Ophthalmic composition containing tafluprost for the treatment of glaucoma

Abstract

The present invention provides a pharmaceutical composition for use in the prevention or treatment of glaucoma, elevated intraocular pressure, ocular hypertension and / or conditions associated therewith, the composition comprising tafluprost and a partially fluorinated alkane. [Selection diagram] None

Description

Technical Field

[0001] The present invention relates to the field of drug therapy. More specifically, the present invention relates to the treatment of diseases and conditions affecting the eye, such as glaucoma, ocular hypertension, ocular hypertension and / or related symptoms.

Background Art

[0002] Ocular hypertension is a frequently occurring eye disorder and is often associated with damage to the optic nerve, in which case the disease is glaucoma. If there is no damage to the optic nerve, the condition is called ocular hypertension. Normal intraocular pressure is generally defined as being in the range of 10 to 21 mmHg. Intraocular pressure mainly results from the balance between the rate of aqueous humor production and the rate of drainage in the eye and is further affected by the thickness and hardness of the cornea. Intraocular pressure typically varies around about 15 to 16 mmHg with an amplitude of up to 6 mmHg. For example, intraocular pressure generally decreases at night due to a decrease in aqueous humor production. Intraocular pressure also responds to various physiological factors such as exercise, heart rate, respiration, water intake, and certain types of systemic or topical drugs.

[0003] Aqueous humor is produced by the ciliary body of the eye and flows from there into the posterior chamber. The composition of aqueous humor is very similar to that of plasma, but differs from plasma in that it has a low protein content. Its main components are water (99%), electrolytes (inorganic ions for maintaining physiological pH), small amounts of albumin and β-globulin, ascorbate, glucose, lactate and amino acids.

[0004] Aqueous humor is distributed from the posterior chamber to the anterior chamber through the pupil of the iris. From there, the aqueous humor flows through the so-called trabecular meshwork. The trabecular meshwork is a spongy tissue region supported by trabecular meshwork cells, and its main function is to drain aqueous humor into a series of canals called Schlemm's canals. From there, the aqueous humor enters the blood circulation. The flow of aqueous humor from the trabecular meshwork to Schlemm's canals occurs through two different pathways: directly to the suprascle veins via the aqueous humor veins, or indirectly to the suprascle veins via the collecting ducts and the intrascleral venous plexus. This trabecular outflow pathway accounts for the majority of the drained aqueous humor. In addition, there is a second major drainage pathway, which is the uveoscleral pathway. This uveoscleral pathway is relatively independent of intraocular pressure and usually accounts for only 5 to 10% of aqueous humor drainage in healthy individuals.

[0005] Various prostanoid receptors have been found in both the trabecular meshwork and uveoscleral tissue. This indicates that prostanoids are involved in regulating aqueous humor production and / or drainage, thereby influencing intraocular pressure. While genes encoding the EP, FP, IP, DP, and TP receptor families are expressed in the trabecular meshwork, the EP and FP receptor families are dominant in the uveoscleral tissue (Toris et al., Surv Ophthalmol. 2008;53, Appendix 1, S107~S120).

[0006] Prostanoids are physiological fatty acid derivatives that represent a subclass of eicosanoids. Prostanoids include prostaglandins, prostamides, thromboxanes, and prostacyclins, all of which are mediators involved in many physiological processes. (PGF) 2αNatural prostaglandins such as PGE2, PGD2, and PGI2 exhibit specific affinities to their respective receptors (FP, EP, DP, IP), but also have a degree of non-selective affinities to other prostaglandin receptors (ibid.). Prostaglandins also directly affect matrix metalloproteinases. These are neutral proteinases expressed in the trabecular meshwork, and they play a role in regulating fluid efflux resistance by degrading the extracellular matrix.

[0007] Several prostaglandin analogs, including latanoprost, bimatoprost, tafluprost, travoprost, and unoprostone, have been found to be effective as topical medications for lowering intraocular pressure. According to some experts, bimatoprost is understood as a prostaglandin, not a prostaglandin derivative.

[0008] Latanoprost, travoprost, tafulprost, and possibly bimatoprost are also potent and selective PGFs. 2α They are agonists. Their net effect is a decrease in intraocular pressure, which is mainly caused by a substantial increase in aqueous humor outflow via the uveoscleral pathway. They also likely increase trabecular meshwork outflow to some extent.

[0009] Various eye drop formulations containing prostaglandin analogs have been developed and are commercially available. Tafluprost is available as a preservative formulation and as a non-preservative formulation in single-dose containers. The strength of the tafluprost formulation is 15 μg / mL (0.0015%) and it also contains the surfactant polysorbate 80. Bimatoprost is also sold as a buffered, isotonic, preservative aqueous solution with a strength of 0.3 mg / mL (0.03%). The strength of commercially available unoprostone formulations is 1.5 mg / mL (0.15%). It contains a buffer, preservative, isotonic agent, and polysorbate 80.

