EA049828B1 - OPHTHALMIC SOLUTION - Google Patents

Abstract

The present invention relates to a preservative-free ophthalmic solution containing latanoprost, timolol, polysorbate 80, disodium edetate, a tonicity adjusting agent, an ophthalmologically acceptable buffering agent, a pH adjusting agent such as hydrochloric acid and/or sodium hydroxide in certain amounts, and water as a solvent, wherein the solution provides high stability of latanoprost.

Description

Field of technology

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

State of the art

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

However, some prostaglandin analogues are poorly soluble in water and tend to adsorb to any part of the dispenser that is in contact with the solution. This phenomenon is particularly important at low concentrations, since delivery of the required amount of active ingredient over a period of time cannot be guaranteed.

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 the solution is reduced and may become too low to have an optimal therapeutic effect.

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

Currently, there are many types of dosing devices available on the market, containing dosing devices having different parts such as a valve base, a distribution valve, an air-capturing element, a filter element, a filter element holder, etc. These parts can be made of different materials and thus it is difficult to adapt the composition of the solution to all the materials of the device that come into contact with the solution.

For liquid preparations containing prostaglandin analogues that exhibit the deficiencies mentioned above, it is necessary to improve the situation with adsorption onto the dispenser and solubility in water.

From the prior art documents, some proposals are known for solving the problem of adsorption of prostaglandin analogues.

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

WO2005/011704 A1 discloses that a 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 the stable storage of a pharmaceutical composition containing prostaglandin(s), wherein the method comprises the step of storing the prostaglandin composition in a container made of polyethylene, preferably low density polyethylene (LDPE), even more preferably in an LDPE container having Purell PE 3020 D resin, which is manufactured using a blow fill seal (BFS) technology.

WO2013038120 describes a device for storing and dosing a pharmaceutical liquid, comprising, on at least part of the inner 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 also come into contact with the liquid composition were not examined.

WO2002/022131 describes an invention wherein the aqueous solubility and adsorption onto a resin container of a prostaglandin analogue is increased by including a nonionic surfactant and/or an antioxidant in an ophthalmic solution.

WO2009/145356 relates to a preservative-free ophthalmic composition comprising PGF2-alpha analogues, 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 this area for a device for storing and dispensing ophthalmic liquid compositions containing a prostaglandin analogue, which provides the ability to guarantee the content of the active ingredient in the solution during a given time interval without adapting the composition of the solution to different device materials.

Description of the invention

The author of the present invention has noticed that for a dosing device that comprises a container, a dispenser and a seal between the dispenser and the container, the above-mentioned methods for eliminating the adsorption of prostaglandin analogues are not effective. The adsorption of said active substances has a negative effect on the content, despite the presence of surfactants and container materials, as described in the prior art documents.

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

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

- 1 049828

The first aspect of the present 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, wherein said sealing gasket is made of a polymer substantially free of ethylene vinyl acetate.

Another aspect of the present 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, wherein said sealing gasket is made of a polymer substantially free of a plasticizer.

A further aspect of the present invention relates to a sealing gasket for a dispensing device according to any of the preceding aspects, wherein said sealing gasket is made of a polymer substantially free of ethylene vinyl acetate.

A further aspect of the present invention relates to a sealing gasket for a dispensing device according to any of the preceding aspects, wherein said sealing gasket is made of a polymer substantially free of plasticizer.

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

A further aspect of the present invention relates to a dispenser for a dispensing device according to any of the preceding aspects, comprising a sealing gasket made of a polymer substantially free of a 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 the ophthalmic liquid composition;

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

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

a dispenser and a sealing gasket, wherein the sealing gasket is made of a polymer that is substantially free of a 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 analogue packaged therein, a dispenser and a sealing gasket, said sealing gasket being made of a polymer substantially free of ethylene vinyl acetate.

Another aspect of the present invention relates to a preservative-free aqueous ophthalmic solution comprising 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 a solvent.

A dosing device is a drug delivery system for storing and dosing a therapeutic solution and is also referred to herein as a device or dispenser.

