Composition based on gellan gum and phenylephrine, production method and use as ophthalmic product

Abstract

To provide a composition capable of gelling on contact with the eye.SOLUTION: The invention relates to a specific composition comprising at least gellan gum and phenylephrine. The invention also relates to a particular method for producing such a composition and to the uses thereof, in particular as a mydriatic ophthalmic product.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a particular composition capable of gelling when it is dropped onto the eye, and to its use as an ophthalmic product, in particular for inducing mydriasis in the eye. The present invention also relates to a particular method for the preparation of such a composition.

[0002] Many eye examinations or eye procedures, such as cataract surgery, require dilation of the pupil, also known as mydriasis.

[0003] Several molecules are known that are capable of causing mydriasis.

[0004] This is especially the case with phenylephrine, more specifically phenylephrine hydrochloride. Phenylephrine is an α-adrenergic receptor agonist with higher affinity for α1 receptors, which are primarily located in the pupil. This allows for active mydriasis to be obtained through contraction of the radial dilator muscle. Phenylephrine is usually used in eye drops under the name Neosynephrine®.

[0005] Another molecule known for its mydriatic action is tropicamide, a competitive antagonist of the M4 receptor, located mainly in the iris. The mydriatic effect of tropicamide is observed 10 minutes after application of the first eye drops. Tropicamide is usually used in eye drops under the name Mydriaticum®.

[0006] Two other molecules can be used to induce mydriasis: - Atropine, which has significant side effects at the systemic level, -Cyclopentolate, which has a short-lasting effect and blocks visual coordination.

[0007] Conventionally, it is known to use a combination of phenylephrine and tropicamide to achieve pupil dilation. This combination acts synergistically to allow efficient dilation of the pupil. Various methods are known for inducing mydriasis using these molecules.

[0008] The most classical method consists of a combination of two eye drops in a liquid solution (Mydriaticum®, i.e. tropicamide 0.5%, and Neosynephrine® 10%, i.e. phenylephrine 10%). However, administration in the form of conventional eye drops generally results in a very low ocular bioavailability of tropicamide and phenylephrine. The physiological defense mechanisms of the eye, in particular eyelid blinking and nasolacrimal drainage, cause a rapid clearance of the ocular surface, which reduces the duration of the mydriatic effect, which must be compensated for by repeated administration over time. To induce effective mydriasis, it is necessary to administer 3-5 drops of eye drops with an interval of 5 minutes between each drop, over a period of 30-45 minutes. This is therefore a restrictive protocol, leading to long patient management times, administration of too large amounts of product, and notable costs in nursing time for the hospital structure. In addition, the physiological defense mechanisms of the eye also cause a high absorption at the systemic level, which can lead to side effects. In particular, the presence of phenylephrine at systemic levels causes profound vasoconstriction and reflex bradycardia, which can be severe in patients already suffering from thermal disorders or arrhythmias.

[0009] An alternative method relies on the administration of solid inserts of phenylephrine and tropicamide. The inserts are osmotic tablets that must be placed in the lower conjunctival sac by a health professional and kept in place for 30-45 minutes to achieve the expected mydriatic effect. The inserts must then be removed by a health professional within a maximum of 2 hours after administration. Thus, patient care time is also long, as is the cost of the osmotic tablets.

[0010] Finally, there is a third method, consisting of anterior chamber injections of tropicamide, phenylephrine and lidocaine, which have recently been marketed. However, this product cannot be used for routine examinations and is only recommended in the preoperative phase due to its method of administration and the presence of anesthetic agents in its composition. In addition, intraocular injections, even with preoperative pupillary dilation, are complex procedures that entail risks for the patient and involve considerable costs.

[0011] There is also a great need for products that are easy to use, inexpensive, and capable of providing an efficient and rapid pupil dilation effect.

[0012] It is an object of the present invention to fulfill this need and overcome the shortcomings of the prior art by providing a composition capable of gelling upon contact with the eye.

[0013] For this purpose, the subject of the present invention is a composition comprising at least gellan gum and phenylephrine.The combination of at least these two molecules allows the composition to be in liquid form and to gel when in contact with the eye due to the fluctuation in ionic environment.The liquid phase thus allows the composition to spread and have a larger absorption surface than in solid form, and the gel phase allows the composition to extend its residence time on the ocular surface.This allows easy administration and high ocular bioavailability of phenylephrine and any other molecules present in the composition.In addition, the composition advantageously has low industrial production costs, especially due to its low viscosity.

[0014] In particular, the subject of the invention is a composition in the form of a solution having a viscosity of less than or equal to 500 mPa.s at a temperature of 20-25 ° C., comprising at least - Gellan gum, -Phenylephrine, a gelation modifier selected from sodium citrate, an organic acid, a salt of an organic acid, and mixtures thereof.

[0015] A subject of the present invention is therefore also the use of non-therapeutic ophthalmic products, in particular compositions for their use as mydriatics or for the treatment of certain ophthalmic pathologies.

[0016] Advantageously, the composition according to the invention makes it possible to obtain effective mydriasis with a single administration of 1 or 2 drops in liquid form, compared to several injections (2 to 8 drops) for conventional eye drops of the prior art. Thus, the amount of phenylephrine, and of tropicamide, if present, is 4 to 8 times less than that required when using eye drops according to the prior art, and therefore the exposure to the risk of local and systemic side effects is low for the patient. Moreover, the invention makes it possible to obtain optimal intensity and duration of mydriasis in less than 10 minutes. Moreover, since a single drop of the composition according to the invention into the eye is sufficient to obtain effective mydriasis, there is no need to utilize highly qualified personnel.

[0017] Use according to the invention is therefore easy, safe and reproducible.

[0018] Other features and advantages will become apparent from the detailed description of the invention that follows. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Thus, the present invention relates to an ophthalmic composition comprising at least gellan gum and phenylephrine. The term "ophthalmic" means suitable for use in the eye of a human or animal.

[0020] In particular, the subject of the invention is a composition in the form of a solution having a viscosity of less than or equal to 500 mPa.s at a temperature of 20-25 ° C., comprising at least - Gellan gum, -Phenylephrine, a gelation modifier selected from sodium citrate, an organic acid, a salt of an organic acid, and mixtures thereof.

[0021] Preferably, the composition also comprises a solvent, preferably water.

[0022] The composition is in the form of a solution having a low viscosity, i.e. a viscosity of less than 500 mPa.s at a temperature between 20° C. and 25° C., preferably a viscosity between 10 mPa.s and 500 mPa.s at a temperature between 20° C. and 25° C. The composition according to the invention may exhibit the property of being shear thinning, i.e. its viscosity changes when the product is sheared. Preferably, the composition according to the invention is -Low shear, viscosity 300-400mPa.s at 25℃; -At high shear, the viscosity is 3-50 mPa.s at 25°C.