[0010] However, ophthalmic antiseptic aqueous formulations have a drawback in that they can cause irritation or hypersensitivity reactions, especially with long-term use such as in the treatment of glaucoma. The most common preservative in the aforementioned formulations is benzalkonium chloride, a quaternary ammonium compound, which is associated with frequent irritation and toxic reactions. This drawback can be avoided with preservative-free disposable containers, but these are expensive. Not only is a container needed for each single dose, but overfilling of the formulation is also required. This means that a significant portion (if not most) of the actual drug remains in the container and is disposed of as waste. Considering the drug in eye drops that is actually administered to the eye, only a portion is effective because the volume of the lacrimal sac is limited, and a significant portion of the administered liquid is excreted by blinking. Another portion is absorbed systemically through the nasolacrimal duct, which can lead to adverse drug effects.

[0011] Taflotan (registered trademark) (tafluprost) 0.0015% ophthalmic solution and related names are approved for the reduction of elevated intraocular pressure in adult patients with open-angle glaucoma and ocular hypertension. Taflotan is a sterile isotonic buffered aqueous solution of tafluprost at a concentration of 15 μg / mL. One drop of the solution contains approximately 0.45 μg of tafluprost and is intended for topical administration to the eye. The recommended daily dose for adults is one drop of eye drop (equivalent to approximately 0.45 μg of tafluprost) to the affected eye, with optimal efficacy obtained when administered at night.

[0012] European Patent No. 2547323 describes a pharmaceutical composition for the treatment of elevated intraocular pressure based on a partially fluorinated alkane. Preferred active ingredients include, for example, poorly water-soluble prostaglandin analogs such as latanoprost, bimatoprost, tafluprost, travoprost, and unoprostone. This composition can be administered topically to the eye.

[0013] International Publication No. 2018 / 033854 describes an ophthalmic aqueous solution for the treatment of ocular hypertension and glaucoma, containing 0.0001 to 0.0010% (w / v) of tafluprost and polyacrylic acid, and substantially free of preservatives. The formulation described in International Publication No. 2018 / 033854 has a lower concentration of active ingredients, is preservative-free, and has lower viscosity than currently available products.

[0014] The object of the present invention is to provide a novel pharmaceutical composition that is useful in methods for preventing or treating glaucoma, elevated intraocular pressure, ocular hypertension, or related conditions, and that overcomes at least one of the limitations or disadvantages associated with prior art formulations. In particular embodiments, the object of the present invention is to provide an ophthalmic composition having the ability to incorporate a substantial amount of poorly water-soluble active pharmaceutical ingredient that is useful in the management of glaucoma, elevated intraocular pressure, ocular hypertension, or related conditions. Further objects of the present invention will become apparent based on the following description, examples, and claims. [Prior art documents] [Patent Documents]

[0015] [Patent Document 1] European Patent No. 2547323 [Patent Document 2] International Publication No. 2018 / 033854 Brochure [Non-patent literature]

[0016] (Non-patent document 1) Toris et al., Surv Ophthalmol.2008;53, Supplement 1, S107~S120 [Overview of the Initiative]

[0017] In a first aspect, the present invention provides a pharmaceutical composition for use in the prevention or treatment of glaucoma, elevated intraocular pressure, ocular hypertension and / or related conditions, comprising tafluprost and a liquid vehicle containing a partially fluorinated alkane. In a further aspect, the present invention provides a kit comprising a pharmaceutical composition for use according to the first aspect of the present invention, the kit comprising a container for holding the pharmaceutical composition and a dropper dispenser for administering the composition. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] [Figure 1] FIG. showing the results of two studies of experimental animals (dogs) (further outlined below) that investigated the pharmacokinetics of intraocular pressure (IOP) after repeated topical ocular administration of taufuprost, compared to administration of Taflotan (registered trademark). [Figure 2] FIG. showing the results of two studies of experimental animals (dogs) (further outlined below) that investigated the pharmacokinetics of intraocular pressure (IOP) after repeated topical ocular administration of taufuprost, compared to administration of Taflotan (registered trademark). DETAILED DESCRIPTION OF THE INVENTION

[0019] In a first aspect, the present invention provides a pharmaceutical composition for use in the prevention or treatment of glaucoma, elevated intraocular pressure, ocular hypertension and / or symptoms associated therewith, the composition comprising taufuprost and a liquid vehicle comprising a partially fluorinated alkane.

[0020] The pharmaceutical composition according to the present invention is useful for the treatment or prevention of glaucoma and / or symptoms associated therewith, such as those described below. Glaucoma, as understood herein, is a term for a condition of the eye that can damage the optic nerve and lead to loss of vision. The primary classification when differentiating different types of glaucoma is open-angle glaucoma and closed-angle (or narrow-angle) glaucoma. Open angle refers to the angle at which the iris and the cornea meet when they are wide open to release the internal pressure by draining the fluid within the eye. If this angle becomes narrow or closed, the pressure increases, and ultimately the optic nerve may be damaged and vision may be lost.

