EA042509B1 - OPHTHALMIC DOSING DEVICE - Google Patents

Description

Technical field

The present invention relates to a dosing device containing an ophthalmic liquid composition containing a prostaglandin analogue.

State of the art

Prostaglandins or prostaglandin analogs are well-known active ingredients commonly administered topically to humans or animals in the form of eye drops for the treatment of glaucoma, and a number of prostaglandin analogs have been researched and developed.

However, some prostaglandin analogs are slightly soluble in water and tend to adsorb to any part of the dispenser that comes into contact with the solution. This phenomenon is especially important at low concentrations, since the required amount of active ingredient cannot be guaranteed to be delivered for some time.

Indeed, if the active ingredient reacts, reversibly or not, with one of the constituent materials of the device, then when it comes into contact with it, its concentration in solution decreases and may become too low to have an optimal therapeutic effect.

One way to solve this problem is to modify the composition of the solution to make the solution stable and inert to the material of the storage and distribution device, even at low concentrations.

Many types of dispensers are currently available on the market, comprising dispensers having various parts such as a valve base, a control valve, an air entrainment element, a filter element, a filter element holder, and so on. These parts can be made from different materials and thus it is difficult to adapt the composition of the solution to all materials of the device in contact with the solution.

For liquid formulations containing prostaglandin analogues exhibiting such disadvantages as mentioned above, it is necessary to improve the situation of adsorption to the dispenser and solubility in water.

Several proposals are known from prior art documents for solving the problem of adsorption of prostaglandin analogues.

WO2002/22106 A1 describes that prostaglandin can be stably stored in a resin container containing polypropylene.

WO2005/011704 A1 describes that prostaglandin can be stably stored in a resin container made from a polymer alloy of polyethylene terephthalate and polyarylate.

WO2010/100656 describes a method for stable storage of a pharmaceutical composition containing prostaglandin(s), wherein the method comprises the step of storing the prostaglandin composition in a polyethylene container, preferably low density polyethylene (LDPE), even more preferably an LDPE container having Purell PE 3020 resin. D, which is made using the technology of blowing-packing-sealing (Blow Fill Seal (BFS)).

WO2013038120 describes a device for storing and dispensing a pharmaceutical liquid, comprising, on at least part of the internal surface of the device, a coating that reduces the adsorption of at least one of the components of the liquid.

However, not only the container, but also other parts of the dosing device that are also in contact with the liquid composition have not been examined.

WO2002/022131 describes an invention wherein the water solubility and adsorption to the resin container of the prostaglandin analog is increased by incorporating a non-ionic surfactant and/or an antioxidant in the ophthalmic solution.

WO2009/145356 relates to a preservative-free ophthalmic composition containing PGF2-alpha analogs, a non-ionic surfactant, a stabilizer, in a container essentially consisting of polyethylene. Specific excipients are required to stabilize the solution.

Thus, there is a need in the art for a device for storing and dispensing ophthalmic liquid compositions containing a prostaglandin analog that provides the ability to guarantee the content of the active ingredient in solution for a given time interval without adapting the solution composition to different device materials.

Description of the invention

The inventor of the present invention has observed that for a dispenser device which includes a container, a dispenser and a seal between the dispenser and the container, the above methods for eliminating the adsorption of prostaglandin analogues are not effective. The adsorption of these active substances adversely affects the content, despite the presence of surfactants and container materials, as described in the documents of the prior art.

The problem solved by the present invention is to provide a dosing device comprising a container with an ophthalmic liquid composition containing a prostaglandin analog packaged therein, a dispenser and a seal that prevents a decrease in the concentration of the prostaglandin analog in the liquid composition.

Dispensing devices currently available on the market contain a gasket having a plasticizer such as ethylene vinyl acetate (Evatane®).

- 1 042509

The first aspect of the present invention relates to a dispensing device containing a container with an ophthalmic liquid composition containing a prostaglandin analogue packaged therein, a dispenser and a sealing gasket, where the said sealing gasket is made of a polymer essentially free of ethylene vinyl acetate.

Another aspect of the present invention relates to a dispensing device comprising a container of an ophthalmic liquid composition containing a prostaglandin analogue packaged therein, a dispenser and a sealing liner, wherein said sealing liner is made from a polymer substantially free of plasticizer.

Another aspect of the present invention relates to a seal for a dispenser according to any of the preceding aspects, wherein said seal is made from a polymer substantially free of ethylene vinyl acetate.

Another aspect of the present invention relates to a seal for a dispenser according to any of the preceding aspects, wherein said seal is made from a substantially plasticizer-free polymer.

Another aspect of the present invention relates to a dispenser for a dispenser according to any of the preceding aspects, comprising a sealing gasket made from a polymer substantially free of ethylene vinyl acetate.

Another aspect of the present invention relates to a dispenser for a dispenser according to any of the preceding aspects, comprising a gasket made from a polymer substantially free of plasticizer.

Another aspect of the present invention relates to a dispensing device for an ophthalmic liquid composition containing a prostaglandin analogue, comprising:

a container for an ophthalmic liquid composition;

dispenser; and a sealing gasket wherein the sealing gasket is made of a polymer substantially free of ethylene vinyl acetate.

Another aspect of the present invention relates to a dosing device for an ophthalmic liquid composition containing a prostaglandin analogue, comprising;

a container for an ophthalmic liquid composition;

dispenser; and a sealing gasket, where the sealing gasket is made of a polymer substantially free of plasticizer.