[0023] All rheological analyses were performed on an Anton Paar MCR102 rheometer and all data were analyzed using dedicated software. The geometry was a stainless steel cone / plane (diameter 50 mm, angle 1° and air gap 100 μm) that provided homogeneous shearing of the samples. The cone was equipped with a solvent trap to prevent evaporation during the measurements. The placement of a Peltier diode at the bottom of the plate allowed the temperature to be controlled with an accuracy of 0.1 °C. All viscosity values ​​presented herein were obtained by this method.

[0024] A solution can gel when its ionic environment changes. Thus, when the composition is dropped on the ocular surface, it is transformed into a gelled form under the effect of monovalent and divalent cations contained in the tear fluid, in particular calcium and magnesium. Upon reaching the ocular surface, the composition according to the invention shows a phase transition, passing from a liquid state to a gel state. This in situ gelation allows the composition according to the invention to have an extended residence time on the ocular surface. Surprisingly, the liquid-gel phase transition is obtained despite the reduction in ionic strength upon administration. This is possible because the composition according to the invention has a higher tonicity than the tear fluid, resulting in gelation during the reduction in ionic strength. This tonicity is particularly related to the presence of at least one gelation regulator selected from sodium citrate, organic acids, and organic acid salts.

[0025] The liquid phase advantageously - Ocular deliverability, safety, and ease of administration; - widening and increasing the contact area, -Easy manufacturing and sterilization, allowing

[0026] The gel phase advantageously -mucosal adhesion, -Long retention time on the ocular surface, -Prolonged and controlled release is possible.

[0027] Upon administration, the composition according to the present invention immediately changes from liquid state to gel state. These rapid gelation kinetics make it possible to prevent the composition from being expelled in liquid state. In addition, the composition according to the present invention can remain in contact with the ocular surface for a long time, retaining its mechanical and rheological properties, despite dilution in tears and blinking of eyelids. This long-term contact is strengthened by mucoadhesion phenomenon. These characteristics make it possible to release phenylephrine and any other active molecules at effective concentrations quickly and sustained over time.

[0028] According to another advantage, the diffusion activity of phenylephrine and the activity of any other active molecules present in the composition is preserved.

[0029] In addition, the compositions according to the present invention are non-toxic to the ocular surface and do not interfere with the patient's vision.

[0030] All these characteristics and advantages are related to the specific selection of gellan gum in combination with phenylephrine. Although there are certainly many polymers known to be used in gellable solutions, only gellan gum makes it possible to meet all of these characteristics: - Constituting a selected vector for ocular administration of an active substance, - is of biological origin and has the properties of a sugar, making it biocompatible and biodegradable; - a polyelectrolyte that is negatively charged at neutral pH due to the acetate and glycerate groups present on its tetrasaccharide units, its polysaccharide chains are organized into a temporary and reversible three-dimensional network that provides favorable viscoelastic properties even at very low concentrations, it is soluble in aqueous media, - its shear-thinning properties allow good local tolerance by reducing the risk of irritation during eyelid blinking, its non-anisotropic behavior allows it to reconstitute and recover its initial viscosity after each eyelid shear; -It has good adhesive power, - its viscosity and elasticity facilitate its persistence on the ocular surface, allowing for prolonged residence; - forms a clear and permeable gel that allows the patient to maintain their vision; - forms a matrix network during gelation in the presence of cations, imparting sustained release properties; -No harm to eyes.

[0031] Preferably, the gellan gum is a deacetylated gum. The deacetylated form allows for a clear gel to be obtained, for example, KELCOGEL CG-LA®. The gellan gum may optionally be an acetylated gellan gum, for example, KELCOGEL CG-HA®.

[0032] The composition according to the invention preferably comprises up to 0.6% gellan gum (weight percentage of gellan gum / volume of composition), in particular 0.05-0.6% (inclusive), in particular 0.1-0.6% (inclusive) and in particular 0.1-0.5% (inclusive). Very preferably, the composition according to the invention comprises 0.05-0.25% gellan gum (weight percentage of gellan gum / volume of composition), in particular 0.1-0.5%.

[0033] These concentrations of gellan gum are preferred to obtain the benefits and characteristics of the composition according to the invention.

[0034] The compositions according to the invention preferably contain at least 0.1% phenylephrine (weight percentage of phenylephrine / volume of composition), even more preferably 0.1-10%. These phenylephrine concentrations are compatible with the molecular association with gellan gum in the compositions according to the invention and also make it possible to obtain an effective mydriatic effect without side effects.

[0035] According to a preferred embodiment, the phenylephrine is a salt of phenylephrine, in particular phenylephrine hydrochloride.

[0036] The composition according to the invention, in addition to gellan gum, phenylephrine and optional solvent, also comprises a gelation regulator that accelerates the gelation phase when the composition is dropped on the eye. The composition according to the invention preferably comprises at least one gelation regulator, in particular selected from sodium citrate, organic acids, salts of organic acids and mixtures thereof. Sodium citrate is preferred. Sodium citrate allows better hydration of gellan gum chains during the preparation of the stock solution. Due to its properties as a cation chelating agent, it is able to capture residual cations contained in gellan gum. Thus, in the absence of cations, gellan gum chains are more elongated and the polymer is better hydrated. This gives the composition better gelation properties and a higher viscosity. This also allows a reduction in the hydration temperature of gellan gum. In addition, the presence of sodium citrate makes it possible to reduce the degradation of phenylephrine, which is sensitive to oxidation.

[0037] The gelation modifier selected from sodium citrate, organic acids, salts of organic acids, and mixtures thereof is preferably present in an amount of 0.01 to 0.2% by weight (inclusive) of gelation modifier (sodium citrate, and / or organic acids, and / or salts of organic acids, and / or mixtures thereof) per volume of the composition.

[0038] In addition to this or these gelation modifier(s), the compositions according to the invention may optionally contain at least one other gelation modifier, preferably selected from chelating agents and mixtures thereof. The chelating agent is preferably present at 0.01% to 0.2% by weight (inclusive) of the volume of the chelating agent / composition.

[0039] This includes, for example: -EDTA, - sodium, potassium or calcium tartrate, or tartaric acid, - Potassium citrate, magnesium or citric acid.

[0040] Advantageously, the presence of a chelating agent makes it possible to reduce the degradation of phenylephrine, which is sensitive to oxidation.

[0041] The compositions according to the invention may also contain at least one antioxidant, which may be, for example, ascorbic acid, malic acid, citric acid or their sodium equivalents, sodium ascorbate, sodium maleate, EDTA, or sodium citrate.

[0042] The compositions according to the invention may also contain other ingredients, in particular tropicamide, for a synergistic mydriatic action with phenylephrine. Preferably, tropicamide is present in the composition in an amount of at least 0.1% (weight percentage of tropicamide / volume of composition), and even more preferably, the composition contains 0.1-10% (inclusive) tropicamide.