[0021] The pharmaceutical composition according to the present invention is also useful for the treatment or prevention of increased intraocular pressure (IOP) and / or symptoms associated therewith, such as the symptoms described below. IOP as understood herein constitutes a major risk factor for the development of glaucoma. IOP is the main cause of optic nerve damage and is characterized by excessive fluid pressure within the eye. This can be due to various reasons, such as blockage of the drainage ducts, narrowing or closure of the angle between the iris and the cornea. An increase in IOP is a major risk factor for glaucomatous visual field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss.

[0022] Furthermore, the pharmaceutical composition according to the present invention is useful for the treatment or prevention of ocular hypertension and / or symptoms associated therewith, such as the symptoms described below. The term ocular hypertension as understood herein means a condition in which an increase in intraocular fluid pressure is observed, but generally without optic nerve damage or visual field loss. Elevated intraocular pressure is an important risk factor for glaucoma. For most individuals, the normal range of intraocular pressure is between 10 mmHg and 21 mmHg. Therefore, most individuals with consistently elevated intraocular pressure above 21 mmHg, especially if they also have other risk factors, usually receive treatment to prevent vision loss due to glaucoma that may be caused by ongoing ocular hypertension. Ocular hypertension can be considered as a result of an imbalance between the fluid entering the eye through the ciliary body and the fluid exiting the eye through the trabecular meshwork. <000,098><000,099><000,100]The composition for use according to the present invention is experimental C 25 H 34 It contains the active ingredient tafluprost having F2O5 and a molecular weight of 452.5 g / mol (CAS number 209860-87-7). Tafluprost is a colorless to yellowish lightly viscous liquid. It is a prostaglandin F2-alpha analogue and more specifically, a prostanoid selective FP receptor agonist that is thought to lower intraocular pressure (IOP) by increasing the outflow of aqueous humor. Studies in animals and humans have suggested that the main mechanism of action is an increase in the uveoscleral pathway.

[0024] In preferred embodiments, the pharmaceutical composition for use according to the present invention contains about 0.0020% to about 0.0050% (w / v) of the active ingredient tafluprost, preferably about 0.0025% to about 0.0045% (w / v) of the active compound tafluprost, and more preferably about 0.0030% to about 0.0040% (w / v) of the active ingredient tafluprost. In most preferred embodiments, the pharmaceutical composition for use according to the present invention contains about 0.0025% to about 0.0035% (w / v) of the active ingredient tafluprost. In the present invention, the pharmaceutical composition for use according to the present invention may contain about 0.0030% (w / v) of tafluprost relative to the total volume of the composition.

[0025] Unless otherwise specified, the term "%(w / v)" as used throughout this specification in relation to the pharmaceutical compositions of the present invention indicates the amount of a component of the composition (e.g., tafluprost) as a percentage by weight of the total volume of the composition (where "w" represents weight and "v" represents volume). For example, 0.005%(w / v) can be understood as relating to 0.05 mg of the component in 1 mL of the composition, and 0.1%(w / v) corresponds to 1.0 mg of the component in 1 mL of the composition. Unless otherwise specified, the term "%(w / w)" refers to the amount of a component of the composition as a percentage by weight of the total weight of the composition (where "w" represents weight). Unless otherwise specified, the term "%(v / v)" refers to the amount of a component of the composition as a percentage by volume of the total volume of the composition (where "v" represents volume).

[0026] In this specification, the term “about” as used in relation to parameters such as, for example, the concentration of tafluprost in a composition or the amount of tafluprost contained in a single dose of a composition includes not only the defined numerical values ​​themselves, but also any values ​​that fall within the range of variation normally observed when measuring or determining these parameters using standard techniques and apparatus known in the art.

[0027] The pharmaceutical composition according to the present invention further comprises a partially fluorinated alkane. The active ingredient tafluprost, as described above, can be dissolved or suspended in a liquid vehicle containing a partially fluorinated alkane, as described below, and is preferably dissolved. The terms “partially fluorinated alkane” or “SFA,” as used synonymously throughout this specification, refer to a compound consisting of a fully fluorinated hydrocarbon segment bonded to a non-fluorinated hydrocarbon segment. Both segments may be branched or linear. However, both segments are preferably unbranched linear segments.

[0028] In preferred embodiments, the pharmaceutical composition comprises a partially fluorinated alkane or a mixture of two or more different partially fluorinated alkanes. However, preferably, the pharmaceutical composition comprises only one partially fluorinated alkane.

[0029] In the present invention, preferred partially fluorinated alkanes are those of general formula (I). CF3 (CF2) n (CH2) m CH3(I) Here, index n is an integer selected from 3 to 7, and m is an integer selected from 4 to 7.

[0030] The alternative nomenclature for certain partially fluorinated alkanes, as set forth in parentheses below and which may be used further herein, is based on the general formula FnHm, where F represents a linear, fully fluorinated hydrocarbon segment, H represents a linear, unfluorinated hydrocarbon segment, and n and m are the number of carbon atoms in each segment. For example, F4H5 can be used to represent 1-perfluorobutylpentane or CF3(CF2)3-(CH2)4CH3 (or sometimes represented as formula F(CF2)4(CH2)5H), which has a linear, fully fluorinated segment F (n=4) having four carbon atoms and a linear, unfluorinated hydrocarbon segment (m=5) having five carbon atoms. Furthermore, F6H8 can be used to represent 1-perfluorohexyl-octane or CF3(CF2)5-(CH2)7CH3 (or sometimes represented as formula F(CF2)6(CH2)8H), which has a linear, fully fluorinated segment F(n=6) with six carbon atoms and a linear, unfluorinated hydrocarbon segment (m=8) with eight carbon atoms.

