represents the ratio of concentrations of a (not ionized) compound between two phases, one being a water- saturated octanolic phase and the other an octanol-saturated aqueous phase.
  • the octanol-water partition coefficient is typically expressed in logarithm form and is indicated as log Kow or log P (https://www.sciencedirect.com/topics/chemistry/octanol- water-partition-coefficient). This parameter may for example be obtained by using experimental procedures, as known by persons skilled in the art. Positive values for log Kow indicate some hydrophobic character, with larger values showing more hydrophobicity. 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.
  • 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.
  • octanol-water partition coefficient results in improved stability of the acetylsalicylic acid since hydrolysis is reduced.
  • the octanol-water partition coefficient in some embodiments is from about -1.4 to about 0.
  • Non-limiting examples 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 -0.43 approx.).
  • 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 K ow 1 to 1.05 approx.).
  • the octanol-water partition 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-water partition coefficient of from about 5.0 include oleic acid (log Kow 7.73), isopropyl myristate (log K ow 7.71), and stearyl alcohol (log K ow 7.4), and oils, such as mineral oil (log Kow 6).
  • T he carrier in some embodiments is selected from a group of non-aqueous carriers comprising castor oil, mineral oil, coconut oil, palm oil, 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.
  • non-aqueous carriers comprising castor oil, mineral oil, coconut oil, palm oil, 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,
  • T he carrier in some embodiments is selected from a group of non-aqueous carriers consisting of castor oil, mineral oil, coconut oil, palm oil, 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.
  • S qualene is a polyunsaturated hydrocarbon having a chemical formula of C30H50.
  • Squalane is a saturated derivative of squalene and has a chemical formula of C30H62.
  • 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 upon storage of the liquid composition.
  • the carrier has a storage-stabilising effect on acetylsalicylic acid.
  • 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 has been prepared, is still present in the composition after 30 days of storage at 25 °C.
  • the carrier in some embodiments provides a storage-stabilising effect on acetylsalicylic acid to the extent that at most 20%, such as 15%, or 10%, of the amount of acetylsalicylic acid is degraded after 30 days of storage at 25 °C.
  • the carrier in some embodiments provides a storage-stabilising effect on 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 been prepared, is still present in the composition after 60 days of storage at 25 °C.
  • the carrier in some embodiments provides a storage-stabilising effect on acetylsalicylic 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.
  • T he 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 as pharmaceutical preparations, the solvents and carriers used, as well as the resulting compositions, must be physiologically acceptable.
  • physiologically acceptable is used in its conventional meaning in the field of pharmaceutical preparations, i.e., a substance or composition which does not disturb or harm the normal biological functions of an individual who uses the substance 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.
  • a physiologically acceptable composition includes, but is not limited to, being immunologically acceptable, meaning it does not disturb or harm the body’s natural immune response, when being administered according to the user instructions.
  • T he solvent(s) forming part of the herein disclosed compositions in some embodiments is selected from solvents which are suitable for cutaneous administration.
  • the carrier(s) forming part of the herein disclosed compositions in some embodiments is selected from carriers which are suitable for cutaneous administration.
  • 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 used for local treatment, i.e., not for systemic treatment, affecting the whole body.
  • composition in some embodiments is in any cutaneously applicable administration form which does not require rubbing of the affected skin, e.g., solutions, emulsions, dispersions, liposomal compositions, sprays, etc.
  • I t is preferable to select solvents and carriers which are environmentally acceptable, 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 some embodiments present in an amount ranging from about 5% – 30%, such as from about 7% - 25%, such as from 10% – 20%.
  • compositions 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 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.
  • the castor in some embodiments is in an amount ranging from about 50% - 95% v/v, such as from about 60% - 90% v/v, such as from 70% – 80% v/v.
  • the dimethyl sulfoxide in some embodiments is in an amount ranging from about 5% – 30% v/v, such as from about 7% - 25% v/v, such as from 10% – 20% v/v.
