Kit for stabilizing prostaglandin emulsions

Abstract

Kit (1) containing an oil-in-water emulsion (2) and a stabilizing container (3); wherein the oil-in-water emulsion (2) is contained in the stabilizing container (3); wherein the stabilizing container (3) is an aluminium container; and the 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.

Description

FIELD OF THE INVENTION

[0001] The invention relates to a kit containing a stabilizing container, wherein the stabilizing container contains 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 particularly useful for stabilizing emulsions for ophthalmic use. BACKGROUND OF THE INVENTION

[0002] Glaucoma causes damage to the optic nerve, leading to visual field loss, and remains the most common cause of irreversible blindness worldwide. Because the disease is generally progressive and irreversible, early detection and treatment are crucial to controlling its progression. Lowering intraocular pressure (IOP) is an effective way to prevent optic nerve damage. The estimated number of patients worldwide in 2020 was 76 million, and this is expected to rise to 95 million by 2030. Prostaglandin F 2alpha and analogues thereof are known for their effectiveness in reducing IOP. Latanoprost, in particular, reduces elevated IOP and is the most commonly prescribed prostaglandin analogue in Europe.

[0003] WO 2006 / 050836 A2 and WO 2007 / 042262 A2 (NOVAGALI PHARMA SA) disclose ophthalmic cationic oil-in-water 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 "ophthalmic 0.005% latanoprost solution" (Xalatan®, Pfizer, USA).

[0004] Ocular surface disease (OSD) represents an emerging problem in the management of glaucoma, with up to 60% of glaucoma patients experiencing dry eyes. OSD is a multifactorial ocular condition that can involve tear film degradation and ocular surface damage. It negatively impacts quality of life and impairs the maintenance of glaucoma eye drop treatment, which can affect the efficacy of the therapy.

[0005] WO 2011 / 061298 A1 (NOVAGALI PHARMA SA) discloses a composition comprising a prostaglandin F 2alpha or analogue, for use in the treatment of ocular surface conditions, including corneal and conjunctival lesions.

[0006] Although they provided a highly significant therapeutic improvement at the time, the ophthalmic use of prior art prostaglandin emulsions was limited by practical problems. Indeed, it has unfortunately been discovered that cationic oil-in-water emulsions comprising prostaglandins can be unstable upon storage, with the applicant, in particular, finding that exposure to light severely compromised the stability of such emulsions. Therefore, there remains a need for means to ensure stability, particularly photostability, of ophthalmic vehicles for prostaglandin delivery to the eye.

[0007] The applicant surprisingly found that conditioning a cationic oil-in-water emulsion comprising a prostaglandin in a stabilizing container, which is an aluminum container (in particular, an aluminum bag), effectively prevented destabilization of the emulsion. Stabilization of the emulsion can be estimated by measuring parameters such as, for example, pH, conductivity, amount of prostaglandin, and / or amount of impurities. Accordingly, the applicant hereby provides a kit according to the invention comprising an aluminum container in which the emulsion is conditioned. The invention paves the way for widespread use of cationic oil-in-water emulsions comprising prostaglandins for ocular treatment, 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 bag. According to one embodiment, the oil-in-water emulsion is further contained in a conditioning container placed within the stabilizing container. In one embodiment, the stabilizing container comprises at least two of the conditioning containers, preferably at least five of the conditioning containers. In one embodiment, the conditioning container is a polyethylene container and / or a unit-dose container, preferably a low-density polyethylene (LDPE) container.

[0010] According to one embodiment, the prostaglandin is selected from latanoprost, isopropylunoprostone, travoprost, bimatoprost, and mixtures thereof; wherein the prostaglandin is preferably 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 non-ionic 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, in weight percent based on 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, in weight percent based on the total weight of the oil-in-water emulsion. In one embodiment, the oil-in-water emulsion is an ophthalmic composition.

[0011] According to one embodiment, the oil-in-water emulsion is for use in the treatment of an ocular disease or condition; wherein the ocular disease or condition is preferably glaucoma, ocular hypertension, and / or 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] Furthermore, a method for producing a kit according to the invention is described, which method does not form part of the present invention, which method comprises the following step: conditioning an oil-in-water emulsion as defined hereinbefore in a stabilizing container and, optionally, a conditioning container, thereby obtaining the kit according to the invention; wherein the stabilizing container is an aluminum container.

[0014] Furthermore, a method for stabilizing an oil-in-water emulsion as defined hereinbefore is also described, which method comprises the following step: conditioning an oil-in-water emulsion as defined hereinbefore in a stabilizing container and, optionally, a conditioning container, whereby the oil-in-water emulsion is stabilized; wherein the stabilizing container is an aluminum container.