[0043] The composition according to the invention may also contain at least one cellulose derivative. It may preferably be hydroxyethylcellulose (e.g. Natrosol 250M®, Natrosol 250G®) and / or hydroxypropylmethylcellulose. Cellulose derivatives, especially hydroxyethylcellulose and hydroxypropylmethylcellulose, are well tolerated and, in combination with gellan gum, show suitable viscosity and texture properties. They allow to further improve the viscosity, mucoadhesion and release properties of the active molecules of the composition according to the invention.

[0044] Preferably, the cellulose derivative is present in an amount of 0-2% (inclusive) by weight of cellulose derivative / volume of the composition, even more preferably 0-1% (inclusive). According to one embodiment, the composition according to the invention comprises 0-1% hydroxyethylcellulose and 0-1% hydroxypropylmethylcellulose.

[0045] The composition according to the invention may be obtained by any suitable manufacturing / preparation method.

[0046] Preferably, the composition according to the invention is obtained by carrying out a preparation method comprising the following steps: - preparation of a solution A comprising at least gellan gum, a gelation regulator chosen from sodium citrate, an organic acid, a salt of an organic acid and mixtures thereof, and optionally also a chelating agent, and / or an organic acid, and / or an antioxidant, and / or water, - preparation of a solution B comprising at least phenylephrine and optionally also tropicamide and / or a cellulose derivative and / or water, -Solution A is mixed with solution B, solution A represents 20-40% and solution B represents 60-80%, the percentages being determined by weight of the total weight of the mixture of the two solutions.

[0047] Very preferably, the solution containing gellan gum (Solution A) is poured into the solution containing phenylephrine (Solution B), which allows to obtain a homogenous, clear, fluid and low viscosity preparation.

[0048] Preferably, solution A is prepared by carrying out the following steps: dissolving gellan gum, a gelling modifier selected from sodium citrate, an organic acid, a salt of an organic acid and mixtures thereof, and optionally a chelating agent and / or an antioxidant, in water, preferably with stirring; * Heat the solution at 60°C to 90°C, preferably with stirring, *Continue stirring for 1 to 15 minutes. * Stop heating and continue stirring until the temperature reaches 15℃~30℃. *Optionally, sterile filtration is performed, preferably with a filter having a porosity of 0.22 μm or less.

[0049] Preferably, solution B is prepared by carrying out the following steps: * Phenylephrine and possibly tropicamide are dissolved in water. *Stir for 1-3 hours until completely dissolved. Optionally, dissolving the cellulose derivative, *Optionally, sterile filtration is performed, preferably with a filter having a porosity of 0.22 μm or less.

[0050] Preferably, the mixing of solution A and solution B is carried out by carrying out the following steps: *Stir solution A, preferably slowly for greater homogeneity, * Stir while adding solution B, preferably slowly for greater homogeneity, *Continue stirring until a uniform mixture is obtained.

[0051] The compositions according to the invention are preferably stored in single-dose containers suitable for ophthalmic use. They are preferably stored at ambient temperature and / or under conditions that allow their preservation until use.

[0052] The composition according to the invention can be used as an ophthalmic product, in particular as a non-therapeutic ophthalmic product.The invention is therefore aimed at such a use.Indeed, the composition is characterized in that it gels when it is dropped onto the surface of the eye under the effect of monovalent and divalent cations contained in the tear fluid.

[0053] In particular, the present invention relates to the use of the above-mentioned composition as a mydriatic ophthalmic product.Indeed, the composition according to the present invention can be used on the human or animal eye to induce mydriasis, in particular before an operation or examination of said eye.Using the composition according to the present invention, mydriasis can be induced in less than 10 minutes and can last for more than 120 minutes.

[0054] The use according to the invention preferably consists in applying at least one drop to the eye. Indeed, one drop is sufficient to induce rapid and long-lasting pupil dilation.

[0055] Independently of its non-therapeutic use for inducing pupil dilation before eye examinations or surgery to facilitate these procedures, the composition according to the invention can be used as a medicine in the treatment of eye pathologies, and in particular in the treatment of uveitis (anterior and posterior uveitis, i.e. a reaction of the uvea secondary to trauma or surgery, preventing or arresting the formation of posterior synechiae) and / or keratitis. In fact, the induced dilation makes it possible to treat these pathologies.

[0056] The invention is illustrated by examples of compositions according to the invention and test results which demonstrate the effects of the invention, in particular the film spreading effect. EXAMPLES

[0057] Example 1: Exemplary gellan-phenylephrine compositions The composition of Example 1 is - Gellan gum 0.5% -Sodium citrate 0.05% -Phenylephrine 9% -Water QS, consisting of

[0058] The composition is obtained by carrying out the following steps: - preparing solution A in tank 1, i.e. * Dissolve gellan gum and sodium citrate in water while stirring. * Heat the solution to 75°C while stirring. Continue stirring for 5 minutes. *Turn off the heat and continue stirring until it cools down to room temperature. *Transfer to tank 3 in a sterile filtered state. - preparing solution B in tank 2, i.e. * Dissolve phenylephrine in water. Continue stirring for approximately 1 hour and 45 minutes until completely dissolved. *Transfer to tank 3 in a sterile filtered state. Final mixing in tank 3, i.e. *Stir solution A, *Add solution B while stirring. *Continue stirring until a uniform mixture is obtained.

[0059] Example 2: Exemplary gellan-phenylephrine compositions The composition of Example 2 is - Gellan gum 0.2% -Sodium citrate 0.08% -0.1% hydroxyethylcellulose and / or 0.1% hydroxypropylmethylcellulose -Phenylephrine: 9% -Water QS, consisting of

[0060] The composition is obtained by carrying out the following steps: - preparing solution A in tank 1, i.e. * Dissolve gellan gum and sodium citrate in water while stirring. * Heat the solution to 75°C while stirring. Continue stirring for 5 minutes. * Turn off the heat and continue stirring until it returns to room temperature. *Transfer to tank 3 in a sterile filtered state. - preparing solution B in tank 2, i.e. * Dissolve phenylephrine in water. Continue stirring for approximately 1 hour and 45 minutes until completely dissolved. * Dissolve hydroxyethyl cellulose and / or hydroxypropyl methylcellulose with stirring. *Transferred to tank 3 in a sterile filtered state, Final mixing in tank 3, i.e. *Stir solution A, *Add solution B while stirring. *Continue stirring until a uniform mixture is obtained.

[0061] Example 3: Exemplary gellan-phenylephrine compositions The composition of Example 3 is - Gellan gum 0.2% -Sodium citrate 0.1% -Phenylephrine 7% -Tropicamide 0.5% -Water QS, consisting of.

