OIL-IN-WATER EMULSION COMPRISING HYALURONIC ACID AND DEXPANTHENOL

Abstract

The present invention relates to an oil-in-water emulsion comprising an aqueous phase and a lipid phase. The emulsion is characterized by the presence of an aqueous phase comprising hyaluronic acid or its salt, and dexpanthenol. The emulsion is particularly suitable for ophthalmic use.

Description

Title of the invention: OIL-IN-WATER EMULSION COMPRISING HYALURONIC ACID AND DEX-PANTHENOL FIELD OF THE INVENTION.

[0001] The present invention relates to an oil-in-water type emulsion comprising an aqueous phase and a lipid phase. The emulsion is characterized by the presence of an aqueous phase which comprises hyaluronic acid or its salt, and dexpanthenol (also called Panthenol, provitamin B5, D-panthenol). The emulsion according to the invention is suitable for ophthalmological use, in particular for topical ophthalmic treatment. BACKGROUND OF THE INVENTION.

[0002] The ocular surface is a complex environment that provides the transition between the external environment and the intraocular structures. The eyelids constitute the first line of defense of the ocular surface and participate in the maintenance of the tear film that covers the conjunctival epithelium, in particular thanks to the lacrimal glands and the Meibomian glands located in the lower and upper eyelids.

[0003] The tear film is a thin film of tears. This fluid is secreted continuously at a rate of 1pl / min, and is thus constantly renewed.

[0004] The tear film plays several roles: it helps keep the ocular surface moist, it provides the smooth surface that allows for undistorted vision, it protects the cornea and connective epithelium from external aggressions, and it transports biological substances useful for the physiology of the eye, including oxygen.

[0005] The tear film is composed of three layers: a lipid layer, an aqueous layer and a mucin layer. The lipid layer, approximately 100 μm thick, is secreted by the Meibomian glands and helps stabilize the tear film. The aqueous layer, rich in water and nutrients, enzymes, antibacterial and healing agents, nourishes, hydrates and protects the corneoconjunctival epithelium. Finally, the mucin layer ensures the anchoring of the tear film.

[0006] The ocular surface, and in particular the tear film, is an essential component for the eye and more generally for vision. Alteration of the tear film can be the cause of more or less serious problems such as pain in the eyes, redness, headaches or even vision problems, but can also be the cause of certain pathologies such as dry eye, visual stress, keratitis or conjunctivitis.

[0007] Many compositions exist including tear substitutes, also called artificial tears. These compositions based on sodium chloride, cellulose derivatives or carbomers, make it possible to increase the viscosity of the solutions and obtain better persistence. More recently, lipid emulsion-type compositions and / or solutions based on hyaluronate or hyaluronic acid have been developed (EP 2 560 616, EP 3 231 417, EP 2 3297 626).

[0008] However, there is a continuing need to improve the effectiveness of the compositions and in particular their stability, as well as to reduce the undesirable effects associated with their use.

[0009] The present invention thus relates to a composition which aims to solve all or part of these problems. The composition according to the invention has in particular improved stability and presents little or no discomfort when applied to the eye compared to the compositions of the state of the art. BRIEF DESCRIPTION OF THE INVENTION.

[0010] The present invention relates to a composition, and more particularly to an oil-in-water type emulsion comprising an aqueous phase and a lipid phase. The aqueous phase comprises hyaluronic acid or its salt and dexpanthenol.

[0011] Preferably, the hyaluronic acid is crosslinked hyaluronic acid.

[0012] Advantageously, the aqueous phase additionally comprises glycerol.

[0013] The oil-in-water emulsion also comprises a lipid phase which notably comprises phospholipids and triglycerides. Advantageously, the lipid phase is free of surfactants. According to one embodiment, the lipid phase may comprise an antioxidant such as lipoic acid.

[0014] The invention also relates to the use of the emulsion according to the invention in the treatment or prevention of ophthalmic conditions, in particular dry eye, allergies and / or inflammations in the eye. DESCRIPTION OF FIGURES

[0015] [Fig.l] represents the result of a Lumisizer® stability analysis of the state-of-the-art reference emulsion, Emulsion 1, without dexpanthenol.

[0016] [Fig.2] represents the result of a stability analysis using Lumisizer® of emulsion 4, according to the invention.

[0017] [Fig.3] represents the comparative results of analysis of the evolution of the size of the lipid droplets of Emulsions 1 and 2, devoid of dexpanthenol.

[0018] [Fig.4] represents the result of a stability analysis with Lumisizer® of emulsion 3, comparative, without dexpanthenol.

[0019] [Fig.5] represents the result of a stability analysis using Lumisizer® of emulsion 5, according to the invention.

[0020] [Fig.6] represents the result of a stability analysis with Lumisizer® of emulsion 6, according to the invention. DETAILED DESCRIPTION OF THE INVENTION

[0021] The invention relates to an oil-in-water type emulsion comprising an aqueous phase and a lipid phase, the aqueous phase comprising hyaluronic acid or its salt and dexpanthenol.

