New anesthetic composition

Abstract

The present invention relates to a new deep eutectic system and a new anesthetic composition thereof.

Description

[0001] NEW ANESTHETIC COMPOSITION

[0002] The present invention relates to a new deep eutectic system and a new anesthetic composition thereof.

[0003] BACKGROUND OF THE INVENTION

[0004] Skin wounds and other injuries often require very painful procedures such as laceration repair and debridement. Systemic analgesia and sedation including intravenous morphine or nitrous oxide oxygen mixture can be efficient but may be considered disproportionate in terms of dosage, action duration, medical cost, and resource consumption, for the management of a very located injury and a short-lasting procedure during which pain is increased.

[0005] Procedural analgesia can be achieved through local anesthetic infiltration. However, this involves repeated injections into the wound which may cause tissue edema and surgical site distortion. Moreover, anesthetic infiltration is itself very painful and most often, it must be supplemented with systemic analgesia or sedation. The main advantages of topical administration are the elimination of injection which means no additional pain and no wound distortion and the limited systemic absorption with minimized risk.

[0006] These considerations have led to the development of topical anesthetic formulations, which comprise in general one or more amide anesthetics and / or one or more ester anesthetic to obtain faster, longer-lasting analgesia and to reduce toxicity. Available topical anesthetic formulations in the prior art include, without limitation, TAC (Tetracaine+Adenaline+Cocaine), LAT (Lidocaine+adrenaline+Tetracaine) or LET (Lidocaine+Epinephrine+Tetracaine) gel, lidocaine oral spray and EMLA (eutectic mixture of local anesthetics) cream. Each of these treatments brings its own set of characteristics related to their anesthetic concentration, form (base vs. hydrochloride), and suitability for application. The efficacy of existing topical preparations varies with their concentrations, formulations, and the nature of the injury. To date, there is no topical anesthetic combination that meets the needs for various skin injuries, such as lacerations, trauma abrasions, bums and leg ulcers. Additionally, available preparations are not capable of pain control (as an isolated treatment) during painful procedures, such as wound cleaning, debridement, or laceration repair. For example, LAT or LET gels typically contain 4% hydrochloride salt of lidocaine and 0.5% hydrochloride salt of tetracaine. Due to its gel texture and low anesthetic concentration, anesthetic effect of LAT or LET gel is rather insufficient for severe and very aching lesions requiring painful procedures such as exploration, cleaning, debridement, and repair. TAC gel comprising typically 0.5% tetracaine and 11.8% cocaine is more effective for severe injuries, but the presence of cocaine provides extra inconveniences, such as drug toxicity, legal and safety concerns. As to commercially available EMLA® cream, which contains typically 2.5% lidocaine and 2.5% prilocaine in their base form, its long action delay requires product application 2 to 3 hours before the procedure. AMETOP® gel, comprising 4.0% tetracaine in its base form, has a more rapid onset of action, about an hour, which is still quite long. Anesthetic eflficacity of these products is very limited, so that they are only suitable for superficial procedures in pediatrics, such as vaccine administration or venous puncture. They cannot be used (as an isolated treatment) for pain control during medical procedures applied to deep injuries. Due to their low solubility in water (below to 2%), slow diffusion capacity and non-sterile formulation, these products are intended for application on healthy skin, should not be used in the treatment of skin injuries.

[0007] There is therefore still a strong need of providing new topical anesthetic compositions (compatible with healthy as well as wounded skin) that not only reach higher concentrations in deeper tissues but also act swiftly and maintain efficacy over an extended period without precipitating systemic side effects.

[0008] SUMMARY OF THE INVENTION

[0009] Working on this problematic, the Inventors have unexpectedly found out that acetate salt or lactate salt of an amide anesthetic, e.g. lidocaine, and acetate salt or lactate salt of an ester anesthetic, e.g. tetracaine, can form a deep eutectic system (DES) which remains at liquid state even at low temperature, e.g. at 4 °C. Most surprisingly, this DES is soluble in water in any proportion. This high-water solubility makes it possible to obtain new anesthetic compositions with high concentrations of both amide anesthetics and ester anesthetics. In addition, it is surprising to observe that the new DES can further dissolve up to 15% by weight of any local anesthetics in their basic form. This allows increasing the pH of the mixture to mimic physiological pH or to achieve a pH value compatible with polymers that require a pH value above 7 for reticulation. In addition, the new DES also unexpectedly demonstrates a higher penetration capacity than the eutectic system formed by lidocaine and tetracaine in their base form. These unparalleled proprieties of the new DES make it possible to be used as an efficient anesthetic which produces both the advantage of tetracaine and of lidocaine, i.e. high potency and long action duration as tetracaine and rapid onset and versatility as lidocaine. Based on these new DES, the inventors provide new anesthetic compositions, which are more effective, patient-friendly and reduce the need for systemic analgesics and their associated side effects. The anesthetic compositions of the invention offer a more nuanced approach that balances immediacy and duration of analgesia with an elevated safety profile. This balanced approach ensures that while the onset of action is accelerated to provide swift relief, the duration of efficacy is extended, minimizing the need for repeated dosing and reducing the risk of systemic complications. The implications of such a novel anesthetic composition go far beyond treating burns and deep wounds. It paves the way for a new generation of local anesthetic formulations across various medical applications, from minor topical procedures to more significant surgical interventions.

[0010] Accordingly, the present invention relates to a deep eutectic system, which comprises (i) at least one amide anesthetic salt, and (ii) at least one ester anesthetic salt, wherein said amide anesthetic salt is an acetate salt or a lactate salt and wherein said ester anesthetic salt is an acetate salt or a lactate salt.

[0011] According to an embodiment, the molar ratio between amide anesthetic salt and ester anesthetic salt is 0.7-1.3: 1, particularly 0.75-1.25: 1, more particularly 0.8-1.2: 1.