A dispenser, as described in this description, should also be understood to mean a closure system that is suitable for ejecting or dispensing individual drops of liquid.

The sealing washer, also called an o-ring or disc, sits between the container and the dispenser, sealing the connection. The sealing washer can either be inserted into the dispenser or fixed on 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 washable solid eye inserts. In a particular embodiment, the term ophthalmic liquid composition refers to a solution.

As used herein, the term "essentially free" gasket refers to a gasket made from a polymer that does not include ethylene vinyl acetate or a plasticizer, or that includes 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 a plasticizer.

As used herein, the expression "essentially free" gasket refers to a gasket made from a polymer that does not include

- 2 049828 ethylene vinyl acetate or a plasticizer, or in which it is present in such a low concentration that it does not exhibit its adsorption effect.

The inventors of the present invention have unexpectedly discovered that the stability, in terms of undesirable adsorption of the active substance of an ophthalmic liquid composition containing a prostaglandin analogue, in a dosing device with a sealing gasket made of a polymer substantially free of ethylene vinyl acetate or a plasticizer, is unexpectedly increased compared to the same composition in devices with a sealing gasket made of a polymer with a plasticizer.

In addition, the inventors of the present invention have found that adsorption of prostaglandin in the dispensing device can be prevented to a significant extent. Testing in the assay confirmed that the prostaglandin product, which was stored in the dispensing device of the invention with a sealing gasket substantially free of plasticizer or ethylene vinyl acetate, meets the specification requirements both at the time of release and at the end of the shelf life (e.g., HPLC analysis shows 95-105% at the time of release and 90-105% at the end of the shelf life). Additional laboratory testing confirmed that the absence of plasticizer or ethylene vinyl acetate in the sealing gasket surprisingly does not have an adverse effect on the packaging 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, it is understood that numerical values preceded by the term approximately include the exact stated value, as well as a certain deviation from such value, namely, a deviation of ±5% from the stated value. It is understood that numerical ranges defined by lower and upper limits also include the stated limits.

Detailed description of the invention

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

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

The invention also relates to a dosing device comprising a container with an ophthalmic liquid composition containing a prostaglandin analogue packed therein, a dispenser and a sealing gasket made of a polymer substantially free of a plasticizer.

Part of the invention also relates to a sealing gasket for a dosing device according to any of the preceding aspects, wherein it is made of a polymer substantially free of ethylene vinyl acetate.

Furthermore, the invention relates to a sealing gasket for a dosing device according to any of the preceding aspects, wherein it is made of a polymer substantially free of a plasticizer.

The invention also relates to a dispenser for a dispensing device according to the invention, comprising a sealing gasket made of a polymer substantially free of ethylene vinyl acetate.

Moreover, it relates to a dispenser for a dispensing device according to any of the preceding aspects, comprising a sealing gasket made of a polymer substantially free of plasticizer.

The invention also relates to a preservative-free ophthalmic solution comprising 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 a solvent.

As shown in comparative stability tests 1, 2, 5 and 6 (Tables 1, 2, 5 and 6), unexpectedly, the tested ophthalmic liquid formulations containing a prostaglandin analogue (latanoprost, travoprost or tafluprost) were more stable when stored in a dispensing device containing a sealing gasket that was made of a polymer substantially free of ethylene vinyl acetate or any other plasticizer, compared to equivalent formulations that were stored in dispensing devices with a sealing gasket made of PE/EVA, which contains ethylene vinyl acetate (EVA).

In a first embodiment of the present invention, optionally in combination with one or more features of the various embodiments described above or below, the dosing device comprises an ophthalmic liquid composition comprising a prostaglandin analogue.

- 3 049 828 landin, packed in a container, wherein the prostaglandin analogue is a prostaglandin F2a analogue. In a preferred embodiment, the prostaglandin F2a analogue is selected from esters of prostaglandin F2a analogues. In a more preferred embodiment, the ester of the prostaglandin F2a analogue is selected from the group consisting of latanoprost, travoprost and tafluprost.