[0015] Furthermore, a method for producing a package according to the invention is also described, which method, however, is not part of the present invention, comprising the following step: packaging together at least two kits according to the invention, whereby the package according to the invention is obtained. DEFINITIONS

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

[0017] "Approximately" is used here to mean approximately, roughly, approximately, or within a range of. The term "approximately" before a number means plus or minus 10% of the value of the number. When used in conjunction with a range of numbers, the term "approximately" 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" are synonymous and refer to a compound for therapeutic use, as well as to health. Typically, an active ingredient has a pharmaceutical effect and / or may be indicated for treating or preventing a disease or condition, as defined below. Preferably, the active ingredient is for use in the treatment of an ocular disease or condition.

[0019] “Between [lower value] and [upper value]” and the like defines a range of numbers that excludes (i.e., does not include) both the upper value and the lower value.

[0020] "Droplet size" of an emulsion refers to the peak droplet size or the mean droplet size, preferably the peak droplet size, of the dispersed phase. Droplet size can be measured by methods known in the art, e.g., by light scattering after dilution in water using a high-performance particle sizer (such as a Zetasizer 2000 or a Zetasizer Nano ZS, Malvern Instruments, UK).

[0021] "Emulsion," according to common knowledge in the art, refers 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. Stability of an emulsion is typically achieved by incorporating at least one surfactant into the emulsion. The surfactant may, for example, be present in the surface of the droplets of the emulsion.

[0022] "Oil-in-water emulsion" refers to an emulsion where 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 for and / or suitable for administration into the eye of a subject. Typically, an ophthalmic composition has a pharmaceutical effect and / or may be indicated for treating an ocular disease or condition.

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

[0025] "Pharmaceutically acceptable" with respect to a substance or composition means 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 will not produce an adverse, allergic, or otherwise inappropriate reaction when administered to a subject, preferably a human. For administration to humans, compositions should meet sterility, pyrogenicity, general safety, and purity standards as required by regulatory authorities, such as the Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

[0026] "Pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable excipient, carrier, or vehicle. It includes any and 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 one active ingredient together with at least one pharmaceutically acceptable excipient. A pharmaceutical composition is 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 hereinafter. A pharmaceutical composition is preferred for use in the treatment of an ocular disease or condition.

[0028] "Prodrug" refers to an active ingredient that, after administration, is converted (i.e., metabolized) into a drug (i.e., an active ingredient) in the body. 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] "In a range from [lower value] to [upper value]" and other similar recitations define a numerical range that includes (i.e., encompasses) both the upper value and the lower value. Furthermore, any range so defined in the present application should be construed to include 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, more preferably a human. Preferably, the subject is a patient, i.e., a subject who is awaiting or receiving medical care, or who is or will be the subject of a medical procedure. Preferably, the subject is affected by an eye disease or condition.

[0033] "Topical administration" refers to the administration of a composition to the surface of an eye, such as the cornea or inner eyelid. Topical administration can be performed, for example, using an eye dropper.

[0034] "Treat" or "treatment" or "mitigation" refers to both therapeutic treatment and prophylactic or preventive measures, the goal being to prevent or slow (mitigate) the progression of the targeted disease or condition in a subject in need thereof. Those in need of treatment include those who already have the disease or condition, those predisposed to exhibiting 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 in one or more of the following: reduction in the number of pathogenic cells; reduction in the percentage of all cells that are pathogenic; relief, to some extent, of one or more of the symptoms associated with the particular disease or condition; reduced morbidity and mortality; and / or improvement in quality of life aspects. The foregoing parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician. Preferably, the treatment includes a step of administering an active agent as defined hereinabove.In the invention, the disease or condition is an ocular disease or 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 technique in the art for stabilizing an emulsion is to impart an electrostatic charge to the surface of the droplets of the dispersed phase, resulting in more droplet repulsion and less droplet coalescence. Colloidal particles dispersed in an emulsion are electrically charged due to their ionic and / or dipolar characteristics. This charge is referred to in the art as the "zeta potential" and reflects the degree of repulsion or attraction between particles. Zeta potential can be measured by methods known in the art, e.g., by measuring electrophoretic mobility using a zetameter (such as a Zetasizer 2000 or Zetasizer Nano ZS, Malvern Instruments, UK). Electrophoretic mobility is converted into zeta potential values ​​using the Smoluchowsky or Henry equation. DETAILED DESCRIPTIONKit

[0037] 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. Stabilizing container

[0038] The kit according to the invention comprises a stabilizing container forming an "intermediate container" or "secondary packaging" whose main function is to stabilize the oil-in-water emulsion contained therein, compared to an emulsion not contained in the stabilizing container.

[0039] In the invention, the stabilizing container provides stabilization of the emulsion. Advantageously, the stabilizing container provides photostability of the emulsion due to its opacity.

[0040] Advantageously, the emulsion is stabilized with respect to pH, for example, no significant decrease in the pH of the emulsion is observed during storage. Advantageously, the emulsion is stabilized with respect to conductivity, for example, no significant increase in the conductivity of the emulsion is observed during storage. Advantageously, the emulsion is stabilized with respect to the amount of active ingredient, i.e., prostaglandin (prostaglandin test), for example, no significant decrease in the amount of prostaglandin in the emulsion is observed during storage. Advantageously, the emulsion is stabilized with respect to the amount of impurities (impurities test), 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 with respect to pH, conductivity, amount of prostaglandin (prostaglandin test) and / or amount of impurities (impurities test).