[0062] The composition is obtained by carrying out the following steps: - preparing solution A in tank 1, i.e. * Dissolve gellan gum and sodium citrate in water while stirring. * Heat the solution to 75°C while stirring. Continue stirring for 5 minutes. * Turn off the heat and continue stirring until it returns to room temperature. *Transfer to tank 3 in a sterile filtered state. - Preparation of solution B in tank 2, i.e. * Dissolve phenylephrine and tropicamide in water. Continue stirring for about 2 hours until completely dissolved. *Transferred to Tank 3 in a sterile filtered state Final mixing in tank 3, i.e. *Stir solution A, *Add solution B while stirring. *Continue stirring until a uniform mixture is obtained.

[0063] Example 4: Exemplary gellan-phenylephrine compositions The composition of Example 4 is - Gellan gum 0.2% -Sodium citrate 0.05% -Phenylephrine 8% -Tropicamide 0.6% -Water: QS,

[0064] The composition is obtained by carrying out the following steps: - preparing solution A in tank 1, i.e. * Dissolve gellan gum and sodium citrate in water while stirring. * Heat the solution to 75°C while stirring. Continue stirring for 5 minutes. * Turn off the heat and continue stirring until it returns to room temperature. *Transfer to tank 3 in a sterile filtered state. - preparing solution B in tank 2, i.e. * Dissolve phenylephrine and tropicamide in water. Continue stirring for about 2 hours until completely dissolved. *Transfer to tank 3 in a sterile filtered state. Final mixing in tank 3, i.e. *Stir solution A, *Add solution B while stirring. *Continue stirring until a uniform mixture is obtained.

[0065] Example 5: Exemplary gellan-phenylephrine compositions The composition of Example 5 is - Gellan gum 0.15% -Sodium citrate 0.09% -Hydroxyethylcellulose 0.25% -Phenylephrine 5% -Tropicamide 0.5% -Water QS, consisting of

[0066] The composition is obtained by carrying out the following steps: - preparing solution A in tank 1, i.e. * Dissolve gellan gum and sodium citrate in water while stirring. * Heat the solution to 75°C while stirring. Continue stirring for 4 minutes. * Turn off the heat and continue stirring until it returns to room temperature. *Transfer to tank 3 in a sterile filtered state. - preparing solution B in tank 2, i.e. * Dissolve phenylephrine and tropicamide in water. Continue stirring for about 2 hours until completely dissolved. * Dissolve hydroxyethyl cellulose and / or hydroxypropyl methylcellulose with stirring. *Transfer to tank 3 in a sterile filtered state. Final mixing in tank 3, i.e. *Stir solution A, *Add solution B while stirring. *Continue stirring until a uniform mixture is obtained.

[0067] Tests and Results In the study presented below, three compositions according to the invention were tested and are shown in Table 1. [Table 1]

[0068] I. In Vitro Studies Demonstrating the Liquid State of Compositions According to the Invention Prior to Administration and Their Gelification in the Presence of Artificial Tears Compositions A, B, and C were evaluated with respect to pH, osmolality and clarity, and their rheological properties, as well as their viscosity and their gelling power.

[0069] transparency As a reference, the percentage of light transmittance in the visible light spectrum of 400-800 nm wavelengths relative to water was measured using a UV-Vis Perkin-Elmer Lambda 25 spectrometer. Measurements were performed three times, and the average value ± SD value for each composition was calculated.

[0070] pH measurement The pH of the compositions was measured using a previously calibrated pH meter. Compositions were tested in triplicate for pH and the mean ± SD values ​​were calculated.

[0071] Osmolarity The osmolality of the compositions was tested using an automatic osmometer. Before use, the device was calibrated with sterile distilled water (0 mOsm / L) to obtain a standard solution of 300 mOsm / L. Measurements were performed in triplicate, and the mean ± SD value of each composition was calculated.

[0072] Rheology Research All rheological analyses were performed on a rheometer and all data were analyzed using dedicated software. The geometry was a stainless steel cone / plane (diameter 50 mm, angle 1° and air gap 100 μm) that provided homogeneous shearing of the samples. The cone was equipped with a solvent trap to prevent evaporation during the measurements. A Peltier diode placed under the plate allowed the temperature to be controlled with an accuracy of 0.1 °C.

[0073] Evaluation of viscoelastic behavior and gelation The viscoelastic behavior of the in situ gelling system was evaluated before and after the addition of simulated tear fluid (STF) at 25 °C and 35 °C, respectively. Oscillatory experiments were performed. The storage modulus G' and the loss modulus G" were measured. Experiments were performed with frequency and amplitude values ​​belonging to the linear viscoelastic region, where G' remains unchanged and the sample does not undergo structural changes. The frequency was 1 Hz and the amplitude was 0.1%. Results correspond to the mean ± SD of n = 6 experiments.

[0074] STF was added in a ratio of 7:30, which corresponds to the ratio of physiological tear volume to the injected eye drop composition, the physiological volume of tear being 7 μl and the average volume of one drop of eye drop being 30 μl.

[0075] The composition of the STF is shown in Table 2. [Table 2]

[0076] Flow behavior and viscosity The flow properties of the in situ gels described above were determined after addition of STF at 35°C. After 2 min, the shear rate was increased from 0.1 to 5000 S -1 (upward curve). Then, the shear rate was gradually increased to 5000s -1 Hold for 30 seconds and then press 5000s -1 From 0.1s -1 (Descending curve). Results are the mean ± SD of n = 6 experiments.

number

[0077] The viscosity curves were fitted according to the following intersection equation:

[0078] where η represents the apparent viscosity at a given shear rate (mPa.s), γ is the shear rate (s -1 ) and η0 is the zero shear viscosity (mPa.s), η∞ is the viscosity at infinite shear (mPa.s), where C is the time constant(s) and conversely, 1 / C gives the critical shear rate, which is a useful indicator of shear rate. m is a cross constant, but is dimensionless and is a measure of the dependence of viscosity on shear rate. A value of zero for m indicates Newtonian behavior, while values ​​of m tending toward 1 indicate increasing shear-thinning behavior.

[0079] Evaluation of viscoelastic behavior and gelation Vibration experiments were primarily used to determine whether compositions according to the invention, with or without STF, are liquids or gels.

[0080] The higher the value of G', the more pronounced the elastic properties. Conversely, the higher the value of G" the more pronounced the viscous properties. By extrapolation, it can be considered that when the value of G" is greater than the value of G', the preparation exhibits a predominantly viscous behavior (i.e., similar to a liquid). Conversely, when the value of G' is greater than the value of G", the preparation exhibits a predominantly elastic behavior (i.e., similar to a solid). The tangent of the phase angle, which is a useful quantifier of the presence and degree of elasticity in a fluid, can then be calculated as follows: tan δ=G" / G'. Thus, a viscous state (liquid type) is observed when tan δ>1. When tan δ≦1, a gel state (solid type) is observed. Beyond this critical gel point, the preparation does not necessarily appear to be cohesive, but may be in the form of a fluid gel, also called a "weak gel". This behavior is highly sought for ocular administration.