Another aspect of the present invention relates to a dispensing device comprising a container with a preservative-free ophthalmic aqueous solution containing a prostaglandin analog packaged therein, a dispenser and a seal, said seal being made from a polymer substantially free of ethylene vinyl acetate.

Another aspect of the present invention relates to a preservative-free aqueous ophthalmic solution containing latanoprost optionally in combination with timolol or a pharmaceutically acceptable salt thereof, polysorbate 80, disodium edetate, a tonicity adjusting agent, a buffering agent, optionally a pH adjusting agent and water as solvent.

By dispensing device is meant a drug delivery system for storing and dispensing a therapeutic solution, and is also referred to herein as a device or dispenser.

A dispenser, as described herein, is also to be understood as a closure system which is suitable for ejection or distribution of individual liquid droplets.

A sealing gasket, also called an o-ring or disc, sits between the container and dispenser to seal the connection. The sealing gasket can either be inserted into the dispenser or fixed to the top of the container neck.

As used herein, the term ophthalmic liquid composition refers to various dosage forms suitable for topical ophthalmic delivery or eye drops, including solutions, suspensions, emulsions, reconstitution powders, gels, and erodible solid ophthalmic inserts. In a specific embodiment, the term ophthalmic liquid composition refers to a solution.

As used in the context of the invention, the term essentially free of gasket refers to a gasket made from a polymer that does not include ethylene vinyl acetate or a plasticizer, or that contains less than 5%, preferably less than 4%, more preferably less than 3%, more preferably less than 2%, more preferably less than 1%, and even more preferably 0% ethylene vinyl acetate or plasticizer.

As used within the scope of the invention, the term substantially free gasket refers to a gasket made from a polymer that does not include ethylene vinyl acetate or a plasticizer, or in which it is in such a low concentration that it does not exhibit its adsorption effect.

The inventors of the present invention surprisingly discovered that the stability in terms of undesirable adsorption of the active substance of an ophthalmic liquid composition containing an analog

- 2 042509 prostaglandin, in a dosing device with a seal made of a polymer essentially free of ethylene vinyl acetate or a plasticizer, unexpectedly increased compared to the same composition in devices with a seal made of a polymer with a plasticizer.

In addition, the present inventors have found that the adsorption of prostaglandin in the dosing device can be prevented to a great extent. Testing in the assay confirmed that the prostaglandin product, which was stored in a dispenser of the invention with a seal substantially free of plasticizer or ethylene vinyl acetate, met the specifications both at release and at the end of the shelf life (e.g., HPLC analysis demonstrates 95-105% at the time of release and 90-105% at the end of the shelf life). Additional lab testing confirmed that the absence of a plasticizer or ethylene vinyl acetate in the gasket does not surprisingly adversely affect packing density.

In the present description, as well as in the claims, it is understood that expressions in the singular form also include the plural form, unless the context clearly indicates otherwise. Moreover, the numerical values preceded by the term approximately are intended to include the exact indicated value as well as a certain deviation from such a value, namely, a deviation of ±5% from the indicated value. It is understood that the numerical ranges defined by the lower and upper limits also include the indicated limits.

Detailed description of the invention

All terms as used within the scope of the invention in this application, unless otherwise indicated, should be understood in their usual meaning, known in this field. Other more specific definitions for certain terms used in this application are as described below and are intended to apply uniformly throughout the description and claims, unless another express definition provides a broader definition.

The invention relates to a dispensing device comprising a container with an ophthalmic liquid composition containing a prostaglandin analogue packed therein, a dispenser and a sealing gasket made from a polymer substantially free of ethylene vinyl acetate.

In addition, the invention relates to a dispensing device comprising a container with an ophthalmic liquid composition containing a prostaglandin analogue packaged therein, a dispenser and a sealing liner made of a polymer substantially free of plasticizer.

Part of the invention also relates to a seal for a dispenser according to any of the preceding aspects, where it is made from a polymer substantially free of ethylene vinyl acetate.

In addition, the invention relates to a seal for a dispenser according to any of the preceding aspects, where it is made from a polymer substantially free of plasticizer.

The invention also relates to a dispenser for a dispenser according to the invention, comprising a seal made from a polymer substantially free of ethylene vinyl acetate.

Moreover, it relates to a dispenser for a dispenser according to any of the preceding aspects, comprising a seal made from a polymer substantially free of plasticizer.

The invention also relates to a preservative-free ophthalmic solution containing latanoprost, optionally in combination with timolol or a pharmaceutically acceptable salt thereof, polysorbate 80, disodium edetate, a tonicity adjusting agent, a buffering agent, an optional pH adjusting agent, and water as solvent.

As shown in Comparative Stability Tests 1, 2, 5, and 6 (Tables 1, 2, 5, and 6), surprisingly, the ophthalmic liquid compositions tested, prostaglandin analog content (latanoprost, travoprost, or tafluprost), were more stable when stored. in a dispenser containing a gasket that was made from a polymer substantially free of ethylene vinyl acetate or any other plasticizer, compared to equivalent formulations stored in dispensers with a gasket made from PE/EVA that contains ethylene vinyl acetate ( EVA).

In a first embodiment of the present invention, optionally in combination with one or more of the features of the various embodiments described above or below, the dispenser comprises an ophthalmic liquid composition containing a prostaglandin analog packaged in a container, wherein the prostaglandin analog is a prostaglandin F2a analog. In a preferred embodiment, the prostaglandin F2a analog is selected from esters of prostaglandin F2a analogs. In a more preferred embodiment, a complex

- 3 042509 Prostaglandin F2a analogue ester is selected from the group consisting of latanoprost, travoprost and tafluprost.

The adsorption phenomenon is especially important for esters of prostaglandin F2a analogues.

