PROSTAGLANDIN EMULSION STABILIZATION KIT

Abstract

KIT FOR STABILIZING PROSTAGLANDIN EMULSIONS The present invention relates to a kit (1) containing an oil-in-water emulsion (2) which is contained in a stabilizing container (3); the stabilizing container (3) being an aluminum container, and the emulsion (2) comprising at least one prostaglandin, at least one oil selected from triglyceride oils, at least one cationic agent selected from quaternary ammonium compounds, at least one non-ionic surfactant selected from polysorbates and sorbitan esters, and water. Preferably, the emulsion (2) is further contained in at least one packaging container (4), which is placed in the stabilizing container (3). The stabilizing container (3) may be in the form of a pouch having two walls (5) connected together by a peripheral zone (6). The present invention also relates to a package comprising a plurality of kits (1).Abstract figure: Fig. 1.

Description

Title of the invention: PROSTAGLANDIN EMULSION STABILIZATION KIT FIELD OF THE INVENTION

[0001] The invention relates to a kit containing a stabilizing container, the stabilizing container containing an oil-in-water emulsion comprising at least one prostaglandin. In particular, the stabilizing container is an aluminum container. The kit of the invention is useful, in particular, for stabilizing emulsions for ophthalmic use. STATE OF THE ART

[0002] Glaucoma causes damage to the optic nerve, resulting in visual field loss, and remains the leading cause of irreversible blindness worldwide. Since the disease is usually progressive and irreversible, early detection and treatment to control progression are essential. Reducing intraocular pressure (IOP) is an effective way to prevent damage to the optic nerve. The estimated number of patients worldwide in 2020 was 76 million, and this figure is expected to increase to 95 million by 2030. Prostaglandin F2aipha and its analogues are known for their ability to lower IOP. In particular, latanoprost reduces elevated IOP and is the most prescribed prostaglandin analogue in Europe.

[0003] WO 2006 / 050836 A2 and WO 2007 / 042262 A2 (NOVAGALI PHARMA SA) disclose cationic oil-in-water ophthalmic emulsions comprising a prostaglandin for use in the treatment of ocular diseases or conditions, including ocular hypertension and glaucoma. The disclosed emulsions significantly increase the chemical stability of prostaglandins compared to the commercial product "latanoprost ophthalmic solution 0.005%" (Xalatan®, Pfizer, USA).

[0004] Ocular surface disease (OSD) represents an emerging problem in glaucoma management, with up to 60% of glaucoma patients experiencing dry eye. OSD is a multifactorial ocular condition that may involve degradation of the tear film as well as lesions on the ocular surface. It negatively influences quality of life and compromises adherence to glaucoma eye drop treatment, which may influence the effectiveness of therapy.

[0005] Document WO 2011 / 061298 Al (NOVAGALI PHARMA SA) discloses a composition comprising a prostaglandin F2aipha or an analogue, intended to be used in the treatment of surface eye conditions, including corneal and conjunctival lesions.

[0006] Although they represented at the time a very significant therapeutic improvement, the ophthalmic use of prostaglandin emulsions of the art was limited by practical problems. Indeed, it was unfortunately discovered that cationic oil-in-water emulsions comprising prostaglandins can be unstable during storage, in particular the Applicant discovered that exposure to light had a considerable impact on the stability of such emulsions. Thus, there is still a need for means to ensure the stability, in particular the photostability, of ophthalmic vehicles for the ocular administration of prostaglandin.

[0007] The Applicant has surprisingly discovered that packaging a cationic oil-in-water emulsion comprising a prostaglandin in a stabilizing container which is an aluminum container (in particular, an aluminum pouch), effectively prevents destabilization of the emulsion. The stabilization of the emulsion can be evaluated by measuring parameters such as, for example, pH, conductivity, the amount of prostaglandin and / or the amount of impurities. Thus, the Applicant hereby proposes a kit according to the invention, comprising an aluminum container in which the emulsion is packaged. The invention opens the way to a widespread use of cationic oil-in-water emulsions comprising prostaglandins for the treatment of the eyes, in particular for the treatment of glaucoma, ocular hypertension or OSD. SUMMARY

[0008] The present invention relates to a kit containing an oil-in-water emulsion and a stabilizing container; wherein the oil-in-water emulsion is contained in the stabilizing container; wherein the stabilizing container is an aluminum container; and wherein the oil-in-water emulsion comprises: at least one prostaglandin, at least one oil selected from triglyceride oils, at least one non-ionic surfactant selected from polysorbates and sorbitan esters, at least one cationic agent selected from quaternary ammonium compounds, and water.

[0009] According to one embodiment, the stabilizing container is in the form of a pouch. According to one embodiment, the oil-in-water emulsion is further contained in a packaging container, which is placed in said stabilizing container. In one embodiment, the stabilizing container comprises at least two of the packaging containers, preferably at least five of the packaging containers. In one embodiment, the packaging is a polyethylene container and / or a single-dose container, preferably a low-density polyethylene (LDPE) container.

[0010] According to one embodiment, the prostaglandin is selected from latanoprost, isopropyl unoprostone, travoprost, bimatoprost, and mixtures thereof; preferably the prostaglandin is latanoprost. According to one embodiment, the oil-in-water emulsion comprises: at least one prostaglandin comprising latanoprost, at least one oil comprising medium-chain triglycerides, at least one non-ionic surfactant comprising polysorbate 80, at least one cationic agent comprising cetalkonium chloride, at least one osmotic agent comprising glycerol, and water.According to one embodiment, the oil-in-water emulsion comprises from about 0.001 to 0.02% w / w of the at least one prostaglandin, from about 0.2 to 2.5% w / w of the at least one oil, from about 0.01 to 0.2% w / w of the at least one nonionic surfactant, from about 0.001 to 0.02% w / w of the at least one cationic agent, from about 0.5 to 6% w / w of at least one osmotic agent, and from about 94 to 99% w / w of the water, by weight relative to the total weight of the oil-in-water emulsion. In one embodiment, the oil-in-water emulsion comprises: about 0.005% w / w latanoprost, about 1% w / w medium chain triglycerides, about 0.05% w / w polysorbate 80, about 0.005% w / w cetalkonium chloride, about 2.4% w / w glycerol, and water, by weight based on the total weight of the oil-in-water emulsion.According to one embodiment, the oil-in-water emulsion is an ophthalmic composition.

[0011] According to one embodiment, the oil-in-water emulsion is intended to be used in the treatment of an ocular disease or an ocular condition; preferably, the ocular disease or ocular condition is glaucoma, ocular hypertension and / or an ocular surface disease.

[0012] The present invention also relates to a package comprising at least two kits according to the invention, preferably comprising 6, 12, 18 or 24 kits.

[0013] The present invention also relates to a method of manufacturing a kit according to the invention, wherein the method comprises the following step: packaging an oil-in-water emulsion as defined above in a stabilizing container and, optionally, a conditioning container, to thereby obtain the kit according to the invention; wherein the stabilizing container is an aluminum container.

[0014] The present invention also relates to a method for stabilizing an oil-in-water emulsion as defined above, wherein the method comprises the following step: packaging an oil-in-water emulsion as defined above in a stabilizing container and, optionally, in a packaging, thereby to stabilize the oil-in-water emulsion; wherein the stabilizing container is an aluminum container.