[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, the applicant believes that a decrease in pH may be caused by the presence of acidic degradation products in the emulsion and / or by water loss in the emulsion (i.e., concentration of the emulsion). In one embodiment, the acidic degradation products comprise degradation product(s) of the prostaglandin (e.g., "acid-free latanoprost," which is the active ingredient of which latanoprost is a prodrug) and / or degradation product(s) of at least one excipient (e.g., at least one free fatty acid resulting from the degradation of medium-chain triglycerides (MCT)).Water loss may occur even when the emulsion is contained in a conditioning container (as described hereinafter), for example, water loss of an emulsion conditioned in an LDPE vial and not enclosed in a sealed bag may be up to 20% after about 3 years of storage under standard conditions. According to one embodiment, the water loss in the oil-in-water emulsion is equal to or less than about 5% (w / w), preferably equal to or less than about 1% (w / w), more preferably equal to or less than about 0.5% (w / w), more preferably equal to or less than about 0.1% (w / w), in weight percent based on the total weight of the oil-in-water emulsion (or in weight percent based on the total weight of water in the oil-in-water emulsion); after about 3 years of storage under standard conditions.

[0043] Stabilization of the emulsion can be estimated, for example, by a photostability test as described in Example 2 hereinafter.

[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, further 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 that define an enclosure configured to contain the emulsion. The stabilizing container is an aluminum container, meaning that at least a substantial portion, namely more than 50%, of the walls of the enclosure are covered by aluminum. For example, at least about 80%, or about 90%, or about 100% of a total surface area of ​​the walls of the enclosure is covered by aluminum. In the invention, "covered by aluminum" and the like includes embodiments wherein the walls are at least partially made of aluminum, such that a portion of their surface area is made of aluminum and is thereby covered by aluminum, or, in the case of a multi-layer enclosure, comprises at least one layer of aluminum. The surface covered by aluminum may be further covered by a protective layer, such as a protective film, to prevent damage to the aluminum.In the invention, "aluminum" in the stabilizing container is not limited to high-purity aluminum (i.e., "elemental" aluminum, referred to as "Al"), but also includes any aluminum-based material known in the art or commercially available that includes small amounts of impurities or additives necessary for the manufacture of the material, handling of the material, stability over time, etc. Aluminum can be in various forms such as, for example, sheets or coatings / coatings. For example, aluminum can be applied to internal and / or external surfaces of the walls, or incorporated into a layer within the walls of the container.

[0046] The parts of the stabilizing container which are not made of aluminum may, for example, be made of plastics (e.g. polymers, in particular 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 an aluminum / polyethylene container, i.e., a polyethylene-based container at least partially covered by aluminum (as defined hereinbefore). 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 covered by aluminum. In one embodiment, the walls of the enclosure of the stabilizing container comprise at least polyethylene terephthalate (PET), extruded ethylene / methacrylic acid copolymer ("EXTR.PE"), and aluminum ("ALU").

[0048] The stabilizing container can be in various forms such as, for example, bags (e.g., pouches, sachets, and the like), boxes, ampoules, bottles, cans, flasks, jars, vials, and the like. According to one embodiment, the stabilizing container is in a form selected from bags (e.g., pouches), boxes, bottles, cans, and jars. In a preferred embodiment, the stabilizing container is in the form of a bag. A bag can, for example, be made of two walls connected by a peripheral region which at least partially closes the bag around the enclosure. Typically, each of the walls can be formed from a flexible sheet, for example with a polygonal (especially rectangular) contour (including square sheets).Typically, the peripheral region extends along at least about 70%, or about 75%, or about 80% of the length of the side of the sheets. For example, if the sheets are rectangular, the peripheral region may extend along three sides of the sheets, preferably four sides of the sheets. Optionally, the bag may further comprise a third sheet, typically a folded sheet, joined along at least one side of each of the two sheets around the peripheral region, thereby increasing the internal volume of the bag.

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

[0050] According to a first embodiment, the stabilizing container is open, ie it includes at least one opening which represents a limited portion of the total surface area of ​​the container, such as, for example, less than about 30% or about 25% or about 20% of the total surface area of ​​the container.

[0051] According to a second embodiment, the stabilizing container is closed, i.e., it includes either no opening or only openings that represent a negligible proportion of the total surface area of ​​the stabilizing container, such as, for example, less than about 1%, or about 0.1%, or about 0.01% of the total surface area of ​​the stabilizing container. Preferably, a closed stabilizing container includes no opening. The stabilizing container can be closed by any method known in the art, such as, for example, by sealing the container. In one embodiment, the stabilizing container is sealed. The stabilizing container can be sealed by any method known in the art, such as, 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 a zipper, to allow storage in a closed configuration and temporary opening during use.