In another embodiment of the present invention, optionally in combination with one or more of the features of the various embodiments described above or below, the dosing device as described herein comprises an ophthalmic liquid composition that contains a prostaglandin analogue at a concentration of up to 100 micrograms/milliliter .

The adsorption phenomenon is especially important at low concentrations (eg, up to 100 micrograms/milliliter of active ingredient) because the delivery of the required amount of active ingredient over time is not guaranteed and the optimal therapeutic effect cannot be ensured.

In a preferred embodiment of the present invention, optionally in combination with one or more of the features of the various embodiments described above or below, a dispenser is provided wherein the ophthalmic liquid composition is preferably an aqueous solution, emulsion or suspension, and more preferably an aqueous solution.

The most commonly used ophthalmic dosage forms are solutions.

The ophthalmic liquid composition of the invention may also contain conventional excipients used in ophthalmic compositions such as surfactants, antioxidants, tonicity agents, buffering agents, and the like.

The term surfactant refers to a compound that reduces surface tension between two liquids or between a liquid and a solid. Materials commonly used as surfactants include: (a) non-ionic surfactants such as polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, glycerol monostearate, polyethylene glycols, acetyl alcohol, cetostearyl alcohol, stearic alcohol and poloxamers; (b) anionic surfactants such as potassium laurate, triethanolamine stearate, sodium lauryl sulfate and alkyl polyoxyethylene sulfates; and (c) cationic surfactants such as chitosans; and their mixtures.

In one embodiment of the present invention, optionally in combination with one or more features of the various embodiments described above or below, the dispenser comprises an ophthalmic liquid composition further comprising a surfactant. In a preferred embodiment, the surfactant is a non-ionic surfactant to solubilize and prevent adsorption of prostaglandin analogs to the dosing device. In a more preferred embodiment, the non-ionic surfactant is selected from the group consisting of polysorbate 80, polysorbate 60, polysorbate 40, poly(oxyethylene)sorbitan monolaurate, poly(oxyethylene)sorbitan trioleate, polysorbate 65, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 40, polyoxyl 40 stearate, and mixtures thereof. Neon surfactants can be used alone or in combination. In an even more preferred embodiment, the nonionic surfactant is Polysorbate 80 or Polyoxyethylene Hydrogenated Castor Oil 40.

The term antioxidant refers to a compound that prevents the oxidation of other molecules. Examples of a suitable antioxidant include ethylenediaminetetraacetic acid (also known as edetic acid) and its salts (eg, disodium edetate), dibutylhydroxytoluene, and the like.

The term tonicity adjusting agent refers to a compound designed to reduce local irritation by preventing osmotic shock at the site of application. Examples of the tonicity adjusting agent include sodium chloride, potassium chloride, calcium chloride, propylene glycol, glycerin, sorbitol, mannitol, and the like.

The term buffering agent refers to a substance capable of neutralizing both acids and bases in a solution and thereby maintaining the original acidity or basicity of the solution. Specific examples of buffers include, but are not limited to, boric acid, sodium tetraborate, citric acid, sodium hydrogen phosphate, s-aminocaproic acid, and the like.

As is well known to the person skilled in the art, a buffering agent is a system, usually consisting of an acid and its conjugate base. The preparation of buffer agents is well known, thus, for example, a phosphate buffer is generally prepared as a mixture of dihydrogen phosphate ion and hydrogen phosphate, for example using sodium dihydrogen phosphate (NaH ₂ PO ₄ , or sodium monophosphate) preferably sodium dihydrogen phosphate monohydrate

- 4 042509 (NaH ₂ PO ₄ H ₂ O), and sodium hydrogen phosphate (Na ₂ HPO ₄ , or sodium diphosphate). Similarly, an acetate buffer can be made with acetic acid and sodium acetate; citrate buffer can be made with citric acid and sodium citrate; or a borate buffer can be prepared, for example, with boric acid and disodium tetraborate.

The method for preparing eye drops containing a prostaglandin analogue may be any conventional method of preparation without the need for a specific procedure or operation. The pH of the eye drop solution according to the invention is preferably adjusted to a value of 3 to 8, in particular 4 to 7. As pH adjusting agents, conventional pH agents such as sodium hydroxide and/or hydrochloric acid can be used.

In another embodiment of the present invention, optionally in combination with one or more features of the various embodiments described above or below, the dosing device preferably contains a preservative-free ophthalmic liquid composition.

As used herein, a preservative-free ophthalmic solution means an ophthalmic solution of the present invention that does not contain a preservative such as quaternary ammonium salts, eg benzalkonium chloride (BAC). Other pharmaceutically acceptable preservatives for ophthalmic solutions are, for example, boric acid-polyol zinc chloride or chlorine oxide compounds, chlorhexidine gluconate, benzethonium chloride, sorbic acid, potassium sorbate, ethyl p-hydroxybenzoate and butyl p-hydroxybenzoate.

One of skill in the art will appreciate that any substance known to provide a preservative effect should be excluded in this context, regardless of any other function the substance may concurrently have in a liquid formulation.

Preservatives are often added to ensure that the solution is sterile after the device is first opened. However, these preservatives, which may contribute to the solubilization of the active ingredient and its stabilization in solution, are currently not recommended as they may be toxic and have tolerability problems, especially in the context of long-term treatment, for example in glaucoma. Thus, a preservative-free liquid composition is preferred within the scope of the present invention. Thus, the solubilization of the active ingredient and its stability in the device is likely to deteriorate.