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

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

The adsorption phenomenon is particularly important at low concentrations (e.g. down to 100 micrograms/milliliter of active ingredient), since delivery of the required amount of active ingredient over time is not guaranteed and the optimal therapeutic effect cannot be achieved.

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

The most commonly used ophthalmic dosage forms are solutions.

The ophthalmic liquid composition according to the invention may also contain conventional excipients used in ophthalmic compositions, such as surfactants, antioxidants, tonicity adjusting agents, buffering agents, etc.

The term surfactant refers to a compound that reduces the surface tension between two liquids or between a liquid and a solid. Materials frequently used as surfactants include: (a) nonionic surfactants such as fatty alcohol ethers of polyoxyethylene, fatty acid esters of sorbitan, fatty acid esters of polyoxyethylene, sorbitan esters, glycerol monostearate, polyethyleneglycols, acetyl alcohol, cetostearyl alcohol, stearyl 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 mixtures thereof.

In one embodiment of the present invention, optionally in combination with one or more features of the various embodiments described above or below, the dosing device comprises an ophthalmic liquid composition further comprising a surfactant. In a preferred embodiment, the surfactant is a non-ionic surfactant for a solubilizing effect and to prevent adsorption of prostaglandin analogues onto the dosing device. In a more preferred embodiment, the nonionic 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. The nonionic surfactants can be used individually 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 other molecules from being oxidized. Examples of suitable antioxidants include ethylenediaminetetraacetic acid (also known as edetic acid) and its salts (e.g., disodium edetate), dibutylhydroxytoluene, etc.

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

The term buffering agent refers to a substance capable of neutralizing both acids and bases in a solution, 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, ε-aminocaproic acid, etc.

As is well known to those skilled in the art, a buffer substance is a system typically consisting of an acid and its conjugate base. The preparation of buffering agents is well known, thus, for example, a phosphate buffer is typically prepared as a mixture of dihydrogen phosphate ion and hydrogen phosphate, for example using sodium dihydrogen phosphate (NaH ₂ PO ₄ ,

- 4 049828 or sodium monophosphate), preferably sodium dihydrogen phosphate monohydrate (NaH ₂ PO ₄ -H ₂ O), and sodium hydrogen phosphate (Na ₂ HPO ₄ , or sodium diphosphate). Similarly, an acetate buffer can be prepared with acetic acid and sodium acetate; a citrate buffer can be prepared with citric acid and sodium citrate; or a borate buffer can be prepared, for example, with boric acid and disodium tetraborate.

The method for producing eye drops containing a prostaglandin analogue may be any conventional method of production without the need for a specific technique or action. 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 substances for adjusting the pH, 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 dispensing device preferably comprises a preservative-free ophthalmic liquid composition.

In the present description, a preservative-free ophthalmic solution means an ophthalmic solution of the present invention that does not contain a preservative such as quaternary ammonium salts, for example 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.

It will be clear to one skilled in the art that any substance known to provide a preservative effect must be excluded in this context, regardless of any other function that the substance may simultaneously have in the liquid preparation.

Preservatives are often added to ensure the sterility of the solution after the device is first opened. However, these preservatives, which may contribute to the solubilization of the active ingredient and its stabilization in the solution, are currently not recommended because they may be toxic and have tolerability problems, especially in the context of long-term treatment, such as glaucoma. Therefore, 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 are likely to be impaired.

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

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

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 about 0.050 mg/ml and even more preferably at a concentration of 0.050 mg/ml;

polysorbate 80 in 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 adjust the osmolarity to a value in the range of 250-320 mOsm/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 adjusting agent is sodium chloride; and an ophthalmologically acceptable buffering agent, preferably selected from acetate, citrate, phosphate and borate buffers, more preferably from 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 to about 6.0; and water as a solvent;

wherein, more preferably, the tonicity adjusting 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

- 5 049828 or 4.6 mg/ml.