[0015] The present invention also relates to a method of manufacturing a package according to the invention, in which the method comprises the following step: packaging together at least two kits according to the invention, thereby obtaining the package according to the invention. DEFINITIONS

[0016] In the present invention, the following terms and expressions have the following meanings:

[0017] “Approximately” is used here to mean approximately, roughly, around of or in the region of. The term "about" preceding a figure means plus or minus 10% of the value of that figure. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the limits above and below the stated numerical values ​​by 10%.

[0018] “Active ingredient” and “therapeutic agent” or “pharmacologically active agent” "active" are synonyms and refer to a compound for therapeutic use, and relate to health. In general, an active ingredient exhibits a pharmaceutical effect and / or may be indicated for treating or preventing a disease or condition, as defined below. Preferably, the active ingredient is intended for use in the treatment of an ocular disease or condition.

[0019] “Between [lower value] and [higher value]” and the like define a range numeric value that excludes (i.e., does not include) both the upper and lower values.

[0020] The "droplet size" of an emulsion refers to the maximum droplet size or the average droplet size, preferably the maximum droplet size, of the dispersed phase. The droplet size can be measured by methods known in the art, for example by light scattering after dilution in water using a high-performance particle size analyzer (such as a Zetasizer 2000 or a Zetasizer Nano ZS, Malvem Instruments, RU).

[0021] “Emulsion”, in accordance with general knowledge in the art, makes reference to a macroscopically homogeneous but microscopically heterogeneous mixture of two or more liquids that are normally immiscible due to liquid-liquid phase separation. In an emulsion, one liquid (the "dispersed phase") is dispersed in the other (the "continuous phase") in the form of droplets. The stability of an emulsion is usually achieved by the inclusion of at least one surfactant in the emulsion. The surfactant may, for example, be present on the surface of the emulsion droplets.

[0022] “Oil-in-water emulsion” refers to an emulsion in which the phase The dispersed phase is significantly more lipophilic than the continuous phase. Typically, the dispersed phase is oil-based and / or the continuous phase is water-based.

[0023] “Ophthalmic composition” refers to a composition intended to be administered into the eye of a subject and / or which is suitable for administration into the eye of a subject. Generally, an ophthalmic composition exhibits a pharmaceutical effect and / or may be indicated for treating an ocular disease or condition.

[0024] “Ophthalmic treatment” refers to the treatment of a disease or condition ocular in a subject in need thereof. Generally, an ophthalmic treatment comprises a step of administering an ophthalmic composition as defined herein into the eye of a subject.

[0025] By "pharmaceutically acceptable" with reference to a substance or composition is meant that the substances or composition are compatible with each other and / or are not harmful to the subject, preferably a human, to whom the substance or composition is administered. In particular, it does not produce adverse or allergic reactions or other unpleasant reactions when administered to a subject, preferably a human. For administration to a human, the compositions must meet the standards of sterility, pyrogenicity, general safety and purity required by regulatory bodies such as, for example, the office of the Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

[0026] “Pharmaceutically acceptable excipient” refers to an excipient, pharmaceutically acceptable carrier or vehicle. It includes all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption-delaying agents, and the like.

[0027] “Pharmaceutical composition” refers to a composition comprising at least at least one active ingredient in association with at least one pharmaceutically acceptable excipient. A pharmaceutical composition is intended for therapeutic use and relates to health. In particular, a pharmaceutical composition may be indicated for treating or preventing a disease or condition, as defined below. Preferably, a pharmaceutical composition is intended for use in the treatment of an eye disease or condition.

[0028] “Prodrug” refers to an active ingredient which, after administration, is converted within the body (i.e., metabolized) into a drug (i.e., an active ingredient). Typical examples of prodrugs are ester, ether, and amide derivatives of drugs.

[0029] “Prostaglandin” refers indifferently to prostaglandins, their derivatives, precursors, prodrugs and / or analogues, as well as pharmaceutically acceptable salts and / or solvates thereof.

[0030] “Quaternary ammonium compound” or “quaternary ammonium salt” are synonyms and refer to a salt of a quaternary ammonium cation.

[0031] “Ranging from [lower value] to [higher value]” and other enumerations similar define a numerical range that includes (i.e., encompasses) both the upper value and the lower value. Moreover, any range so defined in this application should be interpreted as including an explicit disclosure of the corresponding narrower range “between [lower value] and [upper value]”.

[0032] “Subject” refers to a warm-blooded animal, preferably a mammal, of more preferably a human. Preferably, the subject is a patient, i.e., a subject who is waiting to receive or is receiving medical care, or who is / will be the subject of a medical procedure. Preferably, the subject has an eye disease or an eye condition.

[0033] “Topical administration” refers to the administration of a composition to the surface of an eye, for example on the cornea or inner eyelid. Topical administration can, for example, be done using an eye dropper.

[0034] “Treat” or “treatment” or “relief” refers to both a therapeutic treatment and prophylactic or preventive measures; the objective being to prevent or slow down (mitigate) the targeted disease or condition in a subject in need thereof. Individuals in need of treatment include those who already have the disease or condition, as well as those who are likely to have the disorder or those in whom the disorder is to be prevented. A subject is successfully “treated” for a disease or condition if, after receiving a therapeutic amount of a substance or composition, the subject exhibits an observable and / or measurable effect on one or more of the following: reduction in the number of pathogenic cells; reduction in the percentage of total cells that are pathogenic; relief to some extent of one or more of the symptoms associated with the specific disease or condition; reduction in morbidity and mortality; and / or improvement in quality of life.The above parameters for evaluating the success of a treatment and the improvement of the disease are readily measurable by routine procedures well known to physicians. Preferably, the treatment comprises a step of administering an active ingredient, as defined above. In the invention, the disease or condition is an ocular disease or ocular condition, i.e., a pathological disorder or condition affecting the eye of a subject.

[0035] “Triglyceride” refers to a triester derived from glycerol and exactly three fatty acids.

[0036] "Zeta potential" is defined as follows. A well-known approach in the art for stabilizing an emulsion is to impart an electrostatic charge to the surface of the droplets of the dispersed phase, which will result in greater droplet repulsion and less droplet coalescence. Colloidal particles dispersed in an emulsion are electrically charged due to their ionic characteristics and / or dipolar attributes. This charge is referred to in the art as "zeta potential" and reflects the magnitude of repulsion or attraction between the particles. Zeta potential can be measured by methods known in the art, for example, by measuring electrophoretic mobility using a zetameter (such as a Zetasizer 2000 or a Zetasizer Nano ZS, Malvem Instruments, UK). The electrophoretic mobility is then converted to zeta potential values ​​by the Smoluchowsky or Henry equation. DETAILED DESCRIPTION

[0037] Kit The present invention relates to a kit containing an oil-in-water emulsion and a stabilizing container; - wherein the oil-in-water emulsion is contained in the stabilizing container; - wherein the stabilizing container is an aluminum container; and - wherein the oil-in-water emulsion comprises: • at least one prostaglandin, • at least one oil selected from triglyceride oils, • at least one non-ionic surfactant selected from polysorbates and sorbitan esters, • at least one cationic agent selected from quaternary ammonium compounds, and • water.