[0081] The values ​​of storage modulus (G'), loss modulus (G"), and phase angle tangent (tan δ) are shown in Table 7.

[0082] The results obtained are shown in the following tables (Table 3: pH and osmolality, Table 4: permeability, Tables 5 and 6: viscosity and thixotropy, Table 7: viscoelastic behavior and gelation). [Table 3]

[0083] The three compositions according to the invention exhibit similar pH and osmolality. With a pH value of 6.45 to 6.50, the pH value is slightly acidic but close enough to neutral, within the appropriate pH range for ophthalmic use.

[0084] For osmolality, values ​​of 430-440 mOsm / L have been identified. At first glance, these results show a relatively large deviation from isotonicity (300-320 mOsm / L). However, these high osmolality values ​​are mostly only due to the high percentage of phenylephrine hydrochloride in the composition, which is necessary to achieve mydriasis. The osmolality of commercially available mydriatics containing 10% phenylephrine hydrochloride has been shown to exceed 900 mOsm / L. Thus, while relatively higher than physiological osmolality, the osmolality concentration of the composition according to the invention is optimized and halved compared to mydriatics used in the prior art. [Table 4]

[0085] The light transmittance percentage of the composition according to the present invention is more than 90% throughout the visible range, which makes it suitable for ophthalmic use.In addition, by increasing the HEC concentration, a slight decrease in transmittance is evident, which may be attributed to the inherent properties of the polymer. [Table 5] [Table 6]

[0086] The three examples of compositions according to the present invention show flow behavior and viscosity suitable for ocular administration. Composition A firstly shows very low viscosity under high shear rate, but is restored almost immediately when shear is stopped. Compositions B and C with viscosity modifier are more suitable because they show higher viscosity at high shear rate, followed by delayed and incomplete recovery at rest. Shear-thinning behavior presents substantial advantages for compositions intended to remain on the ocular surface. High viscosity at rest when the eye is open and low viscosity under eyelid shear avoid irritation and discomfort. [Table 7]

[0087] Before the addition of STF, the three compositions according to the invention show liquid-type behavior with very low storage and loss modulus values, and phase angle tangents greater than 1. Liquid-like behavior before administration is a prerequisite for an in situ gelling delivery system that allows good flow and the ability to form drops. Thus, the compositions according to the invention are suitable for easy, safe and reproducible ocular administration.

[0088] After addition of STF, the composition according to the invention undergoes a liquid / gel transition. In fact, the storage modulus increases 30-fold and the observed phase angle tangent is less than 1. These measurements make it possible to evaluate in vitro gelation due to ionic interactions between the composition according to the invention and the monovalent and divalent cations of the tear fluid.

[0089] II. In vitro study simulating eyelid blinking to determine the rheological behavior of the composition according to the invention on the ocular surface To complete the previous observations, two rheological experiments were developed: Compositions according to the invention were subjected to a series of simulated eye blinks (i.e., high shear rates followed by rest periods) to predict the rheological behavior over time on the ocular surface.

[0090] Rotation Measurement The first test measures the viscosity for the remaining interval after the blink. After each simulated blink, the viscosity reaches a minimum due to shear thinning behavior and then recovers during the rest period. The results corresponding to the shear cycles (viscosity) are presented in Table 8. [Table 8-1] [Table 8-2] [Table 8-3]

[0091] The results are consistent with the rheological behavior and thixotropy studies. -1 The order of magnitude of the viscosity at is the same as that observed previously. As a non-thixotropic hydrogel, the viscosity of composition A platformed at its initial value almost instantly during the rest period, resulting in a constant viscosity over the 10 simulated blink cycles. In contrast, as thixotropic hydrogels, the viscosity of compositions B and C recovered during the rest interval without reaching the initial plateau. This delay resulted in a small loss of viscosity with each blink. Thus, after two cycles, compositions B and C exhibit lower viscosities than composition A, which was originally the least viscous composition.

[0092] Vibration Measurement This test measures the storage (G') and loss (G") moduli during the rest interval. The tan δ parameter was used to evaluate the gel state of the compositions. At each simulated blink, tan δ reached a maximum due to partial destruction of the three-dimensional network of the gel and then recovered during the rest period. The results are shown in Table 9. [Table 9-1] [Table 9-2]

[0093] Composition A exhibits a tan δ<1 through 10 cycles. Thus, the gel network resists the high shear of simulated eye blinking and Composition A remains in a gel state.

[0094] Composition B also remains in a gel state through 10 cycles, except at higher shear rates.

[0095] Composition C exhibits a tan δ<1 during the rest period of the first two cycles and then disintegrates.

[0096] III. In Vitro Studies Aimed at Demonstrating the Mucoadhesive Properties of the Compositions According to the Invention Tensile Strength Test The maximum hydrogel detachment force (Fmax) was measured and compared in the presence and absence of the mucin film. The detachment force results are shown in Table 10. [Table 10]

[0097] When comparing the values ​​of Fmax in the presence of mucin to those without mucin as described herein by Fmax, a significant increase was observed for all compositions according to the invention (p<0.001).

[0098] This indicates a positive interaction between the hydrogel and mucin. Thus, the hydrogel can be retained by interacting with the mucin associated with the ocular surface, which increases eye retention time.

[0099] The studies and results presented in points I, II and III show that all compositions according to the invention exhibit physicochemical properties suitable for ophthalmic use. Appropriate viscosity and in situ gelling ability, as well as shear thinning behavior favorable for ocular administration in terms of patient comfort, are demonstrated. The optional addition of HEC makes it possible to improve the viscosity while reducing the resistance of the gel to shear stress. In addition, HEC enhanced the mucoadhesive properties of the composition. The ocular residence time was then evaluated in vivo to allow a better understanding of the importance of each parameter. In fact, the ocular residence time results from the combination of the effects of all the parameters evaluated individually in vitro.

[0100] Therefore, the compositions according to the present invention show many advantages compared to the eye drops of the prior art, especially in terms of their capacity to increase the residence time on the ocular surface to more than 3 hours, and therefore in terms of their bioavailability.This increase in bioavailability leads to better efficacy of treatment, while allowing a reduction in the frequency of administration, and therefore a reduction in the amount of drug administered.In addition, the compositions according to the present invention show reduced side effects due to reduced absorption at the systemic level.

[0101] IV. In vitro studies to study the release of active molecules at the origin of the mydriatic effect using methods with and without membranes Different in vitro release studies of ophthalmic semi-solid gallenic acid forms have been conducted using different devices.

