Composition based on c. cassia essential oil and uses thereof

Abstract

The invention relates to a topical composition comprising an essential oil of C. cassia, and to the use thereof for treating wounds and burns, treating or preventing ORL or cutaneous bacterial infections, and washing and disinfecting the skin, in particular the skin of the hands.

Description

[0001] COMPOSITION BASED ON C. CASSIA ESSENTIAL OIL AND USES THEREOF

[0002] TECHNICAL FIELD

[0003] The present invention relates to the field of compositions intended for the treatment of wounds, including burns, ENT infections and disinfection, particularly of hands.

[0004] TECHNOLOGICAL BACKGROUND

[0005] The skin is the first barrier protecting the body from external aggressions. This organ is composed of several layers of tissue. We distinguish (i) the epidermis which is the outermost part of the skin, (ii) the dermis, a connective tissue made up of fibroblasts and an extracellular matrix which ensures the functions of cohesion and nutrition of the skin, and (iii) the hypodermis made up of adipocytes.

[0006] The epidermis is made up of several cellular layers of keratinocytes. Among others, we distinguish the germinative layer of the epidermis, called the basal layer, containing, in particular, skin stem cells, the spinous layer, Stratum spinosum, made up of several layers of polygonal cells, the granular layer, Stratum granulosum, comprising one to three layers of flattened cells containing cytoplasmic inclusions, the keratohyaline grains, and finally, the horny layer, Stratum corneum which is composed of anucleated and keratin-rich cells called comeocytes which correspond to the terminal stage of keratinocyte differentiation.

[0007] As a barrier organism, the skin is our first defense against the external environment and is subject to numerous external aggressions that can alter its integrity. A breach in the skin exposes our body to risks of infection, particularly bacterial, which are increased when the healing process is slowed, for example due to an underlying pathology or repeated external aggressions. Indeed, the skin flora includes a plurality of microorganisms including pathogenic bacterial species such as Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli.

[0008] The development of therapeutic solutions that promote both skin healing and infection control while exhibiting low cytotoxicity represents a major challenge in the current context, particularly due to the ever-increasing emergence of bacterial strains resistant to conventional antibiotics. There is therefore currently a need for new topical compositions for the treatment of superficial wounds of the skin and mucous membranes.

[0009] SUMMARY OF THE INVENTION

[0010] According to a first aspect, the invention relates to a topical composition comprising:

[0011] - from 1.0% to 5.0% by weight of a polymeric agent,

[0012] - at most 0.50% by weight of essential oil of Cinnamomum cassia,

[0013] - optionally an anesthetic agent,

[0014] - a buffering agent, in water, the percentages being expressed by weight relative to the total weight of the composition.

[0015] In a preferred embodiment, the polymeric agent is hyaluronic acid.

[0016] Thus, according to a certain aspect, the invention relates to a topical composition, preferably sprayable, consisting essentially of:

[0017] - from 1.0% to 5.0% by weight of a hyaluronic acid,

[0018] - at most 0.50% by weight of essential oil of Cinnamomum cassia,

[0019] - a buffering agent present in a concentration ranging from 10 mM to 200 mM„ and

[0020] - optionally an anesthetic agent present in a content of at most 1% by weight, in water, the percentages being expressed by weight relative to the total weight of the composition and said composition having a pH of 6.0 to 8.0.

[0021] In a particular embodiment, the polymeric agent, preferably hyaluronic acid, is present in a content of 1.0% to 4.0%, preferably 1.5% to 2.5% by weight and the essential oil of Cinnamomum cassia is present in a content of 0.025% to 0.50%, preferably 0.04% to 0.25%, and more preferably 0.05% to 0.20% by weight.

[0022] In some embodiments, said hyaluronic acid is a mixture of low molecular weight hyaluronic acid molecules and high molecular weight hyaluronic acid molecules in a LMW-AH / HMW-AH mass ratio ranging from 2 to 10, preferably from 3 to 7, and more preferably from 4 to 6.

[0023] More specifically, the hyaluronic acid is preferably a mixture of low molecular weight hyaluronic acid (LMW-AH) molecules having a weight average molecular mass (Mw) of less than 50 kDa and high molecular weight hyaluronic acid (HMW-AH) molecules having a weight average molecular mass (Mw) of greater than 600 kDa, the LMW-AH / HMW-AH mass ratio being in a range of 3 to 7 or 4 to 6.

[0024] Cinnamomum cassia essential oil is typically obtained by distillation, preferably by steam distillation of C. cassia bark. In some embodiments, the C. cassia oil comprises from 70% to 90% by weight of trans-cinnamic aldehyde, from 1% to 6% by weight of cinnamyl acetate and from 3 to 15% of trans-2-methoxycinnamaldehyde.

[0025] In some embodiments, the composition further comprises a local anesthetic agent. The local anesthetic agent is typically present in an amount of at most 5%, preferably at most 1% by weight, for example at most 0.5% by weight. A preferred local anesthetic is lidocaine or a pharmaceutically acceptable salt thereof.

[0026] In certain embodiments, the composition according to the invention is further characterized by at least 1, 2 or 3 of the following characteristics:

[0027] - the composition has a pH ranging from 6.0 to 8.0, preferably from 6.5 to 7.5

[0028] - the composition has an osmolarity ranging from 300 to 400 mOsm, preferably 320 to 380 mOsm

[0029] - the composition has a viscosity ranging from 10 cP to 100 cP.

[0030] The buffering agent may be present in a concentration ranging from 15 mM to 150 mM, preferably from 25 to 75 mM, for example about 50 mM.

[0031] In certain embodiments, the topical composition according to the invention is characterized in that it further comprises:

[0032] - one or more additional cosmetically or pharmaceutically acceptable excipients selected from the group consisting of pH adjusting agents, osmotic agents, antioxidant agents, thickening agents, gelling agents, perfumes, flavorings and combinations thereof and / or

[0033] - one or more additional active agents chosen from the group consisting of moisturizing agents, vitamins, soothing agents, anti-inflammatory agents and their combinations.

[0034] The excipient(s) and / or additional active agent(s) together representing at most 10%, preferably at most 5% by weight of the total weight of the composition.

[0035] In a particular embodiment, the topical composition according to the invention consists essentially of:

[0036] - from 1.5% to 2.5% by weight of a polymeric agent, preferably hyaluronic acid, said polymeric agent being a mixture of low molecular weight hyaluronic acid molecules (LMW-AH) and high molecular weight hyaluronic acid molecules (HMW-AH) according to a LMW-AH / HMW-AH mass ratio in a range from 4 to 6,

[0037] - from 0.04% to 0.25% by weight of essential oil of Cinnamomum cassia,

[0038] - from 0% to 1.0% by weight of an anesthetic agent, said anesthetic agent being lidocaine,

[0039] - a buffering agent present in a concentration ranging from 25 to 75 mM, said buffering agent being chosen from TRIS buffers, phosphate buffers and their mixtures, in water, the percentages being expressed by weight relative to the total weight of the composition.

[0040] In one embodiment, the topical composition according to is characterized in that it consists essentially of:

[0041] - from 1.5% to 2.5% by weight of hyaluronic acid, said hyaluronic acid being a mixture of low molecular weight hyaluronic acid molecules (LMW-AH) having an Mw of less than 50 kDa and high molecular weight hyaluronic acid molecules (HMW-AH) having an Mw of greater than 600 kDa, according to a LMW-AH / HMW-AH mass ratio in a range of 4 to 6,

[0042] - from 0.04% to 0.25% by weight of essential oil of Cinnamomum cassia,

[0043] - from 0% to 1.0%, preferably from 0% to 0.5% by weight of an anesthetic agent, said anesthetic agent being lidocaine or a pharmaceutically acceptable salt thereof, and

[0044] - a buffering agent present in a concentration ranging from 25 to 75 mM, said buffering agent being chosen from TRIS buffers, phosphate buffers and their mixtures, in water, the percentages being expressed by weight relative to the total weight of the composition.

[0045] The topical composition according to the invention may be further characterized in that the hyaluronic acid is a mixture of HMW-AH having an Mw ranging from 800 kDa to 1200 kDa and LMW-AH with an Mw ranging from 10 kDa to 30 kDa, said mixture having a LMW-AH / HMW-AH mass ratio of 4 to 6.