  • a composition comprising acetylsalicylic acid, a first and a second excipient is a composition comprising: ( i) acetylsalicylic acid in a concentration ranging 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, (ii) dimethyl sulfoxide in an amount ranging from about 5% – 30% v/v, such as 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 from about 60% - 90% v/v, such as from 70% – 80% v/v.
  • a composition comprising acetylsalicylic acid, a first and a second excipient is a composition comprising: ( i) acetylsalicylic acid in a concentration ranging 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, ( 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.
  • a composition comprising acetylsalicylic acid, a first and a second excipient is a composition comprising: ( i) acetylsalicylic acid in a concentration ranging from about 30 mg/ml to about 100 mg/ml, ( ii) dimethyl sulfoxide in an amount ranging from about 5% – 30% v/v, such as 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.
  • a composition comprising acetylsalicylic acid, a first and a second excipient is a composition comprising: ( i) acetylsalicylic acid in a concentration ranging from about 30 mg/ml to about 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 from about 75% - 90% v/v.
  • a composition comprising acetylsalicylic acid, a first and a second excipient is a composition comprising: (i) acetylsalicylic acid in a concentration ranging from about 30 mg/ml to about 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.
  • the term “about”, when used together with a specified amount or concentration, may be replaced by “ ⁇ l-5%” of the amount or concentration as specified.
  • 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.
  • the third excipient is a non-aqueous carrier which may be described in terms of its octanol-water partition coefficient. All detailed information above in relation to the octanol-water partition coefficient of the second excipient is relevant also in relation to the third excipient.
  • T he third excipient in some embodiments is a physiologically acceptable non- aqueous carrier.
  • T he third excipient in some embodiments 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 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.
  • physiologically acceptable non-aqueous carriers comprising castor oil, mineral oil, coconut oil, palm oil, soyabean oil, canola oil, olive oil, diethylene glycol monoethyl ether, polyethylene glycol (PEG), benzyl alcohol, propylene glycol, oleic acid, stearic acid, isopropyl myristate,
  • T he third excipient in some embodiments is selected from a group of physiologically acceptable non-aqueous carriers consisting of castor oil, mineral oil, coconut oil, palm oil, 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.
  • physiologically acceptable non-aqueous carriers consisting of castor oil, mineral oil, coconut oil, palm oil, soyabean oil, canola oil, olive oil, diethylene glycol monoethyl ether, polyethylene glycol (PEG), benzyl alcohol, propylene glycol, oleic acid, stearic acid, isopropyl myri
  • composition comprising acetylsalicylic acid, a first and a second excipient, and optionally a third excipient, in some embodiments further comprises at least one compound of Formula (I), wherein: R 1 is H or C1-2-alkyl, R 2 is H or C1-2-alkyl, or R 1 and R 2 together with the atoms to which they are attached form a piperidyl heterocycle; R 3 is C1-4-alkyl, and R 4 is H or CH 3 .
  • R 1 is H or C1-2-alkyl
  • R 2 is H or C1-2-alkyl, or R 1 and R 2 together with the atoms to which they are attached form a piperidyl heterocycle
  • R 3 is C1-4-alkyl
  • R 4 is H or CH 3 .
  • a compound of Formula (I) in some embodiments is present in the composition in the form of a single enantiomer or a racemate, having a chiral centre as shown by asterisk below:
  • T he at least one compound of Formula (I) in some embodiments is selected from lidocaine, 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.
  • the composition comprising acetylsalicylic acid, a first and a second excipient, and optionally a third excipient in some embodiments further comprises at least one compound selected from a group of amino amide local anaesthetics.
  • the compound selected from the group of amino amide local anaesthetics in some embodiments is lidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine, etidocaine, or levobupivacaine.
  • Another non-limiting example of an amino amide local anaesthetic is articaine.