[0012] In a particular embodiment, the amide anesthetic is selected from the group consisting of lidocaine, mepivacaine, prilocaine, ropivacaine, etidocaine, levobupivacaine and bupivacaine.

[0013] In another particular embodiment, the ester anesthetic is selected from the group consisting of tetracaine, procaine, chloroprocaine and proparacaine.

[0014] In a more particular embodiment, the DES of the invention comprises (i) lidocaine acetate and / or lidocaine lactate and (ii) tetracaine acetate and / or tetracaine lactate.

[0015] The present invention also relates to a pharmaceutical composition comprising a deep eutectic system of the invention and a pharmaceutically acceptable vehicle.

[0016] According to an embodiment, the pharmaceutical composition of the invention comprises:

[0017] - 0.5-50% wt of total amide anesthetic(s), and

[0018] - 0.5-50% wt of total ester anesthetic(s).

[0019] In a more particular embodiment, the pharmaceutical composition of the invention comprises: - 0.5-15% wt of total amide anesthetic(s), and

[0020] - 0.5-15% wt of total ester anesthetic(s).

[0021] In another embodiment, the pharmaceutical composition of the invention further comprises at least one additional active pharmaceutical ingredient.

[0022] In a particular embodiment, said additional active pharmaceutical ingredient is selected from the group consisting of a local anesthetic base, an antiseptic, an antifungal, and an antibacterial, a vasoconstrictor, a vasodilator, a nonsteroidal anti-inflammatory drug (NS AID), an opioid and a corticoid. More particularly, said additional active pharmaceutical ingredient may be selected from chlorhexidine, ketoconazole, naphazoline and mupirocin.

[0023] According to a particular embodiment, said pharmaceutical composition is formulated in a solution, an injectable solution, a hydrogel, a bioadhesive spray, a lyophilisat, or a cream. More particularly, said pharmaceutical composition may be a topical anesthetic composition.

[0024] The present invention also relates to a DES of the invention or a pharmaceutical composition of the invention for use for in the prevention or the treatment of pain. In particular, the DES or the pharmaceutical composition comprising the DES may be used to prevent or treat nociceptive pain. In particular, this includes pain associated with medical procedures, such as dental procedures, dermatological procedures, and minor surgical procedures. It also covers pain associated with venous access procedure, pain associated with severe bums, leg ulcers, diabetic foot ulcers, pressure ulcers, and other chronic wounds. Additionally, it can be used for pain during obstetric procedures, pain related to insect bites and stings, and acute pain resulting from sports injuries.

[0025] The present invention also relates to a method for preventing or treating pain in a subject in need thereof, comprising administering an effective amount of a DES or a pharmaceutical composition of the invention.

[0026] BRIEF DESCRIPTION OF THE FIGURES

[0027] Figure 1 shows the permeability of a deep eutectic system formed by lidocaine lactate and tetracaine lactate in ratio 1 : 1 (Fig. 1A) and of an eutectic system formed by lidocaine base and tetracaine base in ratio 1 : l(Fig. IB). The permeability was measured by strat-m® with a synthetic membrane and evaluated by the percentage of passed-through lidocaine or tetracaine compared to the total amount of lidocaine or tetracaine of the tested formulation.

[0028] Figure 2 shows the drug permeability of two formulations of the invention (K90 and P407, which are formulations F2 and F4 of table 3, respectively) compared with that of EMLA® cream. The drug permeability was measured by strat-m® with a synthetic membrane. The passed-through lidocaine was detected as a tracer of drug permeation. The amount of passed- through lidocaine for each drug (Fig. 2A) and the percentage of passed-through lidocaine compared to the total amount of lidocaine in each drug (Fig. 2B) were determined. The total amount of passed-through tetracaine for formulations F2 and F4 (Fig. 2C) and the percentage of passed-through tetracaine compared to the total amount of tetracaine in each formulation (Fig. 2D) were also determined.

[0029] Figure 3 shows photos illustrating the transformation of state during the preparation of a DES of the invention formed by lactate salt of lidocaine and lactate salt of tetracaine. A: photo taken immediately after putting together equimolar amounts of lactic acid lidocaine base, tetracaine base, and pure lactic acid. B: photo taken just at the beginning of mixing process using a pestle at room temperature. C: photo taken after 5 minutes of mixture at room temperature using a pestle. D: photo taken after 10 minutes of mixture using a pestle at room temperature.

[0030] Figure 4 shows FT-IR spectra of a DES of the invention formed by lactate salt of lidocaine and lactate salt of tetracaine (A) and that of a comparative eutectic system formed by lidocaine base and tetracaine base (B).

[0031] DETAILED DESCRIPTION OF THE INVENTION

[0032] Deep eutectic system

[0033] The present invention provides a deep eutectic system (DES) comprising (i) at least one amide anesthetic salt, and (ii) at least one ester anesthetic salt, wherein said amide anesthetic salt is an acetate salt or a lactate salt and wherein said ester anesthetic salt is an acetate salt or a lactate salt.

[0034] The present invention is based on unexpected experimental results according to that (i) an acetate salt or a lactate salt of an amide anesthetic and an acetate salt or a lactate salt of an ester anesthetic can form a DES and (ii) that said system is soluble in water in any proportion. In addition, the DES of the invention remains at liquid state, even at 4°C or lower temperature.

[0035] Said DES makes it possible to provide a water-soluble pharmaceutical composition comprising high concentrations of one or more amide anesthetics and of one or more ester anesthetics. This significant progress overcomes limitations in the anesthetic compositions of prior art with respect to low anesthetic concentrations.

[0036] The term “deep eutectic system (DES)” as used herein refers to a homogenous mixture of two or more components that form a super-lattice that melts or solidifies at a temperature far below than any of the individual components’ melting point. The eutectic point is the lowest temperature at which the liquid phase is stable at a given pressure. The eutectic point of the DES of the present invention is far below than 0°C. Without being combined with a theory, the strong hydrogen bonding interactions between an amide anesthetic and an ester anesthetic may be responsible for significant lowering of melting point in a DES of the invention.