[0046] According to an additional aspect, the invention relates to a topical composition as described herein for use in the treatment of a wound of the skin or mucous membranes, and / or in the treatment or prevention of bacterial infections of the skin or the ENT sphere, in particular of the throat and mouth and / or in the treatment or prevention of acne. In certain embodiments, the composition is used to promote healing and disinfection at the level of a wound. The wound can be of any type. The wound can be superficial or non-superficial. The wound can be chosen from the group consisting of irritations, redness, cuts and micro-cuts, scratches, cracks, chapped skin, blisters, crevices, bedsores, in particular superficial type I or II, insect bites, spots, in particular acne, post-operative wounds, in particular sutures, and burns.Preferably, the topical composition according to the invention is sprayable and is therefore preferably applied by spraying onto the skin or mucous membranes.

[0047] According to a further aspect, the invention relates to a medical device for administration in the form of a spray or aerosol comprising the topical composition as defined herein. The device may comprise a pressurized bottle provided with a valve associated with an actuator and a diffuser allowing the formation of a spray.

[0048] According to another aspect, the invention relates to the use of the topical composition as described herein for washing and disinfecting the skin, in particular the hands, preferably without rinsing.

[0049] According to an additional aspect, the invention relates to the use of a hyaluronic acid as defined herein as an agent for stabilizing the dispersion of an essential oil of C. Cassia in an aqueous solution and / or as an agent for increasing the antibacterial activity, in particular bactericidal, of said essential oil of C. cassia.

[0050] DETAILED DESCRIPTION OF THE INVENTION

[0051] In this context, the inventors sought to develop a new topical composition that can both promote healing and prevent bacterial infections. The inventors also sought to develop a topical composition that is easy to use for the patient, i.e., can be used for self-medication, and safe, i.e., does not exhibit significant cytotoxicity.

[0052] Due to the ever-increasing emergence of resistant bacterial strains and the ever-increasing number of preservatives that can be authorized in pharmaceutical and cosmetic products, the Inventors have endeavored to search for a new agent that can be used both as an antibacterial agent and a preservative.

[0053] Essential oils are described as cosmetic or therapeutic agents of interest that can exert numerous biological activities, including antibacterial. Among essential oils, Cinnamomum cassia essential oil has been identified as an effective essential oil against different bacterial strains, in planktonic or biofilm form. However, its high cytotoxicity is a barrier to its use in the cosmetic or pharmaceutical field, as a preservative or antibacterial agent.

[0054] Surprisingly, the inventors have shown that it is possible to potentiate the antibacterial effect of C. cassia essential oil in an aqueous medium by formulating it using a polymeric agent capable of forming a hydrogel. More specifically, the inventors have shown that it is possible to very significantly reduce the minimum bactericidal concentration (MBC) of C. cassia essential oil without increasing its cytotoxicity by formulating it with a polymeric agent of the hyaluronic acid type in an aqueous medium buffered at physiological pH. Without wishing to be bound by any theory, the inventors are of the opinion that hyaluronic acid makes it possible to disperse C. cassia essential oil in the form of microdroplets and therefore to obtain an oil-in-water emulsion. Such a formulation makes it possible to potentiate the antibacterial activity of C. cassia essential oil without increasing its cytotoxicity.In other words, hyaluronic acid, which does not exert a bactericidal effect in itself, allows to potentiate the antibacterial activity of C. cassia, making possible its use at non-cytotoxic concentrations, namely less than 0.2% by weight. Advantageously, the essential oil of C. Cassia acts both as an antibacterial agent, in particular bactericidal, and as a preservative, thus avoiding the use of conventional preservatives that are increasingly controversial due to their toxicity.

[0055] Remarkably, the inventors have also shown that the topical composition thus obtained is particularly stable: it has low turbidity, it is homogeneous and can, in certain cases, be transparent. Furthermore, the inventors have not observed any phase separation or coalescence phenomena during storage, and no degradation reaction of the essential oil or hyaluronic acid between them.

[0056] The inventors have also shown that it is possible to formulate a stable and usable topical composition in the form of a spray comprising a high content of hyaluronic acid, greater than 1.0%, whereas commercial spray-type compositions have a low content of hyaluronic acid, of the order of 0.2% by weight.

[0057] Finally, advantageously, the Inventors have shown that the combined use of high and low molecular weight hyaluronic acid not only stabilizes the essential oil of C. cassia in solution, but also promotes healing mechanisms.

[0058] Finally, the inventors have shown that the essential oil of C. cassia exerts a bactericidal activity against different bacterial strains, including antibiotic-resistant strains, involved in skin and ENT infections. Composition according to the invention

[0059] Thus, the present invention relates to a topical composition, said composition comprising:

[0060] - from 1.0% to 5.0% by weight of a polymeric agent

[0061] - at most 0.5% by weight of essential oil of Cinnamomum cassia,

[0062] - a buffering agent, and

[0063] - optionally an anesthetic agent, in water, the percentages being expressed by weight relative to the total weight of the composition.

[0064] The term "topical composition" means a composition suitable for application to the skin and / or mucous membranes. The topical composition according to the invention is typically intended for use on skin or mucous membrane wounds, in particular to promote healing or as a disinfectant agent. The topical composition according to the invention may also be intended for use in the treatment or prevention of bacterial infections of the skin or the ENT area, in the treatment or prevention of acne, or in washing and disinfecting the skin, in particular the hands.

[0065] The composition according to the invention is liquid. It is in the form of an oil-in-water (o / w) emulsion, the oily phase being the essential oil of C. cassia. The essential oil of C. cassia is dispersed in the aqueous phase in the form of microdroplets stabilized by the polymeric agent. As illustrated in the examples, the combination of C. cassia oil with a polymeric agent makes it possible to obtain emulsions, of low turbidity or even transparent, and particularly stable without phase separation or coalescence during storage.

[0066] In some embodiments, the C. cassia essential oil is present in a content of at most 0.50%, preferably 0.02% to 0.5%, or 0.02% to 0.4%, or 0.02% to 0.30% or 0.02% to 0.25%, for example 0.025% to 0.25%, by weight relative to the total weight of the composition. The content of C. cassia essential oil is chosen so as to minimize cellular toxicity while providing a high antibacterial effect. For example, the C. Cassia essential oil may be present in a content of about 0.10%, 0.15% or 0.20% by weight relative to the total weight of the composition.

[0067] In other embodiments, the content of polymeric agent is in a range of from 1.0% to 5.0%, preferably from 1.0% to 4.0% or even from 1.0% to 3.0% or from 1.5% to 2.5% by weight relative to the total weight of the composition. For example, the polymeric agent may be present in a content of about 1.8% by weight.

[0068] The composition optionally comprises an anesthetic agent. In other words, in some embodiments, the composition according to the invention comprises an anesthetic agent while in other embodiments, the composition is devoid thereof. The anesthetic agent is preferably suitable for topical administration. The anesthetic agent is intended to reduce the sensations of pain in the subject at the wound. Preferred anesthetics are described later in the description. The anesthetic agent is generally present in a content of at most 10.0%, preferably at most 5.0% by weight, more preferably at most 1% by weight relative to the total weight of the composition.

[0069] In some embodiments, the composition may further comprise one or more additional excipients or active agents.

[0070] Examples of additional excipients or active agents are provided below. Preferably, these possible additional active agents or excipients represent at most 20% by weight or at most 10% by weight, more preferably at most 5% by weight or even at most 4%, 3%, 2% or 1% by weight relative to the total weight of the composition.

[0071] Thus, in certain embodiments, the composition according to the invention comprises or consists essentially of:

[0072] - from 1.0% to 5.0%, preferably from 1.0% to 4.0% or even from 1.5% to 3.0% or from 1.5% to 2.5% by weight of a polymeric agent,

[0073] - from 0.02% to 0.50%, preferably from 0.025% to 0.30%, more preferably from 0.04% to 0.25%, for example from 0.05% to 0.20% by weight of essential oil of Cinnamomum cassia,

[0074] - from 0% to 5%, preferably from 0% to 3%, more preferably from 0% to 1% by weight of an anesthetic agent,

[0075] - from 0% to 20%, preferably from 0% to 10%, more preferably from 0% to 5% of one or more additional excipients or active ingredients, and

[0076] - a buffering agent, in the water.

[0077] As used herein, the expression "consists essentially of" means that the ingredients cited in the embodiment considered represent more than 95% by weight, preferably more than 96%, 97% 98%, 99%, 99.5% or 99.9% by weight relative to the total weight of the composition of the embodiment considered. In another embodiment, the composition according to the invention comprises or consists essentially of:

[0078] - from 1.0% to 5.0%, preferably from 1.0% to 4.0% or even from 1.5% to 2.5% by weight of a polymeric agent,

[0079] - from 0.02% to 0.5%, preferably from 0.025% to 0.30%, more preferably from 0.04% to 0.25%, for example from 0.05% to 0.20% by weight of essential oil of Cinnamomum cassia,

[0080] - from 0% to 5%, preferably from 0% to 3%, more preferably from 0% to 1% by weight of an anesthetic agent,

[0081] - from 0% to 5% by weight of one or more additional excipients or active ingredients, and

[0082] - a buffering agent, in the water.