  • the concentration of the amino amide local anaesthetic, such as the compound of Formula (I), 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 term “about”, when used together with a specified amount or concentration, may be replaced by “ ⁇ l-5%” of the amount or concentration 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 least two compounds of Formula (I) in combination with an amino amide local anaesthetic compound 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 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 of compounds having a relatively fast onset of action and a relatively short duration of action
  • the second compound in some embodiments is selected from a group of compounds 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.
  • 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.
  • the composition in some embodiments comprises at least three compounds selected 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 by Formula (I).
  • the first compound in some embodiments is selected from a group of compounds having a relatively fast onset of action and a relatively short duration of action
  • the second and third compound may be selected from a group of compounds having 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 selected from the group of amino amide local anaesthetics is a combination of lidocaine, bupivacaine, and ropivacaine.
  • Another non-limiting example of a suitable combination of three compounds from the group of amino amide local anaesthetics is lidocaine in combination with levobupivacaine and ropivacaine.
  • each of the amino amide local anaesthetics in the composition 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.
  • a further object of the present invention is to provide a composition comprising acetylsalicylic acid (ASA) and at least two compounds providing a prolonged pain- reducing effect.
  • ASA acetylsalicylic acid
  • 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: R 1 is H or C 1-2 -alkyl, R 2 is H or C1-2-alkyl, or R 1 and R 2 together with the atoms to which they are attached form a piperidyl heterocycle; R 3 is C 1-4 -alkyl, and R 4 is H or CH3.
  • S aid composition in some embodiments is in liquid form.
  • a composition may be described as “in liquid form” if it is flowable or pourable when the composition is at room temperature. In some embodiments the composition has a viscosity of less than about 8cP at 25oC.
  • the composition is in liquid form when it has a viscosity of less than about 8cP at 25oC.
  • S aid composition in some embodiments is essentially water-free.
  • the term “essentially water-free” has been defined further above.
  • T he compound of Formula (I) may be present in said composition in the form of 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 from lidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine, etidocaine, and levobupivacaine.
  • the compounds of Formula (I) belong to a group of local anaesthetics.
  • the compounds of Formula (I) belong to a group of amino amide local anaesthetics.
  • said composition comprising acetylsalicylic acid in some embodiments further comprises at least two compounds selected from a group of amino amide local anaesthetics.
  • T he at least two compounds selected from the group of amino amide local anaesthetics in some embodiments is selected from lidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine, etidocaine, or levobupivacaine.
  • Another non-limiting example of an amino amide local anaesthetic is articaine.
  • each of the amino amide local anaesthetics in the composition 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.
  • S aid composition in some embodiments comprises at least two compounds selected 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 of compounds having a relatively fast onset of action and a relatively short duration of action
  • the second compound in some embodiments is selected from a group of compounds 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.
  • 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.
  • S aid composition in some embodiments comprises at least three compounds selected 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 by Formula (I).
  • the first compound in some embodiments is selected from a group of compounds having a relatively fast onset of action and a relatively short duration of action
  • the second and third compound in some embodiments is selected from a group of compounds having 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, selected from the group of amino amide local anaesthetics, is a combination of lidocaine, bupivacaine, and ropivacaine.
  • Another non-limiting example of a suitable combination of three compounds from the group of amino amide local anaesthetics is lidocaine in combination with levobupivacaine and ropivacaine.
  • T he above-described composition comprising acetylsalicylic acid and one or more compounds selected from a group of amino amide local anaesthetics, such as one or more compounds of Formula (I), in some embodiments further comprises 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.
  • a non-aqueous solvent has been defined, described, and exemplified further above 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.
  • a non-aqueous carrier has been defined, described, and exemplified further above 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 of this second composition.
  • S aid composition in some embodiments further comprises a third excipient, which is a non-aqueous carrier.
  • the third excipient when present, is a different compound 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.
  • a ny one of the herein disclosed compositions in some embodiments further comprises 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.