[0052] In one embodiment, the stabilizing container has a water vapor permeability equal to or less than about 0.50 g / m 2 .day, preferably equal to or lower than about 0.25 g / m 2 .day, more preferably equal to or lower than about 0.05 g / m 2 .day (at about 23°C and about 0% relative humidity (RH)). In one embodiment, the stabilizing container has an oxygen permeability equal to or less than about 0.50 cc / m 2 .day, preferably equal to or lower than about 0.25 cc / m 2 .day, more preferably equal to or lower than about 0.05 cc / m 2 .day (at about 38 °C and about 90% relative humidity (RH)). Conditioning container

[0053] According to one embodiment, the oil-in-water emulsion is further contained in a conditioning container, i.e., at least one conditioning container forming an "inner container" or "primary packaging" containing the emulsion is placed in the stabilizing container. In the invention, the conditioning container is used to condition the emulsion, which includes, for example, safely storing the emulsion until it is used (e.g., until ophthalmic treatment). Typically, the conditioning container encloses the emulsion so that the emulsion does not come into direct contact with the stabilizing container, which is advantageous in terms of safety and durability since the stabilizing container comprises aluminum. The conditioning container may have additional functions, such as, for example, enabling easy handling and / or administration of the emulsion (e.g.,if the conditioning container is an eye dropper) or maintaining the sterility of the emulsion.

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

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

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

[0057] In one embodiment, the conditioning container is a single-dose container (or "single-use container") or a multi-dose container (or "multi-use container"). In a preferred embodiment, the conditioning 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 conditioning container is an eye pipette or an eye 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 conditioning containers. In one embodiment, the stabilizing container contains at least five of the conditioning containers. In a preferred embodiment, the stabilizing container contains exactly five of the conditioning containers. In a preferred embodiment, the conditioning containers are bonded to one another, e.g., the conditioning containers together form a strip in which the containers are adjacent to one another in a transverse direction perpendicular to the direction of extension. Two adjacent containers of the strip are connected to one another by a separable line between corresponding outer surfaces of their walls so that they can be separated prior to use. Such a strip can be produced during the manufacturing process of the conditioning containers according to methods known in the art.

[0060] According to a preferred embodiment, the conditioning container is closed, i.e., it includes either no opening or only openings that represent a negligible proportion of the total surface area of ​​the conditioning container, such as, for example, less than about 1%, or about 0.1%, or about 0.01% of the total surface area of ​​the conditioning container. Preferably, a closed conditioning container includes no opening. The conditioning container can be closed by any method known in the art, such as, for example, blow-fill-seal (BFS) technology. BFS is an automated manufacturing process for plastic containers, wherein the containers are blow-molded, filled, and sealed; the three steps are carried out in a continuous operation. Oil-in-water emulsion

[0061] In the invention, the triglyceride oil is contained in the dispersed phase of the oil-in-water emulsion and the water is contained 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 water is the main component of the continuous phase. In this embodiment, according to common terminology in the art, it may be stated that the oil "is" the dispersed phase and water "is" the continuous phase, although the dispersed phase and the continuous phase may in fact comprise other components dissolved or suspended therein, such as, for example, active ingredients, surfactants, additives, etc.

[0063] Although it may be possible for some substances to qualify simultaneously as an oil, a cationic agent, and / or a non-ionic surfactant, in the emulsion according to the invention, the oil, the cationic agent, and the non-ionic surfactant refer to three different substances, i.e., in the emulsion of the invention, the "oil" component cannot simultaneously be 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 which fulfills at least the function of oil, another of which fulfills at least the function of non-ionic surfactant, and another of which fulfills at least the function of cationic agent.In other words, in the emulsion of the invention, the oil, the cationic agent and the non-ionic surfactant are different substances from each other.

[0064] According to one embodiment, the prostaglandin is selected from latanoprost, isopropylunoprostone, 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 latanoprost. In one embodiment, the emulsion comprises the prostaglandin in an amount ranging from about 0.001 to 0.02% (w / w), preferably from about 0.002 to 0.01% (w / w), more preferably about 0.005% (w / w), in weight percent based on the total weight of the emulsion.