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 said buffering substances may be sufficient to achieve the desired pH value, or it may be necessary to add an additional substance for adjusting the pH, 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 dispensing device of the invention is an aqueous solution that essentially consists of latanoprost, polysorbate 80, sodium edetate, a tonicity adjusting agent, a buffer system, optionally a pH adjusting agent and water as a solvent according to the advantageous features described above.

In a further embodiment of the present invention, optionally in combination with one or more features of the various embodiments described above or below, the dosing device comprises an ophthalmic liquid composition comprising a prostaglandin analogue in combination with at least one additional pharmaceutically active substance, preferably a β-blocker, more preferably timolol or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the ophthalmic liquid composition comprises 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 dispensing device 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, a tonicity adjusting agent and a buffering agent.

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

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 about 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 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 in 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 in 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 in a concentration of about 0.2 mg/ml, and even more preferably in a concentration of 0.2 mg/ml;

a tonicity adjusting agent in an amount sufficient to adjust 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 adjusting agent is sodium chloride;

an ophthalmologically acceptable buffering agent, 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 to about 6.0; and water as a solvent.

When timolol is used as its pharmaceutically acceptable salt, the preferred concentrations stated are based on an equivalent amount of timolol.

Preferably, the composition is free of preservatives. In one embodiment, the ophthalmic composition contained in the dispensing device of the invention is an aqueous solution that essentially consists of latanoprost, timolol or a pharmaceutically acceptable salt thereof, polysorbate 80, sodium edetate, a tonicity adjusting agent, a buffer system, optionally a pH adjusting agent, and water as a solvent, preferably

- 6 049828 crucible embodiments and quantities described above.

As shown in the examples, namely in stability tests 3 and 4, the obtained aqueous ophthalmic solutions of latanoprost containing a very low concentration of surfactant (polysorbate 80) and antioxidant (disodium edetate), which are free of preservatives, were unexpectedly not only very stable in terms of the amount of latanoprost, but also 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 comprising:

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 about 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 in 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;

a tonicity adjusting agent in an amount sufficient to adjust 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 adjusting agent is sodium chloride;

an ophthalmologically acceptable buffering agent, 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 to about 6.0; and water as a solvent.

Preferably, said ophthalmic composition essentially consists of said ingredients, i.e. latanoprost, optionally 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.

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

Plasticizers are also called softeners because they also provide softness, which helps ensure the packaging remains airtight.

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

The dispensing device with a sealing gasket made of polyethylene, essentially free of plasticizer, meets the tightness requirements of USP NF. The water loss is 0.74% when calculated after 365 days at 25°C/40 RH.

Moreover, the product in the dosing device of the present invention meets the water loss requirements specified in the EMA guideline; Stability Testing of New Drug Substances and Products.

The container is also referred to in this description as a bottle, reservoir, or tank.

In one embodiment of the present invention, optionally in combination with one or more features of the various embodiments described above or below, the dispensing device comprises an ophthalmic liquid composition comprising a prostaglandin analogue packaged in a container made of a polymer selected from the group consisting of polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polyvinyl chloride, acrylic

- 7 049 828 resins, polystyrene, polymethyl methacrylate, nylon 6 and mixtures thereof. In a preferred embodiment, the container is made of a polymer selected from the group consisting of polyethylene (PE) and polypropylene (PP). These polymers may be high-density or low-density polymers, such as high-density polyethylene (HDPE).

Containers made of PP, as well as PE, are impact-resistant and lightweight. These materials are well known and have been used for decades. As for extractable substances, 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, the sealing gasket for the dispensing device as described herein is made of 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 plasticizer on the adsorption of prostaglandin analogues to sealing gaskets was investigated during storage for three months at 25°C/40%RH.

1. Obtaining compositions of prostaglandin analogues.

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. to pH 6.0 Hydrochloric acid, diluted q.s. to pH 6.0 Water for injection 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 z,o 1 M sodium hydroxide/1 M hydrochloric acid q.s. to pH 4.6-6.8 Water for injection Up to 1 ml

1.3. Composition 3.

Substance [mg/ml] Tafluprost 0.015 mg Glycerin 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 049828

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. to pH 5.5-6.5 Sodium hydroxide/1 M q.s. to pH 5.5-7.5 Highly purified water Up to 1 ml

2. Manufacturing of the container.

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

3. Manufacturing of the dispenser.

The capping system consists of a pump system used in a snap-on bottle.