[0031] Therefore, the partially fluorinated alkanes used in the composition of the present invention are, for example, CF3(CF2)3-(CH2)4CH3(F4H5), CF3(CF2)3-(CH2)5CH3(F4H6), CF3(CF2)3-(CH2)6CH3(F4H7), CF3(CF2)3-(CH2)7CH3(F4H8), CF3(CF2)4-(CH2)4CH3(F5H5), and CF3(CF2)4-(C The partially fluorinated alkane may be selected from H2)5CH3(F5H6), CF3(CF2)4-(CH2)6CH3(F5H7), CF3(CF2)4-(CH2)7CH3(F5H8), CF3(CF2)5-(CH2)4CH3(F6H5), CF3(CF2)5-(CH2)5CH3(F6H6), CF3(CF2)5-(CH2)6CH3(F6H7), and CF3(CF2)5-(CH2)7CH3(F6H8). More preferably, the partially fluorinated alkane may be selected from CF3(CF2)3-(CH2)4CH3(F4H5) and CF3(CF2)5-(CH2)7CH3(F6H8).

[0032] In preferred embodiments, the pharmaceutical composition for use according to the present invention comprises a partially fluorinated alkane of formula (I), selected from 1-perfluorohexyl octane (CF3(CF2)5-(CH2)7CH3(F6H8)) and 1-perfluorobutyl pentane (CF3(CF2)3-(CH2)4CH3(F4H5)). In particular preferred embodiments of the present invention, the partially fluorinated alkane of formula (I) is 1-perfluorohexyl octane (CF3(CF2)5(CH2)7CH3(F6H8)).

[0033] The liquid SFAs described above are chemically and physiologically inert, colorless, and stable. Their typical densities range from 1.1 to 1.7 g / cm³. 3 They fall within a certain range, and their surface tension can be as low as 19 mN / m. FnHm type SFAs are insoluble in water, but they also exhibit some amphiphilicity, and their lipophilicity increases in correlation with increasing size of the non-fluorinated segments.

[0034] The inventors have found that SFA is particularly suitable as a carrier or vehicle in ophthalmic compositions. This is based on the fact that the eye is surprisingly well tolerant of SFA, as demonstrated in preclinical studies. This is quite surprising, as organic or non-aqueous solvents, with the exception of oily compounds, are typically highly irritating or even extremely harmful when administered to the eye.

[0035] A pharmaceutical composition of the present invention comprising "a certain (a)" partially fluorinated alkane should be understood herein as comprising at least one partially fluorinated alkane of formula (I) described above. However, optionally, a composition may comprise more than one, for example, a mixture of two or more partially fluorinated alkanes of formula (I), i.e., a mixture of any one of the partially fluorinated alkane species described above.

[0036] In further embodiments, the pharmaceutical composition may comprise a liquid vehicle comprising the partially fluorinated alkane of formula (I) specified above. In this context, the term “one (a)” partially fluorinated alkane should be understood as at least one partially fluorinated alkane, but may also include a selection of more than one or more partially fluorinated alkane compounds. Thus, in one embodiment, the liquid vehicle may comprise more than one partially fluorinated alkane of formula (I) specified above.

[0037] Where used herein, the terms “consists” and related terms “consisting” or “consist” should be understood to mean that there are no other features other than those preceding the term. In the context of a composition, if any other components or elements other than those preceding such terms are present in the composition, they are present only in trace or residual amounts that do not provide any technical advantage or validity to the purposes of the present invention, and can be further understood by the terms “essentially” or “substantially” used in conjunction with these terms (e.g., “essentially from”). It should be understood that the above definition of such other components or elements includes isomers or olefin impurities arising from the synthesis of partially fluorinated alkanes that cannot be quantitatively removed during purification and are present only in trace or residual amounts that do not provide any technical advantage or validity to the purposes of the present invention. In contrast, the terms “comprising” or related terms such as “comprises” or “comprise” in the context of this composition should be understood to mean that other features other than those preceding the term may be present in the composition.

[0038] In further embodiments, the pharmaceutical composition as defined in any of the embodiments described above may contain a partially fluorinated alkane, or optionally a mixture of partially fluorinated alkanes, in amounts of at least 90%(v / v), 95%(v / v), 98%(v / v), 98.5%(v / v), 99%(v / v), 99.5%(v / v), 99.8%(v / v), or at least 99.9%(v / v) of the total volume of the composition. In preferred embodiments of the present invention, the pharmaceutical composition for use of the present invention contains partially fluorinated alkanes in a proportion of 98.5% to 99.5%(v / v) of the total volume of the composition.