[0038] Stabilization container The kit according to the invention comprises a stabilizing container which forms an “intermediate container” or “secondary packaging”, the main function of which is to stabilize the oil-in-water emulsion which it contains, relative to an emulsion not contained in the stabilizing container.

[0039] In the invention, the stabilizing container ensures the stabilization of the emulsion. Advantageously, the stabilizing container ensures the photo stability of the emulsion thanks to its opacity.

[0040] Advantageously, the emulsion is stabilized in terms of pH, for example no significant decrease in the pH of the emulsion is observed during storage. Advantageously, the emulsion is stabilized in terms of conductivity, for example no significant increase in the conductivity of the emulsion is observed during storage. Advantageously, the emulsion is stabilized in terms of the amount of active ingredient, i.e. prostaglandin (prostaglandin assay), for example no significant decrease in the amount of prostaglandin in the emulsion is observed during storage. Advantageously, the emulsion is stabilized in terms of the amount of impurities (impurity assay), for example no significant increase in the amount of impurities (e.g., prostaglandin degradation products) in the emulsion is observed during storage.Preferably, the emulsion is stabilized in terms of pH, conductivity, amount of prostaglandin (prostaglandin assay) and / or amount of impurities (impurity assay).

[0041] Advantageously, no significant decrease and / or increase in the osmolarity of the emulsion is observed during storage. Advantageously, no significant decrease and / or increase in the droplet size of the emulsion is observed during storage. Advantageously, no significant decrease and / or increase in the zeta potential of the emulsion is observed during storage.

[0042] Without being bound by any theory, Applicant believes that the decrease in pH may be caused by the presence of acidic degradation products in the emulsion and / or by a loss of water in the emulsion (i.e., concentration of the emulsion). In one embodiment, the acidic degradation products comprise one or more prostaglandin degradation products (e.g., "latanoprost free acid," which is the active ingredient of which latanoprost is a prodrug) and / or one or more degradation products of at least one excipient (e.g., at least one free fatty acid resulting from the degradation of medium-chain triglycerides (MCTs)).Water loss may occur even when the emulsion is contained in a packaging container (as described below), for example, water loss from an emulsion packaged in an LDPE bottle and not contained in a sealed pouch may be as high as 20% after about 3 years of storage under standard conditions. In one embodiment, the water loss in the oil-in-water emulsion is less than or equal to about 5% w / w, preferably less than or equal to about 1% w / w, more preferably less than or equal to about 0.5% w / w, more preferably less than or equal to about 0.1% w / w, by weight relative to the total weight of the oil-in-water emulsion (or by weight relative to the total weight of water). in oil-in-water emulsion); after approximately 3 years of storage under standard conditions.

[0043] The stabilization of the emulsion can be evaluated, for example, by photostability tests as described in Example 2 below.

[0044] Advantageously, the emulsion is stabilized by the stabilizing container for at least 6 months, preferably at least 1 year, more preferably at least 2 years, even more preferably at least 3 years; when stored under normal conditions such as, for example, about 25°C and about 40% relative humidity (RH).

[0045] The stabilizing container has peripheral walls defining a housing configured to receive the emulsion. The stabilizing container is an aluminum container, i.e., at least a substantial portion, namely more than 50%, of the walls of the housing are coated with aluminum. For example, at least about 80% or about 90% or about 100% of a total surface area of ​​the walls of the housing are coated with aluminum. Herein, "aluminum coated" and the like encompass embodiments in which the walls are at least partially made of aluminum, such that a fraction of its surface area is made of aluminum and thus coated with aluminum or, in the case of a multi-layer housing, at least one layer comprises aluminum. The aluminum-coated surface may be further coated with a protective layer, for example, a protective film, to prevent deterioration of the aluminum.In the invention, the "aluminum" in the stabilizing container is not limited to high purity aluminum (i.e., "elemental" aluminum, denoted "Al"), but also encompasses any aluminum-based material known in the art or commercially available that includes small amounts of impurities or additives necessary for the preparation of the material, handling of the material, stability over time, etc. The aluminum may be in various forms such as, for example, foils or coatings. The aluminum may be, for example, applied to the internal and / or external surfaces of the walls, or included in a layer within the walls of the container.

[0046] The parts of the stabilizing container that are not made of aluminum may be made of, for example, plastics (e.g., polymers, especially polyolefins, or rubber), glass, metal, paper (e.g., cardboard), biomaterials, or any mixture and / or combination thereof.

[0047] In a preferred embodiment, the stabilizing container is a polyethylene-aluminum container, i.e., a polyethylene-based container at least partially coated with aluminum (as defined above). The aluminum-polyethylene container may, for example, be a polyethylene-based container wherein at least about 80%, at least about 90%, or about 100% of the total surface area of ​​the container is coated with aluminum. In one embodiment, the walls of the stabilizing container housing comprise at least one of polyethylene terephthalate (PET), an extruded ethylene-methacrylic acid copolymer (“EXTR.PE”), and aluminum (“ALU”).

[0048] The stabilizing container may be in various forms such as, for example, bags (e.g., pouches, sachets, bags, etc.), boxes, ampoules, bottles, cans, flasks, pots, vials, and the like. In one embodiment, the stabilizing container is in a form selected from bags (e.g., pouches), boxes, bottles, cans, and pots. In a preferred embodiment, the stabilizing container is in the form of a pouch. A pouch may, for example, consist of two walls joined together by a peripheral zone at least partially closing the pouch around the housing. Typically, each of the walls may be formed of a flexible sheet, for example of a polygonal (particularly rectangular) outline (particularly square sheets).Typically, the peripheral area extends at least about 70% or about 75% or about 80% of the side length of the sheets. For example, if the sheets are rectangular, the peripheral area may extend along three sides of the sheets, preferably four sides of the sheets. Optionally, the pouch may further comprise a third sheet, typically a folded sheet, adhered along at least one side of each of the two sheets around the peripheral area, thereby increasing the internal volume of the pouch.

[0049] In a preferred embodiment, the stabilizing container is an aluminum-polyethylene foil pouch.

[0050] According to a first embodiment, the stabilization container is open, that is to say that it comprises at least one opening which represents a limited fraction of the total surface area of ​​the container such as, for example, less than approximately 30% or approximately 25% or approximately 20% of the total surface area of ​​the container.

[0051] According to a second embodiment, the stabilization container is closed, i.e., it does not include any openings or only openings that represent a negligible fraction of the total surface area of ​​the stabilization container such as, for example, less than about 1% or about 0.1% or about 0.01% of the total surface area of ​​the stabilization container. Preferably, a closed stabilization container does not include any openings. The stabilization container may be closed by any method known in the art, for example, by sealing the container. In one embodiment, the stabilization container is sealed. The stabilization container may be sealed by any method known in the art, for example, heat sealing (a sealing method that uses a combination of heat, time, and pressure). The stabilizing container may include a sealable or reversible opening such as, for example, a zipper, to allow storage in a closed configuration and temporary opening during use.