[0083] In certain embodiments, the composition according to the invention comprises or consists essentially of:

[0084] - from 1.0% to 5.0%, preferably from 1.0% to 4.0% or even from 1.5% to 3.0% or from 1.5% to 2.5% by weight of a polymeric agent

[0085] - from 0.02% to 0.50%, preferably from 0.025% to 0.30%, more preferably from 0.04% to 0.25%, for example from 0.05% to 0.20% by weight of essential oil of Cinnamomum cassia,

[0086] - from 0% to 5%, preferably from 0% to 1% by weight of an anesthetic agent, and

[0087] - a buffering agent, in the water.

[0088] By way of example, the composition according to the invention may consist essentially or consist of:

[0089] - from 1.5% to 2.5% by weight of a polymeric agent,

[0090] - from 0.04% to 0.25%, preferably from 0.05% to 0.20% by weight of essential oil of Cinnamomum cassia,

[0091] - 0% to 1% by weight of an anesthetic agent, and

[0092] - a buffering agent, in the water.

[0093] The water present in the composition is preferably of cosmetic or pharmaceutical grade. Preferably, the water is purified or even deionized. It may be water for injection, sterilized or non-sterilized.

[0094] The buffering agent may be any biocompatible buffering agent, in particular pharmaceutically or cosmetically acceptable, for buffering a composition at a pH of between 6.0 and 8.0, preferably between 6.5 and 7.5. Typically, the buffering agent may have a pKa of between 5.5 and 8.5, preferably between 6.0 and 8.0, for example 6.5 to 7.5. Examples of buffering agents of interest are provided below.

[0095] The composition according to the invention has a pH suitable for application to the skin, typically a pH between 6.0 and 8.0, preferably ranging from 6.5 to 7.5.

[0096] The viscosity of the composition is generally adjusted according to its mode of administration.

[0097] In certain embodiments, the composition according to the invention has a viscosity of less than 200 cP, preferably less than 200 cP. The viscosity of the composition according to the invention may be in a range from 10 to 90 cP, for example from 20 to 80 cP or from 20 to 70 cP, said viscosity being determined with a rheometer. By way of example, the composition according to the invention may have a viscosity of approximately 20 to 50 cP. Such a viscosity is suitable for administration by spraying.

[0098] In certain embodiments, the composition according to the invention is a sprayable composition, i.e. intended to be applied to the skin or to the mucous membranes by spraying. In an additional embodiment, the composition according to the invention has an osmolarity greater than 200 mOsm and less than 450 mOsm. The composition according to the invention may have an osmolarity ranging from 250 to 400 mOsm, preferably from 300 to 400 mOsm, for example from 320 to 360 mOsm.

[0099] Cinnamomum cassia essential oil

[0100] Cinnamomum cassia is a tree species in the Lauraceae family, native to China. It is also called Chinese cinnamon. For the purposes of the invention, Cinnamomum cassia essential oil (also referred to herein as C. cassia essential oil) refers to a lipophilic extract obtained from an aerial part of Cinnamomum cassia by any suitable process, in particular by supercritical fluid extraction, for example by supercritical CO2, or by distillation.

[0101] The aerial parts of C. Cassia include, but are not limited to, leaves, stems, branches, bark, and combinations of these.

[0102] In a particular embodiment, the essential oil of C. cassia is obtained from the bark of C. cassia, preferably by distillation, for example by hydrodistillation or by steam distillation. A preferred method of preparation is steam distillation.

[0103] For all useful purposes, it is recalled that C. cassia is a species distinct from Ceylon cinnamon (commonly called Cinnamon or Cinnamon in English), namely Cinnamomum verum and that consequently, an extract of C. cassia necessarily has a qualitative and quantitative composition distinct from an extract of C. verum obtained by a similar process. In a preferred embodiment, the essential oil of C. cassia is characterized in that it comprises at least 70% by weight of trans-cinnamaldehyde.

[0104] In some embodiments, the C. cassia essential oil comprises:

[0105] - at least 70% trans-cinnamaldehyde,

[0106] - from 0.1% to 10% of cinnamyl acetate and

[0107] - from 0.5% to 20% of tran.s-2-methoxycinnamaldehyde, the percentages being expressed by weight relative to the total weight of the essential oil.

[0108] In some embodiments, the C. Cassia essential oil contains at most 2.0% by weight of eugenol and at most 8% by weight of coumarin.

[0109] In a preferred embodiment, the essential oil of C. cassia is characterized in that it comprises:

[0110] - 70% to 90% trans-cinnamaldehyde,

[0111] - from 0.1% to 6% of cinnamyl acetate and

[0112] - from 3% to 15% of trans-2-methoxycinnamaldehyde, the percentages being expressed by weight relative to the total weight of the essential oil.

[0113] Preferably, the essential oil comprises at most 0.5% by weight of eugenol and at most 4.0% of coumarin, typically between 1.5% and 4.0% by weight of coumarin.

[0114] In certain embodiments, the essential oil of C. cassia may be substituted (replaced) in the composition according to the invention by an essential oil of another species of Cinnamomum provided that said essential oil comprises at least 70% of / / Y / rt.s-cinnamaldehyde. Preferably, the essential oil of another species of Cinnamomum has a composition similar to that of the essential oil of C. cassia as described above.

[0115] The polymeric agent:

[0116] The polymeric agent is chosen from polymeric agents capable of forming a hydrogel in aqueous solution, at a physiological pH, typically between pH 6 and 8. Preferably, the polymeric agent is capable of forming a film on the surface of the skin after application of the composition according to the invention.

[0117] Preferably, it is a polymer of natural origin. The polymeric agent may be chosen in particular from proteins such as collagen, gelatin or elastin and polysaccharides. The polysaccharides of interest include in particular glycosaminoglycans, for example hyaluronic acid, dextran, pectin, cellulose and its derivatives such as carboxymethylcellulose and salts thereof, hydroxypropylmethylcellulose (HPMC) or hydroxypropylcellulose (HPC), chitosan, alginates, agar-agar, carrageenans, gums such as xanthan gum, gellan gum, gum arabic, konjac gum, and tara gum, and mixtures thereof.

[0118] The inventors have shown that hyaluronic acid is a polymeric agent particularly suitable for the implementation of the composition according to the invention. Indeed, hyaluronic acid has various biological properties enabling it to promote wound healing.

[0119] Furthermore, as shown in the examples, hyaluronic acid is capable of stabilizing C. cassia essential oil in water in the form of an oil-in-water emulsion. The C. cassia essential oil is thus dispersed in the form of microdroplets stabilized by the hyaluronic acid molecules. As indicated above, the Inventors have also shown that hyaluronic acid is capable of potentiating the antibacterial activity of C. Cassia essential oil, including against antibiotic-resistant bacterial strains. It is thus possible to use a low concentration of C. cassia oil, while maintaining high antibacterial activity and minimizing the risks of toxicity.

[0120] Thus, in a preferred embodiment, the composition according to the invention comprises hyaluronic acid (also referred to hereinafter as HA) as a polymeric agent.

[0121] The inventors have also shown that it is advantageous to incorporate hyaluronic acids with different molecular weights into the composition. Indeed, high molecular weight hyaluronic acids allow the formation of a protective film on the wound and maintain its hydration thanks to their hygroscopic property while low molecular weight hyaluronic acids directly promote the healing and re-epithelialization process.

[0122] In the context of the present invention, a hyaluronic acid has a high molecular weight (hereinafter HMW-AH) if its weight-average molecular mass (Mw) is greater than 600 kDa, preferably greater than 700 kDa or even greater than 800 kDa. Preferably, the weight-average molecular mass of the HMW-AH is less than 2000 kDa, preferably less than 1700 kDa or even less than 1500 kDa. Preferably, the average molecular mass of the HMW-AH is in a range from 600 kDa to 1500 kDa, for example from 800 kDa to 1200 kDa or from 900 kDa to 1100 kDa. In the context of the present invention, a hyaluronic acid has a low molecular weight (hereinafter LMW-AH) if its weight average molecular mass (Mw) is less than 50 kDa, or even less than 40 kDa. The weight average molecular mass of the LMW-AH is preferably at least 1 kDa. Typically, the average molecular weight of the LMW-AH can be in a range from 5 kDa to 25 kDa.