[0037] According to the invention, the DES comprises at least one amide anesthetic lactate or acetate salt and at least one ester anesthetic lactate or acetate salt.

[0038] Amide anesthetics and ester anesthetics are two classes of local anesthetics.

[0039] The term “local anesthetic” refers to a medication that causes a temporary loss of sensation, including pain, in a specific body part without depressing the level of consciousness or causing unconsciousness. Local anesthetics work by inhibiting the rapid inflow of sodium ions necessary for impulse generation within nerve fibers, thereby preventing the transmission of pain signals.

[0040] In general, local anesthetics bear an aromatic group whose liposolubility allows for diffusion through nerve sheaths and nerve cell membranes, an amino tail whose hydrosolubility permits molecular dissociation and binding of the drug molecules with the sodium channels, and an ester or amide linkage which connects the aromatic group and the amino tail.

[0041] The term “amide anesthetic” refers to a class of local anesthetics which have an amide as intermediate linkage between an aromatic ring and a tertiary amine. Examples of amide anesthetics include lidocaine, mepivacaine, prilocaine, ropivacane, articaine, etidocaine, levobupivacaine and bupivacaine. The term “ester anesthetic” refers to a class of local anesthetics which have an ester as intermediate linkage between an aromatic ring and a tertiary amine. Examples of ester anesthetics can be cited are tetracaine, procaine, chloroprocaine, proparacaine, coaine, oxybuprocaine, and benzocaine.

[0042] In a particular embodiment of the present invention, the amide anesthetic is lidocaine or any amide anesthetic having one or more quantum descriptor values comparable to those of lidocaine. The term “an amide anesthetic having one or more quantum descriptor values comparable to those of lidocaine” means that quantum descriptor values of an amide anesthetic differ by less than 15% from lidocaine’s quantum descriptor value. For instance, mepivacain, prilocaine, ropivacaine, etidocaine, levobupivacaine and bupivacaine have quantum descriptor values comparable to those of lidocaine.

[0043] In another particular embodiment of the invention, the ester anesthetic is tetracaine or any ester anesthetic having one or more quantum descriptor values comparable to those of tetracaine. The term “ an ester anesthetic having one or more quantum descriptor values comparable to those of tetracaine” means that quantum descriptor values of an ester anesthetic differ by less than 15% from tetracaine’s quantum descriptor values. For instance, procaine, chloroprocaine and proparacaine have quantum descriptor values comparable to those of tetracaine.

[0044] The term “quantum descriptors” refers to any descriptor derived from quantum chemical calculations of a molecule and aiming to capture the electronic structure and reactivity of said molecule. Examples of quantum descriptors used within the scope of the present invention include pKa, Average Local Ionization Energy (ALIE) at pH6, Highest Occupied Molecular Orbital (HOMO) energy at pH 6, Lowest Unoccupied Molecular Orbial (LUMO) energy at pH 6, H0M0-LUM0 energy gap, chemical hardness, chemical potential, and electrophilicity.

[0045] All these descriptors reflect reactivity, solubility, and / or stability of a molecule. In particular, pK is an indicator of molecule’s solubility and stability in different pH environments. ALIE at pH6, HOMO energy at pH6, LUMO energy at pH6 and the H0M0-LUM0 energy gap describe a molecule’s reactivity and stability. Chemical hardness describes molecule’s resistance to change in electron distribution and relates to molecule’s stability; chemical potential is indicative of the tendency of a molecule to gain or lose electrons and relates to molecule’s reactivity. Electrophilicity is indicative of the likelihood of being an electron acceptor and influences solubility and reactivity of a molecule.

[0046] The values of above quantum descriptors may be calculated according to any suitable methods which are available in the prior art. In a particular embodiment, the amide anesthetic is selected from the group consisting of lidocaine, mepivacaine, prilocaine, ropivacaine, etidocaine, levobupivacaine and bupivacaine. In another particular embodiment, the ester anesthetic is selected from the group consisting of tetracaine, procaine, chloroprocaine, and proparacaine. In a more particular embodiment, the amide anesthetic is lidocaine and the ester anesthetic is tetracaine.

[0047] According to an embodiment of the invention, the DES comprises more than one amide anesthetic salts and more than one ester anesthetic salts. The term “more than one amide anesthetic salts” should be understood as (i) different salts, i.e. lactate salt and acetate salt, of the same amide anesthetic or (ii) salts of different amide anesthetics, e.g. lidocaine lactate and prilocaine lactate. The term “more than one ester anesthetic salts” should be understood as (i) different salts, i.e. lactate salt and acetate salt, of the same ester anesthetic or (ii) salts of different ester anesthetics, e.g. tetracaine lactate and procaine lactate.

[0048] In a particular embodiment, the DES comprises both lactate salt and acetate salt of a same amide anesthetic and / or of a same ester anesthetic. In a more particular embodiment, the DES comprises both lactate salt and acetate salt of an amide anesthetic and of an ester anesthetic.

[0049] In another particular embodiment, the DES comprises lactate salt of an amide anesthetic and lactate salt of an ester anesthetic. In still another particular embodiment, the DES comprises acetate salt of an amide anesthetic and acetate salt of an ester anesthetic.

[0050] In a more particular embodiment of the invention, the DES comprises lidocaine acetate and tetracaine acetate.

[0051] In another more particular embodiment of the invention, the DES comprises lidocaine lactate and tetracaine lactate.

[0052] In still another more particular embodiment of the invention, the DES comprises lidocaine acetate, lidocaine lactate, tetracaine lactate and tetracaine acetate.

[0053] In a particular embodiment, the molar ratio between amide anesthetic salt(s) and ester anesthetic salt(s) in a DES is 0.7-1.3: 1, that is to say for 1 molar of ester anesthetic salt(s) in said system, there is from 0.7 to 1.3 molar of amide anesthetic salt(s).