[0022] The emulsion according to the invention is a stable emulsion. According to the invention, the physical stability of the lipid phase is determined by the percentage of infrared (IR) light passing through an emulsion sample subjected to centrifugal force (analysis carried out with a dispersion analyzer of the Lumisizer® type from the company LUM GmbH, https: / / lum-france.fr / lumisizer-fr.html). This equipment has a high-performance optical system which makes it possible to analyze the speeds of droplets and particles for the study of creaming and sedimentation phenomena as well as their particle size distributions. This centrifugation technology makes it possible to evaluate the physical stability of samples under accelerated conditions. Stability predictions can extend up to one year.

[0023] The stability of the emulsion can also be analyzed by the average size of the lipid droplets which remains constant over time. The average size of the droplets can be measured using a high-resolution particle measuring and counting device of the AccuSizer® type, marketed by the company Entegris. According to the invention, the stability of the emulsion is reflected by a reduction in IR transmission of 20%, preferably less than 15%, more preferably less than 10% and / or by a variation in the size of the lipid droplets of 10%, preferably 5%.

[0024] Aqueous Phase

[0025] The term "emulsion" means a heterogeneous mixture of two immiscible liquids, preferably finely dispersed in each other. According to the invention, the emulsion is of the oil-in-water type, that is to say that the oily phase, also called the dispersed phase, is uniformly mixed with the aqueous phase, also called the continuous phase.

[0026] The oil-in-water emulsion according to the invention comprises an aqueous phase and a lipid phase. The aqueous phase comprises hyaluronic acid or its salt and dexpanthenol.

[0027] Hyaluronic acid is a natural biopolymer found in the tear film, outer cornea, and vitreous humor. This glycosaminoglycan (GAG), a long-chain linear polymer, includes functional hydrophilic groups in its structure such as carboxyl, hydroxyl, and acetamide groups, which allows it to form hydrogen bonds with water. Due to its properties, hyaluronic acid Hyaluronic acid has viscoelastic properties and has high water retention. Hyaluronic acid, due to its physiological properties and natural profile, is thus used in many ophthalmic compositions.

[0028] According to the invention, the composition, and more particularly the aqueous phase, comprises hyaluronic acid or a physiologically acceptable salt thereof.

[0029] According to one embodiment, the hyaluronic acid is present in the form of sodium hyaluronate.

[0030] According to the invention, the hyaluronic acid has a molecular weight of between 10 kDa and 10,000 kDa, between 50 kDa and 10,000 kDa, preferably between 250 kDa and 5,000 kDa. In another embodiment, the hyaluronic acid has a molecular weight of between 500 kDa and 1,500 kDa. Advantageously, the hyaluronic acid according to the invention has a molecular weight of approximately 1,000 kDa.

[0031] Yet, in another embodiment, the hyaluronic acid is crosslinked.

[0032] According to the invention, a crosslinked hyaluronic acid designates several hyaluronic acid molecules linked intramolecularly or intermolecularly by means of crosslinking agents. The native hyaluronic acid molecules can have a molecular weight of between 150 kDa and 2000 KDa. The crosslinking agents used can be 1,4-butanediol diglycidyl ether (BDDE), divinylsulfone (DVS), chloro-methylpyridinium iodide (CMPI). Such crosslinked hyaluronic acids are described in patents, for example in patent application WO 2009 / 077620.

[0033] According to a particular embodiment, the crosslinked hyaluronic acid is chosen to have a kinematic viscosity at 25°C less than or equal to 0.5 cm2 / s in aqueous solution at 0.05% by weight.

[0034] Hyaluronic acids and their salts, crosslinked or not, are commercially available, notably marketed by the companies Fidia, Contipro, Shiseido, HTL, etc.

[0035] The emulsion comprises hyaluronic acid or its salt, optionally crosslinked, with a content ranging from 0.01 to 5% by weight relative to the total weight of the emulsion. In another embodiment, the hyaluronic acid content is between 0.01 and 4% by weight, preferably between 0.01 and 3% by weight, more preferably between 0.01 and 2% by weight relative to the total weight of the emulsion. In yet another embodiment, the emulsion comprises between 0.01 and 1% by weight of hyaluronic acid, preferably between 0.01 and 0.5% by weight, more preferably between 0.01 and 0.2% by weight relative to the total weight of the emulsion. Advantageously, the oil-in-water type emulsion comprises hyaluronic acid or its salt, optionally crosslinked, with a content of 0.1 to 0.2% by weight relative to the total weight of the emulsion.

[0036] The aqueous phase comprises, in addition to hyaluronic acid, dexpanthenol.

[0037] Dexpanthenol, also called panthenol or provitamin B5, corresponds to the alcohol of pantothenic acid. This compound is particularly known for its moisturizing and humectant properties, and is generally used for the treatment of superficial skin lesions and irritations. At the ophthalmic level, dexpanthenol prevents epithelial dryness and maintains the integrity of the ocular surface.

[0038] According to the invention, the aqueous phase of the oil-in-water type emulsion comprises dexpanthenol with a content of between 1 and 5% by weight relative to the total weight of the composition. In one embodiment, the emulsion comprises dexpanthenol with a content ranging from 1 to 4% by weight, preferably from 1 to 3%, and more preferably from 1.5 to 3% by weight relative to the total weight of the emulsion.