[0123] Thus, in a particular embodiment, the composition according to the invention comprises both high molecular weight hyaluronic acid molecules (HMW-AH) and low molecular weight hyaluronic acid molecules (LMW-AH).

[0124] Preferably, the HMW-AH has an average molecular weight of 600 kDa to 1500 kDa, preferably 800 kDa to 1200 kDa and the LMW-AH has an average molecular weight of 5 kDa to 30 kDa for example 5 kDa to 25 kDa or 10 kDa to 30 kDa.

[0125] Typically, the LMW-AH / HMW-AH mass ratio is in a range from 1 to 100, preferably from 1 to 50 or even from 2 to 25.

[0126] In some embodiments, the LMW-AH / HMW-AH mass ratio is in a range of 1 to 10 or 3 to 7, for example 4 to 6 or 4.5 to 5.5 such as a mass ratio of about 5.

[0127] By way of example, the composition according to the invention may comprise:

[0128] - 0.1% to 0.8%, for example 0.2% to 0.4% by weight of HMW-AH and

[0129] - 0.90% to 4.2%, for example from 1.4% to 1.6% by weight of LMW-AH, the percentages being expressed by weight relative to the total weight of the composition.

[0130] In some embodiments, the HMW-AH has a weight average molecular weight (Mw) of 0.90 MDa to 1.10 MDa, e.g., 0.95 MDa to 1.05 MDa, and the LMW-AH has a weight average molecular weight (Mw) of 10 kDa to 20 kDa, e.g., 14 kDa to 18 kDa, or 15 kDa to 17 kDa.

[0131] The HMW-AH content can also be adjusted to obtain a suitable viscosity, in particular as described above.

[0132] The buffering agent

[0133] The composition according to the invention is an aqueous solution comprising a buffering agent. Typically, it is possible to use any biocompatible buffering agent, in particular pharmaceutically or cosmetically acceptable, making it possible to buffer the composition at a pH between 6.0 and 8.0, preferably between 6.5 and 7.5. The buffering agents of interest include, but are not limited to, phosphate buffers (e.g., monobasic or dibasic potassium or sodium phosphate), citrate buffers (e.g., sodium or potassium citrate), trisaminomethane (TRIS)-based buffers, e.g., TRIS. HCl and TRIS glycine, and mixtures thereof.

[0134] For example, the buffer used can be PBS (phosphate buffered saline) or TBS (Tris buffered saline).

[0135] The molar concentration of the buffer is typically between 10 and 200 mM, for example from 15 mM to 150 mM, for example from 25 to 75 mM. The molar concentration of the buffering agent can be adjusted so as to obtain a suitable osmolarity, in particular as described above.

[0136] The anesthetic agent

[0137] In certain embodiments, the composition according to the invention may comprise an anesthetic agent. Preferably, it is a local anesthetic agent suitable for application to the skin or to mucous membranes. The anesthetic may be chosen from ester or amide type anesthetics, for example from lidocaine, prilocaine, tetracaine, articaine, bupivacaine, cinchocaine, etidocaine, levobupivicaine, mepivacaine, ropivacaine, trimecaine, their pharmaceutically acceptable salts and their combinations, preferably lidocaine, prilocaine, tetracaine, their pharmaceutically acceptable salts and their combinations.

[0138] Preferably, the anesthetic agent is lidocaine or one of its pharmaceutically acceptable salts.

[0139] The content of anesthetic agent in the composition according to the invention varies according to the anesthetic used and the wounds to be treated. Typically, the content of anesthetic agent in the composition according to the invention is at most 10% by weight, preferably at most 5% or 1% by weight, for example from 0.1% to 0.5% by weight.

[0140] By way of illustration, the composition according to the invention may comprise lidocaine or a pharmaceutically acceptable salt in a weight content of approximately 0.3%.

[0141] Potential additional excipients

[0142] In some embodiments, the composition may comprise one or more additional excipients. These excipients are optional. The optional excipient(s) are cosmetically or pharmaceutically acceptable. The optional excipient(s) may be selected in particular from the group consisting of antioxidant agents, preservatives, neutralizing agents such as aminomethyl propanol, pH adjusting agents, for example NaOH or HCl, osmotic agents, surfactants, emulsifiers, thickening agents, perfumes, flavors, and combinations thereof.

[0143] Preferred preservatives include benzoic acid, sorbic acid, benzylic acid, and salts thereof, preferably sodium or potassium, benzalkonium chloride, and combinations thereof.

[0144] Antioxidant agents include, but are not limited to, tocopherol, tocopheryl acetate, ascorbic acid and its salts and esters, including ascorbyl palmitate or stearate, carvacrol, or plant extracts, including rosemary.

[0145] Osmotic agents include inorganic salts such as NaCl or KCl, and organic salts, including carboxylic acids such as citrate salts.

[0146] Thickening or gelling agents include collagen, starches, and cellulose and its derivatives, for example, HPMC, HPC, or carboxymethylcellulose (also known as carmellose) and its salts.

[0147] As mentioned above, the presence of C. cassia essential oil in the form of microdroplets stabilized by the polymeric agent increases its antibacterial effect. C. cassia essential oil therefore acts as a preservative within the composition.

[0148] Thus, in certain embodiments, the composition according to the invention is free of any preservative or bactericidal agent chosen from parabens, triclosan, cetylpyridinium, phenoxyethanol, thiazolinone derivatives such as methylchloroisothiazolinone (MIT) and antibiotic agents.

[0149] In some embodiments, the composition according to the invention does not comprise ethanol. Generally, it does not comprise lower alcohol (i.e., C1-C5 alcohol).

[0150] In other embodiments, the composition according to the invention is free of any preservative or bactericidal agent cited in the present description other than the essential oil of C. cassia.

[0151] Preferably, the composition according to the invention is free of any preservative or bactericidal agent other than the essential oil of C. cassia.

[0152] In certain embodiments, the composition according to the invention comprises one or more additional excipients selected from the group consisting of pH adjusting agents, osmotic agents, thickening or gelling agents, perfumes, flavors, antioxidant agents and combinations thereof.

[0153] When present, the additional excipient(s) preferably represent at most 15%, or even at most 10%, 5%, 4%, 3%, 2%, 1%, 0.5% by weight relative to the total weight of the composition.

[0154] It goes without saying that the additional excipient(s) potentially present are chosen according to the intended use and the intended area of ​​application (skin, mucous membrane).

[0155] Potential additional active ingredients

[0156] The composition according to the invention may further comprise one or more additional active agents (also referred to herein as optional), for example vitamins, a moisturizing or humectant agent such as glycerin, a soothing or anti-inflammatory agent, for example panthenol, allantoin, licochalcone A, bisabolol, avenanthramides, madecassic acid, niacinamide or liquorice extracts, birch extracts, oat extracts, in particular oat plantlets, Epilobium augustifolium extracts, Calendula officialis extracts, an additional healing agent such as Aloe vera or Centella asiatica extracts or Asiatic acid, a sanitizing agent, for example copper or zinc sulfate. The composition according to the invention may comprise one or more additional plant extracts, in particular chosen from essential oils.

[0157] When present, the optional active ingredient(s) preferably represent at most 5%, or even at most 4%, 3%, 2%, 1%, 0.5% or 0.1% by weight relative to the total weight of the composition.

[0158] In certain embodiments, the composition according to the invention comprises one or more additional active agents chosen from soothing agents, vitamins, in particular vitamins C and D as well as their derivatives and moisturizing agents.

[0159] In certain embodiments, the composition according to the invention is devoid of any additional healing agent other than the polymeric agent, in particular those cited in the present description.

[0160] In certain embodiments, the essential oil of C. cassia is the only essential oil present in the composition according to the invention as an active ingredient.

[0161] In another embodiment, the essential oil of C. cassia is the only plant extract present in the composition according to the invention as an active ingredient. It goes without saying that the additional active ingredient(s) potentially present are chosen according to the intended use and the intended area of ​​application (skin, mucous membrane). For example, soothing, healing or sanitizing agents are preferably used in a composition intended to be applied to the skin.

[0162] In some embodiments, the composition is free of any antiseptic agent other than C. cassia oil, such as chlorhedexine, benzalkonium, biclothymol, chlorexydine, hexamidine, amylmetacresol and dichlorobenzyl alcohol.

[0163] Preferably, when present, the additional excipient(s) and the optional active ingredient(s) together represent at most 20% or at most 10%, preferably at most 5.0%, more preferably at most 3.0% by weight or even at most 2.0%, 1.5%, or 1.0% by weight relative to the total weight of the composition.