  • T he amount or concentration of a penetration enhancer, present in any one of the herein disclosed compositions may suitably be much lower than the amount or concentration of the non-aqueous solvent, and/or the amount or concentration of the non-aqueous carrier.
  • 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 fatty acid is stearic acid. Stearic acid can act as a non-aqueous carrier and as a penetration enhancer. It is to be understood that if a compound included in the composition as carrier also acts as a penetration enhancer, there is no need to add more of the same compound to the composition to achieve its effect as penetration enhancer.
  • a ny one of the herein disclosed compositions in some embodiments is in the form of (i) a liquid under an inert atmosphere, or (ii) a nanoformulation.
  • a n inert atmosphere in some embodiments is provided by an inert gas, such as nitrogen, helium, or argon. In one embodiment the inert gas is nitrogen.
  • nanoformulation is intended to mean a formulation containing 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 presently disclosed compositions, is a liposomal emulsion.
  • compositions in some embodiments comprises acetylsalicylic 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.
  • compositions comprising acetylsalicylic acid, at least one compound 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.
  • 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.
  • 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.
  • 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 concentration of bupivacaine 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 castor oil and/or palm oil in some embodiments is in an amount ranging from about 50% - 95% v/v, such as from about 60% - 90% v/v, such as from 70% – 80% v/v.
  • the dimethyl sulfoxide or dimethyl isosorbide in some embodiments is in an amount ranging from about 5% – 30% v/v, such as from about 7% - 25% v/v, such as from 10% – 20% v/v.
  • compositions comprising acetylsalicylic acid, at least one compound 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 to about 100 mg/ml, ( ii) lidocaine, (iii) optionally ropivacaine or bupivacaine, (iv) dimethyl sulfoxide, or dimethyl isosorbide, in an amount ranging from about 5% - 30% v/v, and (v) castor oil and/or palm oil in an amount ranging from about 70% - 95% v/v.
  • 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.
  • 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 concentration of bupivacaine 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.
  • a further embodiment of a composition comprising acetylsalicylic acid, at least one 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 from about 5% - 30% v/v, and (iv) castor oil and/or palm oil in an amount ranging from about 50% - 95% v/v.
  • 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.
  • 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.
  • a further embodiment of a composition comprising acetylsalicylic acid, at least one 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.
  • the concentration of acetylsalicylic acid in some embodiments is from about 40 mg/ml to about 60mg/ml.
  • 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.
  • the castor oil in some embodiments is in an amount ranging from about 60% - 90% v/v, such as from 70% – 80% v/v.
  • the dimethyl sulfoxide in some embodiments is in an amount ranging from about 7% - 25% v/v, such as from 10% – 20% v/v.
  • a composition comprising acetylsalicylic acid, at least 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) dimethyl isosorbide, (v) 1-methoxy-2-propanol or white soft paraffin, and (vi) propylene glycol.
  • 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 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.
  • 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.
  • 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 dimethyl isosorbide in some embodiments is in an amount ranging from about 5% – 30% v/v, such as from about 7% - 25% v/v, such as from 10% – 20% v/v.
  • a composition comprising acetylsalicylic acid, at least 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • kits of parts comprising the above-disclosed product and a packaging.
  • the product may be contained in the packaging under an inert atmosphere.
  • the inert 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. A ny one of the herein disclosed compositions may be for use in the treatment of skin irritation in a human.
  • 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.
  • 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, an insect bite, an insect sting, a scratch, a dermatological disorder, such as eczema or cold sores, or a burn, such as sunburn.
  • T he compositions may be for use in the treatment of skin irritation by cutaneous administration, in particular by administration locally at the site of skin irritation. T he skin irritation to be treated may be located in the epidermis. To treat skin irritation in a human, any one of the herein disclosed compositions may be administered in one single application or in multiple applications, depending on the cause of the skin irritation and/or the severity of the skin irritation.
  • F or example causes which normally generate skin irritation for 1-2 days if untreated, 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.