[0039] In another embodiment, the emulsion, and more particularly the aqueous phase, comprises between 1.5 and 2.8% by weight of dexpanthenol, between 1.6 and 2.7% by weight, between 1.8 and 2.5% by weight, or between 1.8 and 2.4% by weight relative to the total weight of the emulsion. Advantageously, the aqueous phase has a dexpanthenol content of approximately 1.9% by weight, approximately 2% by weight, approximately 2.1% by weight or approximately 2.2% by weight relative to the total weight of the emulsion. In a preferred embodiment, the dexpanthenol is present with a content of approximately 2% by weight relative to the total weight of the emulsion.

[0040] The oil-in-water emulsion according to the invention thus comprises an aqueous phase and a lipid phase, the aqueous phase comprising hyaluronic acid and dexpanthenol as defined above. The hyaluronic acid is in an acid form or in a salt form, and may optionally be crosslinked hyaluronic acid.

[0041] The aqueous phase may further comprise glycerol.

[0042] According to the invention, the aqueous phase of the emulsion comprises glycerol with a content of between 0.1 and 5% by weight relative to the total weight of the emulsion. In one embodiment, the glycerol content is between 0.1 and 4% by weight, preferably between 0.1 and 3% by weight, more preferably between 0.1 and 2% by weight relative to the total weight of the emulsion. In another embodiment, the glycerol content is between 0.1 and 1.8% by weight, preferably between 0.1 and 1.5% by weight, even more preferably between 0.2 and 1.2% by weight relative to the total weight of the emulsion. In yet another embodiment, the aqueous phase of the emulsion comprises glycerol with a content ranging from 0.3 to 1.2% by weight, from 0.5 to 1.2% by weight, from 0.6 to 1.1% by weight, from 0.7 to 1.1% by weight, or from 0.7 to 1% by weight of glycerol relative to the total weight of the emulsion.Advantageously, the aqueous phase of the oil-in-water type emulsion according to the invention comprises approximately 0.7% by weight of glycerol, approximately 0.8% by weight, approximately 0.9% by weight. weight or approximately 1% by weight of glycerol relative to the total weight of the emulsion.

[0043] The emulsion according to the invention therefore comprises an aqueous phase as defined and a lipid phase. The aqueous phase according to one embodiment comprises hyaluronic acid or its salt, preferably crosslinked, dexpanthenol and glycerol. In one embodiment, the aqueous phase comprises between 0.01 and 5% of hyaluronic acid or its salt, between 1 and 5% of dexpanthenol and between 0.1 and 5% of glycerol, the percentages being expressed by weight relative to the total weight of the emulsion. In a preferred embodiment, the hyaluronic acid or its salt is in a crosslinked form.

[0044] Lipid Phase

[0045] The emulsion according to the invention of the oil-in-water type also comprises by definition a lipid phase. This is characterized by the presence of phospholipids and triglycerides.

[0046] Phospholipids are lipids comprising a phosphate group. A distinction is made between phospholipids consisting of groups of sphingosine, also called sphingenine, a fatty acid, a phosphate and a nitrogenous alcohol, and phospholipids consisting of two fatty acids, a molecule of glycerol-3-phosphate and a nitrogenous alcohol.

[0047] The phospholipids may be chosen from phosphoacylglycerides, also called phosphoacylglycerols, phosphosphingolipids, phosphonosphingolipids, phosphoglycolipids and phosphosacharolipids. According to the invention, the phospholipids are phosphatidylcholines also called lecithins, i.e. lipids consisting of a choline residue, a phosphate group, a glycerol residue and two fatty acid residues. According to the invention, the term "lecithin" also designates phospholipids extracted from living organisms comprising predominantly phosphatidylcholines. The term "predominantly" means a mixture comprising phospholipids of which at least 50% of the compounds are phosphatidylcholines, preferably at least 60%, more preferably at least 70%. In a preferred embodiment, the lecithins according to the invention comprise at least 80% of phosphatidylcholine type compounds, or even at least 85%.Advantageously, the phosphatidylcholine content in the phospholipid mixture is at least 90%, at least 92%, at least 95%, or even at least 98%. Although lecithins refer to phospholipids extracted from natural products, it is understood that synthetic lecithins may also be used.

[0048] According to the invention, lecithins are extracted from natural products, such as egg yolks, soybeans, rapeseed, canola, corn or sunflower.

[0049] Lecithins can be used alone or in combination, several lecithins of different origin and / or nature then being present in the emulsion.