In one embodiment, the ophthalmic liquid composition contained in the dispenser of the invention is an aqueous solution containing latanoprost as the active ingredient, the non-ionic surfactant Polysorbate 80, disodium edetate as an antioxidant, a tonicity agent, and a buffering agent.

In a preferred embodiment, said ophthalmic liquid composition is an aqueous solution containing:

latanoprost at a concentration in the range of 0.010-0.100 mg/ml, preferably in the range of 0.020-0.080 mg/ml, more preferably in the range of 0.030-0.070 mg/ml, even more preferably in the range of 0.040-0.060 mg/ml, even more preferably at a concentration of approximately 0.050 mg/ml, and even more preferably at a concentration of 0.050 mg/ml;

polysorbate 80 at a concentration in the range of 0.1-10.0 mg/ml, preferably in the range of 0.1-5.0 mg/ml, more preferably in the range of 0.2-1.0 mg/ml, even more preferably in the range of 0.30-0.70 mg/ml, even more preferably in the range of 0.40-0.60 mg/ml, even more preferably at a concentration of 0.50 mg/ml, and even more preferably 0.50 mg /ml;

disodium edetate at a concentration in the range of 0.1-0.5 mg/ml, preferably in the range of 0.1-0.4 mg/ml, more preferably at a concentration of about 0.2 mg/ml, and even more preferably 0 .2 mg/ml;

a tonicity adjusting agent in an amount sufficient to correct the osmolarity to a value in the range of 250-320 mosmol/kg, preferably wherein the tonicity adjusting agent is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, propylene glycol, glycerol, sorbitol, mannitol and mixtures thereof, and more preferably the tonicity agent is sodium chloride; and an ophthalmologically acceptable buffer, preferably selected from acetate, citrate, phosphate and borate buffers, more preferably phosphate buffer;

optionally a pH adjusting agent such as hydrochloric acid and/or sodium hydroxide to adjust the pH of the solution to a value in the range of 5.5-6.5, preferably in the range of 5.8-6.2, more preferably up to about 6.0 ; and water as a solvent;

where, more preferably, the tonicity agent is sodium chloride in an amount in the range of 1.0-9.0 mg/ml; preferably in the range of 4.0-6.0 mg/ml; more preferably in the range of 4.0-5.0 mg/ml, and even more preferably in an amount of about 4.6 mg/ml.

- 5 042509

It is understood that said aqueous composition has a pH value in the range of 5.5-6.5, preferably in the range of 5.8-6.2, more preferably about 6.0, and even more preferably the pH is 6.0. The use of these buffering agents may be sufficient to achieve the desired pH, or it may be necessary to add an additional pH adjusting agent in general and an acid and/or base, such as hydrochloric acid and/or sodium hydroxide, to adjust the pH to the desired value. .

Preferably, said composition is free of preservatives. In some embodiments, the ophthalmic composition contained in the dispenser of the invention is an aqueous solution that essentially consists of latanoprost, polysorbate 80, sodium edetate, a tonicity agent, a buffer system, optionally a pH adjusting agent, and water as solvent according to the advantageous features described above.

In a further embodiment of the present invention, optionally in combination with one or more of the features of the various embodiments described above or below, the dosing device comprises an ophthalmic liquid composition comprising a prostaglandin analog in combination with at least one additional pharmaceutically active agent, preferably a β-blocker , more preferably timolol or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the ophthalmic liquid composition contains a combination of latanoprost and timolol or a pharmaceutically acceptable salt thereof as active ingredients. A preferred pharmaceutically acceptable salt of timolol is timolol maleate.

In one embodiment, the ophthalmic liquid composition contained in the dispenser of the invention is an aqueous solution containing latanoprost and timolol or a pharmaceutically acceptable salt thereof as active ingredients, a non-ionic surfactant Polysorbate 80, disodium edetate as an antioxidant that regulates tonicity. substance and buffer substance.

In a preferred embodiment, said ophthalmic liquid composition is an aqueous solution containing:

latanoprost at a concentration in the range of 0.010-0.100 mg/ml, preferably in the range of 0.020-0.080 mg/ml, more preferably in the range of 0.030-0.070 mg/ml, even more preferably in the range of 0.040-0.060 mg/ml, even more preferably at a concentration of approximately 0.050 mg/ml, and even more preferably at a concentration of 0.050 mg/ml;

timolol or a pharmaceutically acceptable salt thereof, preferably timolol maleate, at a concentration in the range of 1-10 mg/ml, preferably in the range of 2-8 mg/ml, more preferably in the range of 3-7 mg/ml, even more preferably in the range 4-6 mg/ml, even more preferably at a concentration of about 5.0 mg/ml and even more preferably at a concentration of 5.0 mg/ml;

polysorbate 80 at a concentration in the range of 0.1-10.0 mg/ml, preferably in the range of 0.1-5.0 mg/ml, more preferably in the range of 0.2-1.0 mg/ml, even more preferably in the range of 0.30-0.70 mg/ml, even more preferably in the range of 0.40-0.60 mg/ml, even more preferably at a concentration of 0.50 mg/ml, and even more preferably at a concentration of 0, 50 mg/ml;

disodium edetate at a concentration in the range of 0.1-0.5 mg/ml; preferably in the range of 0.1-0.4 mg/ml; more preferably at a concentration of about 0.2 mg/ml, and even more preferably at a concentration of 0.2 mg/ml;

tonicity agent in an amount sufficient to adjust the osmolarity to a value in the range of 250-320 mosmol/kg, preferably wherein the tonicity agent is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, propylene glycol, glycerol, sorbitol, mannitol and mixtures thereof, and more preferably the tonicity agent is sodium chloride;

an ophthalmologically acceptable buffer, preferably selected from acetate, citrate, phosphate and borate buffers, more preferably a phosphate buffer;

optionally a pH adjusting agent such as hydrochloric acid and/or sodium hydroxide to adjust the pH of the solution to a value in the range of 5.5-6.5, preferably in the range of 5.8-6.2, more preferably up to about 6.0 ; and water as a solvent.