  • a composition comprising acetylsalicylic acid but not comprising any amino amide local anaesthetic may require a higher number of applications than a composition 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.
  • 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.
  • composition may be essentially water-free.
  • 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.
  • 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 may comprise: 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), formic acid, 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
  • S aid composition may optionally be mixed with one or more excipients selected 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, a fatty ester, or a fatty amine.
  • the definition, description and examples of penetration enhancers 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: R 1 is H or C1-2-alkyl, R 2 is H or C1-2-alkyl, or R 1 and R 2 together with the atoms to which they are attached form a piperidyl heterocycle; R 3 is C1-4-alkyl, and R 4 is 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), formic acid, 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
  • the method for manufacture may further comprise dissolving acetylsalicylic acid and at least one compound of Formula (I), (I) wherein: R 1 is H or C1-2-alkyl, R 2 is H or C1-2-alkyl, or R 1 and R 2 together with the atoms to which they are attached form a piperidyl heterocycle; R 3 is C1-4-alkyl, and R 4 is 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), formic acid, dihydrolevoglucosenone, and cyclopentyl methyl ether (CPME), optionally with the provision that the non-aqueous solvent is not selected from methanol, ethanol, or isoprop
  • T he at least one compound of Formula (I) may be selected from lidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine, etidocaine, and levobupivacaine.
  • lidocaine, bupivacaine, ropivacaine, mepivacaine, prilocaine, etidocaine, and levobupivacaine all belong to a group of amino amide local anaesthetics.
  • the method for manufacturing of the composition may alternatively comprise dissolving at least one compound selected from a group of amino 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.
  • 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.
  • the concentration of the amino amide local anaesthetic 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.
  • use of the verb “to comprise” and its conjugations does not exclude the presence of elements or steps other than those stated.
  • the article “a” or “an” preceding an element does not exclude the presence of a plurality of such elements.
  • ASA formulated with solvent DMSO and carrier castor oil 0.1 g acetylsalicylic acid (ASA) was dissolved in 10 ml dimethyl sulfoxide (DMSO) to prepare a liquid solution of acetylsalicylic acid at a concentration of 10 mg/ml of acetylsalicylic acid.
  • DMSO dimethyl sulfoxide
  • the liquid solution of acetylsalicylic acid was then mixed with 90 ml castor oil to prepare a composition in the form of an ointment, suitable for cutaneous application.
  • the ointment was stored in a sealed, coloured glass bottle at room temperature and at 40°C, respectively. 100 ⁇ l samples were collected at different time points post preparation.
  • ASA acetylsalicylic acid
  • Example 2 ASA and local anaesthetics formulated with solvent DMSO and carrier 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 40 mg/ml of acetylsalicylic acid.
  • DMSO dimethyl sulfoxide
  • lidocaine, 0.4 g ropivacaine and 0.4 g bupivacaine were each dissolved in 10 ml dimethyl sulfoxide (DMSO) to prepare a liquid solution of lidocaine, ropivacaine and bupivacaine, respectively, at a concentration of 40 mg/ml of each.
  • DMSO dimethyl sulfoxide
  • the thus prepared four different types of liquid solution were then mixed at a ratio of 1:1:1:1, to prepare a mixed liquid solution containing acetylsalicylic acid, lidocaine, ropivacaine and bupivacaine at a concentration of 10 mg/ml of each.
  • a composition in the form of an ointment suitable for cutaneous application.
  • the ointment was stored in a sealed, coloured glass bottle at room temperature and at 40°C, respectively.
  • 100 ⁇ l samples were collected at different time points post preparation.50-time dilutions in acetonitrile were subjected to HPLC analysis.
  • Stability of acetylsalicylic acid in the composition is shown 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).
  • ASA acetylsalicylic acid
  • ASA acetylsalicylic acid
  • Example 3 ASA and local anaesthetics formulated with solvent DMSO and carriers 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 40 mg/ml of acetylsalicylic acid.