[0050] The phospholipid content in the lipid phase of the emulsion according to the invention is between 0.01 and 3% by weight relative to the total weight of the emulsion. According to one embodiment, the phospholipid content is between 0.01 and 2.5% by weight, preferably between 0.01 and 2% by weight, more preferably between 0.01 and 1% by weight relative to the total weight of the emulsion. In another embodiment, the lipid phase of the emulsion comprises between 0.01 and 0.8% by weight of phospholipids, between 0.01 and 0.6% by weight, between 0.01 and 0.5% by weight, between 0.01 and 0.2% by weight, or even between 0.01 and 0.1% by weight of phospholipids relative to the total weight of the emulsion. In a preferred embodiment, the lipid phase comprises from 0.01 to 0.09% by weight of phospholipids, more preferably from 0.01 to 0.075% by weight, even more preferably from 0.01 to 0.05% by weight relative to the total weight of the emulsion.Advantageously, the phospholipid content is about 0.02% by weight, about 0.03% by weight or about 0.04% by weight relative to the total weight of the emulsion.

[0051] The lipid phase of the emulsion comprises, in addition to phospholipids, triglycerides. These compounds are glycerides in which the hydroxyl groups of the glycerol are esterified by fatty acids. According to the invention, the triglycerides are medium-chain triglycerides, that is to say that the fatty acid residues comprise from 4 to 22 carbon atoms, preferably from 8 to 22 carbon atoms. It is understood that the hydroxyl groups can be esterified with identical or different fatty acids independently of each other. Thus, the triglycerides according to the invention can be simple triacylglycerols or mixed triacylglycerols.The fatty acids of the triglycerides of the emulsion according to the invention are preferably chosen from saturated fatty acids such as capric acid, caprylic acid, palmitic acid, unsaturated fatty acids such as oleic acid, palmitoleic acid, polyunsaturated fatty acids, in particular polyunsaturated omega-3 or omega-6, such as linoleic acid, alpha-linolenic acid, docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA), and mixtures thereof.

[0052] The triglyceride content in the lipid phase of the emulsion is between 0.01 and 5% by weight relative to the total weight of the emulsion. In one embodiment, the triglyceride content is between 0.01 and 3% by weight, preferably between 0.01 and 2% by weight, more preferably between 0.01 and 1% by weight relative to the total weight of the emulsion. In another embodiment, the lipid phase of the emulsion comprises from 0.02 to 0.8% by weight of triglycerides, preferably from 0.05 to 0.5% by weight and more preferably from 0.1 to 0.3% by weight relative to the total weight of the emulsion, in particular from 0.1 to 0.25% by weight, or from 0.1 to 0.2% by weight relative to the total weight of the emulsion. Advantageously, the lipid phase of the emulsion according to the invention comprises between 0.15 and 0.18% by weight of triglycerides relative to the total weight of the emulsion. In particular, the phase lipid according to the invention comprises approximately 0.15% by weight of triglycerides, approximately 0.16% by weight, approximately 0.17% by weight, or approximately 0.18% by weight relative to the total weight of the emulsion.

[0053] In one embodiment, the lipid phase of the emulsion comprises phospholipids, triglycerides and lipoic acid or its salt. The content of lipoic acid or its salt is between 0.005 and 0.02% by weight relative to the total weight of the composition. In another embodiment, the content of lipoic acid is between 0.005 and 0.015% by weight, and preferably between 0.008 and 0.012% by weight relative to the total weight of the emulsion. Advantageously, the content of lipoic acid is approximately 0.009% by weight, approximately 0.01% by weight or approximately 0.011% by weight relative to the total weight of the emulsion.

[0054] The lipid phase of the emulsion does not comprise additional surfactants or surfactants capable of increasing its stability and can be characterized as a “surfactant-free” or “surfactant-free” emulsion. “Surfactant-free” or “surfactant-free” or “surfactant-free” means a surfactant concentration of less than or equal to 0.01% by weight relative to the total weight of the emulsion, or even equal to 0% by weight.

[0055] Said additional surfactants or surfactants are usual surfactants for the preparation of emulsions, in particular chemical synthesis products, in particular chosen from the list of products authorized by the regulations, such as polysorbates, polyethylene glycols and their derivatives, polyoxyethylene-40-stearate, sorbitan esters, polyoxyethylene-polyoxypropylene copolymers, polyvinyl alcohols, and polyvinylpyrrolidone polymers.

[0056] The phospholipids included in the composition of the emulsion according to the invention as defined above, and in particular the lecithins, are not chemical surfactants used as surfactants in the preparation of emulsions in the field of cosmetics or pharmacy. This absence of usual additional chemical surfactants makes it possible to avoid the side effects associated with these products, in particular irritations of the eye or the mucous membranes near the eye.

[0057] Other Features

[0058] The emulsion according to the invention has a pH ranging from 5.5 to 8. According to one embodiment, the pH of the emulsion is between 6 and 8 and preferably between 6 and 7. Advantageously, the pH of the emulsion ranges from 6.2 to 7.2, in particular from 6.5 to 6.9. In particular, the pH of the emulsion is approximately 6.7.

[0059] In order to maintain the pH of the emulsion at a desired value, the aqueous phase may also comprise a buffer, such as a phosphate, borate, acetate or citrate buffer. The buffer is added to the emulsion, and in particular to the aqueous phase, in an amount appropriate to adjust the pH to the desired value.