[0102] All drug release experiments were performed using two cell models, namely, a standard cell without a membrane and a USP4 (through-cell) apparatus with a semi-solid form adapter with a membrane (USP-NF, 2013). This study was carried out to investigate the in vitro release profiles of compositions A, B, and C, as well as the effect of HEC on the release mechanism.

[0103] STF (pH 7.4) was used as the dissolution medium.

[0104] In vitro drug release assessment using standard cells Six standard cells with a diameter of 22.6 mm were used in all experiments to mimic the aqueous environment of the ocular surface. The automated system was operated in a closed configuration and connected to a peristaltic pump. The dissolution medium was manually sampled and analyzed by HPLC-UV. In each cell, ruby ​​beads with a diameter of 5 mm and glass beads with a diameter of 1 mm were placed at the base of the flow cell to ensure laminar flow. Approximately 300 μL of hydrogel was placed in the bed of glass beads. During the test, 150 mL of STF was circulated in each cell at flow rates of 3, 8 and 15 mL / min. A temperature of 35 ± 0.5 °C was maintained throughout the test. Aqueous solutions of 5% PHE and 0.5% TPC were also tested and used as references. Results are the mean ± SD of n = 6 experiments. Drug release profiles obtained in the closed configuration were plotted, i.e., cumulative drug release percentage (Mt / M1, %) versus time (t, min).

[0105] In vitro drug release assessment using semi-solid adaptors To evaluate the diffusion profiles of PHE and TPC from the hydrogels, an adapter for semi-solid forms (USP36-NF31:(1724)) semi-solid pharmaceuticals-performance tests, 2013) was used. The adapter was designed for use with the 22.6 mm cell of the USP4 device.

[0106] The adapter consists of two basic components: a reservoir where the product is introduced and a ring where the membrane is held. 1200 μL of hydrogel was placed in the reservoir and the ring, once fitted with a cellulose acetate membrane (0.45 μm), was screwed onto the reservoir with a specific tool. Then, with the membrane facing downwards, the adapter was slipped onto the cylindrical part of the cell. A closed system was also applied. The flow rate was set to 15 mL / min. The test procedure was the same as previously described for the standard cell.

[0107] The release of active agents from semi-solid forms is a complex phenomenon. Two main mechanisms are generally involved. The release can be governed either by Fickian diffusion (case I) or by relaxation / erosion of the system (transport case II). In many cases, both mechanisms are involved and the release is therefore referred to as anomalous release.

[0108] The Peppas-Sahlin model was used to quantify the contribution of diffusion and erosion to the release of active ingredients from in situ gelling delivery systems. The Peppas-Sahlin equation can be transformed. The diffusion and erosion percentages at time t were obtained by Zeng's equation, assuming a value of 0.5 for the geometry of the system.

[0109] A similarity factor f2, a model-independent method, was calculated for pairwise comparison of all release profiles. First, the release performance was compared with PHE and TPC. Then, the comparison between compositions A, B, and C was performed at each flow rate.

[0110] In addition, the 25%, 50%, and 80% release times (T25, T50, and T80, respectively) were calculated from the Peppas-Sahlin equation.

[0111] The results obtained without the semi-solid adapter are shown in Tables 11 (3 mL), 12 (8 mL) and 13 (15 mL). [Table 11] [Table 12] [Table 13]

[0112] The above results showed that in standard dissolution cells, in USP 4 devices approved by the FDA, the in situ gelling delivery system showed a fast but sustained release over time. All control solutions (CTRL) released more than 80% of the drug within 10 minutes, while the 80% release time (T80) for compositions A, B, and C reached 30 to 180 minutes depending on the flow. The prolonged release of the drug over time can be explained by two phenomena: either the release of the drug from the matrix is ​​due to diffusion or the release of the drug is the result of the erosion of this matrix. A slight initial release was observed, which is an asset for the rapid induction of mydriasis expected after administration.

[0113] To compare release profiles, the FDA recommends a model-independent approach. It is aimed at considering the similarity factor f2, which allows easy comparison of profiles. A value of 100 for the factor f2 means that the two compared profiles are completely identical, while a value of 50 corresponds to a difference of 10% at all time points. Thus, if the value of f2 is between 50 and 100, the two profiles are considered similar (i.e., less than 10% difference). The values ​​of f2 obtained by comparing the PHE and TPC release profiles of compositions A, B and C at three different flow rates are summarized in Table 14 (Similarity factor f2: pairwise contrast of release profiles of active agents at flow rates of 3, 8 and 15 mL / min, intra-compositional comparison of PHE and TPC release profiles, intra-compositional comparison of PHE release profiles, and intra-compositional comparison of TPC release profiles). [Table 14]

[0114] The times for 25, 50 and 80% of the total amount released were also calculated from the Peppas-Sahlin model equation and the average values ​​are shown in Table 15. For all compositions according to the invention, an increase in flow rate resulted in a decrease in T25, T50 and T80. [Table 15]

[0115] V. Tolerance and cytotoxicity testing of human corneal cells, HCE line Cytotoxicity assay in human corneal epithelial cells Human corneal epithelial (HCE) cell lines were cultured in Dulbecco's essential medium (Eurobio, Les Ulis, France) supplemented with 10% fetal bovine serum (Eurobio), 1% glutamine (Eurobio), and 1% penicillin and streptomycin (Eurobio). Cultures were maintained at 37°C in a humidified incubator with 5% CO2.

[0116] The same number of cells (9 × 10 4 Cells were seeded at 100 μL of solution (cells / mL). After 24 hours, the cells reached approximately 70%-80% confluence. The cells were washed with PBS and incubated in situ with 100 μL of gel for 30 minutes. White gels (compositions A, B and C without active ingredients), 5% PHE and 0.5% TPC control solution, 1.29% NaCl control solution (exhibiting the same osmolality as the in situ gel), and commercial eye drops (sterile unit dose of 0.5% Mydriaticum® and 10% Neosynephrine®) were used as controls. The cells were then washed with PBS. Neutral red test was performed immediately after incubation and after 24 hours of recovery in culture medium. The experiment was performed in triplicate.

[0117] The neutral red test (Fluka, Buchs, Switzerland) is a cell viability test based on the ability of viable cells to incorporate neutral red, a weak cationic dye that easily penetrates the cell membrane by non-ionic diffusion and accumulates in lysosomes. It binds to anionic sites within the lysosomal matrix. Lysosomal membrane integrity is closely linked to cell viability and is assessed by neutral red fluorescence (excitation at 535 nm, emission at 600 nm). After 3 h of incubation at 37 °C, cells were washed with PBS and incubated with 200 μL per well of neutral red solution (50 μg / mL) according to the protocol validated by Borenfreund and Puerner. After 3 h of incubation at 37 °C in a humid atmosphere of 5% CO2, wells were washed with PBS to remove any remaining unincorporated dye. The dye was then released from the cells using 200 μL of lysis solution (1% acetic acid, 50% ethanol, and 49% H2O) per well, and the fluorescence was then measured using a microplate fluorometer (Safire, Tecan, Lyon, France).