When timolol is used as its pharmaceutically acceptable salt, these preferred concentrations refer to an equivalent amount of timolol.

Preferably, the composition is free of preservatives. In one embodiment, the ophthalmic composition contained in the dispenser of the invention is an aqueous solution which essentially consists of latanoprost, timolol or a pharmaceutically acceptable salt thereof, polysorbate 80, sodium edetate tonicity adjusting agent, a buffer system optionally adjusting the pH of the substance and water as solvent, in the preferred embodiments and amounts described above.

- 6 042509

As shown in the examples, namely stability tests 3 and 4, the resulting aqueous ophthalmic solutions of latanoprost, containing a very low concentration of surfactant (polysorbate 80) and antioxidant (disodium edetate), which are free of preservatives, unexpectedly were not only very stable in terms of the amount of latanoprost, and the amount of impurities was remarkably low (see Tables 2 and 3). Thus, another aspect of the invention relates to a preservative-free ophthalmic solution containing:

latanoprost at a concentration in the range of 0.010-0.100 mg/ml, preferably in the range of 0.020-0.080 mg/ml, more preferably in the range of 0.030-0.070 mg/ml, even more preferably in the range of 0.040-0.060 mg/ml, even more preferably at a concentration of approximately 0.050 mg/ml, and even more preferably at a concentration of 0.050 mg/ml;

optionally, timolol or a pharmaceutically acceptable salt thereof, preferably timolol maleate, at a concentration in the range of 1-10 mg/ml, preferably in the range of 2-8 mg/ml, more preferably in the range of 3-7 mg/ml, even more preferably in the range of 4-6 mg/ml, even more preferably at a concentration of about 5.0 mg/ml and even more preferably at a concentration of 5.0 mg/ml;

polysorbate 80 at a concentration in the range of 0.1-10.0 mg/ml, preferably in the range of 0.1-5.0 mg/ml, more preferably in the range of 0.2-1.0 mg/ml, even more preferably in the range of 0.30-0.70 mg/ml, even more preferably in the range of 0.40-0.60 mg/ml, even more preferably at a concentration of 0.50 mg/ml, and even more preferably at a concentration of 0, 50 mg/ml;

disodium edetate at a concentration in the range of 0.1-0.5 mg/ml, preferably in the range of 0.1-0.4 mg/ml, more preferably at a concentration of about 0.2 mg/ml, and even more preferably at concentration 0.2 mg/ml;

tonicity agent in an amount sufficient to adjust the osmolarity to a value in the range of 250-320 mosmol/kg, preferably wherein the tonicity agent is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, propylene glycol, glycerol, sorbitol, mannitol and mixtures thereof, and more preferably the tonicity agent is sodium chloride;

an ophthalmologically acceptable buffer, preferably selected from acetate, citrate, phosphate and borate buffers, more preferably a phosphate buffer;

optionally a pH adjusting agent such as hydrochloric acid and/or sodium hydroxide to adjust the pH of the solution to a value in the range of 5.5-6.5, preferably in the range of 5.8-6.2, more preferably up to about 6.0 ; and water as a solvent.

Preferably, said ophthalmic composition essentially consists of said ingredients, i. latanoprost, optionally timolol or a pharmaceutically acceptable salt thereof, polysorbate 80, disodium edetate, tonicity adjusting agent, buffering agent, optional pH adjusting agent, and water.

Plasticizers are additives that increase the plasticity or decrease the viscosity of a polymer. Examples of plasticizers are ethylene vinyl acetate (EVA, a copolymer of ethylene and vinyl acetate), rubber-like materials such as butyl rubber.

Plasticizers are also referred to as softeners as they also provide softness which helps to ensure that the package is airtight.

In a further embodiment of the present invention, optionally in combination with one or more of the features of the various embodiments described above or below, the dosing device includes a container with an ophthalmic liquid composition containing a prostaglandin analogue packaged therein, a dispenser and a sealing gasket, where the specified sealing gasket made of a polymer selected from the group consisting of polyethylene, polypropylene, polytetrafluoroethylene and mixtures thereof. In a preferred embodiment, the polymer of the gasket is polyethylene.

A dispenser with a seal made of polyethylene substantially free of plasticizer satisfies USP NF sealing requirements. The water loss is 0.74% when calculated after 365 days at 25°C/40 RH.

Moreover, the product in the dispenser of the present invention satisfies the water loss requirements defined in the EMA guidelines; Stability Testing of New Drug Substances and Products.

The container is also referred to herein as a bottle, reservoir, or container.

In one embodiment of the present invention, optionally in combination with one or more of the features of the various embodiments described above or below, the dosing device comprises an ophthalmic liquid composition containing a prostaglandin analogue packaged in a container made from a polymer selected from the group consisting of polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polyvinyl chloride, acrylic resins, polystyrene, polymethyl methacrylate, nylon 6 and mixtures thereof. In a preferred embodiment, the container is made from a polymer selected from the group consisting of polyethylene (PE) and

- 7 042509 polypropylene (PP). These polymers can be high density or low density polymers such as high density polyethylene (HDPE).

Containers made from PP as well as PE are impact resistant and lightweight. These materials are well known and have been used for decades.