[0054] In a more particular embodiment, the molar ratio between amide anesthetic salt(s) and ester anesthetic salt(s) is 0.75-1.25: 1. In a still more particular embodiment, the molar ratio is 0.8- 1.2: 1. The molar concentration of amide anesthetic salt(s) in a DES is the total molar concentration of all cationic amide anesthetics in the DES. The molar concentration of ester anesthetic salt(s) in a DES is the total molar concentration of all cationic ester anesthetics in the DES.

[0055] The deep eutectic systems according to the invention can be obtained by contacting at room temperature (i) an amide anesthetic, (ii) an ester anesthetic with (iii) acetated acid and / or lactate acid in a specific range of molar ratio. Said molar ratio may be adapted by a skilled person according to the final molar ratio between the amide anesthetic salt(s) and the ester anesthetic salt(s) to be reached in a DES.

[0056] Pharmaceutical composition

[0057] The present invention also relates to pharmaceutical compositions comprising a DES of the invention.

[0058] As used herein, the term “pharmaceutical composition” refers to a composition which can be used as a final medicinal product or drug.

[0059] In a preferred embodiment, said pharmaceutical composition comprises a DES of the invention in a therapeutically effective amount and a pharmaceutically acceptable carrier.

[0060] As used herein, the term “effective amount” or “effective dose” refers to an amount sufficient to inhibit, reduce, relieve, alleviate pain of a subject at a reasonable benefit / risk ratio. Determination of an effective amount is well within the general knowledge of those skilled in the art. Generally, the effective amount can vary with the specific compound, the use or administration route, the desired effect, the duration of the effect and side effects, the subject's history, age, condition, sex, as well as the severity and type of the medical condition in the subject, and administration of other pharmaceutically active agents. Accordingly, an effective amount of a DES described herein is an amount sufficient to inhibit or reduce the level of pain in a subject during a desired duration.

[0061] In a particular embodiment, the pharmaceutical composition comprises 0.5-50% wt of total amide anesthetic(s) and 0.5-50% wt of total ester anesthetic(s).

[0062] In a more particular embodiment, the pharmaceutical composition comprises 0.5-25% wt of total amide anesthetic(s) and 0.5-25% wt of total ester anesthetic(s). In a still more particular embodiment, the pharmaceutical composition comprises 0.5-15% wt of total amide anesthetic(s) and 0.5-15 % wt of total ester anesthetic(s).

[0063] Particularly, the pharmaceutical composition comprises 1.5-7.5% wt of total amide anesthetic(s) and 1.5-7.5% wt of total ester anesthetic(s).

[0064] Most particularly, the pharmaceutical composition comprises 2.5-5% wt of total amide anesthetic(s) and 2.5-5% wt of total ester anesthetic(s).

[0065] In another particular embodiment, the pharmaceutical composition comprises 5-100 mg / ml of total amide anesthetic(s) and 5-100 mg / ml of total ester anesthetic(s). In a more particular embodiment, the pharmaceutical composition comprises 15-75 mg / ml of total amide anesthetic(s) and 15-75mg / ml of total ester anesthetic(s). Most particularly, the pharmaceutical composition comprises 25-50 mg / ml of total amide anesthetic(s) and 25-50 mg / ml of total ester anesthetic(s). For the sake of clarity, the terms “ester anesthetic” and “amide anesthetic” used within the context of a pharmaceutical composition according to the present invention should be understood as “cationic ester anesthetic” and “cationic amide anesthetic”, respectively.

[0066] The weight percentage used within the context of a pharmaceutical composition according to the present invention is calculated with respect to the total weight of a pharmaceutical composition.

[0067] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical active ingredient within or to the subject such that it may perform its intended function. A carrier must be “acceptable” in the sense of being compatible with other ingredients of the formulation, including the DES of the invention, and not injurious to the subject. Some examples of materials that may serve as pharmaceutically acceptable carriers include: polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), ethyl cellulose; oils, i.e. peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; biocompatible polymers, such as poly (acrylic acid) (PAA), copolymers comprising PAA block, poloxamers; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. A carrier must also be “acceptable” in the sense of being compatible with the formulations of the pharmaceutical composition. For example, suitable acceptable pharmaceutically acceptable carrier for a pharmaceutical composition formulated as hydrogel may comprise distilled water and gelling agents, such as poloxamers, poly (vinyl alcohol) (PVA), poly (ethylene glycol) (PEG), poly (ethylene oxide) (PEO), poly (2-hydroxyethyl methacrylate) (PHEMA), poly (acrylic acid) (PAA), copolymers comprising PAA block, and poly (acrylamide) (PAAm), etc. For another example, a pharmaceutical composition formulated as a bioadhesive spray may comprise distilled water and bioadhesive polymers, such as chitosan, gelatin alginate, PAA, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, xanthan gum or other natural gums.

[0068] The pharmaceutical composition of the invention may be formulated for administration in semisolid or liquid form. Typically, the pharmaceutical composition of the invention may be formulated as being suitable for topical, sublingual, ocular, nasal, transmucosal, transdermal or parenteral, i.e. subcutaneous, or intramuscular administration. A skilled person can choose the suitable formulation according to the administration route and the therapeutic indication of the pharmaceutical composition. For instance, an aqueous solution, a spray, a hydrogel, a cream, ointment, or a patch may be suitable formulations for topical application. Typically, an aqueous solution can be a suitable formulation for fast skin penetration, while an hydrogel or a cream are more adapted formulations for controlled and extended drug release. The high water content and porous structure of hydrogels mimic the native extracellular matrix, making them particular suitable for mucosal application. A cream enriched with skin conditioners can be more suitable for sensitive skin application. Bioadhesive sprays with their propriety of forming an adhesive film on mucosal membrane or skin are suitable formulations for targeted and localized delivery of high quantity of active agents with prolonged drug-contact time and enhanced drug absorption in a site-specific manner.