[0060] The emulsion according to the invention may also comprise an antioxidant agent, such as lipoic acid or its sodium salt, taurine, vitamin C, vitamin A, vitamin E, vitamin D or riboflavin. Depending on the chemical nature of the antioxidant agent, lipophilic or hydrophilic, the latter will be in the lipid phase or in the aqueous phase. Advantageously, the emulsion according to the invention comprises an antioxidant agent which is lipophilic, in particular lipoic acid or its sodium salt, present in the lipid phase of the emulsion. The presence of the antioxidant agent in the lipid phase is particularly appropriate when the fatty acids of the triglycerides are unsaturated fatty acids, more particularly polyunsaturated.

[0061] In one embodiment, the aqueous phase of the oil-in-water emulsion comprises hyaluronic acid or its salt, optionally crosslinked, dex-panthenol, glycerol and a buffer, preferably a citrate buffer. In a preferred embodiment, the aqueous phase comprises 0.01 to 5% of hyaluronic acid, preferably crosslinked hyaluronic acid, 1 to 5% of dexpanthenol, 0.1 to 5% of glycerol, and a citrate buffer, the percentages being expressed by weight relative to the total weight of the emulsion. In another embodiment, the aqueous phase comprises 0.01 to 2% hyaluronic acid, preferably crosslinked hyaluronic acid, 1 to 3% dexpanthenol, 0.1 to 2% glycerol, and a citrate buffer, the percentages being expressed by weight relative to the total weight of the emulsion.In yet another embodiment, the aqueous phase comprises 0.01 to 1% hyaluronic acid, preferably crosslinked hyaluronic acid, 0.1 to 2% dexpanthenol, 0.1 to 1% glycerol, and a citrate buffer, the percentages being expressed by weight relative to the total weight of the emulsion.

[0062] The oil-in-water emulsion also comprises a lipid phase. The latter comprises phospholipids, triglycerides and lipoic acid. In one embodiment, the lipid phase comprises 0.01 to 3% phospholipids, 0.01 to 5% triglycerides and 0.005 to 0.02% lipoic acid, the percentages being expressed by weight relative to the total weight of the emulsion. In another embodiment, the lipid phase of the emulsion comprises 0.01 to 1% phospholipids, 0.01 to 1% triglycerides, and 0.005 to 0.02% lipoic acid, the percentages being expressed by weight relative to the total weight of the emulsion. In yet another embodiment, the lipid phase comprises 0.01 to 0.1% phospholipids, 0.01 to 0.5% triglycerides, and 0.005 to 0.02% lipoic acid, the percentages being expressed by weight relative to the total weight of the emulsion.

[0063] The emulsion according to the invention is particularly suitable for topical use in the treatment or prevention of eye conditions. This emulsion must therefore meet specific technical characteristics of ophthalmic compositions. The components must be "compatible with ophthalmic use", that is to say that they must not, individually or combined in the composition, cause side reactions outside the effect sought by the emulsion. In particular, the emulsion must not cause parasitic irritations or allergic-type reactions.

[0064] The emulsion must in particular be sterile so as not to contain pathogenic agents likely to cause ophthalmic complications. According to the invention, the term "sterile" designates the absence of germs within the meaning of the European Pharmacopoeia 2.6.1.

[0065] Many ophthalmic compositions include preservatives to prevent or limit contamination. Examples of preservatives are quaternary ammoniums, including benzalkonium chloride, alkyl dimethyl benzyl ammonium, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzothonium chloride, ce-talkonium chloride, mercurial preservatives, such as phenyl mercuric nitrate / acetate / borate, thiomersal, alcoholic preservatives, such as chlorobutanol, benzyl alcohol, phenylethanol, phenylethyl alcohol, carboxylic acids, such as sorbic acid, phenols, in particular methyl / propyl paraben, amidines, such as chlorhexidine digluconate, and / or chelating agents such as EDTA alone or in combination with at least one other preservative.

[0066] The emulsion according to the invention is preservative-free. For the purposes of the invention, the term "preservative-free" or "without preservatives" means a preservative content of less than or equal to 10 ppm, in particular less than or equal to 1 ppm, or even equal to 0 ppm.

[0067] According to another aspect of the invention, the emulsion may comprise at least one preservative, but preferably at a low concentration. In this case, the preservative content is less than or equal to 0.1% by weight relative to the total weight of the emulsion, in particular less than or equal to 0.05% by weight, or even less than or equal to 0.01% by weight.

[0068] When present, the preservative is found in the aqueous phase of the emulsion.

[0069] Advantageously, the emulsion according to the invention has a low viscosity close to that of water, in particular a dynamic viscosity at a shear rate of 100 s 1 at 25°C, less than or equal to 10 1 Pa.s. According to a particular embodiment, the viscosity of the emulsion is between 1.5.103 and 8.102 Pa.s, and very particularly between 3.103 and 6.102 Pa.s at a shear rate of 100 s1.

[0070] The emulsion according to the invention is particularly suitable for use topical in the treatment or prevention of ophthalmic conditions, particularly in the form of eye drops, preferably of low viscosity as defined above.