[0052] In one embodiment, the stabilization container has a water vapor permeability of less than or equal to about 0.50 g / m2.day, preferably less than or equal to about 0.25 g / m2.day, more preferably less than or equal to about 0.05 g / m2.day (at about 23°C and about 0% relative humidity (RH)). In one embodiment, the stabilization container has an oxygen permeability of less than or equal to about 0.50 cc / m2.day, preferably less than or equal to about 0.25 cc / m2.day, more preferably less than or equal to about 0.05 cc / m2.day (at about 38°C and about 90% relative humidity (RH)).

[0053] Packaging containerAccording to one embodiment, the oil-in-water emulsion is further contained in a packaging container, i.e., in the stabilizing container is placed at least one packaging container that forms an "inner container" or "primary package", which contains the emulsion. In the invention, the packaging container is used to package the emulsion, which includes, for example, the safe preservation of the emulsion over time until its use (e.g., until ophthalmic treatment). Typically, the packaging container encloses the emulsion, so that the emulsion is not directly in contact with the stabilizing container, which is advantageous in terms of safety and durability, since the stabilizing container comprises aluminum.The packaging container may have additional functions such as, for example, allowing easy handling and / or administration of the emulsion (for example, if the packaging container is an eye drop) or maintaining the sterility of the emulsion.

[0054] The packaging container may be made, for example, of plastics (e.g., polymers, in particular polyolefins, or rubber), glass, metal, paper (e.g., cardboard), biomaterials, or the like, or any mixture and / or combination thereof. In one embodiment, the packaging container is made of a material suitable for packaging medicaments such as, for example, pharmaceutically acceptable polymers. In one embodiment, the packaging container is partially or entirely made of a transparent or translucent material. In a preferred embodiment, the packaging container is a polyethylene container such as, for example, polyethylene terephthalate, high-density polyethylene (HDPE), or low-density polyethylene (LDPE). In a Another preferred embodiment, the packaging container is a low density polyethylene (LDPE) container.

[0055] The packaging container may extend along an extension axis between a lower end and a dispensing end through which the emulsion may be dispensed. The packaging container may be in various forms such as, for example, ampoules, bottles, cans, vials, jars, vials, and the like. In one embodiment, the packaging container is in a form selected from ampoules, bottles, vials, and vials. In a preferred embodiment, the packaging container is in the form of a vial.

[0056] In a preferred embodiment, the packaging container is in the form of a low density polyethylene (LDPE) vial.

[0057] In one embodiment, the packaging container is a single-dose container (or "single-use container") or a multi-dose container (or "multi-use container"). In a preferred embodiment, the packaging container is a single-dose container. The single-dose container may comprise, for example, from about 0.1 ml to about 0.5 ml of the emulsion, preferably from about 0.2 ml to about 0.4 ml of the emulsion, more preferably about 0.2 ml or about 0.3 ml of the emulsion. In one embodiment, the single-dose container comprises about 0.2 ml of the emulsion. In one embodiment, the single-dose container comprises about 0.3 ml of the emulsion.

[0058] In one embodiment, the packaging container is an eye drop or dropper, such that its shape allows for easy administration of the emulsion into the eye of a subject.

[0059] In one embodiment, the stabilizing container contains at least two of the packaging containers. In one embodiment, the stabilizing container contains at least five of the packaging containers. In a preferred embodiment, the stabilizing container contains exactly five of the packaging containers. In a preferred embodiment, the packaging containers are bonded to each other, for example, the packaging containers together form a strip in which the containers are adjacent to each other in a transverse direction perpendicular to the direction of extension. Two adjacent containers of the strip are bonded to each other by a frangible line between the respective outer surfaces of their walls so that they can be separated before use.Such a strip may be manufactured during the manufacturing process of the packaging containers according to methods known in the art.

[0060] According to a preferred embodiment, the packaging container is closed, i.e., it does not comprise any openings or only openings that represent a negligible fraction of the total surface area of ​​the packaging container such as, for example, less than about 1% or about 0.1% or about 0.01% of the total surface area of ​​the packaging container. Preferably, a closed packaging container does not comprise any openings. The packaging container may be closed by any method known in the art, for example according to blow-fill-seal (BFS) technology. BFS is an automated manufacturing process for plastic containers, in which the containers are blow-formed, filled and sealed; all three steps being carried out in a continuous operation.

[0061] Oil-in-water emulsion In the invention, the triglyceride oil is included in the dispersed phase of the oil-in-water emulsion and the water is included in the continuous phase of the oil-in-water emulsion.

[0062] According to one embodiment, the triglyceride oil is the main component of the dispersed phase and the water is the main component of the continuous phase. In this embodiment, according to terminology commonly used in the art, it may be indicated that the oil "is" the dispersed phase and the water "is" the continuous phase, although the dispersed phase and the continuous phase may in fact comprise other components solubilized or suspended therein such as, for example, active ingredients, surfactants, additives, etc.

[0063] Although some substances may optionally be simultaneously referred to as oil, cationic agent and / or non-ionic surfactant, in the emulsion according to the invention, oil, cationic agent and non-ionic surfactant designate three different substances, i.e. in the emulsion of the invention, the "oil" component cannot be at the same time the "non-ionic surfactant" component or the "cationic agent" component, etc. In other words, the emulsion of the invention systematically comprises at least three different substances in addition to water, at least one of them fulfilling at least the function of the oil, another of them fulfilling at least the function of a non-ionic surfactant, and another of them fulfilling at least the function of the cationic agent.In other words, in the emulsion of the invention, the oil, the cationic agent and the non-ionic surfactant are substances distinct from each other.

[0064] According to one embodiment, the prostaglandin is selected from latanoprost, isopropyl unoprostone, travoprost, bimatoprost, and mixtures thereof. In a particular embodiment, the prostaglandin comprises latanoprost. In a preferred embodiment, the prostaglandin consists essentially of, or consists of en, latanoprost. In one embodiment, the emulsion comprises prostaglandin in an amount ranging from about 0.001 to 0.02% w / w, preferably about 0.002 to 0.01% w / w, more preferably about 0.005% w / w, by weight relative to the total weight of the emulsion.

[0065] According to one embodiment, the triglyceride oil is present in the emulsion within an oil selected from vegetable oils, animal oils and semi-synthetic oils obtained from vegetable and / or animal oils. In one embodiment, the triglyceride oil is a fractionated oil obtained from at least one vegetable oil, or a mixture thereof. In one embodiment, the triglyceride oil is selected from short-chain triglycerides (i.e., C1-C5 triglycerides), medium-chain triglycerides (i.e., C6-C12 triglycerides), long-chain triglycerides (i.e., C13-C21 triglycerides), or very-long-chain triglycerides (i.e., C22 or higher triglycerides, typically C22-C34). In a particular embodiment, the triglyceride oil comprises medium-chain triglycerides (MCTs).In a preferred embodiment, the triglyceride oil consists essentially of, or consists of, medium chain triglycerides (MCTs). MCTs may in particular be prepared from fractionated vegetable oils such as, for example, palm kernel oils or coconut oils. Typically, the specific gravity of MCTs ranges from 0.93 to 0.96. In one embodiment, the emulsion comprises the oil in an amount ranging from about 0.2 to 2.5% w / w, preferably about 0.5 to 1.5% w / w, more preferably about 1% w / w, by weight relative to the total weight of the emulsion.