[0065] According to one embodiment, the triglyceride oil in the emulsion is present in 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. According to one embodiment, the triglyceride oil is selected from short-chain triglycerides (i.e., C1-C5 triglycerides), medium-chain triglycerides (i.e., C6-C 12 triglycerides), long chain triglycerides (i.e. C 13 -C 21 triglycerides) or very long chain triglycerides (ie C 22 or longer, typically C 22 -C 34Triglycerides). In a particular embodiment, the triglyceride oil comprises medium-chain triglycerides (MCT). In a preferred embodiment, the triglyceride oil consists essentially of or consists of medium-chain triglycerides (MCT). MCT can be produced in particular from fractionated vegetable oils such as, for example, palm kernel oils or coconut oils. Typically, an MCT density is in a range of 0.93 to 0.96. In one embodiment, the emulsion comprises the oil in an amount in a range of about 0.2 to 2.5% (w / w), preferably from about 0.5 to 1.5% (w / w), more preferably about 1% (w / w), in weight percent based on 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). Polysorbates are ethoxylated sorbitan esters. In a particularly preferred embodiment, the non-ionic surfactant comprises Polysorbate 80, such as commercial grade "super-refined" Polysorbate 80. In a preferred embodiment, the non-ionic surfactant consists essentially of or consists of Polysorbate 80. According to 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 non-ionic surfactant in an amount ranging from about 0.01 to 0.2% (w / w), preferably from about 0.02 to 0.1% (w / w), more preferably about 0.05% (w / w), in weight percent based on the total weight of the emulsion.

[0067] According to one embodiment, the quaternary ammonium compound is selected from cetalkonium halide, benzalkonium halide, lauralkonium halide, cetrimide, hexadecyltrimethylammonium halide, tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide, cetrimonium halide, benzethonium halide, behenalkonium halide (or benzyldocosyldimethylammonium halide), cetethyldimonium halide, cetylpyridinium halide, benzododecinium halide, chlorallylmethenamine halide, myristalkonium halide (or benzyldimethyltetradecylammonium halide), stearalkonium halide, or mixtures thereof. In one embodiment, the quaternary ammonium compound comprises 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 ranging from about 0.001 to 0.02% (w / w), preferably from about 0.002 to 0.01% (w / w), more preferably about 0.005% (w / w), in weight percent based on the total weight of the emulsion.

[0068] According to one embodiment, the water is selected from tap water, saline (salt water), distilled water, and ultrapure water. The water can, for example, be "water for injection" (also known as aqua ad iniectabilia or aqua ad injectionem). In one embodiment, the emulsion comprises the water in an amount ranging from about 94 to 99% (w / w), preferably from about 95 to 98% (w / w), more preferably about 96.5% (w / w), in weight percent based on the total weight of the emulsion. In one embodiment, the emulsion comprises the water in an amount sufficient to reach 100% (w / w) based on the total amount of the emulsion components that are not water (in weight percent based on the total weight of the emulsion), which can be expressed as "qs water" ("sufficient 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 or glycerol), 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 from about 1 to 4% (w / w), more preferably about 2.4% (w / w), in weight percent 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, solubilizing agents, stabilizers, thickeners, 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, thimerosal, and mixtures thereof. In one embodiment, the emulsion is free of any preservative commonly used in pharmaceutical compositions (especially 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 comprising 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 the water.

[0073] In one embodiment, the oil-in-water emulsion comprises: at least one prostaglandin comprising 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 the water.

[0074] 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, and / or from about 0.2 to 2.5% (w / w) of the at least one oil, and / or from about 0.01 to 0.2% (w / w) of the at least one non-ionic surfactant, and / or from about 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 from about 94 to 99% (w / w) of the water (or qs water), in weight percent based on the total weight of the oil-in-water emulsion.

[0075] In one embodiment, the oil-in-water emulsion comprises: of about 0.001 to 0.02% (w / w) of 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 non-ionic 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 the water, preferably from about 94 to 99% (w / w) of the water (or qs water), in weight percent based on the total weight of the oil-in-water emulsion.

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

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

[0078] According to one embodiment, the emulsion has a droplet size in a range of about 125 to 300 nm, preferably in a range of about 150 to 275 nm, more preferably in a range of about 175 to 225 nm. A 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, dispersion of the oily phase by magnetic stirring or use of a homogenizer (e.g., 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 in a range of about 20 to 75 mV, preferably in a range of about 30 to 65 mV, more preferably in a range of about 40 to 55 mV. Incorporating a cationic agent into the emulsion (as described hereinabove) is one way to render it cationic by imparting a positive charge to it.

[0080] Advantageously, the emulsion has a conductivity in a range of about 5 to 35 µS / cm, preferably in a range of about 10 to 30 µS / cm, more preferably in a range of about 15 to 25 µS / cm.

[0081] Advantageously, the emulsion has an osmolarity in a range of about 200 to 350 mOsm / kg, preferably in a range of about 250 to 300 mOsm / kg, more preferably in a range of about 270 to 285 mOsm / kg.

[0082] Advantageously, the emulsion has a pH in a range of about 3.5 to 6, preferably in a range of about 4 to 5.5, more preferably in a range of about 4.5 to 5.

[0083] The emulsion of the invention can advantageously be sterilized 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 can be sterilized by heat or steam sterilization according to methods known in the art, preferably by heat sterilization. Other kit versions

[0084] 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 an adhesive label. In one embodiment, the kit further comprises instructions for use placed on and / or in the stabilizing container. In one embodiment, the instructions are for using the oil-in-water emulsion.