[0071] The emulsion according to the invention may have lacrimimetic properties, that is to say that it has, once deposited at the level of the eye, a structure close to or identical to the lacrimal liquid. Thus, according to the invention, the emulsion is hypo-osmolar and has an osmolarity less than or equal to 290 mOsm / L ranging from 210 to 290 mOsm / L. According to one embodiment, the osmolarity of the emulsion is between 230 and 270 mOsm / L. Advantageously, the emulsion has an osmolarity of approximately 250 mOsm / L.

[0072] The hypoosmolarity of the emulsion has the advantage of compensating for the hyperosmolarity associated with dry eyes.

[0073] The osmolarity of the emulsion is adjusted by adding an appropriate quantity of salt or polyalcohol, in particular sodium chloride, potassium chloride, sodium bicarbonate, potassium bicarbonate or glycerol, trehalose, erythritol, sorbitol, mannitol. A person skilled in the art will be able to determine the quantity and the salt to be added to obtain a hypoosmolar emulsion as defined above.

[0074] Generally, for an emulsion suitable for topical use in the treatment or prevention of ophthalmic conditions, in particular in the form of eye drops, the emulsion comprises at least 90% by weight of water relative to the total weight of the emulsion. According to one embodiment, the emulsion comprises at least 95% by weight of water, preferably at least 97% by weight, or even at least 99% by weight relative to the total weight of the emulsion.

[0075] The emulsion according to the invention may further comprise one or more active agents, in particular an active therapeutic agent. The active agent is in particular intended to act on the eye. The active agent, in particular for ophthalmic use, may be chosen from antiseptics, antibiotics, anti-inflammatories, anti-allergics, anti-glaucomatous agents, anti-dryness agents, vasoconstrictors, anesthetics, mydriatics, miotics, or even diagnostic products and products for the treatment of retinal disorders. It is understood that components having a pharmacological or mechanical activity may be considered.

[0076] It is also possible to add other ingredients to the emulsion of the invention. In particular, the aqueous phase may comprise compounds promoting the restoration of the aqueous layer of the tear film or tear replacement products. Such compounds are known to those skilled in the art. Examples that may be mentioned are sodium, potassium, calcium, chloride and bicarbonate ions, or a buffer solution, zinc, copper, glutathione, lactoferrin, levocamitin, resveratrol, ginkgosides, curcuminoids, N-acetylcarnosine, trehalose, agar agar, hydroxypropyl guar, citicoline, homotaurine, carrageenans, chitosan, heparosan, etc.

[0077] Examples of formulations according to the invention are given in Tables 1 to 9 below.

[0078] [Tableauxl] Component Concentration (%) Triglycerides 0.10-0.30 Phospholipids 0.01-0.05 Lipoic acid 0.01-0.03 Linear hyaluronic acid 0.10-0.50 Dexpanthenol 3.00-5.00 Glycerol 0.10-1.00 Citrate buffer 0.30-1.00 Water Qs 100

[0079] [Tables2] Component Concentration (%) Triglycerides 0.10-0.30 Phospholipids 0.01-0.05 Vitamin A 0.01-0.03 Cross-linked hyaluronic acid 0.20-0.50 Dexpanthenol 2.00-4.00 Glycerol 0.10-1.00 Phosphate buffer 0.30-1.00 Water Qs 100

[0080] [Tables 3] Component Concentration (%) Triglycerides 0.10-0.30 Phospholipids 0.01-0.05 Vitamin A 0.01-0.03 Linear hyaluronic acid 0.10-0.50 Dexpanthenol 2.00-4.00 Glycerol 0.10-1.00 Phosphate buffer 0.30-1.00 Water Qs 100

[0081] [Tables 4] Component Concentration (%) Triglycerides 0.10-0.30 Phospholipids 0.01-0.05 Vitamin E 0.02-0.04 Linear hyaluronic acid 0.10-0.50 Dexpanthenol 1.00-4.00 Sodium chloride 0.50-1.00 Citrate buffer 0.30-1.00 Water Qs 100

[0082] [Tables 5] Component Concentration (%) Triglycerides 0.10-0.30 Phospholipids 0.01-0.05 Vitamin D 0.03-0.07 Cross-linked hyaluronic acid 0.10-0.50 Dexpanthenol 1.00-4.00 Glycerol 0.50-2.00 Citrate buffer 0.30-1.00 Water Qs 100

[0083] [Tableauxô] Component Concentration (%) Triglycerides 0.10-0.30 Phospholipids 0.01-0.05 Lipoic acid 0.01-0.03 Cross-linked hyaluronic acid 0.10-0.30 Dexpanthenol 1.00-3.00 Glycerol 0.50-1.00 Citrate buffer 0.30-1.00 Water Qs 100

[0084] [Paintings?] Component Concentration (%) Triglycerides 0.20-0.50 Phospholipids 0.02-0.06 Lipoic acid 0.01-0.03 Cross-linked hyaluronic acid 0.30-0.50 Dexpanthenol 1.00-3.00 Sodium chloride 0.50-1.00 Phosphate buffer 0.30-1.00 Water Qs 100