[0039] In the present invention, the partially fluorinated alkane may be present in an amount of about 98 to 99.8% (w / w), preferably 98.5 to 99.5% (w / w), and more preferably about 99.0 to 99.5% (w / w), relative to the total weight of the composition. Preferably, the partially fluorinated alkane contained in the pharmaceutical composition for use in the present invention is present in an amount of up to about 99.4% (w / w), and more preferably about 99.4% (w / w), relative to the total weight of the pharmaceutical composition.

[0040] In further embodiments, the pharmaceutical composition may further comprise a solubilizer. As used herein, the term “solubilizer” refers to a compound or combination of compounds that enhances or promotes the solubility of the active ingredient tafluprost in a selected liquid vehicle containing a partially fluorinated alkane as described above. In preferred embodiments, as already stated above, tafluprost is completely dissolved in the partially fluorinated alkane and optionally in the solubilizer.

[0041] The solubilizer, which may be optionally included in the pharmaceutical composition, is preferably present in an amount of up to 3% (v / v), or preferably up to 2% (v / v), relative to the total volume of the pharmaceutical composition. In a preferred embodiment, the solubilizer is present in an amount of up to 1.5% (v / v), preferably up to 1.4% (v / v), and more preferably up to 1.0% (v / v), relative to the total volume of the pharmaceutical composition. In another preferred embodiment of the present invention, the solubilizer is present in an amount of about 0.5% to 1.5% (v / v), preferably about 0.5% to 1.0% (v / v), relative to the total volume of the pharmaceutical composition.

[0042] The solubilizer, which may be optionally included in this pharmaceutical composition, is preferably present in an amount of up to 1% (w / w), preferably up to 0.8% (w / w), and more preferably up to 0.6% (w / w), relative to the total weight of the pharmaceutical composition. In a preferred embodiment, the solubilizer is present in an amount of 0.2 to 0.7% (w / w), preferably 0.4 to 0.6% (w / w), relative to the total weight of the pharmaceutical composition. In the present invention, the solubilizer may be present in an amount of up to about 0.6% (w / w), relative to the total weight of the pharmaceutical composition, preferably about 0.6% (w / w), relative to the total weight of the composition.

[0043] In some embodiments, the solubilizer may be a liquid excipient such as an organic cosolvent and / or an oil selected from glyceride oils, liquid waxes and liquid paraffins, or an organic solvent exhibiting high biocompatibility.

[0044] Examples of potentially useful liquid excipients include oily excipients that can be used in combination with one or more SFAs, such as triglyceride oils, mineral oils, medium-chain triglycerides (MCTs), oily fatty acid isopropyl myristate, oily fatty alcohols, sorbitol and fatty acid esters, oily sucrose esters, or any other substances that are physiologically tolerable to the eye. In one preferred embodiment, the liquid vehicle comprises a solubilizer in the form of a liquid excipient.

[0045] Further examples of potentially useful solubilizers used herein are organic solvents. Preferred organic solvents include glycerol, propylene glycol, polyethylene glycol, and ethanol.

[0046] In preferred embodiments, the pharmaceutical composition may contain ethanol as a solubilizer, preferably in an amount of up to 1.5% (v / v), more preferably up to 1.4% (v / v), and most preferably up to 1.0% (v / v). In preferred embodiments, the pharmaceutical composition contains ethanol in an amount of 0.5% to 1.5% (v / v), preferably 0.5% to 1.0% (v / v), relative to the volume of the pharmaceutical composition. In the present invention, the pharmaceutical composition for use of the present invention may contain ethanol in an amount of about 1% (v / v) relative to the total volume of the pharmaceutical composition.

[0047] In a preferred embodiment, the pharmaceutical composition may contain ethanol as a solubilizer, preferably in an amount of up to 1% (w / w), more preferably up to 0.8% (w / w). In a preferred embodiment, the pharmaceutical composition contains ethanol in an amount of 0.5% to 1.5% (w / w), preferably 0.5% to 1.0% (w / w), more preferably 0.5% to 0.7% (w / w), relative to the total weight of the pharmaceutical composition. In a preferred embodiment, the pharmaceutical composition contains ethanol in an amount of about 0.6% (w / w), relative to the total weight of the pharmaceutical composition.

[0048] The pharmaceutical compositions for use according to the present invention may also contain, or may not contain, further excipients such as, for example, preservatives, more specifically, preservatives and / or surfactants. However, in preferred embodiments, the pharmaceutical compositions according to the present invention are substantially preservative-free.

[0049] In preferred embodiments, the pharmaceutical compositions for use according to the present invention are substantially water-free. As understood herein, the terms “substantially water-free” or “essentially water-free” in relation to a component of a composition mean that the component is present in trace amounts or less, and that, if present in trace amounts, the component makes no technical contribution to the composition.

[0050] In further preferred embodiments, the pharmaceutical composition for use according to the present invention is substantially free of water and / or preservatives.