[0085] According to one embodiment, the kit further comprises at least one adhesive label. In one embodiment, the adhesive label is adhered to the stabilizing container and / or to the conditioning container, preferably to the conditioning container. According to one embodiment, the kit further comprises at least one print. In one embodiment, the print is applied to the stabilizing container and / or to the conditioning container, preferably to the stabilizing container. pack

[0086] The present invention also relates to a package comprising at least one or 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 package comprises at least one packaging container forming an “outer container” or “tertiary packaging” in which the kits are contained, such as, for example, bags, boxes, or the like.

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

[0089] According to one embodiment, the package further comprises at least one adhesive label. In one embodiment, the adhesive label is glued to the packaging container. According to one embodiment, the package further comprises at least one print. In one embodiment, the print is applied to the packaging container. Medical uses

[0090] According to one embodiment, the oil-in-water emulsion contained in the kit according to the invention, as described above, is for use as a medicament. According to one embodiment, the kit according to the invention, as described above, is for use as a medicament. According to one embodiment, the package according to the invention, as described above, is for use as a medicament.

[0091] According to one embodiment, the emulsion, kit and / or pack is 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, simplex glaucoma (also referred to as "open-angle glaucoma" or "chronic simple glaucoma"), glaucoma acutum (also referred to as "acute angle-closure glaucoma" or "acute angle-closure glaucoma"), or normal tension glaucoma. In a further preferred embodiment, the glaucoma is simplex glaucoma. In a particular embodiment, the ocular disease or condition is ocular hypertension.In a particular embodiment, the eye disease or condition is an 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 package is a medicament or a medical device.

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

[0095] According to one embodiment, the emulsion as described above is used in the manufacture of a medicament for treating an ocular disease or condition. According to one embodiment, the kit and / or package according to the invention as described above is used in the manufacture of a medicament for treating an ocular disease or condition. Method for preparing a kit and stabilization method

[0096] Further, a method for producing a kit according to the invention as described hereinabove is described, the method comprising the step of conditioning an oil-in-water emulsion as described hereinabove in a stabilizing container, thereby obtaining the kit according to the invention; wherein the stabilizing container is an aluminum container.

[0097] Further described is a method for stabilizing an oil-in-water emulsion as described hereinabove, the method comprising the step of: conditioning an oil-in-water emulsion as described hereinabove 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 conditioning container and the conditioning container is placed in the stabilizing container.

[0099] The method of manufacturing a kit may further comprise a step of conditioning the emulsion in at least one conditioning container.

[0100] Conditioning the emulsion may, for example, include a step of pouring the emulsion into the stabilizing container or conditioning container. Conditioning the emulsion may optionally include at least one sterilization step of the stabilizing container and / or conditioning container before and / or after the emulsion is placed in the container.

[0101] In the above methods, the oil-in-water emulsion, the stabilizing container, and / or the conditioning container may each independently be as described above in the embodiments of the kit according to the invention. "Stabilizing" has the same meaning as described above in the embodiments of the kit according to the invention. Method for producing a package

[0102] Further, a method for producing a package according to the invention as described hereinabove is described, the method comprising the step of: packaging together at least two kits according to the invention as described hereinabove, thereby obtaining the package according to the invention.

[0103] Packaging the kits may, for example, include a step of wrapping the kits together with tape, paper, polymer film, or the like. Packaging the kits may also, for example, include 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. BRIEF DESCRIPTION OF THE DRAWINGS Fig. Figure 1 is a drawing showing a kit 1 according to the invention containing an oil-in-water emulsion 2 contained in a stabilizing container 3. Fig. 2 is a drawing showing the kit of Fig. 1, with the upper part of the stabilizing container 3 removed. Fig. 3 is a drawing showing a detail of the kit of Fig. 1, namely an oil-in-water emulsion 2 contained in a conditioning container 4. Fig. Figure 4 is a drawing showing an embodiment of the invention, wherein the kit 1 contains five conditioning containers 4 which together form a strip 7. EXAMPLES

[0104] The invention is further illustrated by the following examples. Example 1: Oil-in-water emulsion and conditioning thereof Materials and methods

[0105] Materials: The components used to prepare the oil-in-water emulsions were purchased from commercial suppliers and used without further purification. The aluminum pouches (stabilizing containers) were made from sheets cut into a commercially purchased PET 12 µm / EXTR.PE 10 gsm / ALU 9 µm / EXTR.PE 30 gsm outer packaging (CONSTANTIA TOBEPAL, Spain).

[0106] Procedure - Heat sterilization: Heat sterilization is carried out according to Ph. Eur. 5.1.1 (e.g. European Pharmacopoeia Section 5.0, Section 5.1.1: “Procedures for manufacturing sterile products”) at a temperature of at least 121 °C for at least 15 min.

[0107] Method - Preparation of oil-in-water emulsions: The oily and water phases of the emulsion were prepared separately and heated to an appropriate temperature. The prostaglandin and the cationic agent were dissolved in the oily phase. The non-ionic surfactant was dissolved in the aqueous phase. An initial coarse emulsion was created 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 preparation using heat sterilization.