[0118] The results of the cytotoxicity test are shown in Table 16. [Table 16]

[0119] Firstly, the compositions according to the invention induce a significant decrease in viability when applied to HCE cells without recovery after 24 hours (p<0.001). No effect on cell viability was observed for the 1.29% NaCl control solution, which showed an osmolality value of 430 mOsm / L (viability 98.7±6.0%). Therefore, the relatively high osmolality of compositions A, B and C was not considered to be a parameter inducing toxicity.

[0120] A control solution containing 5% PHE and 0.5% TPC was then tested. A significant decrease in viability was observed (p<0.001), similar to that observed for compositions A, B and C (p>0.05). In addition, commercially available PHE (Neosynephrine® 10%) and TPC (Mydriaticum® 0.5%) eye drops were tested individually. Again, Neosynephrine® 10% induced a significant decrease in viability with values ​​similar to those of compositions A, B and C (p>0.05). Mydriaticum® 0.5% induced a small decrease in cell viability, but still did not exceed 39.3±16.1%. Thus, the apparent toxicity exhibited by compositions A, B and C must be mainly due to toxicity induced by PHE, but also by TPC.

[0121] Finally, ocular cell membrane integrity was not altered by the in situ gel compositions without PHE and TPC (compositions A', B' and C') and remained above 100%. The neutral red assay showed no significant difference in viability after exposure to compositions A', B' and C' and untreated cells (p>0.05). Thus, the developed administration system did not induce toxicity, which was attributed to the active ingredients. Nevertheless, the FDA and EMA, among others, widely use and approve the use of PHE and TPC. In addition, PHE and TPC are used as one-time mydriatic treatments and are not intended for chronic ocular administration. Thus, the toxicity of the developed composition was not greater than that of commercially available eye drops. Furthermore, ocular toxicity may be reduced due to the lower amount of PHE and TPC required to induce effective mydriasis using the in situ gelling delivery system.

[0122] VI. In vivo imaging studies of the efficacy of compositions according to the present invention on pupil dilation and persistence at the site of administration. In vivo experiments were performed in unanesthetized rabbits kept in containment boxes, but the head was allowed to move freely, allowing normal eyelid and eye movements throughout the experiment.

[0123] One drop of the preparation was carefully administered into the conjunctival sac of the animals using a plastic Pasteur pipette. The contralateral eye was not treated and used as a control. The volume of the drops of the different compositions and control solutions was measured and no significant variation was observed (28.6 ± 0.8 μL to 30.1 ± 1.2 μL). A flexible slider was placed on the rabbit's cheek and images of both eyes were recorded using a Canon EOS 350D equipped with a Canon EF 100 mm f / 2.8 macro lens that provides zoom and autofocus, allowing to photograph the eye area with high precision and to focus on the area of ​​interest. The rabbit was placed under surgical lighting (Halux LED 20 PSX, Derungs medical lighting) to maintain constant illumination of the eye and to avoid physiological variations in pupil dilation. Collections were performed before administration (reference image) and up to 5 hours after administration of the composition.

[0124] Compositions A, B and C according to the invention were compared with a control solution (CTRL) (5% phenylephrine and 0.5% tropicamide in sterile water) and with commercially available eye drops (CED); Mydryaticum® (tropicamide 0.5%) and Neosynephrine® (phenylephrine hydrochloride 10%). For the commercially available eye drops, the standard protocol used clinically was followed. Four drops of each eye drop were instilled at 5 min intervals from t0 to t35. Finally, mydriatic kinematic data were obtained by analyzing the images using Image J open source image processing software. Pupil diameter was measured and the diameter subtracted from the baseline diameter was plotted against time to express pupil dilation. The area under the curve (AUC) was calculated. Results are the mean ± standard deviation of n=3 experiments performed on three different rabbits. Each rabbit had a minimum washout period of 48 h between the two experiments.

[0125] At the end of the protocol, the rabbits were sent to a shelter by an approved association; no sacrifice was required.

[0126] Effective mydriasis is defined as an increase in pupillary diameter of 5 mm or more from the baseline diameter (t0) and the absence of a pupillary reflex.

[0127] Compositions A, B, and C provide effective pupil dilation in less than 10 minutes and maintain sufficient dilation for more than 3 hours. In contrast, the control solution achieves effective pupil dilation in about 20 minutes and maintains sufficient effect for less than 1 hour. It is important to note that one drop of the composition developed according to the present invention contains the same amount of PHE and TPC as one drop of the control solution. Thus, the same amount of PHE and TPC was instilled.

[0128] The area under the curve was calculated and significant differences were observed between compositions A, B, and C compared to the control solution, demonstrating the direct effect of the in situ gelling composition on bioavailability (Table 17). This significant increase in pupil dilation can be explained by the long residence time and sustained drug release previously evaluated for the developed in situ gelling delivery system. [Table 17]

[0129] The results for in vivo residence time (Table 18) and in vivo mydriasis (Table 19) are shown below. [Table 18] [Table 19]

[0130] Upon administration of the CED, effective mydriasis was achieved in approximately 20 minutes and was maintained for 3 hours. Except for the first 20 minutes, during which the mydriasis intensity after CED administration was significantly lower than that of Compositions A, B, and C, the mydriasis intensity profiles were then comparable.

[0131] All compositions according to the invention allowed effective mydriasis after administration of a single drop. Moreover, sufficient mydriasis was obtained faster than with the reference protocol. The intensity and duration of mydriasis induced by compositions A, B, and C were similar to that obtained after administration of CED.

[0132] Therefore, the composition according to the present invention can be considered as a promising alternative to existing treatments. Effective mydriasis can be induced after instillation of a single drop of liquid, which gels when administered to the ocular surface, increasing the residence time, increasing the sustained release of the drug, and dramatically increasing bioavailability.

[0133] In addition, the amounts of PHE and TPC administered according to the CED protocol were 8 and 4 times greater, respectively. Nevertheless, pupil dilation was slow to appear and did not last long. This highlights the low bioavailability and high rate of elimination of active agents on the ocular surface after administration of classical eye drops.

[0134] Thus, the present invention results in a reduced risk of side effects. On the one hand, using the in situ gelling delivery system developed in CED, local irritation to the ocular surface area could be reduced, since the total amount of active ingredient required to induce mydriasis is small. PHE and TPC have shown significant cytotoxicity in human corneal epithelial cells. During the experiment, discomfort resulting in an increase in blinking frequency was observed after administration of one drop of phenylephrine (Neosyneffrine® 10%) (5-6 additional blinks within 30 seconds of administration). No increase in blink frequency or discomfort was observed after administration of compositions A, B, and C. This effect may be due to the high osmolality (>900 mOsm / L) of phenylephrine eye drops. A tingling sensation has been reported many times in humans after administration of these eye drops. Thus, patient comfort can be improved by the use of the in situ gelling delivery system. On the other hand, systemic side effects can be reduced due to a reduction in the elimination of the drug from the ocular surface, potentially absorbed systemically. This is because increased ocular residence time allows PHE and TPC to be retained in the ocular surface area, leading to increased amounts of drug being locally absorbed.