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

The sealing gasket made of EVA-free PE is 100% PE.

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

4. Testing method.

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

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

A mixture of phase A (acetonitrile, water and phosphoric acid 85%) and phase B (acetonitrile) was used as the mobile phase, supplied by gradient elution.

The dispensing device was stored in an inverted position to ensure complete contact of the solution with the sealing gasket.

The loss of prostaglandin analogue present in the preparation refers to the difference (%) between the concentration of prostaglandin analogue present in the liquid preparation after a given period of time and the initial concentration of prostaglandin analogue present in the preparation.

4.1 Stability Test 1.

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

Table 1

Conc. (%) % loss Day 0 1 month Comparative example 1 Composition 1 HDPE container Dispenser with PE/EVA sealing gasket 99.6 95.5 4.1 Example 1 Composition 1 HDPE container Dispenser with sealing 100,0 98.7 1,3

- 9 049828

PE gasket Example 2 Composition 1 Container PP Dispenser with sealing gasket PE 100,0 97.6 2,4 Example 3 Composition 1 PORE container Dispenser without sealing gasket 100,1 99.7 0,4

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

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

The results obtained in Example 3 demonstrated that the sealing gasket material was responsible for the adsorption of the active ingredient in the dosing device 4. However, the sealing gasket 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. (%) % loss Day 0 1 month Comparative example 2 Composition 1 HDPE container Dispenser with PE/EVA sealing gasket 99.6 97.1 2.6 Example 4 Composition 1 HDPE container Dispenser with PE sealing gasket 100,0 99,0 1,0 Example 5 Composition 1 PP container Dispenser with PE sealing gasket 100,0 99.1 0.9

As shown in Table 2, at lower temperature, the adsorption of the active ingredient onto the dispenser decreased for all examples.

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

4.3. Stability Test 3.

The latanoprost formulation (Formulation 1) in an HDPE container with a PE sealed dispenser 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 major impurities were determined by HPLC.

Latanoprost concentration 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.

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Table 3

Month 0 1 3 5 6 9 Latanoprost 100,0 98.7 101.3 101.2 100,1 99.2 Impurity A CLOD CLOD < LOD CLOD CLOD CLOD Impurity B CLOD CLOD < LOD CLOD CLOD CLOD Impurity E 0,1 0,12 0.35 0.31 0.34 0.36 Any other single impurity CLOD CLOD < LOD CLOD CLOD CLOD Sum of impurities, not including impurities A, B, E with LOD <LOD < LOD <LOD CLOD CLOD

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

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

4.4 Stability Test 4.

A comparative stability test was conducted comparing three batches of the composition and dosing device according to the invention (latanoprost ophthalmic composition of Formulation 1 in an HDPE container with a dispenser with a PE sealing liner) (batches 1-A, 1-B and 1-C) against three batches of a 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 inventive and reference compositions were subjected to stability testing 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.

Table 4

Latanoprost Impurity E Sum of impurities 9 months 12 months 9 months 12 months 9 months 12 months Party 1A 96.4 96.7 0.49 0,60 CLOQ CRT IB Party 98.9 98.9 0.45 0.54 CRT CRT IC Party 97.8 96.2 0.43 0.52 0,1 0,12 Ref-A (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 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 (expiration date n.d. 93.8 (analyzed 08/09.2018) n.d. 0.56 (analyzed 08/09.2018) n.d. 4.98 (analyzed 08/09.2018) expiration date 09.2019)

It was unexpectedly found that, compared to the reference composition containing VAC in

- 11 049828 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 higher 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. (%) % loss Day 0 3 months After storage for 3 months Comparative example 3 Composition 2 PORE container Dispenser with PE/EVA sealing gasket 103.1 100.3 2.8 Example 6 Formulation 2 HDPE container Dispenser with PE sealing gasket 100.6 100.6 0,0

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.