With regard to extractables, they are considered safe and neutral for the contents of the package.

In a further embodiment of the present invention, optionally in combination with one or more features of the various embodiments described above or below, a seal for a dispenser as described herein is made from a polymer selected from the group consisting of polyethylene, polypropylene, polytetrafluoroethylene and mixtures thereof. In a preferred embodiment, the polymer is polyethylene.

Examples

The effect of the plasticizer on the adsorption of prostaglandin analogs to gaskets was examined during storage for three months at and 25°C/40%RH.

1) Obtaining compositions of analogues of prostaglandins.

1.1) Composition 1.

Substance [mg/ml] Latanoprost 0.050 Polysorbate 80 0.50 Disodium edetate 0.20 Sodium chloride 4.61 Sodium diphosphate 1.6 Sodium dihydrogen phosphate monohydrate 7.7 Sodium hydroxide solution q.s. up to pH 6.0 Hydrochloric acid, diluted q.s. up to pH 6.0 Water for injections Up to 1 ml

1.2) Composition 2.

Substance [mg/ml] Travoprost 0.04 Sodium chloride 3.5 Boric acid 3.0 Polyoxyethylene (40) hydrogenated castor oil 2.0-5.0 propylene glycol 7.5 Mannitol 3.0 1 M sodium hydroxide/1 M hydrochloric acid q.s. up to pH 4.6-6.8 Water for injections Up to 1 ml

1.3) Composition 3.

Substance [mg/ml] Tafluprost 0.015 mg Glycerol 22.5 mg Sodium dihydrogen phosphate dihydrate 2.0 mg Disodium edetate 0.5 mg Polysorbate 80 0.75 mg Highly purified water Up to 1.0 ml

- 8 042509

1.4. Composition 4

Substance [mg/ml] Latanoprost 0.05 Timolol maleate 6.83 Sodium chloride 4.3 Polysorbate 80 0.5 Disodium edetate 0.2 Sodium diphosphate 2.6 Sodium dihydrogen phosphate monohydrate 6.2 Hydrochloric acid, diluted q.s. up to pH 5.5-6.5 Sodium hydroxide / 1 M q.s. up to pH 5.5-7.5 Highly purified water Up to 1 ml

2) Making a container.

The bottles were made by injection-blow molding polypropylene (PP) or polyethylene (PE). All bottles were eye drop containers having the same shape.

3) Manufacturing of the dispenser.

The capping system consists of a pumping system used in a snap bottle.

The PE/EVA gasket contains 30% Evatane® 28-05 which has less than 10% ethylene vinyl acetate (EVA).

The gasket made of PE without EVA is 100% PE.

Before filling the device with ophthalmic solution, the container and dispenser are sterilized by any convenient method, including, but not limited to, ethylene oxide, autoclaving, irradiation, and the like, or a combination thereof. Preferably, sterilization is carried out using gamma radiation or using ethylene oxide.

4) Method of testing.

After storage under various conditions for up to three months, the content of the prostaglandin analog in each bottle was determined by high performance liquid chromatography (HPLC), similar to the amount of impurities in the results of stability tests 3 and 4.

The HPLC method with diode array detection (DAD) was used. The analysis was carried out using analytical columns with L40 stationary phase (according to USP) or using a set of two analytical columns connected by a connector: one column with stationary phase L40 and a second column with stationary phase L10 (designations L40 and L10 according to USP).

The mobile phase used was a mixture of phase A (acetonitrile, water and phosphoric acid 85%) and phase B (acetonitrile) fed by gradient elution.

The dosing device was stored upside down to ensure full contact of the solution with the sealing gasket.

Loss of a prostaglandin analog present in a formulation refers to the difference (%) between the concentration of the prostaglandin analog present in the liquid formulation after a given period of time and the initial concentration of the prostaglandin analog present in the formulation.

4.1) Stability test 1.

The results obtained after storage at 25°C/40%RH are presented in table. 1.

- 9 042509

Table 1

Conc. (%) % a loss Day 0 1 month Comparative Example 1 Composition 1 HDPE container Dispenser with PE/EVA gasket 99.6 95.5 4.1 Example 1 Composition 1 HDPE container Dispenser with PE seal 100.0 98.7 1.3 Example 2 Composition 1 PP container Dispenser with PE seal 100.0 97.6 2.4 Example 3 Composition 1 HDPE container 100.1 99.7 0.4

Dispenser without gasket

The concentration of latanoprost in the table means the percentage of latanoprost relative to the declared content (50 µg / ml).

The results in the table. 1 show that the concentration of the active ingredient of formulation 1 (latanoprost) in Examples 1 and 2 is higher than the concentration in Comparative Example 1, and the loss of product in aqueous solution is reduced in Examples 1 and 2. The adsorption of the compound of the present invention onto the ophthalmic dispenser is significantly is inhibited.

The results obtained in Example 3 demonstrated that the seal material was responsible for the adsorption of the active ingredient in the dispenser 4. However, the seal was necessary to ensure the required packing density.

4.2) Stability test 2.

The results obtained after storage at a temperature of 2-8°C are presented in table. 2.

table 2

Conc. (%) % a loss Day 0 1 month Comparative Example 2 Composition 1 HDPE container Dispenser with PE/EVA gasket 99.6 97.1 2.6 Example 4 Composition 1 HDPE container Dispenser with PE seal 100.0 99.0 1.0 Example 5 Composition 1 PP container Dispenser with PE seal 100.0 99.1 0.9

As shown in Table. 2, at a lower temperature, the adsorption of the active ingredient to the dispenser was reduced for all examples.