[0164] In certain embodiments, the topical composition according to the invention does not comprise an additional active ingredient other than the essential oil of C. cassia and the optional anesthetic agent.

[0165] In certain embodiments, the potential additional active ingredients and excipients together represent at most 5%, preferably at most 4%, 3%, 2%, or 1%, by weight of the total weight of the topical composition according to the invention.

[0166] Particular embodiments of the composition according to the invention

[0167] According to a particular aspect, the subject of the invention is a topical composition comprising, preferably consisting essentially of: from 1.0% to 5.0%, preferably from 1.0% to 4.0% or even from 1.5% to 2.5% by weight of hyaluronic acid from 0.02% to 0.50%, preferably from 0.025% to 0.30%, more preferably from 0.04% to 0.25%, for example from 0.05% to 0.20% by weight of essential oil of Cinnamomum cassia, from 0% to 5%, preferably from 0% to 3%, more preferably from 0% to 1% by weight of an anesthetic agent, from 0% to 5% by weight of one or more additional excipients or active ingredients, and a buffering agent, in water, the percentages being expressed by weight relative to to the total weight of the composition. Preferably, the composition is further characterized in that it has one, several or even all of the following characteristics:

[0168] - the hyaluronic acid is present in the form of a mixture of high molecular weight hyaluronic acid molecules (HMW-AH) and low molecular weight hyaluronic acid molecules (LMW-AH) in a LMW-AH / HMW-AH mass ratio in a range from 2 to 10, preferably from 3 to 7, for example from 4 to 6 or from 4.5 to 5.5 such as a mass ratio of approximately 5,

[0169] - C. Cassia essential oil is obtained by distillation, preferably by hydrodistillation or steam distillation of C. Cassia bark,

[0170] - the anesthetic agent is lidocaine or a pharmaceutically acceptable salt thereof, for example a hydrochloride,

[0171] - the buffering agent is present in a concentration of between 10 mM and 100 mM, preferably at a concentration of approximately 50 mM,

[0172] - the buffering agent is chosen from phosphate buffers, TRIS buffers and combinations thereof,

[0173] - the pH of the composition is in the range from 6.5 to 7.5

[0174] - the osmolarity of the composition is in a range from 250 to 450 mOSm, preferably from 300 to 400 mOSm.

[0175] - the composition comprises one or more additional excipients or active agents chosen from pH adjusting agents, osmotic agents, antioxidant agents, thickening or gelling agents, soothing agents, vitamins, moisturizing agents, and combinations thereof.

[0176] - the composition is free from ethanol and any preservative or bactericidal agent other than C. cassia essential oil, including parabens, triclosan, cetylpyridinium, phenoxyethanol, thiazolinone derivatives such as methylchloroisothiazolinone (MIT) and antibiotic agents.

[0177] The hyaluronic acid is preferably a mixture of low molecular weight hyaluronic acid (LMW-AH) molecules having a weight average molecular mass (Mw) of less than 50 kDa and high molecular weight hyaluronic acid (HMW-AH) molecules having a weight average molecular mass (Mw) of greater than 600 kDa.

[0178] According to another particular embodiment, the composition according to the invention comprises or consists essentially of: - 1.5% to 2.5% by weight of hyaluronic acid, the hyaluronic acid being present in the form of an LMW-AH / HMW-AH mixture with a mass ratio ranging from 3 to 7, for example from 4 to 6 or from 4.5 to 5.5

[0179] - from 0.04% to 0.25%, preferably from 0.05% to 0.20% by weight of essential oil of Cinnamomum cassia, said oil preferably being obtained by steam distillation of C. cassia bark

[0180] - from 0% to 1% by weight of a local anesthetic agent, preferably lidocaine, and

[0181] - a buffering agent in a concentration of 10 mM to 100 mM, said buffer preferably being chosen from phosphate buffers, TRIS buffers and combinations thereof, in particular PBS and TBS buffers, in water, the percentages being expressed by weight relative to the total weight of the composition.

[0182] Said composition may further have a pH ranging from 6.5 to 7.5, an osmolarity of 250 to 400 mOSm, and a viscosity of 10 to 100 cP, preferably 10 to 70 cP.

[0183] Method of manufacturing the composition according to the invention

[0184] According to an additional aspect, the invention relates to a process for preparing the composition according to the invention comprising the following steps:

[0185] (a) the dispersion and the polymeric agent in a buffered aqueous solution,

[0186] (b) the possible addition of local anesthetic, and

[0187] (c) adding C. cassia essential oil with stirring.

[0188] In step (a), the polymeric agent is preferably provided in the form of a hyaluronic acid, for example a mixture of high and low molecular weight hyaluronic acids.

[0189] Preferably, the hyaluronic acid is added in the form of a salt, for example a sodium and / or potassium salt. Typically, the polymeric agent is added slowly to the aqueous phase, with stirring.

[0190] The medium is kept stirring for the time necessary for the polymer to hydrate and to obtain a homogeneous dispersion without aggregates. Stirring can be maintained, for example, for a few minutes to a few hours, e.g. from 30 min to 3 h. The buffered aqueous solution can comprise any type of buffering agent as described above. This can in particular be a PBS buffer.

[0191] In step (b), the optional anesthetic is added with stirring. If other excipients or active ingredients are to be incorporated into the composition, they are preferably added in step (b). Stirring is preferably maintained until the anesthetic is dispersed or even completely dissolved.

[0192] In step (c), the essential oil of C. Cassia is added and the medium is stirred for the time necessary to obtain a solution of homogeneous appearance.

[0193] At the end of step (c), an oil-in-water emulsion (i.e. essential oil of C. cassia in the buffered solution) is obtained.

[0194] The method according to the invention may comprise one or more additional steps, in particular a filtration, sterilization or packaging step in a suitable administration device.

[0195] Uses of the composition according to the invention and other objects according to the invention

[0196] The present application also relates to the use of the composition as described above as a composition for the treatment of wounds and / or as a composition for the treatment or prevention of bacterial infections, in particular of the skin or the ENT sphere, in particular the throat. The composition according to the invention can also be used for the treatment of blemished skin or acne-prone skin. In certain embodiments, the composition according to the invention can be used for the treatment of any wound of the skin or mucous membranes such as the mucous membrane of the ENT sphere, in particular the oral cavity or the throat. Typically, the composition according to the invention can be used as a disinfectant and / or wound healing composition.

[0197] Preferably, the composition according to the invention can be used to promote the healing of a wound while preventing its infection by a pathogenic bacteria.

[0198] In a particular embodiment, the composition according to the invention can be used to accelerate the re-epithelialization of a wound.

[0199] In another embodiment, the composition according to the invention can be used to promote skin regeneration, more precisely the regeneration of the epidermis, for example at the level of a skin wound.

[0200] For the purposes of this application, the term “skin” means any part of the skin of the human body, in particular the skin of the face, including the lips and eyelids, the scalp, the neck, the skin of the hands and the skin of the feet.

[0201] The wound may be any type of wound of the skin or mucous membranes. It may be a superficial wound of the skin, or a deeper or more serious wound such as a postoperative wound including dental, in particular a suture, or a burn. The wound may be present on any part of the body, in particular on the face including the lips, on the hands including the fingers, feet, legs, elbows and knees, or even on the oral sphere, for example on the tongue, gums, palate or the inner side of the cheeks. In certain embodiments, the composition according to the invention is used to treat a superficial wound of the skin. The term "superficial wound of the skin" refers to a wound or injury restricted to the epidermis or extending from the epidermis to the dermis or even to the hypodermis.“Superficial” wounds or lesions include, but are not limited to, irritations, redness, cuts and micro-cuts, scrapes, cracks, chapping, blisters, crevices, superficial pressure sores (type I or II), insect bites, spots, including acne spots such as papules and pustules.

[0202] Superficial wounds may result from exposure of the skin to an external aggression, for example cold, sun, or wind, to a chemical treatment or even to a mechanical cause (typically by contact with a sharp, cutting or abrasive surface, by friction or pressure, or even by puncture, for example tattoo). Superficial wounds may be favored by the individual's skin type, for example sensitive, weakened, atopic-prone skin, dry skin and / or aged skin (eg thinned skin). Superficial wounds may also be caused or associated with a disorder or disease, for example cutaneous such as atopic dermatitis, eczema, or dyshidrosis, or by diabetes or an autoimmune disease such as scleroderma. The composition is applied topically, to the wound to be treated, by any known means.