[0085] [Tables 8] Component Concentration (%) Triglycerides 0.20-0.50 Phospholipids 0.02-0.06 Lipoic acid 0.01-0.03 Cross-linked hyaluronic acid 0.30-0.50 Dexpanthenol 1.00-3.00 Sodium chloride 0.50-1.00 Phosphate buffer 0.30-1.00 Water Qs 100

[0086] [Tables9] Component Concentration (%) Triglycerides 0.30-0.60 Phospholipids 0.03-0.05 Lipoic acid 0.02-0.05 Cross-linked hyaluronic acid 0.10-0.40 Dexpanthenol 2.00-4.00 Glycerol 0.80-1.20 Citrate buffer 0.50-1.50 Water Qs 100

[0087] Uses

[0088] The oil-in-water emulsion according to the invention is an ophthalmic emulsion intended to treat or prevent ophthalmic conditions, in particular dry eye, allergies and / or inflammations in the eye.

[0089] The invention therefore relates to an emulsion as defined above for its use in the treatment or prevention of ophthalmic conditions, in particular for the prevention and treatment of dry eye, allergies and / or inflammations in the eye.

[0090] The invention also relates to a method of treating an eye condition in a subject which consists of applying to the eye an emulsion as defined above.

[0091] This emulsion is advantageously applied locally to the eyes. The emulsion according to the invention is thus in the form of an eye drop and is applied in the form of drops according to the usual methods of applying ophthalmic compositions.

[0092] The size of the drops applied is advantageously less than or equal to 50 pL.

[0093] Preparation Process

[0094] The invention further relates to a process for preparing an oil-in-water type emulsion as defined in the description.

[0095] The preparation of the emulsion is carried out according to the usual methods known to those skilled in the art. The process for preparing an oil-in-water type emulsion according to the invention comprises in particular the following steps:

[0096] a) Prepare the concentrated lipid phase by emulsifying at least one phospholipid with at least one triglyceride in water,

[0097] b) Prepare the concentrated aqueous phase by dissolving the hyaluronic acid and the dex- panthenol,

[0098] c) Mix the concentrated emulsion phase into the concentrated aqueous phase by stirring and

[0099] control and adjust the pH as needed, in particular by adding a base or an acid,

[0100] d) Filter the emulsion.

[0101] Step a) is carried out at a temperature between 50 and 90°C. The mixture of at least one phospholipid with at least one triglyceride is preferably carried out at a temperature between 40 and 80°C, and more preferably between 50 and 70°C. The lipid mixture, after addition to an aqueous medium, is emulsified. It undergoes between 1 and 10 cycles at a pressure between 10,000 and 50,000 PSL.

[0102] In parallel, the aqueous phase is prepared according to step b). The mixture of hyaluronic acid and dexpanthenol is carried out with stirring at a temperature above 25°C, preferably above 50°C. During step b), buffer acids and / or bases may be added in order to adjust the pH of the aqueous phase to the desired value.

[0103] Step c) consists of homogeneously mixing the two phases described above.

[0104] Finally, the filtration in step d) is carried out on a sterilizing filter of 0.22 μm. This filter is notably chosen from filters based on polypropylene (PP), polyethersulfone (PES), polytetrafluoroethylene (PTFE), polyester (PE), polycarbonate (PC) or any other material allowing sterilizing filtration to be carried out.

[0105] According to another variant of the process, it is possible during the steps to add an active ingredient for ophthalmic use, or a mechanical agent entering into the emulsion.

[0106] The method further comprises a packaging step, in particular in sterile packaging, and even more particularly in packaging making it possible to preserve the sterile emulsion without preservative.

[0107] The invention relates to a method for stabilizing an oil-in-water emulsion as defined above, comprising hyaluronic acid in its aqueous phase, in particular an emulsion free of usual surfactants, which comprises the addition of dexpanthenol to the aqueous phase to stabilize the emulsion.

[0108] Unless otherwise indicated, percentages, contents and ratios are expressed by weight (w / w).

[0109] An indication of numerical ranges by the end points is intended to include all numbers included in that range (for example, a recitation of 1 to 5 includes, but is not limited to, 1, 1.25, 1.5, 1.75, 2, 2.45, 2.75, 3, 3.80, 4, 4.32, 4.45, and 5).

[0110] The term "approximately" is used herein explicitly or implicitly. Each quantity given in the present description refers to the actual value given, and to the approximation of that given value which would be reasonably deduced on the basis of ordinary skill in the art, including equivalents and approximations due to experimentation and / or measurement conditions for that given value. In general, the term "about" in the context of a given value refers to said value and a range which encompasses said value by + / - 5% of said given value, in particular by + / - 1%. EXAMPLES

[0111] Several emulsions were prepared to compare their stability in comparison with the product called Neovis Total, marketed by the company Horus Pharma, as a reference product. Neovis Total is an oil-in-water emulsion without additional chemical surfactants comprising a triglyceride and a lecithin in its lipid phase and hyaluronic acid and HPMC in its aqueous phase.