[0108] Process for conditioning the oil-in-water emulsions: After preparation, the emulsions were conditioned in low-density polyethylene (LDPE) vials (conditioning containers) using a conventional blow-mold-fill-seal (BFS) process. A strip of five polyethylene containers was then placed in an aluminum bag (stabilizing container), which was sealed by heat sealing. Some of the aluminum bags were then left open for comparison purposes. For comparison purposes, some of the polyethylene containers were not placed in bags. Results

[0109] The oil-in-water emulsion was prepared with the composition as shown in Table 1 below. Table 1 Em#1 ingredient function % (w / w) Oily 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

[0110] The oil-in-water emulsion Em#1 is contained in a number of polyethylene vials placed in an aluminum bag. The kit containing the oil-in-water emulsion Em#1 can be used as described in the Fig. 1-4 shown.

[0111] In the Fig. In the embodiment illustrated in Figure 1, the kit 1 contains an oil-in-water emulsion 2 and a stabilizing container 3 in the form of a rectangular bag containing the emulsion 2. The emulsion 2 is further contained in a conditioning container 4 placed within the stabilizing container 3. The stabilizing container 3 has two walls 5 connected by a peripheral region 6 that completely encloses the bag around the enclosure, thus closing the bag. In this embodiment, the emulsion 2 is stabilized, as demonstrated in Example 2 below.

[0112] In the Fig. In the embodiment illustrated in Figure 2, the upper portion of the stabilizing container 3 has been removed, leaving the bag open. In this embodiment, the emulsion 2 is still stabilized, as demonstrated in Example 2 below. Furthermore, the conditioning container 4 can be removed from the stabilizing container 3 so that the emulsion 2 can be administered to a subject in need (not shown).

[0113] In the Fig. In the embodiment shown in Figure 3, the emulsion 2 is contained in a conditioning container 4 in the form of a vial. The vial includes a housing, a neck, and a removable cap. The conditioning container 4 is also in the form of an eye dropper so that it can be used to deliver the emulsion 2 to the eye of a subject in need (not shown).

[0114] In the Fig.In the embodiment shown in Figure 4, the emulsion 2 is contained in five conditioning containers 4 in the form of vials. The five conditioning containers 4 together form a strip 7.

[0115] After preparation (T0), the oil-in-water emulsion Em#1 had the physical and chemical properties as given in Example 2 below. Example 2: Photostability tests

[0116] In this example, the properties of an oil-in-water emulsion Em#1, stored without a bag, in an open aluminum bag, or in a closed aluminum bag, are analyzed. Materials and processes

[0117] Materials: Mettler Toledo pH and conductivity meters, Roebling 13 / 13 / DR microosmometer or type 16 solvent, and Malvern ZetaSizer Nano ZS.

[0118] Method -pH and conductivity measurement: The test is carried out according to Ph. Eur. 2.2.3 (e.g. European Pharmacopoeia section 5.0, 2.2.3: “Potentiometric determination of pH”) using a potentiometric method and the Mettler Toledo pH and conductivity meter at a temperature of 20 to 25 °C.

[0119] Procedure - Osmolarity measurement: The test is performed according to Ph. Eur. 2.2.35 (e.g. European Pharmacopoeia 7.3, Section 2.2.35: “Osmolality”) using a cryoscopic method and the microosmometer.

[0120] Procedure - Zeta Potential Measurement: The zeta potential of the emulsion droplet is determined by measuring electrophoretic mobility using the Malvern ZetaSizer Nano ZS. A measurement is performed on a sample of the emulsion diluted 1:250 in deionized water.

[0121] Method - Droplet Size Measurement: The droplet diameter of the oil droplet is determined by dynamic light scattering using the Malvern ZetaSizer Nano ZS. A measurement is performed on a sample of the emulsion diluted 1:20 in deionized water.

[0122] Procedure - Prostaglandin Test: Determination of the amount of prostaglandin (specifically latanoprost) is performed by high-performance liquid chromatography (HPLC) under reversed-phase conditions using a C18 silica column as the stationary phase and UV detection. Samples are prepared by simple dilution in deionized water.

[0123] Method - Impurity Test: Determination of impurities (including prostaglandin degradation products) is performed by high-performance liquid chromatography (HPLC) under normal-phase conditions using a pure silica column as the stationary phase and UV detection. Samples are prepared by solid-liquid extraction (solid-phase extraction or SPE). ResultsPhysical Tests

[0124] The physical properties of the oil-in-water emulsion were as shown in Table 2 below. Table 2 Physical tests T0 Placed in bag Open Without bag Appearance Milky-white liquid PH value 4,5 4,5 4,5 3,9 Conductivity (µS / 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 (nm) 213 209 206 209 PdI 0.066 PdI 0.054 PdI 0.119 PdI 0.095