  • DMSO dimethyl sulfoxide
  • lidocaine, 0.4 g ropivacaine and 0.4 g bupivacaine were each dissolved in 10 ml dimethyl sulfoxide (DMSO) to prepare a liquid solution of lidocaine, ropivacaine and bupivacaine, respectively, at a concentration of 40 mg/ml of each.
  • DMSO dimethyl sulfoxide
  • the thus prepared four different types of liquid solution were then mixed at a ratio of 1:1:1:1, to prepare a mixed liquid solution containing acetylsalicylic acid, lidocaine, ropivacaine and bupivacaine at a concentration of 10 mg/ml of each.
  • a composition in the form of an ointment suitable for cutaneous application.
  • the ointment was stored in a sealed, coloured glass bottle at room temperature and at 40 °C, respectively.
  • 100 ⁇ l samples were collected at different time points post preparation. 50-time dilutions in acetonitrile were subjected to HPLC analysis. Stability of acetylsalicylic acid in the composition is shown in Fig. 3. More particularly, Fig.
  • FIG. 3A shows the amount of acetylsalicylic acid (ASA) in the ointment, at multiple time points after preparation, at room temperature (RT).
  • Example 4 Solvent ethanol – comparative example For comparison, each of acetylsalicylic acid, lidocaine, ropivacaine, and bupivacaine, was dissolved separately in ethanol (conc.
  • Example 5 Solvent DMSO, no carrier – comparative example
  • 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 ⁇ l samples were collected at different time points post preparation. 50-time dilutions in acetonitrile were subjected to HPLC analysis. Stability of acetylsalicylic acid in the composition is shown in Fig. 5.
  • acetylsalicylic acid degraded more quickly in DMSO (a non-aqueous solvent which fulfils the requirements as defined herein) 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 example
  • acetylsalicylic acid (ASA) was dissolved in ethyl acetate and the 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 ⁇ l samples were collected at different time points post preparation. 50-time dilutions in acetonitrile were subjected to HPLC analysis.
  • Fig. 6 Stability of 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% propylene glycol at two time points after preparation, at room temperature (RT) and at 40 °C, is shown in Fig.6A, while the amount of ASA in the composition containing 20% ethyl acetate and 80% propylene glycol at two time points after preparation, at room temperature (RT) and at 40 °C, is shown in Fig. 6B.
  • 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 C ompositions comprising acetylsalicylic acid and two amino amide local anaesthetics are prepared as in Examples 2-3 above, with the following variations (a)- (g) of components: (a) A cetylsalicylic acid 10 mg Lidocaine 10 mg Ropivacaine 10 mg D imethyl sulfoxide (DMSO) 1 ml Castor oil 9 ml Oleic acid 1 mg Oleic 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.
  • DMSO non- aqueous solvent used
  • lidocaine, 0.4 g ropivacaine and 0.4 g bupivacaine were each dissolved in 10 ml dimethyl sulfoxide (DMSO) to prepare a liquid solution of lidocaine, ropivacaine and bupivacaine, respectively, at a concentration of 40 mg/ml of each.
  • DMSO dimethyl sulfoxide
  • the thus prepared four different types of liquid solution were then mixed at a ratio of 1:1:1:1, to prepare a mixed liquid solution containing acetylsalicylic acid, lidocaine, ropivacaine and bupivacaine at a concentration of 10 mg/ml of each.
  • a composition in the form of 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 at 40 °C, respectively. 100 ⁇ l samples were collected at different time points post preparation. 50-time dilutions in acetonitrile were subjected to HPLC analysis.