[0066] According to a preferred embodiment, the non-ionic surfactant is selected from polysorbates (trade name "Tween") such as, for example, polysorbate 80 (trade name Tween® 80) or polysorbate 20 (trade name Tween® 20). The polysorbates are ethoxylated sorbitan esters. In a particular preferred embodiment, the non-ionic surfactant comprises polysorbate 80, such as, for example, "super refined" commercial grade polysorbate 80. In a preferred embodiment, the non-ionic surfactant consists essentially of, or consists of, polysorbate 80. In another embodiment, the non-ionic surfactant is selected from sorbitan esters (also known as "Spans") such as, for example, Span™ 20, Span™ 40, Span™ 60, Span™ 65, Span™ 80 or Span™ 85.In one embodiment, the emulsion comprises the nonionic surfactant in an amount of from about 0.01 to 0.2% w / w, preferably from about 0.02 to 0.1% w / w, more preferably from about 0.05% w / w, by weight relative to the total weight of the emulsion.

[0067] According to one embodiment, the quaternary ammonium compound is selected from a cetalkonium halide, a benzalkonium halide, a lauralkonium halide, cetrimide, a hexadecyltrimethylammonium halide, a tetradecyltrimethylammonium halide, a dodecyltrimethylammonium halide, a cetrimonium halide, a benzethonium halide, a behenalkonium halide (or benzyldocosyldimethylammonium halide), a cetethyldimonium halide, a cetylpyridinium halide, a benzododecinium halide, a chloroallylmethenamine halide, a myristalkonium halide (or benzyldimethyltetradecylammonium halide), a stearalkonium halide, or mixtures of these. In one embodiment, the quaternary ammonium compound comprises a cetalkonium halide. In a particular embodiment, the quaternary ammonium compound comprises cetalkonium chloride or bromide.In another particular embodiment, the quaternary ammonium compound comprises cetalkonium chloride (CKC). In a preferred embodiment, the quaternary ammonium compound consists essentially of, or consists of, cetalkonium chloride (CKC). In one embodiment, the emulsion comprises the cationic agent in an amount of from about 0.001 to 0.02% w / w, preferably from about 0.002 to 0.01% w / w, more preferably from about 0.005% w / w, by weight relative to the total weight of the emulsion.

[0068] According to one embodiment, the water is selected from tap water, saline (saline) solution, distilled water and ultrapure water. The water may be, for example, "water for injection" (also known as aqua ad iniectabilia or aqua ad injectionem). In one embodiment, the emulsion comprises water in an amount ranging from about 94 to 99% w / w, preferably about 95 to 98% w / w, more preferably about 96.5% w / w, by weight relative to the total weight of the emulsion. In one embodiment, the emulsion comprises water in an amount sufficient to achieve 100% w / w, based on the total amount of non-water ingredients in the emulsion (by weight relative to the total weight of the emulsion), which may be denoted as "qs water".

[0069] According to one embodiment, the emulsion comprises at least one osmotic agent. In one embodiment, the emulsion comprises at least one osmotic agent selected from glycerol (also known as glycerin), mannitol, sorbitol, xylitol, propylene glycol, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, and mixtures thereof. In one embodiment, the osmotic agent is selected from glycerol, mannitol, sorbitol and mixtures thereof. In a particular embodiment, the osmotic agent comprises glycerol. In a preferred embodiment, the osmotic agent consists essentially of, or consists of, glycerol. In one embodiment, the emulsion comprises the osmotic agent in an amount ranging from about 0.5 to 6% w / w, preferably about 1 to 4% w / w, more preferably about 2.4% w / w, by weight based on the total weight of the emulsion.

[0070] The emulsion may further comprise at least one additive such as, for example, antioxidants, antimicrobials, buffers, chelating agents, pH adjusters, preservatives, solubilizers, stabilizers, thickening agents, viscosity modulating agents or colorants.

[0071] According to one embodiment, the composition does not comprise a preservative selected from benzyl alcohol, boric acid, chlorhexidine, benzalkonium chloride (BAK), mercury salts, thiomersal, and mixtures thereof. In one embodiment, the emulsion is free of any preservative commonly used in pharmaceutical compositions (in particular, ophthalmic pharmaceutical compositions), i.e., the emulsion is "preservative-free."

[0072] According to one embodiment, the oil-in-water emulsion comprises: - at least one prostaglandin including latanoprost, and / or - at least one oil comprising medium chain triglycerides (MCT), and / or - at least one non-ionic surfactant comprising polysorbate 80, and / or - at least one cationic agent comprising cetalkonium chloride (CKC), and / or - at least one osmotic agent comprising glycerol, and - water.

[0073] According to one embodiment, the oil-in-water emulsion comprises: - at least one prostaglandin including latanoprost, - at least one oil comprising medium chain triglycerides (MCT), - at least one non-ionic surfactant comprising polysorbate 80, - at least one cationic agent comprising cetalkonium chloride (CKC), - at least one osmotic agent comprising glycerol, and - water.

[0074] According to one embodiment, the oil-in-water emulsion comprises, by weight relative to the total weight of the oil-in-water emulsion: - from approximately 0.001 to 0.02% w / w of the at least one prostaglandin, and / or - from approximately 0.2 to 2.5% w / w of the at least one oil, and / or - from approximately 0.01 to 0.2% w / w of at least one non-ionic surfactant, and / or - from approximately 0.001 to 0.02% w / w of the at least one cationic agent, and / or - from about 0.5 to 6% w / w of at least one osmotic agent, and / or - approximately 94 to 99% w / w of water (or qs of water).

[0075] According to one embodiment, the oil-in-water emulsion comprises, by weight relative to the total weight of the oil-in-water emulsion: - from approximately 0.001 to 0.02% by weight / weight of the at least one prostaglandin, - from approximately 0.2 to 2.5% by weight / weight of the at least one oil, - from approximately 0.01 to 0.2% weight / weight of at least one non-ionic surfactant, - from approximately 0.001 to 0.02% weight / weight of at least one cationic agent, - from about 0.5 to 6% w / w of at least one osmotic agent, and - water, preferably about 94 to 99% w / w water (or qs of water).

[0076] In a particularly preferred embodiment, the oil-in-water emulsion comprises, by weight relative to the total weight of the oil-in-water emulsion: - approximately 0.001 to 0.02% w / w of latanoprost, - approximately 0.2 to 2.5% w / w medium chain triglycerides (MCT), - approximately 0.01 to 0.2% w / w of polysorbate 80, - from approximately 0.001 to 0.02% w / w of cetalkonium chloride (CKC), - about 0.5 to 6% w / w glycerol, and - water, preferably about 94 to 99% w / w water (or qs of water).

[0077] In a more preferred embodiment, the oil-in-water emulsion comprises, by weight relative to the total weight of the oil-in-water emulsion: - approximately 0.005% w / w of latanoprost, - approximately 1% w / w medium chain triglycerides (MCT), - approximately 0.05% w / w polysorbate 80, - approximately 0.005% w / w cetalkonium chloride (CKC), - approximately 2.4% w / w glycerol, and - water, preferably about 96.5% w / w water (or qs water).