[0135] Comparative test with other gelling polymers Other gelling, viscosifying, and / or mucoadhesive polymers such as poloxamer, carbomer, alginate, or xanthan gum have been tested.

[0136] Poloxamers are not suitable for instillation in accordance with the present invention since they exhibit concentration- and temperature-dependent gelation, and the dilution effect in the presence of tear fluid causes large variations in gelation temperature.

[0137] Alginate will only gel in the presence of calcium ions, and the calcium concentration in tears is too low to allow suitable gelation for the intended applications and purposes of the present invention.

[0138] Xanthan gum causes gelation of the preparation even before its use, which is due in particular to ionic interactions between ionized phenylephrine and the negative charges of the xanthan gum chains.

[0139] Carbomer is a pH gelling polymer. At acidic pH it is a viscous liquid and at neutral pH it is a gel. Administration of acidic solutions to the eye is not optimal for patient tolerance and comfort.

Claims

1. A composition comprising at least gellan gum and phenylephrine.

2. 2. The composition according to claim 1, characterized in that the composition is in the form of a solution having a viscosity of less than or equal to 500 mPa·s at a temperature of 20-25°C.

3. 3. The composition according to claim 1 or claim 2, characterized in that the composition comprises at most 0.6% gellan gum, said percentage being calculated by weight of gellan gum / volume of composition.

4. A composition according to any one of claims 1 to 3, characterized in that the composition comprises 0.1 to 0.5% gellan gum, said percentage being calculated by weight of gellan gum / volume of composition.

5. The composition according to any one of claims 1 to 4, characterized in that said composition comprises at least 0.1% phenylephrine, said percentage being calculated by weight of phenylephrine / volume of composition.

6. 6. The composition according to claim 1, wherein the composition comprises 0.1 to 10% phenylephrine, said percentage being calculated by weight of phenylephrine / volume of composition.

7. The composition according to any one of claims 1 to 6, characterized in that the composition contains at least one other component in addition to phenylephrine and gellan gum.

8. Composition according to any one of claims 1 to 7, characterized in that it also contains tropicamide.

9. A composition according to any one of claims 1 to 8, characterized in that it comprises at least 0.1% of tropicamide, said percentage being calculated by weight of tropicamide / volume of composition.

10. 10. The composition according to any one of claims 1 to 9, characterized in that it comprises from 0.1 to 10% of tropicamide, said percentage being calculated by weight of tropicamide / volume of composition.

11. The composition of any one of claims 1 to 10, further comprising at least one gelation modifier.

12. The composition according to any one of claims 1 to 11, characterized in that the gelation regulator is selected from organic acids, chelating agents, and mixtures thereof.

13. Composition according to any one of claims 1 to 12, characterized in that the composition also comprises at least one antioxidant.

14. The composition according to any one of claims 11 to 13, characterized in that the gelation regulator and / or the antioxidant is at least sodium citrate, an organic acid, or an organic acid salt.

15. 15. The composition of any one of claims 1 to 14, wherein the composition comprises 0.01% to 0.2% of sodium citrate, an organic acid, or an organic acid salt, said percentages being calculated by weight to volume of the composition.

16. Composition according to any one of the preceding claims, characterized in that it also comprises at least one cellulose derivative.

17. The composition according to any one of claims 1 to 16, characterized in that the composition further comprises hydroxyethyl cellulose and / or hydroxypropyl methylcellulose.

18. The composition according to any one of claims 1 to 17, characterized in that the composition further comprises water.

19. A composition according to any one of claims 1 to 18 for its use as an ophthalmic product.

20. The composition according to any one of claims 1 to 18, characterized in that the composition is used as an ophthalmic product and gels when dropped onto the surface of the eye under the effect of monovalent and divalent cations contained in the tear fluid.

21. 21. The composition of claim 19 or claim 20 for use as a mydriatic ophthalmic product.

22. A composition according to any one of claims 19 to 21 for use in the human or animal eye to induce pupil dilation prior to surgery on said eye or prior to examination of said eye.

23. A composition according to any one of claims 19 to 22 for use in the human or animal eye, which induces mydriasis in less than 10 minutes.

24. A composition according to any one of claims 19 to 23 for use in the human or animal eye to induce mydriasis lasting for more than 120 minutes.

25. The composition according to any one of claims 19 to 24, adapted to be applied to the eye in at least one drop.

26. A composition according to any one of claims 1 to 18 for use as a medicament in the treatment of ocular pathologies.

27. The composition according to any one of claims 1 to 26, for use in the treatment of uveitis and / or keratitis.

28. A method for preparing a composition according to any one of claims 1 to 18, comprising the steps of: Step a) of preparing a solution A containing at least gellan gum; Step b of preparing a solution B containing at least phenylephrine; A step c of mixing the solution A and the solution B, When calculated as a percentage by weight of the total weight of the mixture of solution A and solution B, The solution A is 20% to 40% The solution B is 60% to 80%. The preparation method includes:

29. 29. The method according to claim 28, wherein in step c, solution A is mixed into solution B by pouring.

30. The solution A further comprises a chelating agent, an organic acid, an antioxidant, and / or water; The solution B further contains tropicamide, a cellulose derivative, and / or water.

30. A process according to claim 28 or claim 29.

31. The step a includes the following steps: Step a1: dissolving the gellan gum in water with stirring, and optionally further dissolving the chelating agent, the organic acid, and / or the antioxidant; Step a2 of heating the solution obtained in step a1 to 60°C to 90°C while stirring; Step a3 of leaving the mixture while stirring for 1 to 15 minutes; After the step a3, a step a4 of leaving the solution with stirring until the temperature of the solution reaches 15°C to 30°C; Optionally, a step a5 of sterile filtering Inclusive of The step b comprises the following steps: Step b1 of dissolving the phenylephrine in water and optionally further dissolving the tropicamide; Step b2 of stirring the solution in step b1 for 1 hour to 3 hours until the solution is completely dissolved; Optionally, a step b3 of dissolving the cellulose derivative; Optionally, a step b4 of sterile filtering Inclusive of Step c comprises the steps of: Step c1 of stirring the solution A; Step c2 of adding solution A to solution B with stirring; Step c3: continue stirring until a homogeneous mixture is obtained The preparation method according to any one of claims 28 to 30, comprising:

Images