[0051] In a particularly preferred embodiment, the pharmaceutical composition for use according to the present invention comprises 1-perfluorobutyl-pentane (CF3(CF2)3-(CH2)4CH3(F4H5)) or 1-perfluorohexyl-octane (CF3(CF2)5-(CH2)7CH3(F6H8)) and tafluprost dissolved in a liquid vehicle containing up to 1% (v / v) ethanol relative to the total volume of the liquid vehicle.

[0052] In the present invention, the pharmaceutical composition for use according to the present invention may contain tafluprost and, based on the total volume of the pharmaceutical composition, a) at least 99% (v / v) of 1-perfluorohexyl octane (CF3(CF2)5-(CH2)7CH3(F6H8)) and b) up to 1% (v / v) of ethanol. Preferably, the pharmaceutical composition for use according to the present invention consists of tafluprost and, based on the total volume of the pharmaceutical composition, a) at least 99% (v / v) of 1-perfluorohexyl octane (CF3(CF2)5-(CH2)7CH3(F6H8)) and b) up to 1% (v / v) of ethanol.

[0053] In a further preferred embodiment, the pharmaceutical composition for use according to the present invention comprises tafluprost dissolved in a liquid vehicle containing about 99% (v / v) of 1-perfluorohexyl-octane (CF3(CF2)5-(CH2)7CH3(F6H8)) and up to 1% (v / v) of ethanol, relative to the total volume of the liquid vehicle.

[0054] In a further preferred embodiment, the pharmaceutical composition for use according to the present invention comprises tafluprost dissolved in a liquid vehicle which essentially consists of 99% (v / v) 1-perfluorohexyl-octane (CF3(CF2)5-(CH2)7CH3(F6H8)) and 1% (v / v) ethanol based on the total volume of the liquid vehicle.

[0055] As outlined above, the compositions for use according to the present invention are preferably provided as a clear solution in which tafluprost is completely dissolved in a selected liquid vehicle. Furthermore, the compositions for use according to the present invention are preferably provided in a sterile form.

[0056] The pharmaceutical composition for use according to the present invention, comprising tafluprost and a partially fluorinated alkane, may be administered topically to the eye of the subject or by subconjunctival injection to the eye of the subject. However, in preferred embodiments, the pharmaceutical composition for use according to the present invention is administered topically to the eye of the subject.

[0057] As used herein, the term “administer topically” includes all possible methods of administration that enable the liquid pharmaceutical composition to come into contact with the surface of the eye of the subject. Typically, the pharmaceutical composition may be administered to the eye of the subject in the form of a single drop or in the form of multiple drops or droplets. The drops may be administered to the surface of the eye, preferably to any surface area or tissue of the eye accessible for topical administration or ophthalmoscopy, such as the cornea or conjunctiva. The drops or droplets of the composition may be instilled directly into the surface of the eye, such as the corneal surface of the eye, or into a space, i.e., a capsule or pocket, formed by gently pulling down the lower eyelid of the eye.

[0058] As used herein, the term “subconjunctival injection” means the injection of any form of the pharmaceutical composition of the present invention into the conjunctiva of the eye in question. This may include injection of the pharmaceutical composition using a suitable syringe. The term “subconjunctival injection” may also include injection by a medical device or implant, which is inserted into the conjunctiva, for example, through an opening created in the conjunctiva.

[0059] Where used herein, the terms “administration to the eye” or “per eye” refer to the administration of a given dose, e.g., a single dose, of the pharmaceutical composition for use according to the present invention to an individual eye of the subject. However, the treatment of eye diseases as described herein, namely glaucoma, elevated intraocular pressure, ocular hypertension and / or symptoms thereof, should be understood to include treatment involving the administration of the composition for use according to the present invention to each eye of the subject that is developing the disease, i.e., both eyes.

[0060] As used herein, the term “Subject” means a person or animal suffering from, diagnosed with, or at risk of developing glaucoma, elevated intraocular pressure, ocular hypertension, and / or related conditions, but preferably a person.

[0061] In the present invention, the amount of tafluprost administered as a single dose per eye may be in the range of about 0.20 μg to 0.55 μg, preferably in the range of about 0.30 μg to 0.50 μg, and more preferably in the range of 0.30 μg to 0.45 μg. In a preferred embodiment, the amount of tafluprost administered as a single dose per eye may be in the range of 0.30 to 0.40 μg, preferably in the range of 0.30 to 0.35 μg, and more preferably in the range of 0.33 μg.

[0062] The pharmaceutical compositions for use according to the present invention form small droplets. In preferred embodiments of the present invention, when administered from a suitable drop dispenser, the volume of the composition administered in a single dose per eye, referred herein as the “target dose volume per eye,” is in the range of about 6 to 28 μl, more preferably in the range of about 6 to 24 μl, and most preferably in the range of about 6 to 15 μl. In another preferred embodiment of the present invention, the pharmaceutical compositions for use according to the present invention have a target dose volume per eye of the composition in the range of about 8 to 15 μl, preferably in the range of about 9 to 14 μl, and most preferably in the range of about 10 to 12 μl. In the most preferred embodiment of the present invention, the target dose volume per eye of the composition is about 11 μl. This further distinguishes the compositions of the present invention from aqueous tafluprost compositions, such as taflotane®, which are characterized by a droplet size of, for example, about 30 μl.