[0078] According to one embodiment, the emulsion has a droplet size ranging from about 125 to 300 nm, preferably from about 150 to 275 nm, more preferably from about 175 to 225 nm. The droplet size of the emulsion can be adjusted to the desired values ​​according to emulsion preparation methods known in the art such as, for example, dispersing the oil phase by magnetic stirring or using a homogenizer (for example, POLYTRON® PT 6100 or MEGATRON® MT3100 (Kinematica), or Avestin® Emulsiflex C55 or Avestin® Emulsiflex C160).

[0079] Advantageously, the emulsion is a cationic emulsion, i.e., an emulsion having a positive zeta potential, typically a zeta potential greater than or equal to 10 mV. In one embodiment, the cationic emulsion has a zeta potential greater than or equal to about 20 mV or about 30 mV or about 40 mV. In one embodiment, the cationic emulsion has a zeta potential ranging from about 20 to 75 mV, preferably from about 30 to 65 mV, more preferably from about 40 to 55 mV. The inclusion of a cationic agent in the emulsion (as described above) is a means of making it cationic by giving it a positive charge.

[0080] Advantageously, the emulsion has a conductivity ranging from approximately 5 to 35 pS / cm, preferably ranging from approximately 10 to 30 pS / cm, more preferably ranging from approximately 15 to 25 pS / cm.

[0081] Advantageously, the emulsion has an osmolarity ranging from approximately 200 to 350 mOsm / kg, preferably ranging from approximately 250 to 300 mOsm / kg, more preferably ranging from approximately 270 to 285 mOsm / kg.

[0082] Advantageously, the emulsion has a pH ranging from approximately 3.5 to 6, preferably ranging from approximately 4 to 5.5, more preferably ranging from approximately 4.5 to 5.

[0083] The emulsion of the invention is advantageously sterilizable by methods known in the art, in accordance with safety requirements in the ophthalmic field. In particular, the emulsion retains its structure and / or properties when sterilized. For example, the emulsion may be sterilizable by heat or steam sterilization according to methods well known in the art, preferably by heat sterilization.

[0084] Other kit embodiments According to one embodiment, the kit further comprises instructions for use. In one embodiment, the instructions for use are printed on a leaflet (e.g., a folded leaflet) or on a sticker. In one embodiment, the kit further comprises instructions for use that are placed on and / or in the stabilizing container. In one embodiment, the instructions relate to the use of the oil-in-water emulsion.

[0085] According to one embodiment, the kit further comprises at least one sticker. In one embodiment, the sticker is affixed to the stabilization container and / or to the packaging container, preferably to the packaging container. According to one embodiment, the kit further comprises at least one print. In one embodiment, the print is applied to the stabilization container and / or to the packaging container, preferably to the stabilization container.

[0086] Packaging The present invention also relates to a package comprising at least two kits according to the invention, as described above. In other words, the package comprises "a plurality of" kits according to the invention. According to one embodiment, the package comprises 6, 12, 18 or 24 kits.

[0087] According to one embodiment, the packaging comprises at least one packaging container which forms an "outer container" or a "tertiary packaging", in which the kits are included, for example bags, boxes or the like.

[0088] According to a preferred embodiment, the packaging further comprises instructions for use. In one embodiment, the instructions for use are printed on a leaflet (e.g., a folded leaflet) or on a sticker. In one embodiment, the packaging further comprises instructions for use that are placed on and / or in the packaging container. In one embodiment, the instructions relate to the use of the oil-in-water emulsion.

[0089] According to one embodiment, the packaging further comprises at least one sticker. In one embodiment, the sticker is affixed to the packaging container. According to one embodiment, the packaging further comprises at least one print. In one embodiment, the print is applied to the packaging container.

[0090] Medical uses According to one embodiment, the oil-in-water emulsion included in the kit according to the invention, as described above, is intended to be used as a medicament. According to one embodiment, the kit according to the invention, as described above, is intended to be used as a medicament. According to one embodiment, the packaging according to the invention, as described above, is intended to be used as a medicament.

[0091] According to one embodiment, the emulsion, kit and / or package are for use in the treatment of an ocular disease or condition. In a preferred embodiment, the ocular disease or condition is glaucoma, ocular hypertension and / or ocular surface disease (OSD). In a particular embodiment, the ocular disease or condition is glaucoma such as, for example, open-angle glaucoma (also referred to as "wide-angle glaucoma" or "chronic simple glaucoma"), angle glaucoma closed (also referred to as "narrow-angle glaucoma" or "acute congestive glaucoma") or normal-tension glaucoma. In another preferred embodiment, the glaucoma is open-angle glaucoma. In a particular embodiment, the eye disease or condition is ocular hypertension. In a particular embodiment, the eye disease or condition is ocular surface disease (OSD) such as, for example, dry eye syndrome or blepharitis.

[0092] According to one embodiment, the emulsion is an ophthalmic composition. According to one embodiment, the emulsion is a pharmaceutical composition.

[0093] According to one embodiment, the kit and / or the packaging are a drug or a medicinal product.

[0094] According to one embodiment, the emulsion, as described above, is to be administered in a therapeutically effective amount to a subject in need thereof, in a method of treating an ocular disease or an ocular condition. According to one embodiment, the kit and / or the package according to the invention, as described above, are used in a method of treating an ocular disease or an ocular condition.

[0095] According to one embodiment, the emulsion, as described above, is used in the manufacture of a medicament for the treatment of an ocular disease or an ocular condition. According to one embodiment, the kit and / or the packaging according to the invention, as described above, are used in the manufacture of a medicament for the treatment of an ocular disease or an ocular condition.

[0096] Method of manufacturing a kit and method of stabilization The present invention also relates to a method of manufacturing a kit according to the invention, as described above, wherein the method comprises the following step: packaging an oil-in-water emulsion, as described above, in a stabilizing container, thereby obtaining the kit according to the invention; wherein the stabilizing container is an aluminum container.

[0097] The present invention also relates to a method of stabilizing an oil-in-water emulsion as described above, wherein the method comprises the following step: packaging an oil-in-water emulsion as described above in a stabilizing container, thereby stabilizing the oil-in-water emulsion; wherein the stabilizing container is an aluminum container.

[0098] According to one embodiment, the oil-in-water emulsion is contained in at least one packaging container and the packaging container is placed in the stabilization container.

[0099] According to one embodiment, the method of manufacturing a kit further comprises a step of packaging the emulsion in at least one packaging container.

[0100] The packaging of the emulsion may, for example, comprise a step of pouring the emulsion into the stabilization container or the packaging container. The packaging of the emulsion may optionally comprise at least one step of sterilizing the stabilization container and / or the packaging container, before and / or after placing the emulsion in the container.

[0101] In the above methods, the oil-in-water emulsion, the stabilizing container and / or the packaging container may each be independently as described above in the embodiments of the kit according to the invention. "Stabilization" has the same meaning as described above in the embodiments of the kit according to the invention.

[0102] Method of manufacturing a packaging The present invention also relates to a method of manufacturing a package according to the invention, as described above, wherein the method comprises the following step: packaging together at least two kits according to the invention, as described above, to thereby obtain the package according to the invention.