[0069] According to an embodiment, the pharmaceutical composition of the invention is formulated as a spray, a hydrogel, a cream, ointment, a patch, as a solution, in particular an injectable solution, as an emulsion, as lyophilisat.

[0070] In a particular embodiment, the pharmaceutical composition of the invention is formulated as an aqueous solution, a hydrogel, a bioadhesive spray, a lyophilisat or a cream.

[0071] In a more particular embodiment, the pharmaceutical composition is a topical anesthetic composition. In a preferable embodiment of the invention, the pharmaceutical composition is a hydrogel.

[0072] The hydrogel according to the invention may comprise any conventional natural or synthetic water-swellable and biocompatible polymers. Examples of synthetic and natural polymers involved in the hydrogel formation include, but not limited to, pol oxamers, polyethylene glycol) (PEG), poly-(vinyl alcohol), poly-(2-hydroxyethyl methacrylate) (HEMA), poly-(N-isopropyl- 2-crylamide), chitosan, hyaluronic acid, gelatin, and sodium alginate.

[0073] In another preferable embodiment of the invention, the pharmaceutical composition is a bioadhesive spray, which is an aqueous solution which can be sterilized by filtration and that, once applied to the wound, is sufficiently dense and above all, bioadhesive to prevent leakage of the solution. The term “bioadhesive” refers to the ability of a material to adhere to a biological tissue for an extended period of time. Said ability is usually conferred by a bioadhesive polymer. Examples of bioadhesive polymer include, but not limited to, chitosan, gelatin alginate, poloxamer, PAA, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, xanthan gum and other natural gums.

[0074] A skilled person can determine the suitable type and amount of polymer in a spray or a hydrogel according to the molecular weight of the polymer and the desired viscosity, gelation temperature and gelation time of the hydrogel or the spray. Generally speaking, a bioadhesive spray or a hydrogel may comprise from 0.5 to 25% wt of biocompatible polymer(s). A hydrogel contains more polymer than a spray.

[0075] In a more particular embodiment, the pharmaceutical composition of the invention is a hydrogel or a bioadhesive spray comprising a poloxamer. The term “poloxamer” refers to a class of triblock copolymers comprising a central polyprolypene oxide (PPO) block flanked by two polyethylene oxide (PEO) blocks. Poloxamers are represented by the following chemical formula:

[0076] HO(C2H4O)a(C3H6O)b(C2H4O)aH

[0077] In the above formula a and b represent whole integers. Generally a is from 2 to 150 and b is from 15 to 70 depending on the particular poloxamer.

[0078] Said poloxamer may be any conventional poloxamer suitable for pharmaceutical use. Examples of pharmaceutical grade poloxamers are poloxamer 407 (P407), poloxamer 338 (P338), and poloxamer 188 (Pl 88). Poloxamers are also known by the trade names Synperonics, Pluronics and Kolliphor. For the generic term “poloxamer”, these copolymers are commonly named with the letter “P” (for pol oxamer) followed by three digits, the first two digits* 100 give the approximate molecular mass of the poly oxypropylene core, and the last digit* 10 gives the percentage polyoxyethylene content (e.g., P407=pol oxamer with a poly oxypropylene molecular mass of 4,000 g / mol and a 70% polyoxyethylene content; P188=pol oxamer with a polyoxypropylene molecular mass of 1,800 g / mol and a 80% polyoxyethylene content). For the Pluronic trade name, coding of these copolymers starts with a letter to define its physical form at room temperature (L=liquid, P=paste, F=flake (solid)) followed by two or three digits. The first digit (two digits in a three-digit number) in the numerical designation, multiplied by 300, indicates the approximate molecular weight of the hydrophobe; and the last digit* 10 gives the percentage polyoxyethylene content (e.g., L61=Pluronic with a polyoxypropylene molecular mass of 1,800 g / mol and a 10% polyoxyethylene content).

[0079] According to the invention, a hydrogel or a spray may typically comprise from 0,25 to 20% wt of poloxamer, in particular from 0.5 to 15% wt, more particularly from 1 to 10%wt of pol oxamer.

[0080] In a particular embodiment, the pharmaceutical composition of the invention is formulated as a hydrogel or a bioadhesive spray which comprises a DES according to the invention, a poloxamer, and optionally at least one additional active pharmaceutical ingredient.

[0081] According to a more particular embodiment of the invention, the pharmaceutical composition is an aqueous solution or a bioadhesive spray which comprises:

[0082] 1.5-7% wt of total amide anesthetic(s),

[0083] 1.5-7 % wt of total ester anesthetic(s),

[0084] 0.5-15 % wt of a poloxamer, and optionally a poly (ethylene glycol).

[0085] According to a still more particular embodiment of the invention, the pharmaceutical composition is an aqueous solution or a bioadhesive spray which comprises:

[0086] 2.5-5% wt of lidocaine,

[0087] 2.5-5 % wt of tetracaine,

[0088] - 1 to 10% wt ofP407,

[0089] - 5-20% wt of PEG400, and optionally one or more additional active pharmaceutical ingredient. The pharmaceutical composition of the present invention may further comprise at least one additional active pharmaceutical ingredient. The presence of a DES of the invention in the pharmaceutical composition allows increasing the solubility of an additional active pharmaceutical ingredient.

[0090] Said additional active pharmaceutical ingredient may be selected from the group consisting of a local anesthetic base, an antiseptic, an antifungal, an antibacterial, a vasoconstrictor, a vasodilator, a nonsteroidal anti-inflammatory drug (NS AID), an opioid and a corticosteroid.

[0091] The local anesthetic base, which can be further comprised in a pharmaceutical composition of the invention can be any local anesthetic in base form known in the art.