[0125] The physical properties of the oil-in-water emulsion Em#1 remain stable when the emulsion is placed in the conditioning containers in pouches, even when the pouch is opened. In contrast, they change significantly when the emulsion is not placed in pouches: pH decreases (approximately 13%) and conductivity increases significantly (approximately 150%). Osmolality, zeta potential, and droplet size remain relatively stable whether the emulsion is placed in pouches or not. Therefore, both the open and closed aluminum pouches stabilize the emulsion Em#1. Prostaglandin test

[0126] The results of the prostaglandin test are shown in Table 3 below. Table 3 Latanoprost T0 Placed in bag Open Without bag Weight (mg) 500,79 499,44 498,63 499,84 Test (% (w / w)) 0,00525 0,00526 0,00524 0,00502

[0127] The prostaglandin tests were repeated once. The values ​​presented in Table 3 above are the mean values ​​obtained from the two tests.

[0128] The amount of latanoprost in the oil-in-water emulsion Em#1 remains stable when the emulsion is dispensed into the conditioning containers in pouches, even when the pouch is opened. In contrast, it decreases significantly when the emulsion is not dispensed into the pouch (approximately 4% decrease). Therefore, both the open and closed aluminum pouches stabilize the emulsion Em#1. Test for contamination

[0129] The results of the impurity test are shown in Table 4 below. Table 4 Contaminants (Name) RRT T0 Placed in bag Open Without bag 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 Acid-free latanoprost / 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 Unknown 0,49 <LOQ <LOQ <LOQ 0,20 Unknown 1,30 ND ND ND 0,15 Unknown 1,38 ND ND ND 0,16 Total known impurities (% (w / w)) 0,63 0,57 0,61 1,8 Total unknown impurities (% (w / w)) 0,16 0,16 0,16 1,1 Total impurities (% w / w) 0,79 0,73 0,77 2,9

[0130] " <LOQ“ bedeutet „Bestimmungsgrenze“ und „ND“ bedeutet „nicht nachgewiesen“.

[0131] The amount of impurities in the oil-in-water emulsion Em#1 remains relatively stable when the emulsion is placed in bags in the conditioning containers, even when the bags are opened. In contrast, it increases significantly when the emulsion is not placed in bags, with a more than threefold increase. Therefore, both the open and closed aluminum bags stabilize the emulsion Em#1. QUOTES CONTAINED IN THE DESCRIPTION

[0000] This list of documents submitted by the applicant was generated automatically and is included solely for the convenience of the reader. This list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions. Cited patent literature

[0000] WO 2006 / 050836 A

[0003] WO 2007 / 042262 A2

[0003] WO 2011 / 061298 A1

[0005]

Claims

[1] Kit (1) containing an oil-in-water emulsion (2) and a stabilizing container (3); wherein the oil-in-water emulsion (2) is contained in the stabilizing container (3); wherein the stabilizing container (3) is an aluminum container; and wherein the 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] Kit according to claim 1, wherein the stabilizing container (3) is in the form of a bag. [3] Kit according to claim 1 or claim 2, wherein the oil-in-water emulsion (2) is further contained in a conditioning container (4) placed in the stabilizing container (3). [4] Kit according to claim 3, wherein the stabilizing container (3) comprises at least two of the conditioning containers (4). [5] Kit according to claim 4, wherein the stabilizing container (3) comprises at least five of the conditioning containers (4). [6] Kit according to one of claims 1 to 5, wherein the conditioning container (4) is a polyethylene container. [7] Kit according to claim 6, wherein the conditioning container (4) is a low density polyethylene (LDPE) container. [8] Kit according to any one of claims 1 to 7, wherein the conditioning container (4) is a single-dose container. [9] Kit according to any one of claims 1 to 8, wherein the prostaglandin is selected from latanoprost, isopropylunoprostone, travoprost, bimatoprost, and mixtures thereof. [10] Kit according to any one of claim 9, wherein the prostaglandin is latanoprost. [11] Kit according to any one of claims 1 to 10, wherein the 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 the water. [12] Kit according to any one of claims 1 to 11, wherein the oil-in-water emulsion (2) comprises: of about 0.001 to 0.02% (w / w) of 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 non-ionic 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, in weight percent based on the total weight of the oil-in-water emulsion. [13] Kit according to any one of claims 1 to 12, wherein the oil-in-water emulsion (2) 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, in percent by weight based on the total weight of the oil-in-water emulsion. [14] Kit according to any one of claims 1 to 13, wherein the oil-in-water emulsion (2) is an ophthalmic composition. [15] A kit according to any one of claims 1 to 14, wherein the oil-in-water emulsion (2) is for use in the treatment of an ocular disease or condition. [16] Kit according to claim 15, wherein the oil-in-water emulsion (2) is for use in the treatment of glaucoma, ocular hypertension and / or ocular surface disease. [17] A package comprising at least two kits (1) according to any one of claims 1 to 16. [18] A package according to claim 17, wherein the package comprises 6, 12, 18 or 24 kits (1).

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