It was also found that the concentration of the active ingredient in Formulation 1 (latanoprost) in Examples 4 and 5 was higher than that in Comparative Example 2.

4.3. Stability test 3.

The composition of latanoprost (Formulation 1) in an HDPE container with a dispenser with a PE seal was subjected to a stability test for 9 months at 25±2°C/60±5% RH, where not only the concentration of the active ingredient (latanoprost) , but also the content of the main impurities were determined by HPLC.

The concentration of latanoprost means the percentage of latanoprost relative to the declared content (50 µg / ml). Impurity concentration means the amount of impurities expressed as % (w/v).

The results are presented in table. 3

Table 3

Month 0 1 3 5 6 9 Latanoprost 100.0 98.7 101.3 101.2 100.1 99.2 Impurity A <LOD <LOD <LOD <LOD <LOD <LOD Impurity B <LOD <LOD <LOD <LOD <LOD <LOD Impurity E 0.1 0.12 0.35 0.31 0.34 0.36 Any other single impurity <LOD <LOD <LOD <LOD <LOD <LOD The amount of impurities, not including impurities A, B, E <LOD <LOD <LOD <LOD <LOD <LOD

LOD in the table means the detection limit of the method.

Surprisingly, not only was the content of the active ingredient very stable, but also the level of impurities was very low despite the fact that the composition did not contain any preservative.

4.4) Stability test 4.

A comparative stability test was conducted comparing three batches of composition and dispenser according to the invention (latanoprost ophthalmic formulation formulation 1 in HDPE container with PE liner dispenser) (lots 1-A, 1-B and 1-C) against three lots of reference latanoprost ophthalmic composition (Ref-A, Ref-B and Ref-C) containing benzalkonium chloride (BAC) as a preservative and stored in a PE container with a screw cap dispenser and a PE tamper-evident cap.

Reference Xalatan® is an aqueous formulation containing 0.05 mg/ml latanoprost and 0.2 mg/ml BAC as a preservative.

Both the compositions according to the invention and the reference compositions were subjected to a stability test at 25±2°C/60±5% RH. The concentration of latanoprost, impurity E and the sum of impurities excluding impurities A, B and E were determined by HPLC after storage for 9 and 12 months. The results are presented in table. 4.

- 11 042509

Table 4

Latanoprost Impurity E The amount of impurities 9 months 12 months 9 months 12 months 9 months 12 months Party 1A 96.4 96.7 0.49 0.60 <LOQ <RT Party 1B 98.9 98.9 0.45 0.54 <RT <RT Party 1C 97.8 96.2 0.43 0.52 0.1 0.12 Ref-A (expiration date expiration date 10.2018) 91.8 (analyzed 07/08.2017) 93.0 (analyzed 10/11.2017) 0.42 (analyzed 07/08.2017) 0.59 (analyzed n 10/11.2017) 2.00 (analyzed 07/08.2017) 2.80 (analyzed And 10/11.2017) Ref-B (expiration date 11.2019) 95.8 (analyzed 08/09/2018) n.d. 0.46 (analyzed 08/09.2018) n.d. 4.16 (analyzed 08/09/2018) n.d. Ref-C (date expiration n.d. 93.8 (analyzed 08/09/2018) n.d. 0.56 (analyzed on 08/09.2018) n.d. 4.98 (analyzed on 08/09.2018)

term validity 09.2019)

Surprisingly, it was found that, compared with the reference composition containing BAC as a preservative, the composition according to the present invention (batches 1A, 1B and 1C), which was free of preservatives, was more stable, so that the content of the active ingredient was more high than in the reference composition, the amount of impurity E was similar, while the amount of other impurities was lower, despite the fact that the composition according to the invention does not contain any preservative.

4.5) Stability test 5.

The results obtained after storage at 25°C/40%RH are presented in table. 5.

Table 5

Conc. (%) % a loss Day 0 3 months After storage in for 3 months Comparative Example 3 Composition 2 HDPE container Dispenser with PE/EVA gasket 103.1 100.3 2.8 Example 6 Formula 2 HDPE container Dispenser with PE seal 100.6 100.6 0.0

In table. 5 shows that there was no loss of the active ingredient of Formulation 2 (Travoprost) in Example 6.

4.6) Stability test 6.

The results obtained after storage at 25°C/40%RH are presented in table. 6.

- 12 042509

Table 6

Conc. (%) % a loss Day 0 1 month 3 months After storage in flow 3 months Comparative Example 4 Composition 3 HDPE container Dispenser with 98.4 94.5 90.0 8.4

PE/EVA seal Example 7 Composition 3 HDPE container Dispenser with PE seal 99.7 99.7 98.0 1.7

The results presented in table. 6 show that the concentration of the active ingredient (tafluprost) of Formulation 3 in Example 7 is higher than the concentration of the active ingredient in Formulation 3 in Comparative Example 4, and the loss of active ingredient in aqueous solution is significantly lower in Example 7. Active Ingredient Adsorption to the ophthalmic dispenser was largely inhibited.

4.7) Stability test 7.

The results obtained after storage at 25°C/40%RH are presented in table. 7.

Table 7

Conc. (%) % a loss Day 0 3 months Example 8 Composition 4 HDPE container Dispenser with PE seal 100.9 100.8 0.1

As shown in Table. The 7% loss of the active ingredient of Formulation 4 (tafluprost) in Example 8 is very low and thus the adsorption of the active ingredient is minimal.

5) Leak test for dosing device.

12 dosing devices were selected and their tare weight was determined.