[0092] Antiseptic used in pharmaceutical compositions according to the present invention are microbicidal (bacteriocidal, fungicidal, and / or viricidal) in their actions, and are intended to provide a reduction in the ambient flora in the anatomic surface onto which they are administered. Examples of antiseptics include, but not limited to, povidone, chlorhexidine, benzalkonium chloride, and chlorobutanol,

[0093] Antifungals and antibacterials that may be used in the pharmaceutical compositions according to the present invention can be any conventional antifungal and antibacterial, in particular those suitable for a topical administration. Examples of antifungals include, but not limited to, ketoconazole, posaconazole, voriconazole, fluconazole, echinocandins, terbinafine, amphotericin B, clotrimazole, nystatin, azoles, caspofungin, isavuconazole, flucytosine, itraconazole, polyenes, amphotericin, anidulafungin, allylamines, butoconazole, griseofulvin, naftifine, ravuconazole. Examples of antibacterials include, but not limited to, mupirocin, retapamulin, silver sulfadiazine, ozenoxacin, erythromycin, mafenide, gentamicin, and a combination of sulfacetamide sodium and sulfur.

[0094] Vasoconstrictors that may be used in the pharmaceutical compositions according to the present invention can be any conventional vasoconstrictor available in the art. Examples that can be cited are naphazoline, epinephrine, norepinephrine, and dopamine, thromboxane, endothelin, angiotensin II, oxymetazoline, phenylephrine, oxymetazoline, xylometazoline, tetryzoline, vasopressin, midodrine, methysergide, dihydroergotamine, angiotensin II, vasopressin, felypressin, norepinephrine, phenylpropanolamine, ulobetasol, metaraminol, sumatriptan, ergotamine, methoxamine, pseudoephedrine. Vasodilators that may be used in the pharmaceutical compositions according to the present invention can be any conventional vasodilator available in the art. Examples that can be cited are nitric oxide, nitroprusside, sildenafil, milrinone, isradipine, theophylline, diltiazem, minoxidil, amlodipine, nimodipine, nisoldipine, rosiglitazone, propranolol, nicardipine, niacin, adenosine, dyphylline, verapamil, nicergoline, nitroglycerin, alprostadil.

[0095] NS AIDs are a class of drugs that reduce pain, prevent blood clots, and reduce inflammation. Examples of NS AID can be cited are aspirin, ibuprofen, naproxen, diclofenac, celecoxib, indomethacin, meloxicam, nabumetone, piroxicam, ketorolac, etodolac and oxaprozin.

[0096] Corticosteroids that may be used in the compositions of the invention may be any conventional corticosteroids including cortisone, hydrocortisone and prednisone.

[0097] Opioids are a class of drugs that are derive from or mimic opium, which is natural substance found in the opium poppy plant. Examples of medically prescribed opioids include morphine, codeine, opium, oxycodone, oxymorphone, hydrocodone, hydromorphone, diamorphine, tramadol, and methadone.

[0098] In a particular embodiment, the pharmaceutical composition comprises a DES of the invention and an antiseptic and / or an antifungal and / or a antibacterial and / or a vasoconstrictor.

[0099] In a more particular embodiment, the pharmaceutical composition comprises at least one additional active pharmaceutical ingredient, which is selected in the group consisting of chlorhexidine, ketoconazole, mupirocin and naphazoline.

[0100] Therapeutic application

[0101] According to the invention, the DES and the pharmaceutical composition as defined above is for use in the treatment or the prevention of pain.

[0102] The term “pain” refers within the context of the present invention to any pain or sensitivity associated with tissue damage. Particularly, the term “pain” as used herein includes, but not limited to any kind of nociceptive pain which may be acute or chronic. The term “nociceptive pain” refers to pain which arises from non-neural tissues damaged by physical or chemical agents such as trauma, surgery, or chemical burns. Examples of nociceptive pains include but are not limited to traumatic or surgical pain, such as pain generated during dental procedures, dermatological procedures, minor surgical procedures, pain during obstetric procedures, pain associated with venous access procedure, injections, skin biopsies, labor pain, pain associated with tissue injuries, such as wounds, sprains, bone fractures, burns, bumps, bruises, leg ulcers, diabetic foot ulcers, pressure ulcer, and pain related to insect bites and stings.

[0103] As used herein, the terms “treatment of pain” or “treating pain” refer to any regimen that can inhibit, delay, stabilize, alleviate, relieve, reduce, remedy of pain in a subject.

[0104] As used herein, the terms “prevention of pain” or “preventing pain” refer to the ability of avoiding the onset of pain in a subject that is likely, susceptible or expected to develop of pain.

[0105] As used herein, the term “subject” refers to an animal, in particular a mammal, more in particular a human being.

[0106] In a particular embodiment, the pharmaceutical composition of the invention is for use for local analgesia or anesthesia. The term “analgesia” as used herein is defined as pain relief without loss of consciousness and without total loss of feeling or movement. The term “anesthesia” as used herein is defined as a loss of feeling or awareness caused by drugs or other substances. Typically, the pharmaceutical composition of the invention can be used in local procedural analgesia in dental procedures, dermatological procedures, and minor surgical procedures. It is also intended for managing pain associated with burns, leg ulcers, diabetic foot ulcers, pressure ulcers, and other chronic wounds. Additionally, it is designed to address pain and discomfort during obstetric procedures. The composition can be used in local anesthetic infusion pumps for continuous postoperative pain management. It is also suitable for treating pain and itching related to insect bites and stings, as well as managing acute pain resulting from sports injuries.

[0107] In a particular embodiment, the pharmaceutical composition of the invention is for use as topical anesthetic in wound cleaning and debridement or laceration repair.

[0108] The compositions as herein described may be administered to the subject by any route, in particular by topical, intramuscular, cutaneous, subcutaneous, dermal, transdermal, transmucosal, sublingual, ocular, or nasal route. Preferably the pharmaceutical compositions herein described are administered to the subject topically.

[0109] The present invention also relates to a method for preventing or treating pain in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of a composition of the invention.