[0112] The same lipid phase was used for all emulsions, the variations relating to the constituents of the aqueous phase, as mentioned below in Table 10. The compositions are prepared to obtain the same viscosity, osmolarity and pH properties as the reference composition. Emulsion 1 is the reference product Néovis Total. Emulsions 1 to 3 represent compositions of the state of the art, or different from the invention, without dexpanthenol. Emulsions 4 to 6 represent the compositions according to the invention with 2% by weight of dexpanthenol relative to the total weight of the emulsion.

[0113] [TableauxlO] Aqueous phase / Emulsion 1 2 3 4 5 6 Dexpanthenol - - - + + + Linear hyaluronic acid + - + - - - Cross-linked hyaluronic acid - + - + + + HPMC + + + - + -

[0114] The sign - indicates the absence of the component. The sign + indicates the presence of the component. The same quantities are used in all emulsions containing the same component. Crosslinked hyaluronic acid, when present, is used in Emulsions 2 and 4 to 6, in the same quantities as linear hyaluronic acid used in Emulsions 1 and 3.

[0115] Comparison 1 - Comparison between Emulsions 1 and 4

[0116] The stability analysis is carried out using a Lumisizer® device. The results are shown in Figures 1 and 2 respectively. [Fig.l] shows a significant phenomenon of opalescence and creaming for the state-of-the-art Emulsion. By comparison, [Fig.2] shows very high stability for composition 4 according to the invention comprising dexpanthenol.

[0117] Comparison 2 - Comparison of Emulsions 1 and 2

[0118] The stability analysis is carried out using an AccuSizer device. The results are shown in [Fig. 3]. The compositions of Emulsions 1 and 2 are identical except for the hyaluronic acid, linear for Emulsion 1 and crosslinked for Emulsion 2. These two Emulsions do not include dexpanthenol. The results shown in [Fig. 3] show essentially identical behavior for the two Emulsions. They confirm that the increase in stability observed for Comparison 1 is indeed due to the presence of dexpanthenol in Emulsion 4.

[0119] Comparison 3 - Comparison between Emulsions 3 and 5

[0120] The stability analysis is carried out using a Lumisizer® device under the same conditions as Comparison 1. The compositions of Emulsions 3 and 5 are identical in every respect except for the presence of dexpanthenol for Emulsion 5 according to the invention. The results shown in Figures 4 and 5 respectively show a clear increase in stability for Emulsion 5 according to the invention.

[0121] Comparison 4 - Comparison between Emulsions 5 and 6

[0122] The stability analysis is carried out using a Lumisizer® device under the same conditions as Comparison 1. The compositions of Emulsions 5 and 6 are identical in every respect except for the presence of HPMC in composition 5, absent from composition 6. The results shown in Figures 5 and 6, respectively, show that the Emulsions according to the invention, with or without HPMC, have similar stability.

Claims

Claims

1. Oil-in-water type emulsion comprising an aqueous phase and a lipid phase, characterized in that: the aqueous phase comprises: - hyaluronic acid or its salt, optionally crosslinked, and - dexpanthenol.

2. Emulsion according to claim 1, characterized in that the hyaluronic acid content is between 0.01 and 5% by weight relative to the total weight of the emulsion.

3. Emulsion according to one of claims 1 or 2, characterized in that the hyaluronic acid is crosslinked hyaluronic acid.

4. Emulsion according to one of claims 1 to 3, characterized in that the dexpanthenol content is between 1 and 5% by weight relative to the total weight of the emulsion.

5. Emulsion according to one of claims 1 to 4, characterized in that the aqueous phase comprises glycerol.

6. Emulsion according to claim 5, characterized in that the glycerol content is between 0.1 and 2% by weight relative to the total weight of the emulsion.

7. Emulsion according to one of claims 1 to 4, characterized in that the lipid phase is free of chemical surfactants.

8. Emulsion according to claim 5, characterized in that the lipid phase comprises: - phospholipids, and - triglycerides.

9. Emulsion according to claim 8, characterized in that the phospholipid content is between 0.01 and 3% by weight relative to the total weight of the emulsion.

10. Emulsion according to one of claims 8 or 9, characterized in that the phospholipids are chosen from lecithins.

11. Emulsion according to one of claims 8 to 10, characterized in that the triglyceride content is between 0.01 and 5% by weight relative to the total weight of the emulsion.

12. Emulsion according to one of claims 1 to 11, characterized in that the lipid phase includes lipoic acid.

13. Emulsion according to claim 12, characterized in that the lipoic acid content is between 0.005 and 0.02% by weight relative to the total weight of the emulsion.

14. Emulsion according to one of claims 1 to 13, characterized in that the aqueous phase comprises: - 0.01 to 5% of crosslinked hyaluronic acid, - 1 to 5% of dexpanthenol, - 0.1 to 5% of glycerol, and - a citrate buffer, the percentages being expressed by weight relative to the total weight of the composition.

15. Emulsion according to one of claims 1 to 14, for use in the treatment or prevention of ophthalmic conditions.

16. Emulsion for use according to claim 15, the ophthalmic conditions of which are characterized in particular by dry eye, allergies and / or inflammations in the eye.

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