Table 6

Conc. (%) % loss After storage for 3 months Day 0 1 month 3 months Comparative example 4 Composition 3 HDPE container Dispenser with PE/EVA sealing gasket 98.4 94.5 90,0 8.4 Example 7 Composition 3 HDPE container Dispenser with PE sealing gasket 99.7 99.7 98,0 1,7

The results shown 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 the active ingredient in the aqueous solution is significantly lower in Example 7. The adsorption of the active ingredient to the ophthalmic dispenser was significantly inhibited.

4.7. Stability Test 7.

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

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Claims (10)

Table 7 Conc. (%) % loss Day 0 3 months Example 8 Composition 4 HDPE container Dispenser with PE sealing gasket 100.9 100.8 0.1 As shown in Table 7, the % 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. Tightness test for the dosing device. 12 dosing devices were selected and their tare weight was determined. Ten test containers were filled with water to their filling capacity. Two containers were filled with glass granules to the same mass as the filled test containers. The closed containers were stored at a temperature of 25±2° and a relative humidity of 40±2%. After 336±1 h (14 days), the mass of the individual containers was recorded and the water mass loss coefficient, in percent per year, was calculated for each bottle: where W _1i = initial mass of each individual bottle (i); W _T =tare weight; W _14i = weight of each individual bottle (i) after 14 days; W _C1 = initial weight of the control container for 1 day; W _C14 = weight of the control container after 14 days. Classification: The dispensing device meets the leak tightness requirements if the percentage loss of water mass does not exceed 2.5% in 1 of 10 NMT containers tested and does not exceed 5.0% per year in any one of them. For the dosing 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 formulation 1, the water loss in the dispensing device of the present invention did not exceed 5%, which is considered a significant change according to the said guideline. The results are presented in Table 8 below. Table 8 Water loss after storage for 3 months 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 dosing device of the present invention meets the tightness requirements as determined by water loss in the EMA Stability Testing of New Drug Substances and Products guideline. CLAUSE OF THE INVENTION 1. Preservative-free ophthalmic solution containing latanoprost in a concentration in the range of 0.010-0.100 mg/ml; timolol or its pharmaceutically acceptable salt in a concentration in the range of 1-10 mg/ml; polysorbate 80 in a concentration in the range of 0.4-0.6 mg/ml; disodium edetate in a concentration in the range of 0.1-0.5 mg/ml; a tonicity-regulating substance in an amount sufficient to bring the osmolarity to a value in the range of 250-320 mOsmol/kg; ophthalmologically acceptable buffering agent; 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. 2. The solution according to claim 1, wherein the concentration of latanoprost is 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 and even more preferably 0.050 mg/ml. 3. The solution according to claim 1 or 2, wherein the pharmaceutically acceptable salt of timolol is timolol maleate. 4. The solution according to paragraphs 1-3, wherein the concentration of timolol or its pharmaceutically acceptable salt is - 13 049828 is 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, wherein when timolol is present as its pharmaceutically acceptable salt, the said concentrations refer to an equivalent amount of timolol. 5. The solution according to item 1 or 2, wherein the concentration of polysorbate 80 is 0.50 mg/ml. 6. The solution according to paragraphs 1-3, wherein the concentration of sodium edetate is in the range of 0.1-0.4 mg/ml, preferably 0.2 mg/ml. 7. The solution according to claims 1-4, wherein the tonicity regulating substance is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, propylene glycol, glycerin, sorbitol, mannitol and mixtures thereof, and is more preferably sodium chloride. 8. The solution according to claims 1-5, wherein the tonicity adjusting substance 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 4.6 mg/ml. 9. The solution according to claims 1-6, wherein the buffer substance is preferably selected from acetate, citrate, phosphate and borate buffers, preferably is a phosphate buffer. 10. The solution according to claims 1-7, wherein the pH is in the range of 5.8-6.2, preferably 6.0. Evra Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2 -