[0110] The invention will now be described with reference to the following examples. EXAMPLES

[0111] Materials and methods

[0112] • Quantum molecular analysis

[0113] Quantum molecular descriptors, which are indicative of solubility and stability of molecules, were calculated by using Jaguar and Maestro programs from the Schrodinger Suite 2019-1. Selection of the B3LYP exchange-correlation functional with the D3 a posteriori correction and the 6-31G++** basis set was driven by their proven effectiveness in accurately modeling molecular behaviors critical to solubility and stability [1,2]. pKas were calculated using the Epik suite included in Maestro Software.

[0114] • Preparation protocols of a deep eutectic system and the formulations

[0115] A deep eutectic system is prepared according to the following protocol.

[0116] Preparation of DES:

[0117] At room temperature, mix (i) an amide anesthetic and (ii) an ester anesthetic with (iii) acetic acid and / or lactic acid in a specific molar ratio to form a deep eutectic system.

[0118] Adjust the molar ratio according to the desired final molar ratio between the amide anesthetic and the ester anesthetic. The final molar ration can be from 0.7: 1 to 1.3: 1.

[0119] A deep eutectic system formed by lactate salt of lidocaine and lactate salt of tetracaine was prepared by mixing lidocaine base, tetracaine base, and lactic acid in equimolar amounts. The components were mixed at room temperature leading the spontaneous formation of a clear homogeneous liquid (Figure 3).

[0120] The pharmaceutical formulations listed in Table 3 below were prepared from said DES.

[0121] Analysis of permeability

[0122] Permeability protocol

[0123] The experiment uses Strat-M® synthetic membranes, which are predictive of human skin diffusion. The formulations were applied to the Strat-M® membrane. The tests were conducted under controlled conditions at 37°C to mimic physiological (or normal body) temperature. The duration of the test was standardized at 24 hours to ensure consistent and comparable results.

[0124] Measurements and analyses

[0125] Detection method: the amount of lidocaine and tetracaine that passed through the membrane was detected and quantified using High-Performance Liquid Chromatography (HPLC).

[0126] Data analysis: the percentages of lidocaine and tetracaine diffused relative to the total amount in each formulation were calculated.

[0127] The results were compared to those of EMLA® cream, which contains a eutectic mixture of lidocaine base and prilocaine base.

[0128] • Fourier-transform infrared (FT-IR) spectroscopy

[0129] FT-IR spectroscopy was performed with a PerkinElmer Frontier spectrometer equipped with an ATR accessory (diamond / ZnSe crystal). Measurements were performed in the 4000-650 cm1range, with a spectral resolution of 4 averaging 32 scans per sample, at ambient temperature. Samples were analyzed directly on the ATR crystal without dilution or solvent.

[0130] FT-IR spectroscopy was conducted on (i) a comparative eutectic system formed by lidocaine base and tetracaine base and (ii) a DES of the invention formed by lactate salt of lidocaine and lactate salt of tetracaine.

[0131] The comparative eutectic system was prepared by mixing lidocaine base and tetracaine base in equimolar amounts using a mortar and pestle at room temperature until a homogeneous solid / pasty blend was obtained. The DES of the invention was prepared according to the method described above. The obtained comparative eutectic system and the DES of the invention were applied neat, without any preparation, directly onto the ATR crystal for spectral acquisition.

[0132] Examples 1: Quantum molecular analysis of amide anesthetics and ester anesthetics

[0133] The chemical and pharmacological similarities among amide anesthetics are analyzed by comparing quantum molecular descriptors of several amide anesthetics. In the same way, the chemical and pharmacological similarities of ester anesthetics are also analyzed among several ester anesthetics. Table 1 below details the comparative analysis of key quantum molecular descriptors across seven amide anesthetics, i.e. lidocaine, prilocaine, mepivacaine, ropivacaine, etidocaine, levobupivacaine and bupivacaine.

[0134] Table 2 below shows the comparative analysis of key quantum molecular descriptors across four ester anesthetics, i.e. tetracaine, procaine, chloroprocaine and proparacaine.

[0135] The data of table 1 and 2 show high chemical and pharmacological similarities among amide anesthetics and among ester anesthetics. These data support that similar chemical characteristics among deep eutectic systems of the invention can be expected.

[0136]

[0137]

[0138]

[0139] Example 2: Analysis of permeability of the deep eutectic system of the invention

[0140] The permeability study was conducted to evaluate the transdermal diffusion capacity of the formulations comprising new deep eutectic system (DES) compared to existing anesthetic formulations. This study is crucial for demonstrating the potential efficacy of the DES formulations for topical applications.

[0141] The permeability of a DES that is formed from lidocaine lactate and tetracaine lactate in a molar ratio of 1 : 1 was compared with an eutectic mixture which is formed from lidocaine base and tetracaine base in a ratio of 1 :1. The drug permeability was evaluated by StratM® using synthetic membranes for transdermal diffusion test, to predict diffusion in human skin. The permeability of cationic lidocaine and tetracaine in the DES and that of lidocaine and tetracaine in base form in the eutectic mixture were determined and shown in Fig. 1 A and IB.

[0142] These results demonstrated that cationic lidocaine and tetracaine in the formulations of the invention exhibited a higher diffusion capacity through the Strat-M® membrane compared to lidocaine and tetracaine in their base form.

[0143] Normally, it is assumed that only neutral compounds pass through StratM® membrane. However, contrary to the expectations based on prior understanding on the behavior of salts in such system, cationic lidocaine and tetracaine can pass through StratM® and even show a higher diffusion capacity than lidocaine and tetracaine in base form. These results predict a better transdermal diffusion capacity of the DES of the invention.