The test containers were filled with water according to the filling capacity. Two containers were filled with glass beads to the same weight as the filled test containers. The closed containers were stored at 25±2° and 40±2% relative humidity. After 336±1 h (14 days), the weight of the individual containers was recorded and the water weight loss coefficient was calculated, in percent per year, for each bottle.

[(W _1i -WT)-(W _14i -WT)-(W _C1 -W _C14 )]x365x100/(W _1i -WT)x14

W _1i = initial weight of each individual bottle (i),

W _T =tare weight,

W _14i = weight of each individual bottle (i) after 14 days,

W _C1 = initial mass of the control container for 1 day,

W _C14 = mass of control container after 14 days.

Classification: The dispenser meets the leak tightness requirements if the percentage water mass loss does not exceed 2.5% in 1 out of 10 tested NMT containers and does not exceed 5.0% per year in any of them.

For the metering device of the present invention, a water loss of 0.74% was determined when calculated over 365 days at 25°C/40 RH.

6) Stability testing.

After 3 months of storage under accelerated stability test conditions, 40°C/NMT 25% RH, for composition 1, the water loss in the dispenser of the present invention did not exceed 5%, which according to the mentioned manual is considered a significant change.

The results are presented in table. 8 below.

-

Claims (15)

Table 8 Water loss after 3 months storage at 40°C/NMT 25% RH Party 1 Party 2 Party 3 Party 4 Party 5 Party 6 3.1% 1.29% 3.2% 1.09% 3.31% 1.07% The above results confirm that the dispenser of the present invention satisfies the tightness requirements as determined by water loss in the EMA Stability Testing of New Drug Substances and Products. CLAIM 1. Dosing device, containing: an ophthalmic liquid composition containing a prostaglandin analog; a container with an ophthalmic liquid composition containing a prostaglandin analogue packed therein; dispenser; and a sealing gasket, where the sealing gasket is made of a polymer essentially free of ethylene vinyl acetate. 2. The dosing device of claim 1, wherein the prostaglandin analog is a prostaglandin F2a analog, preferably a prostaglandin F2a analog ester, and more preferably a prostaglandin F2a analog ester selected from the group consisting of latanoprost, travoprost and tafluprost. 3. A dispenser according to claim 1 or 2, wherein the ophthalmic liquid composition contains a prostaglandin analog at a concentration of up to 100 micrograms/milliliter. 4. A dispensing device according to any one of the preceding claims, wherein the ophthalmic liquid composition is an aqueous solution, emulsion or suspension, and more preferably an aqueous solution. 5. A dispenser according to any one of the preceding claims, wherein the ophthalmic liquid composition further comprises a surfactant, preferably a nonionic surfactant, more preferably a nonionic surfactant selected from the group consisting of polysorbate 80, polysorbate 60, polysorbate 40 , poly(oxyethylene)sorbitan monolaurate, poly(oxyethylene)sorbitan trioleate, polysorbate 65, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene 40 stearate and mixtures thereof, and even more preferably, the non-ionic surfactant is polysorbate 80 or polyoxyethylene hydrogenated castor oil 40. 6. A dispenser according to any one of the preceding claims, wherein the ophthalmic liquid composition is free of preservatives. 7. A dispensing device according to any one of the preceding claims, wherein the ophthalmic liquid composition contains at least one additional pharmaceutically active agent, preferably a β-blocking agent, more preferably timolol or a pharmaceutically acceptable salt thereof. 8. Dispensing device according to any one of the preceding claims, wherein the seal is made from a polymer selected from the group consisting of polyethylene, polypropylene, polytetrafluoroethylene and mixtures thereof, preferably polyethylene, and/or the container is made from a polymer selected from the group consisting of polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polyvinyl chloride, acrylic resins, polystyrene, polymethyl methacrylate, nylon 6 and mixtures thereof, and preferably the container is made of polyethylene (PE) or polypropylene (PP). 9. A dispensing device according to any one of the preceding claims, wherein the ophthalmic liquid composition is an aqueous solution containing: latanoprost at a concentration in the range of 0.010-0.100 mg/ml; polysorbate 80 at a concentration in the range of 0.2-1.0 mg/ml; disodium edetate at a concentration in the range of 0.1-0.5 mg/ml; a tonicity agent in an amount sufficient to correct the osmolarity to a value in the range of 250-320 mosmol/kg; an ophthalmologically acceptable buffer; optionally a pH adjusting agent such as hydrochloric acid and/or sodium hydroxide to adjust the pH to a value in the range of 5.5-6.5; and water as a solvent. 10. The dosing device according to claim 9, where the tonicity agent is selected from the group - 14 042509 consisting of sodium chloride, potassium chloride, calcium chloride, propylene glycol, glycerin, sorbitol, mannitol and mixtures thereof, more preferably the tonicity agent is sodium chloride. 11. A dosing device according to claim 9 or 10, wherein the buffer is preferably selected from acetate, citrate, phosphate and borate buffers, preferably a phosphate buffer. 12. A dosing device according to any one of claims 9 to 11, wherein the ophthalmic liquid composition contains timolol or a pharmaceutically acceptable salt thereof as the second active ingredient. 13. A seal for a dispenser according to any one of the preceding claims, wherein said seal is made from a polymer substantially free of ethylene vinyl acetate. 14. The gasket according to claim 13, wherein said gasket is made from a polymer selected from the group consisting of polyethylene, polypropylene, polytetrafluoroethylene and mixtures thereof, preferably polyethylene. 15. A dispenser for a dispenser according to any one of claims 1 to 12, comprising a sealing gasket according to claim 13 or 14. ^gj) Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2