[0103] Packaging the kits may include, for example, a step of packaging the kits with adhesive tape, paper, polymer film, or the like. Packaging the kits may also include, for example, a step of placing the kits together in a packaging container (or "outer container" or "tertiary packaging") such as, for example, bags, boxes, or the like. DESCRIPTION OF FIGURES

[0104] [Fig.l] [Fig.l] is a drawing showing a kit 1 according to the invention containing an oil-in-water emulsion 2 contained in a stabilizing container 3.

[0105] [Fig.2] [Fig.2] is a drawing showing the kit of [Fig.l], in which the part upper part of the stabilization container 3 has been removed.

[0106] [Fig.3] [Fig.3] is a drawing showing a detail of the kit of [Fig.l], i.e. an oil-in-water emulsion 2 contained in a packaging container 4.

[0107] [Fig.4] [Fig.4] is a drawing showing an embodiment of the invention in which the kit 1 contains five packaging containers 4, which together form a strip 7. EXAMPLES

[0108] The invention is illustrated in more detail by the following examples.

[0109] Example 1: Oil-in-water emulsion and its packaging

[0110] Materials and Methods Materials: The ingredients used for the preparation of oil-in-water emulsions were purchased from commercial suppliers and used without further purification. The aluminum pouches (stabilization container) were made from sheets cut from a commercially purchased PET 12 pm / EXTR.PE 10 gsm / ALU 9 pm / EXTR.PE 30 gsm overwrap (CONSTANTIA TOBEPAL, Spain).

[0111] Processes - Thermal sterilization: Thermal sterilization is carried out in accordance with Ph. Eur 5.1.1 (e.g., European Pharmacopoeia section 5.0, section 5.1.1: “Processes for the preparation of sterile products”) at a temperature of at least 121°C for at least 15 min.

[0112] Methods - Manufacture of Oil-in-Water Emulsions: The oil and aqueous phases of the emulsion were prepared separately and heated to a suitable temperature. The prostaglandin and the cationic agent were dissolved in the oil phase. The nonionic surfactant was dissolved in the aqueous phase. A first coarse emulsion was generated by magnetic stirring, and the droplet size was then reduced by high shear mixing, high pressure homogenization, or both. The resulting emulsion was sterilized after its preparation using thermal sterilization.

[0113] Methods - Packaging of oil-in-water emulsions: After preparation, the emulsions were packaged in low-density polyethylene (LDPE) bottles (packaging containers) using a conventional blow-fill-seal (BFS) process. Then, a strip of five polyethylene containers was placed in an aluminum pouch (stabilization container), which was closed, i.e., sealed by heat sealing. Then, some of the aluminum pouches were opened for comparison purposes. Some of the polyethylene containers were not placed in a pouch for comparison purposes.

[0114] Results The oil-in-water emulsion was prepared with the composition as shown in Table 1 below. [Tables 1] Em#l Ingredient Function % wt / wt Oil phase latanoprost active ingredient 0.005 medium chain triglycerides (MCT) oily solvent 1.0 polysorbate 80 (Tween® 80) non-ionic surfactant 0.05 aqueous phase cetalkonium chloride (CKC) cationic agent 0.005 glycerol osmotic agent 2.4 water aqueous solvent qs 100

[0115] The oil-in-water emulsion Em#l is contained in a plurality of polyethylene bottles placed in an aluminum pouch. The kit comprising the oil-in-water emulsion Em#l can be represented as illustrated in [Fig.l], [Fig.2], [Fig.3] and [Fig.4].

[0116] In the embodiment shown in [Fig.l], the kit 1 contains an oil-in-water emulsion 2 and a stabilizing container 3 in the form of a rectangular pouch, in which the emulsion 2 is contained. The emulsion 2 is further included in a packaging container 4 which is placed in the stabilizing container 3. The stabilizing container 3 has two walls 5 connected together by a peripheral zone 6 completely closing the pouch around the housing, so that the pouch is closed. In this embodiment, the emulsion 2 is stabilized, as shown in Example 2 below.

[0117] In the embodiment shown in [Fig. 2], the upper portion of the stabilizing container 3 has been removed, so that the pouch is open. In this embodiment, the emulsion 2 is further stabilized, as shown in Example 2 below. In addition, the packaging container 4 can be removed from the stabilizing container 3, so that the emulsion 2 can be administered to a subject in need thereof (not shown).

[0118] In the embodiment shown in [Fig. 3], the emulsion 2 is contained in a packaging container 4 in the form of a bottle. The bottle comprises a housing, a neck and a removable cap. The packaging container 4 is also in the form of an eye drop, so that it can be used to administer the emulsion 2 into the eye of a subject in need thereof (not shown).

[0119] In the embodiment shown in [Fig. 4], the emulsion 2 is contained in five packaging containers 4 in the form of bottles. The five packaging containers 4 together form a strip 7.

[0120] After preparation (T0), the oil-in-water emulsion Em#l had the physical and chemical properties as indicated in Example 2 below.

[0121] Example 2: Photostability tests

[0122] In this example, the properties of an oil-in-water emulsion Em#l stored without a pouch, in an open aluminum pouch, or in a closed aluminum pouch are analyzed.

[0123] Materials and Methods Equipment: Mettler Toledo pH and conductivity meter, Roebling 13 / 13 / DR or Loser Type 16 microosmometer, and ZetaSizer Nano ZS Malvem.

[0124] Methods - Measurement of pH and conductivity: The test is carried out in accordance with Ph.Eur 2.2.3 (e.g., European Pharmacopoeia section 5.0, 2.2.3: “Determination of pH by potentiometry”) using a potentiometric method and the Mettler Toledo pH and conductivity meter at a temperature of 20 to 25 °C.

[0125] Methods - Osmolarity measurement: The test is carried out in accordance with Ph.Eur 2.2.35 (e.g., European Pharmacopoeia 7.3, section 2.2.35: “Osmolality”) using a cryoscopic method and the microosmometer.

[0126] Methods - Zeta potential measurement: The zeta potential of the emulsion droplet is determined by electrophoretic mobility measurement using the ZetaSizer Nano ZS Malvem. The measurement is carried out on a sample of the emulsion diluted 1:250 in deionized water.

[0127] Methods - Droplet size measurement: The droplet diameter of the oil droplet is determined by dynamic light scattering using the ZetaSizer Nano ZS Malvern. The measurement is carried out on an emulsion sample diluted 1:20 in deionized water.

[0128] Method - Prostaglandin Determination: The determination of the amount of prostaglandin (in particular, latanoprost) is carried out by high performance liquid chromatography (HPLC) under reversed phase conditions using a C18 silica chromatographic column as the stationary phase and UV detection. Samples are prepared by simple dilution in deionized water.

[0129] Method - Impurity determination: The determination of impurities (especially prostaglandin degradation products) is carried out by a high performance liquid chromatography (HPLC) method under normal phase conditions using a pure silica chromatographic column as the stationary phase and UV detection. The samples are prepared by solid-liquid extraction (solid phase extraction or SPE).