[0203] For example, the composition may be applied by brushing, dipping, bathing, spraying, or using a dressing, gauze, or any other matrix impregnated with the composition according to the invention or on which said composition is deposited. The composition according to the invention may also be applied to the skin using a cutaneous device allowing its controlled release, said composition being contained in a reservoir within said device.

[0204] As illustrated in the examples, the composition according to the invention has bactericidal activity against several bacterial species involved in skin or ENT infections, including antibiotic-resistant strains.

[0205] Thus, in a particular embodiment, the subject of the invention is the use of the composition according to the invention for treating or preventing a bacterial infection, in particular ENT or cutaneous. The composition according to the invention can be used for preventing or treating an infection caused by a bacterial agent chosen from Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Streptococcus pyogenes and combinations thereof.

[0206] H can be an infection occurring in a pre-existing wound or an infection not related to a pre-existing wound.

[0207] It can be a skin infection, for example impetigo, or an ENT infection, for example tonsillitis and / or bacterial pharyngitis, or more generally a sore throat of bacterial origin.

[0208] For example, the composition according to the invention can be used to treat mouth sores and to treat or prevent sore throats, including bacterial tonsillitis. Typically, the composition according to the invention can be administered in the form of a spray (e.g. a mouthwash) or by dabbing on the mucous membrane.

[0209] It goes without saying that when the composition comprises a local anesthetic agent, for example lidocaine, said composition can also be used to relieve pain, for example at the level of a skin wound or a mucous membrane or at the level of an infected ENT area (eg tonsil, pharynx).

[0210] The inventors have shown that the composition is also bactericidal against C. acnes, the bacterial agent responsible for acne.

[0211] Thus, in certain embodiments, the composition according to the invention is used for the treatment of blemished skin or acne-prone skin, in particular for preventing or treating acne pimples. In a particular embodiment, the composition according to the invention is used for preventing or treating acne vulgaris.

[0212] Finally, in view of its broad-spectrum bactericidal activity, the composition according to the invention can be used as a disinfectant or antiseptic composition. The composition according to the invention can be used in particular to disinfect a surface or as an alternative to a hydroalcoholic gel for cleaning and disinfecting any part of the skin, in particular the hands. In other words, the composition according to the invention can be used as a washing composition with a bactericidal effect on the skin, in particular the hands. Advantageously, the composition according to the invention is used without rinsing.

[0213] It should be noted that the composition according to the invention does not have a drying or irritating effect on the skin, as is traditionally observed with hydroalcoholic gels.

[0214] In the various uses described above, the composition is applied in the form of a spray or an aerosol. Any type of device suitable for this purpose can be used, in particular those using a propellant gas, preferably compressed air. The device may in particular be a pressurized bottle equipped with a valve associated with an actuator and a diffuser allowing the formation of a spray. Reference may in particular be made to the “Bag-on-Valve” system marketed by the company Aptar.

[0215] Once applied to the skin and after evaporation of the water, the composition according to the invention can form a film. In the case of a wound, this protective film can promote wound healing while preventing the development of an infection.

[0216] In the case of the treatment of a wound or a bacterial infection, the application of the composition according to the invention can be repeated until complete healing or complete cure, for example for at least 2 days, or for at least 5 days. Typically the duration of treatment varies from 5 to 10 days depending on the condition to be treated. Longer or shorter durations of application can also be considered. The composition according to the invention is applied at least once, typically e.g. at least once, twice or three times a day.

[0217] In the case of acne treatment, the composition according to the invention can be applied to the skin, particularly to spots, once or twice a day until the spots disappear. The treatment can last a few days or several weeks, for example from 2 weeks to 3 months.

[0218] In the case of washing and disinfecting the skin, for example the hands, the composition according to the invention can be used one to several times a day, for example 1 to 6 times a day. Preferably, the composition is applied to the skin without rinsing.

[0219] According to a particular aspect, the invention also relates to a method for treating a wound at the level of the skin or a mucous membrane comprising the topical application of the composition according to the invention. As indicated above, the composition according to the invention is preferably applied to the wound in the form of a spray (or an aerosol).

[0220] According to another aspect, the invention also relates to a method for treating or preventing a bacterial infection at the level of the skin or a mucous membrane comprising the topical application of the composition according to the invention. As indicated above, the composition according to the invention is preferably applied to the area to be treated in the form of a spray (or an aerosol) or by brushing.

[0221] According to a complementary aspect, the invention also relates to a method for washing and disinfecting the skin, in particular the hands, comprising the topical application of the composition according to the invention. As indicated above, the composition according to the invention can be applied to the area to be treated directly or in the form of a spray (or an aerosol).

[0222] The invention can be implemented in any type of subject, in particular in any type of mammal. Preferably, the subject is a human being. The human subject can be of any age and of any gender. It can be in particular an adult subject, a child or an infant. Preferably, it is an individual aged 6 years or older or even 15 years or older.

[0223] An additional object according to the invention is a device, preferably medical, containing the composition according to the invention and allowing its administration in the form of a spray or an aerosol. The device may comprise a chamber, preferably metallic, sealed, provided with a valve, in which

[0224] (i) said enclosure comprises a hermetic bag, preferably made of aluminum, filled with the composition according to the invention and connected to the valve, and a pressurized propellant gas stored in the space existing between the walls of the enclosure and the bag, and

[0225] (ii) said valve is provided with a diffuser with an actuator which allows the administration of the composition in spray form when the actuator is activated.

[0226] Preferably, the airtight bag allows the composition to be stored under an inert atmosphere, i.e. in the absence of oxygen.

[0227] According to a certain embodiment, the device is suitable for administering the composition to the ENT sphere, in particular to the throat or oral cavity.

[0228] According to another embodiment, the device is suitable for administering the composition to the skin.

[0229] In a further aspect, the invention also relates to the use of a polymeric agent as described herein, in particular a hyaluronic acid as described herein, for increasing the antibacterial activity of C. cassia essential oil in aqueous solution. In another aspect, the invention also relates to the use of a polymeric agent as described herein, in particular a hyaluronic acid as described herein, for stabilizing C. Cassia essential oil in an aqueous solution, preferably in the form of an oil-in-water emulsion.

[0230] In the uses described above, the mass ratio of polymeric agent / C. cassia essential oil may be in a range from 5 to 45, preferably from 7 to 43 and more preferably from 9 to 36. The contents of polymeric agent, preferably hyaluronic acid and C. cassia essential oil may be as described above. Preferably, the aqueous solution comprises a buffering agent as described herein and has a pH of between 6.0 and 8.0, preferably between 6.5 and 7.5.

[0231] Other aspects and advantages of the present invention will appear on reading the following examples, which must be considered as illustrative and in no way as limiting.

[0232] EXAMPLES

[0233] EXAMPLE 1: Process for manufacturing a composition according to the invention

[0234] - List of ingredients: a) Medical grade hyaluronic acid:

[0235] - Medical grade HMW-AH hyaluronic acid with an average molecular weight of approximately 1 MDa

[0236] - Medical grade LMW-AH hyaluronic acid with an average molecular weight of approximately 16 KDa b) 50 mM Tris buffer and pH 7.4 prepared from tris(hydroxymethyl)aminomethane, sodium chloride, hydrochloric acid and water. c) Lidocaine hydrochloride d) Essential oil of C. cassia obtained by distillation of the bark comprising between 70% and 90% by weight of trans-cinnamic aldehyde and from 1% to 6% by weight of cinnamyl acetate and from 3 to 15% of tran.s-2-methoxycinnamaldehyde,

[0237] - Preparation :

[0238] 50% of the total volume of the buffer solution was put into the stirrer. The two hyaluronic acids (powder) were added. The resulting mixture was kept stirring at a speed of approximately 700 rpm for at least 1 hour 30 minutes until the hyaluronic acid aggregates had completely disappeared. The absence of residual aggregates was checked visually. The remaining 50% of buffer was then added to the mixture. Lidocaine hydrochloride in powder form was then added. The mixture was stirred again at 700 rpm until the lidocaine was completely dissolved (usually for approximately 30 minutes). The absence of lidocaine aggregates was checked visually. C. cassia essential oil was then added to the mixture. The mixture was stirred at 700 rpm until a homogeneous mixture was obtained (for approximately 1 hour).

[0239] Composition (mass percentage):

[0240] - 1.8% hyaluronic acid in a LMW-HA / HMW-HA mass ratio of 5.0 - 0.2% C. cassia essential oil,

[0241] - 0.3% lidocaine hydrochloride,

[0242] - 50 mM Tris buffer

[0243] For the biological tests (Example 4): a similar composition but without lidocaine was prepared using a similar method. The pH of the final solution is approximately 7.3 and the osmolarity is approximately 320 mOsm. Indeed, the presence of lidocaine hydrochloride increases the osmolarity and slightly decreases the pH.