[0063] Accordingly, in a preferred embodiment, a pharmaceutical composition for use in the prevention or treatment of glaucoma, elevated intraocular pressure, ocular hypertension and / or symptoms associated therewith, comprising tafluprost and a partially fluorinated alkane, wherein the amount of tafluprost administered in a single dose per eye is provided in a defined volume of the pharmaceutical composition (hereinafter referred to as the "target dose volume per eye of the composition"). In a further preferred embodiment, the target dose volume per eye of the composition (including the amount of tafluprost administered in a single dose per eye) is 30 μl or less, preferably less than 25 μl, more preferably less than 15 μl, and most preferably 11 μl.

[0064] In a preferred embodiment of the present invention, the pharmaceutical composition for use according to the present invention comprises about 0.0025% to 0.0035% (w / v) of tafluprost and a liquid vehicle containing a partially fluorinated alkane.

[0065] In another preferred embodiment of the present invention, the pharmaceutical composition for use according to the present invention comprises tafluprost and a liquid vehicle containing a partially fluorinated alkane, wherein the composition is administered to the eye of a subject, and the amount of tafluprost administered in a single dose per eye is 0.30 to a maximum of 0.50 μg, preferably 0.30 to a maximum of 0.45 μg, and more preferably 0.30 to a maximum of 0.35 μg.

[0066] In a particularly preferred embodiment, the pharmaceutical composition for use according to the present invention comprises about 0.0030% to about 0.0045% (w / v) of tafluprost, and the composition is administered in a single-dose volume of about 11 μl per eye.

[0067] In another preferred embodiment, a pharmaceutical composition for use according to the present invention comprises tafluprost and a liquid vehicle containing 1-perfluorohexyloctane as a partially fluorinated alkane, the composition being administered to the eye of a subject, the tafluprost having a concentration of about 0.0030 to about 0.0050% (w / v), preferably about 0.0030 to about 0.0045% (w / v), and more preferably about 0.0025 to about 0.0035% (w / v), based on the total volume of the composition.

[0068] In another preferred embodiment, the pharmaceutical composition for use according to the present invention comprises tafluprost, 1-perfluorohexyloctane, and ethanol, the composition being administered to the eye of a subject, and the amount of tafluprost administered in a single dose per eye is in the range of about 0.25 μg to about 0.45 μg, preferably in the range of about 0.25 μg to about 0.35 μg, and more preferably in the range of about 0.30 μg to about 0.35 μg.

[0069] Therefore, in a preferred embodiment, the pharmaceutical composition for use according to the present invention is administered once daily. In a further preferred embodiment, a single dose of the pharmaceutical composition for use according to the present invention is administered as a single drop to the eye of the subject.

[0070] Surprisingly, the presence of the SFA described above has been found to enable the preparation of the pharmaceutical composition, which beneficially combines a single dose of tafluprost with a target dose volume of the composition, compared to the known aqueous compositions described above. Specifically, it is possible to achieve an intraocular pressure reduction comparable to that achieved by administering the commercially available composition Taflotan®, characterized by a target dose of 0.45 μg per eye and a target dose volume of 30 μl per eye. As shown in Figure 1, for example, a composition with a target dose of 0.33 μg per eye shows an intraocular pressure reduction comparable to that achieved by Taflotan®. Furthermore, another advantage of the pharmaceutical composition for use according to the present invention is that the composition can be administered in a considerably smaller target dose volume compared to the target dose volume of Taflotan®.

[0071] As an example, in a preferred embodiment, the pharmaceutical composition for use according to the present invention is characterized by a relatively small volume of the composition administered as a single dose (target dose volume of the composition) per eye, for example, about 8 μl to 15 μl, preferably about 10 μl to about 12 μl, more preferably about 11 μl, and so on.

[0072] Furthermore, one troublesome problem associated with administering aqueous compositions with significantly large droplet sizes is that, generally, only a small fraction of the amount of aqueous composition applied topically to the surface of the eye actually remains there. Often, a portion of the relatively large volume of aqueous composition quickly leaks out of the surface of the eye and is wiped away. Therefore, an excess of composition is often required to ensure that a therapeutically effective amount of tafluprost actually reaches the eye.

[0073] Based on this, the pharmaceutical compositions for use of the present invention enable a significant reduction in droplet size and associated target dose volume, and therefore, as outlined above, enable a significant reduction in the total daily dose of tafluprost administered for use in the treatment of glaucoma, elevated intraocular pressure, ocular hypertension and / or associated conditions.

[0074] The pharmaceutical compositions for use in the present invention preferably do not contain surfactants.

[0075] In a second aspect, the present invention provides a kit comprising a pharmaceutical composition for use in the prevention or treatment of glaucoma, elevated intraocular pressure, ocular hypertension and / or related conditions, according to a first aspect of the present invention. The composition comprises tafluprost and a liquid vehicle comprising a partially fluorinated alkane, and the kit comprises a container for holding the pharmaceutical composition and a drop dispenser for administering the composition.