[0144] Example 3: Analysis of permeability of pharmaceutical formulations comprising the deep eutectic system of the invention

[0145] The pharmaceutical formulations detailed in table 3 below were prepared. All these formulations comprise a DES of the invention and present following features :

[0146] - 1 density between 1.01 and 1.05, a density range that is compatible with 0.22 pm membrane and cartridge filters for sterilization filtration;

[0147] - a solution which can be sprayed;

[0148] - sufficient bioadhesive capacity to prevent dripping after administration on wounds.

[0149] The permeability of two formulations (F2 and F4) is compared with that of EMLA® cream. Said cream comprises a eutectic mixture of lidocaine and prilocaine in base form. The results confirm that cationic lidocaine in the formulations F2 and F4 has a better permeability than lidocaine in base form in EMLA® cream (Fig. 2A and 2B). In addition, cationic tetracaine also shows similar diffusion behavior (Fig.2C and 2D). These results confirms that formulations of the invention have a better transdermal diffusion capacity than a formulation comprising lidocaine and / or tetracaine in base form.

[0150] Specifically, the formulations F2 and F4 showed better permeability than the EMLA® cream, which is a proof of superior efficacy for topical applications.

[0151] Transdermal flux of the formulation F4 of table 3 and that of the EMLA® cream were compared. The results are summarized in table 4 below.

[0152] Table 4: Transdermal Flux Comparison: DES vs. EMLA®

[0153] As a conclusion, the results showed in Figures 1 and 2 and table 4 highlight the improved performance of the formulations of the invention compared to existing anesthetic formulations, e.g. EMLA® cream.

[0154] Example 4:

[0155] Physicochemical parameters of (i) a comparative eutectic system formed from lidocaine base and tetracaine base, (ii) a DES of the invention formed by lactate / acetate salt of lidocaine and lactate / acetate salt of tetracaine, and (iii) a mixture of chloride / phosphate of lidocaine and chloride / phostate of tetracaine were compared and summarized in table 5 below. Table 5:

[0156] Only acetate / lactate salts form a DES with water solubility and stability. The comparative eutectic system formed by bases reverts to solid state below 40°C, while the DES of the invention remains liquid at 4°C.

[0157] No eutectic behavior is observed for the mixture of chloride / phosphate of lidocaine and chloride of tetracaine: solid phases persist even at elevated temperatures.

[0158] Example 5: FT-IR spectroscopy FT-IR spectroscopy was conducted on (i) a comparative eutectic system formed from lidocaine base and tetracaine base and (ii) a DES of the invention formed by lactate salt of lidocaine and lactate salt of tetracaine.

[0159] FT-IR spectroscopy spectra of a DES of the invention and that of the comparative eutectic system were shown in Fig. 4 A and 4B. Compared to the comparative eutectic system, the DES of the invention exhibits clear spectral shifts (C=O and O-H bands), indicating new hydrogen bonding networks. Table 6 below summarizes the parameters of the spectra of the comparative eutectic system and that of the DES system.

[0160] Table 6: Comparative FT-IR Data

[0161] The analysis of the spectra shows that the DES of the invention is an eutectic system completely different from the eutectic system formed by lidocaine base and tetracaine base.

Claims

CLAIMS1. A deep eutectic system comprising (i) at least one amide anesthetic salt, and (ii) at least one ester anesthetic salt, wherein said amide anesthetic salt is an acetate salt or a lactate salt and wherein said ester anesthetic salt is an acetate salt or a lactate salt.

2. The deep eutectic system according to claim 1, wherein the amide anesthetic is selected from the group consisting of lidocaine, mepivacaine, prilocaine, ropivacaine, etidocaine, levobupivacaine and bupivacaine.

3. The deep eutectic system according to claim 1 or 2, wherein the ester anesthetic is selected from the group consisting of tetracaine, procaine, chloroprocaine, and proparacaine.

4. The deep eutectic system according to any one claims 1 to 3, wherein the molar ratio between amide anesthetic salt and ester anesthetic salt is 0.7-1.3: 1, in particular 0.75-1.25: 1.

5. The deep eutectic system according to any one of claims 1 to 4, comprising (i) lidocaine acetate and / or lidocaine lactate and (ii) tetracaine acetate and / or tetracaine lactate.

6. A pharmaceutical composition comprising a deep eutectic system according to any one of claims 1 to 5, and a pharmaceutically acceptable vehicle.

7. The pharmaceutical composition according to claim 6, comprising:- 0.5-50% wt, in particular 0.5-15% wt, of total amide anesthetic(s), and- 0.5-50% wt, in particular 0.5-15% wt, of total ester anesthetic(s) .

8. The pharmaceutical composition according to claim 6 or 7, further comprising at least one additional active pharmaceutical ingredient.

9. The pharmaceutical composition according to claim 8, wherein said additional active pharmaceutical ingredient is selected from the group consisting of a local anesthetic base, an antiseptic, an antifungal, an antibacterial, a vasoconstrictor, a vasodilator, a nonsteroidal antiinflammatory drug (NS AID), an opioid and a corticosteroid.

10. The pharmaceutical composition according to claim 9, wherein the additional active pharmaceutical ingredient is selected from chlorhexidine, ketoconazole, naphazoline and mupirocin.

11. The pharmaceutical composition according to any one of claims 6-10, wherein said composition is formulated in a solution, an injectable solution, a hydrogel, a bioadhesive spray, a ly ophili sat, or a cream.

12. The pharmaceutical composition according to any one of claims 6-11, wherein said composition is a topical anesthetic composition.

13. The pharmaceutical composition according to any one of claims 6-12, wherein said composition is for use for local anesthesia or in the prevention or the treatment of pain.

14. The pharmaceutical composition according to claim 13, wherein the pain is nociceptive pain, in particular pain associated with medical procedures, such as pain generated during dental procedures, dermatological procedures, minor surgical procedures, pain associated with venous access procedure, pain associated with severe burns, leg ulcers, diabetic foot ulcers, pressure ulcers, and chronic wounds, pain during obstetric procedures, pain related to insect bites and stings, and acute pain resulting from sports injuries.

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