[0244] - Results :

[0245] A homogeneous mixture is obtained. The mixture has a slight turbidity and a pH of approximately 6.9. The viscosity is approximately 37 cP. The osmolarity is 315 mOsm. This mixture corresponds to the composition according to the invention, which is an oil-in-water emulsion.

[0246] EXAMPLE 2: Characterization of the composition according to the invention

[0247] The composition according to the invention is an emulsion. These characteristics were analyzed by two methods: Optical microscopy and Laser granulometry.

[0248] Optical microscopy: method

[0249] A sample of the composition according to the invention was observed under an optical microscope at different magnifications (x10, x40 and x100), as is and after dilution, with and without a coverslip.

[0250] Laser granulometry: method

[0251] A sample of the composition according to the invention was observed by laser granulometry using a device for laser granulometry for liquids.

[0252] Results obtained

[0253] The composition according to the invention is in the form of an oil-in-water emulsion. The C. cassia oil droplets present in the composition according to the invention are homogeneous in size and morphology, and have an average diameter of less than 5 μm.

[0254] EXAMPLE 3: Study of the stability of the composition according to the invention

[0255] 2 stability studies were carried out:

[0256] • A stability study under so-called accelerated conditions at 40°C • A stability study under stress conditions with centrifugation and with light: LUMifuge® stability analysis

[0257] - Stability study under so-called accelerated conditions at 40°C

[0258] A stability study under accelerated conditions at 40°C for a period of 3 months was carried out. These conditions are known to simulate a stability study under standard conditions of 24 months at 25°C. This study was carried out in an oven.

[0259] At the end of this study, the physicochemical parameters were measured.

[0260] Results obtained:

[0261] No evolution or destabilization of the emulsion was observed. The physicochemical parameters remained within the specification values ​​(i.e. pH 7.5+ / -0.5, Osmolarity 250 to 400 and viscosity 20 to 70cps). A slight decrease in viscosity and osmolarity was observed, which is expected and corresponds to a slight degradation of hyaluronic acid.

[0262] -A stability study under stress conditions with centrifugation and exposure to light: LUMifuge® stability analysis

[0263] The sample was analyzed with LUMifuge®, using the following method:

[0264] 2 hours of centrifugation at 20°C and 1000 xg (g being the acceleration of gravity) with an incident light intensity of 2.

[0265] A second, more aggressive study was then carried out:

[0266] 4 h of centrifugation at 20°C and 2,300 xg (g being the acceleration of gravity) with an incident light intensity of 2.

[0267] Results obtained:

[0268] No evolution or destabilization of the emulsion was observed, which demonstrates the stability of the composition according to the invention.

[0269] EXAMPLE 4: Potentiation of the bactericidal effect of C. cassia oil. Evaluation by comparison of the Minimum Bactericidal Concentration (MBC).

[0270] The Minimum Bactericidal Concentration (MBC) is the lowest concentration of an antibacterial agent required to kill a particular bacterium. It can be determined from broth dilution minimum inhibitory concentration (MIC) tests by subculturing bacteria onto agar plates that do not contain the antibacterial agent being tested. The MBC is identified by determining the lowest concentration of antibacterial agent that reduces the viability of the initial bacterial inoculum to a level greater than or equal to 99.9%.

[0271] Method :

[0272] The determination of the Minimum Bactericidal Concentration (MBC) on Staphylococcus aureus ATCC 29213 is adapted from the ISO 20776-1: 2019 standard by following the recommendations of the standard concerning the culture medium (Mueller-Hinton), the incubation time (18h + / - 2h) as well as the inoculum (2 - 8 x 105 CFU / mL). The incubation is carried out in a 96-well microplate. All concentrations are expressed in mass / mass.

[0273] 4 products were manufactured to determine whether the combination of hyaluronic acid and C. cassia essential oil (0.2%) has a potentiating effect.

[0274] Sample 1: Hyaluronic acid (1.8%) + C. cassia essential oil (0.2%) in 50mM Tris buffer (composition according to the invention prepared according to Example 1 but without the addition of lidocaine)

[0275] Sample 2: Hyaluronic acid (1.8%) in 50mM Tris buffer

[0276] Sample 2 is a control to verify that hyaluronic acid at the concentration used has no antimicrobial effect.

[0277] Sample 3: Hyaluronic acid (1.8%) + neutral oil (0.2%) (sweet almond oil) in 50mM Tris buffer

[0278] Sample 3 is the control of hyaluronic acid combined with an oil with no known antimicrobial effect to ensure that it is not the mixture of an oil and hyaluronic acid that causes an effect.

[0279] Sample 4: corresponds to the essential oil of C. cassia alone (pure) (batch identical to that used for sample 1) to control its antimicrobial effect.

[0280] Samples were diluted to obtain solutions with an equivalent concentration of C. cassia essential oil (or neutral oil) between 0.5% and 0.005%. The bacterial strain was subcultured twice from stock solutions onto Mueller-Hinton (MH) agar plates and incubated at 37°C. 100 pL of each concentration of test product (2X) were placed in microplates in triplicate (3 wells per concentration).

[0281] For the inoculation of S. aureus, the initial suspension was prepared in MH medium, and adjusted between 2 and 8 x 105 CFU / mL (by absorbance measurement OD 600nm) (confirmed by counting 5.93 x 105 CFU / mL) and 100 pL were filled per well. In parallel, several controls were prepared:

[0282] • Strain control: suspension of bacteria + MH

[0283] • Product control: Product + MH

[0284] • Average control: MH

[0285] The plates were incubated aerobically at 37°C for 18 h.

[0286] From wells where no growth was observed, 10 pL was deposited onto MH agar plates.

[0287] Results

[0288] Hyaluronic acid alone (sample 2) or combined with a neutral oil (sample 3) has no notable bactericidal effect (CMB > 0.1%).

[0289] C. cassia essential oil alone (sample 4) showed a CMB value twice as high (results of 0.06%) as the combination with hyaluronic acid (sample 1) (results of 0.03%).

[0290] Therefore, it is the combination of hyaluronic acid with C. cassia essential oil that exhibits optimal bactericidal activity against S. aureus. Hyaluronic acid therefore enhances the bactericidal activity of C. cassia essential oil.

[0291] EXAMPLE 5: Verification of the Minimum Inhibitory Concentration (MIC) of C. cassia oil

[0292] The MIC corresponds to the minimum concentration of an antibacterial agent capable of inhibiting the growth of one or more bacteria of interest. The MIC makes it possible to measure the sensitivity of the pathogen to an antimicrobial agent.

[0293] Method :

[0294] The determination of the MIC is carried out on

[0295] Staphylococcus aureus ATCC 29213 one of the 3 main bacterial strains responsible for skin wound infections

[0296] Staphylococcus aureus USA 300 (Methicillin-resistant Staphylococcus aureus (MRSA)) is the main antibiotic-resistant bacteria responsible for skin wound infections (nosocomial)

[0297] Pseudomonas aeruginosa CIP 82.118 one of the 3 main bacterial strains responsible for skin wound infections Escherichia coli DSM 1576 one of the 3 main bacterial strains responsible for skin wound infections

[0298] Streptococcus pyogenes DSM 20565 main bacterial strain responsible for bacterial throat infections (tonsillitis)

[0299] Cutibacterium acnes CIP 53.117 is the main bacterial strain responsible for bacterial acne.

[0300] The MIC determination was carried out in accordance with ISO 20776-1:2019, in particular by following the recommendations of the standard concerning the culture medium (example: Mueller-Hinton), the incubation time (18h + / - 2h) as well as the inoculum (2 - 8 x 105 CFU / mL). The incubation was carried out in a 96-well microplate. All concentrations are expressed as a mass percentage (mass / mass).

[0301] Staphylococci and S. pyogenes were subcultured twice from stock solutions onto Mueller-Hinton (MH) agar and incubated at 37°C under aerobic conditions for staphylococci and anaerobic conditions for Streptococcus, prior to testing.

[0302] The C. acnes strain was subcultured twice from stock solutions onto Medium 20 (M20) agar plates and incubated at 37°C under anaerobic conditions prior to testing.

[0303] Several dilutions of C. cassia essential oil were prepared in the culture medium (MH or M20) containing 0.15% agar and tested to determine the MIC

[0304] Tested concentrations (mass percentage)%: 0.5 0.4 0.3 0.2 0.1 0.075 0.05 0.025 0.0125 0.005

[0305] 100 μL of each essential oil dilution was added to the microplates. For each concentration, the experiment was triplicated.