[0130] Results Physical Tests: The physical properties of the oil-in-water emulsion were as shown in Table 2 below. [Tables 2] Physical tests T0 In a pocket Open Without pocket Appearance Milky white liquid PH 4.5 4.5 4.5 3.9 Conductivity (pS / cm) 22.5 22.5 22.7 57.2 Osmolality (mOsm / kg) 276 276 279 278 Zeta potential (mV) 47.8 48.4 44.2 47.9 Droplet size ( 213 209 206 209 nm) Pdl 0.066 Pdl 0.054 Pdl 0.119 Pdl 0.095

[0131] The physical properties of the oil-in-water emulsion Em#l remain stable when the emulsion in the packaging containers is placed in a pouch, even when the pouch is opened. On the other hand, they change significantly when the emulsion is not in a pouch: the pH decreases (about 13%) and the conductivity increases considerably (about 150%). The osmolality, zeta potential and droplet size remain relatively stable whether or not the emulsion is placed in a pouch. Therefore, the open or closed aluminum pouch stabilizes the emulsion Em#l.

[0132] Prostaglandin assay: The results of the prostaglandin assay are shown in Table 3 below. [Tables 3] Latanoprost T0 In a pouch Open Without a pouch Weight (mg) 500.79 499.44 498.63 499.84 Dosage (% w / w) 0.00525 0.00526 0.00524 0.00502

[0133] The prostaglandin assays were replicated once. The values ​​shown in Table 3 above are the mean values ​​obtained from the two assays.

[0134] The amount of latanoprost in the oil-in-water emulsion Em#l remains stable when the emulsion in the packaging containers is placed in a pouch, even when the pouch is opened. On the other hand, it decreases significantly when the emulsion is not placed in a pouch (decrease of approximately 4%). Therefore, the open or closed aluminum pouch stabilizes the emulsion Em#l.

[0135] Impurity determination: The results of the impurity determination are shown in Table 4 below. [Tables 4] Impurities (name) RRT T0 In a pouch Open Without a pouch 15-keto latanoprost / 0.33 0.29 0.28 0.89 15-S latanoprost / <LOQ ND 0,11 0,14 5-trans latanoprost / <LOQ ND ND 0,40 latanoprost free acid / 0.30 0.28 0.22 0.34 Unknown 0.36 0.16 0.16 0.16 0.30 Unknown 0.44 <LOQ <LOQ <LOQ 0,25 Inconnue 0,49 <LOQ <LOQ <LOQ 0,20 Inconnue 1,30 ND ND ND 0,15 Inconnue 1,38 ND ND ND 0,16 Impuretés totales connues (% en poids / poids) 0,63 0,57 0,61 1,8 Impuretés totales inconnues (% en poids / poids) 0,16 0,16 0,16 1,1 Impuretés totales (% en poids / poids) 0,79 0,73 0,77 2,9

[0136] " <LOQ » signifie « limite de quantification » et « ND » signifie « non détecté ».

[0137] The amount of impurities in the oil-in-water emulsion Em#l remains relatively stable when the emulsion in the packaging containers is placed in a pouch, even when the pouch is opened. On the other hand, it increases significantly when the emulsion is not placed in a pouch, being multiplied by more than 3. Therefore, the open or closed aluminum pouch stabilizes the emulsion Em#l.

Claims

Claims

1. Kit (1) containing an oil-in-water emulsion (2) and a stabilizing container (3); - wherein said oil-in-water emulsion (2) is contained in said stabilizing container (3); - wherein said stabilizing container (3) is an aluminum container; and - wherein said oil-in-water emulsion (2) comprises: • at least one prostaglandin, • at least one oil selected from triglyceride oils, • at least one non-ionic surfactant selected from polysorbates and sorbitan esters, • at least one cationic agent selected from quaternary ammonium compounds, and • water.

2. A kit according to claim 1, wherein said stabilizing container (3) is in the form of a pouch.

3. A kit according to claim 1 or claim 2, wherein said oil-in-water emulsion (2) is further contained in a packaging container (4), which is placed in said stabilizing container (3).

4. A kit according to claim 3, wherein said stabilizing container (3) comprises at least two of said packaging containers (4), preferably at least five of said packaging containers (4).

5. A kit according to claim 3 or claim 4, wherein said packaging container (4) is a polyethylene container and / or a single-dose container, preferably a low-density polyethylene (LDPE) container.

6. A kit according to any one of claims 1 to 5, wherein said prostaglandin is selected from latanoprost, isopropyl unoprostone, travoprost, bimatoprost, and mixtures thereof; preferably said prostaglandin is latanoprost.

7. A kit according to any one of claims 1 to 6, wherein said oil-in-water emulsion (2) comprises: - at least one prostaglandin comprising latanoprost, - at least one oil comprising medium chain triglycerides, - at least one non-ionic surfactant comprising polysorbate 80, - at least one cationic agent comprising cetalkonium chloride, - at least one osmotic agent comprising glycerol, and - said water.

8. A kit according to any one of claims 1 to 7, wherein said oil-in-water emulsion (2) comprises, by weight relative to the total weight of said oil-in-water emulsion: - from about 0.001 to 0.02% w / w of said at least one prostaglandin, - from about 0.2 to 2.5% w / w of said at least one oil, - from about 0.01 to 0.2% w / w of said at least one non-ionic surfactant, - from about 0.001 to 0.02% w / w of said at least one cationic agent, - from about 0.5 to 6% w / w of at least one osmotic agent, and - from about 94 to 99% w / w of said water.

9. A kit according to any one of claims 1 to 8, wherein said oil-in-water emulsion (2) comprises, by weight relative to the total weight of said oil-in-water emulsion: - about 0.005% w / w of latanoprost, - about 1% w / w of medium chain triglycerides, - about 0.05% w / w of polysorbate 80, - about 0.005% w / w of cetalkonium chloride, - about 2.4% w / w of glycerol, and - water.

10. A kit according to any one of claims 1 to 9, wherein said oil-in-water emulsion (2) is an ophthalmic composition.

11. A kit according to any one of claims 1 to 10, wherein said oil-in-water emulsion (2) is for use in the treatment of an eye disease or an eye condition; preferably, said eye disease or eye condition is glaucoma, ocular hypertension and / or an ocular surface disease.

12. Packaging comprising at least two kits (1) according to any one of claims 1 to 11, preferably comprising 6, 12, 18 or 24 kits (1).

13. A method of manufacturing a kit (1) according to any one of claims 1 to 11, wherein said method comprises the following step: - packaging an oil-in-water emulsion (2) as defined in any one of claims 1 to 11 in a stabilizing container (3) and, optionally, a conditioning container (4), to thereby obtain the kit (1) according to any one of claims 1 to 11; wherein said stabilizing container (3) is an aluminum container.

14. A method of stabilizing an oil-in-water emulsion (2) as defined in any one of claims 1 to 11, wherein said method comprises the following step: - packaging an oil-in-water emulsion (2) as defined in any one of claims 1 to 11 in a stabilizing container (3) and, optionally, a conditioning container (4), thereby stabilizing said oil-in-water emulsion (2); wherein said stabilizing container (3) is an aluminum container.

15. A method of manufacturing a package according to claim 12, wherein said method comprises the following step: - packaging together at least two kits (1) according to any one of claims 1 to 11, thereby obtaining the package according to claim 12.