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Abstract

La présente invention concerne une composition comprenant de l'acide acétylsalicylique, ou un dérivé fonctionnel de celui-ci, et comprenant en outre un premier et un second excipient, le premier excipient étant un solvant non aqueux, et le second excipient étant un support non aqueux, la composition étant sous forme liquide et essentiellement exempte d'eau. L'invention concerne également une composition comprenant de l'acide acétylsalicylique, ou un dérivé fonctionnel de celui-ci, et comprenant en outre au moins deux composés de formule (I), dans laquelle : R1 est H ou alkyle en C1-2, R2 est H ou alkyle en C1-2, ou R1 et R2 conjointement avec les atomes auxquels ils sont reliés, forment un hétérocycle pipéridyle; R3 est alkyle en C1-4, et R4 est H ou CH3. La présente invention concerne en outre un produit comprenant l'une quelconque des compositions divulguées ici, ainsi qu'un kit d'éléments comprenant ledit produit et un emballage. De plus, la présente invention concerne les compositions destinées à être utilisées comme médicament, destinées à être utilisées dans une thérapie par administration cutanée, et/ou destinées à être utilisées dans le traitement de l'irritation de la peau. L'invention concerne en outre un procédé de traitement de l'irritation de la peau chez un être humain, comprenant l'administration de l'une quelconque des compositions divulguées ici audit être humain, ainsi qu'un procédé de fabrication de la composition.
PCT/EP2024/084182 2023-11-29 2024-11-29 Composition et son utilisation comme médicament Pending WO2025114578A1 (fr)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5736126A (en) 1996-03-15 1998-04-07 Van Engelen; H. Wayne Liquid transdermal analgesic
WO2000030611A2 (fr) * 1998-11-24 2000-06-02 Chambord Ltd. Preparation pharmaceutique
WO2000078354A1 (fr) 1999-06-22 2000-12-28 Norway Medical Group Int As Composition topique comprenant de l'acide salicylique d'acetyle
WO2001003774A2 (fr) * 1999-07-07 2001-01-18 Dardai Zoltan Composition pharmaceutique de traitement de la calcification
US6306843B1 (en) * 1997-07-15 2001-10-23 Walter Burghart Method for producing stable acetylsalicylic acid solutions
WO2002045687A2 (fr) 2000-12-05 2002-06-13 Norway Medical Group Int. As Utilisation
US8795693B2 (en) * 2003-08-04 2014-08-05 Foamix Ltd. Compositions with modulating agents
CN105749256A (zh) * 2016-03-02 2016-07-13 卢连伟 一种辅助治疗腱鞘囊肿的巴布剂及其制备方法
WO2020094736A1 (fr) * 2018-11-07 2020-05-14 Sapir Pharmaceuticals Inc. Solutions lipidiques d'ains

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5736126A (en) 1996-03-15 1998-04-07 Van Engelen; H. Wayne Liquid transdermal analgesic
US6306843B1 (en) * 1997-07-15 2001-10-23 Walter Burghart Method for producing stable acetylsalicylic acid solutions
WO2000030611A2 (fr) * 1998-11-24 2000-06-02 Chambord Ltd. Preparation pharmaceutique
WO2000078354A1 (fr) 1999-06-22 2000-12-28 Norway Medical Group Int As Composition topique comprenant de l'acide salicylique d'acetyle
WO2001003774A2 (fr) * 1999-07-07 2001-01-18 Dardai Zoltan Composition pharmaceutique de traitement de la calcification
WO2002045687A2 (fr) 2000-12-05 2002-06-13 Norway Medical Group Int. As Utilisation
US8795693B2 (en) * 2003-08-04 2014-08-05 Foamix Ltd. Compositions with modulating agents
CN105749256A (zh) * 2016-03-02 2016-07-13 卢连伟 一种辅助治疗腱鞘囊肿的巴布剂及其制备方法
WO2020094736A1 (fr) * 2018-11-07 2020-05-14 Sapir Pharmaceuticals Inc. Solutions lipidiques d'ains

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* Cited by examiner, † Cited by third party
Title
REICHARDT C., CHEM. REV., vol. 94, no. 8, 1994, pages 2319 - 2358

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