[0306] For bacterial inoculation, the initial suspension was prepared in MH-0.15% agar for S. aureus and S. pyogenes or M20-0.15% agar for C. acnes. Each bacterial concentration was adjusted between 2 and 8 x 10 5 CFU / mL (by absorbance measurement OD 600nm) and 100 pL were filled per well.

[0307] The initial inoculum was confirmed by counting at 7.83xl0 5 CFU / mL for S. aureus ATCC 29213; 2.47xl0 5 CFU / mL for S. aureus USA 300; 2.00xl0 5 CFU / mL for S. pyogenes; 4.56xl0 5 CFU / mL for C. acnes.

[0308] In parallel, several controls were prepared:

[0309] - Strain control: 100 pL of 0.15% agar medium + 100 pL of bacterial suspension - Product control: 100 pL of product (dX) + 100 pL of 0.15% agar medium

[0310] - Medium control: 200 pL of medium with 0.15% agar

[0311] The plates were incubated at 37°C:

[0312] - 18 hours in a humid chamber for strains of S. aureus

[0313] - 24 hours in anaerobic conditions for S. pyogenes

[0314] - 42 hours in anaerobic conditions for C. acnes

[0315] After incubation, absorbance was measured at 600 nm for each well after shaking the plates.

[0316] Results

[0317] The CMI results obtained are as follows:

[0318] [Table 1]

[0319] All the results obtained show an effectiveness for concentrations of C. cassia lower than 0.05%.

[0320] EXAMPLE 6: Cytotoxicity of C. cassia essential oil

[0321] Method

[0322] The cytotoxicity test based on 1TSO10993-5 on BALB / 3T3 clone A31 fibroblast cells is carried out according to the direct contact method. The composition according to the invention comprising (i) 1.8% hyaluronic acid, 0.2% C. cassia essential oil in 50 mM Tris buffer was diluted to different concentrations and was brought into contact with 30,000 cells for 24 hours at 37°C. The toxicity threshold is set at 70%, i.e. if cell mortality is greater than 30% the product is considered cytotoxic.

[0323] The method for assessing cell viability is the trypan blue staining method. The objective is an absence of cytotoxicity of the product at a concentration of 5 mg / mL.

[0324] Results

[0325] The composition according to the invention exhibits slight cytotoxicity for a concentration of

[0326] 5 mg per mL of medium (results of 69% viability) and no toxicity for a concentration of 2.5 mg / mL (results of 93% viability). The acceptable cytotoxicity threshold was obtained for a concentration of 0.20%.

[0327] The absence of cytotoxicity with the composition according to the invention was therefore obtained for an equivalent concentration of C. cassia essential oil of 0.1% by weight.

Claims

CLAIMS 1. Topical composition consisting essentially of: - from 1.0% to 5.0% by weight of a hyaluronic acid, - at most 0.50% by weight of essential oil of Cinnamomum cassia, - a buffering agent present in a concentration ranging from 10 mM to 200 mM„ and - optionally an anesthetic agent present in a content of at most 1.0% by weight, in water, the percentages being expressed by weight relative to the total weight of the composition and said composition having a pH of 6.0 to 8.

0.

2. Topical composition according to claim 1 characterized in that - hyaluronic acid is present in a content of 1.0% to 4.0%, preferably 1.5% to 2.5% by weight and - the essential oil of Cinnamomum cassia is present in a content of 0.025% to 0.50%, preferably 0.04% to 0.25%, and more preferably 0.05% to 0.20% by weight.

3. Topical composition according to claim 1 or 2, wherein the hyaluronic acid is a mixture of low molecular weight hyaluronic acid (LMW-AH) molecules having a weight average molecular mass (Mw) of less than 50 kDa and high molecular weight hyaluronic acid (HMW-AH) molecules having a weight average molecular mass (Mw) of greater than 600 kDa, the LMW-AH / HMW-AH mass ratio being in a range of 3 to 7.

4. Topical composition according to claim 3, the LMW-AH / HMW-AH mass ratio is within a range of 4 to 6.

5. Topical composition according to any one of claims 1 to 4, in which the essential oil of Cinnamomum cassia is obtained by distillation, preferably by steam distillation, of the bark of C. cassia.

6. Topical composition according to any one of claims 1 to 5, characterized in that it contains at most 1% by weight of a local anesthetic agent, preferably lidocaine or one of its pharmaceutically acceptable salts.

7. Topical composition according to any one of claims 1 to 6, characterized by at least 1, 2 or 3 of the following characteristics: - the composition has a pH ranging from 6.5 to 7.5 and / or - the composition has an osmolarity ranging from 300 to 400 mOsm, preferably 320 to 380 mOsm and / or - the composition has a viscosity ranging from 10 cP to 100 cP.

8. Topical composition according to any one of claims 1 to 7, characterized in that the buffering agent is present in a concentration ranging from 15 mM to 150 mM, preferably from 25 to 75 mM, for example approximately 50 mM.

9. Topical composition according to any one of claims 1 to 8, characterized in that it comprises: - one or more additional cosmetically or pharmaceutically acceptable excipients selected from the group consisting of pH adjusting agents, osmotic agents, antioxidant agents, thickening agents, gelling agents, perfumes, flavorings and combinations thereof and / or - one or more additional active agents chosen from the group consisting of moisturizing agents, vitamins, soothing agents, anti-inflammatory agents and their combinations, the excipient(s) and / or additional active agent(s) together representing at most 5% by weight, preferably at most 2.5% or at most 1.0% of the total weight of the composition.

10. Topical composition according to any one of claims 1 to 9, characterized in that it consists essentially of: - from 1.5% to 2.5% by weight of hyaluronic acid, said hyaluronic acid being a mixture of low molecular weight hyaluronic acid molecules (LMW-AH) having an Mw of less than 50 kDa and high molecular weight hyaluronic acid molecules (HMW-AH) having an Mw of greater than 600 kDa, according to a LMW-AH / HMW-AH mass ratio in a range of 4 to 6, - from 0.04% to 0.25% by weight of essential oil of Cinnamomum cassia, - from 0% to 1.0%, preferably from 0% to 0.5% by weight of an anesthetic agent, said anesthetic agent being lidocaine or a pharmaceutically acceptable salt thereof, and - a buffering agent present in a concentration ranging from 25 to 75 mM, said buffering agent being chosen from TRIS buffers, phosphate buffers and their mixtures, in water, the percentages being expressed by weight relative to the total weight of the composition.

11. A topical composition according to any one of claims 1 to 10, wherein the C. cassia oil comprises from 70% to 90% by weight of trans-cinnamic aldehyde, from 1% to 6% by weight of cinnamyl acetate and from 3 to 15% of trans-2-methoxycinnamaldehyde.

12. Topical composition according to any one of claims 3 to 11, in which the hyaluronic acid is characterized in that it is a mixture of HMW-AH having an Mw ranging from 800 kDa to 1200 kDa and LMW-AH with an Mw ranging from 10 kDa to 30 kDa according to a LMW-AH / HMW-AH mass ratio of 4 to 6.

13. Topical composition according to any one of claims 1 to 12, said composition being sprayable.

14. Topical composition according to any one of claims 1 to 13 for use in the treatment of a wound of the skin or mucous membranes, and / or in the treatment or prevention of bacterial infections of the skin or the ENT area, in particular of the throat and mouth and / or in the treatment or prevention of acne.

15. Topical composition for use according to claim 14, said composition being used to promote healing and disinfection at the level of a wound.

16. Topical composition for use according to any one of claims 14 to 15, wherein the wound is chosen from the group consisting of irritations, redness, cuts and micro-cuts, scratches, cracks, chapping, blisters, crevices, bedsores, especially superficial type I or II, insect bites, spots, especially acne, post-operative wounds, especially sutures, and burns.

17. Medical device for administration in the form of a spray or aerosol comprising the topical composition defined according to any one of claims 1 to 13.

18. Device according to claim 17 characterized in that it comprises a pressurized bottle provided with a valve associated with an actuator and a diffuser allowing the formation of a spray 19. Use of the topical composition defined according to any one of claims 1 to 13 in washing and disinfecting the skin, in particular the hands, preferably without rinsing.

20. Use of a hyaluronic acid preferably as defined in claims 3, 4 and 12 as an agent for stabilizing an essential oil of C. Cassia in the form of a dispersion in an aqueous solution and / or as an agent for increasing the antibacterial activity of said essential oil of C. cassia.

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