[0076] It should be understood that all embodiments described in detail above in connection with pharmaceutical compositions for use according to the first aspect of the present invention may be included in kits according to this second aspect of the present invention.

[0077] As understood herein, a drop dispenser may be a dispenser or applicator means that can be attached to, fixed to, or connected to a container for holding a pharmaceutical composition. Preferably, the drop dispenser is adapted to dispense a single dose in the form of a drop of the pharmaceutical composition according to a first aspect of the present invention. More preferably, the drop dispenser is adapted to dispense a single dose of about 8 μl to about 15 μl, preferably about 10 μl to about 12 μl, or even more preferably, a single dose of about 11 μl.

[0078] A container for holding the pharmaceutical composition as understood herein is preferably of a volume capable of holding a single dose, but more preferably of a volume capable of holding multiple or more doses of the composition.

[0079] The container and / or drop dispenser may preferably be made from a thermoplastic material or polymer. In one embodiment, the container and / or drop dispenser is made from a thermoplastic material selected from polyethylene and polypropylene.

[0080] In one particular embodiment, the drop dispenser is manufactured from a polyethylene material, preferably selected from low-density polyethylene and high-density polyethylene, and more preferably from high-density polyethylene. In another embodiment, the container is manufactured from a polypropylene or polyethylene material, and more preferably from polypropylene.

[0081] Preferably, the container has a volume or internal space that is at least partially filled with the pharmaceutical composition for use according to the present invention. In further embodiments, the ratio of the volume of the pharmaceutical composition in the container to the total volume of the container is between 0.4 and 0.7. The total volume of the container as understood herein refers to the total internal volume formed by the internal dimensions of the container. The volume of the pharmaceutical composition in the container refers to the filling volume, i.e., the volume of the pharmaceutical composition held in the container. For example, in a kit containing a container with a total volume of 3.0 ml, it is preferable that the container holds a volume of 2.0 ml of the pharmaceutical composition according to the present invention. Here, the ratio of the volume of the pharmaceutical composition in the container to the total volume of the container is approximately 0.7.

[0082] Kits provided according to these embodiments may improve the storage and dispensing (i.e., ease and consistency in dispensing) of pharmaceutical compositions according to the first aspect of the present invention.

[0083] In a third aspect, the present invention relates to a method for treating or preventing glaucoma, elevated intraocular pressure, ocular hypertension, or related symptoms, comprising administering a composition comprising tafluprost and a partially fluorinated alkane to a subject, preferably a human eye, having glaucoma, elevated intraocular pressure, ocular hypertension, and / or related symptoms, the method being therapeutically effective in treating glaucoma, elevated intraocular pressure, ocular hypertension, and / or related symptoms.

[0084] In a fourth aspect, the present invention provides a pharmaceutical composition for use in a method of preventing or treating glaucoma, elevated intraocular pressure, ocular hypertension and / or related symptoms, comprising tafluprost and a partially fluorinated alkane, which is therapeutically effective in treating or preventing glaucoma, elevated intraocular pressure, ocular hypertension and / or related symptoms.

[0085] In a fifth aspect, the present invention relates to a method for reducing the total daily dose of tafluprost administered to a human for the treatment of glaucoma, elevated intraocular pressure, ocular hypertension and / or related conditions, comprising administering to the human eye once daily a composition comprising tafluprost and a partially fluorinated alkane, preferably tafluprost dissolved in a partially fluorinated alkane at a concentration of 0.0030% (w / v), thereby reducing the amount of tafluprost per total daily dose by up to 27%, and the amount of tafluprost administered as a single dose per eye is at least as therapeutically effective as administering one drop of an aqueous solution containing 0.0015% (w / v) tafluprost per eye daily.

[0086] In a preferred embodiment of the method according to this fifth aspect of the present invention, a drop of the composition has a drop volume of about 11 μl, and a drop of the 0.0015% (w / v) tafluprost aqueous solution has a drop volume of about 30 μl.

[0087] In a further preferred embodiment of the method according to this fifth aspect of the present invention, systemic exposure to tafluprost is reduced compared to administering one drop of 0.0015% (w / v) tafluprost aqueous solution daily.

[0088] In a further preferred embodiment of the method according to this fifth aspect of the present invention, one or more adverse effects are reduced compared to daily administration of one drop of 0.0015% (w / v) tafluprost aqueous solution. As used herein, the term “adverse effect” means, in its general sense, any undesirable adverse effect caused by a drug, and in this particular case, any undesirable adverse effect caused by topical ocular administration of tafluprost, such as blurred vision, burning and stinging, decreased visual acuity, conjunctivitis, eye pain, headache, cough, swelling of the eye or eyelid, etc.

[0089] In a sixth aspect, the present invention provides a method for reducing the total daily dose of tafluprost administered to a human for the treatment of glaucoma, elevated intraocular pressure, ocular hypertension and / or related symptoms, comprising administering one drop once daily to the eye of a human having glaucoma, elevated intraocular pressure, ocular hypertension and / or related symptoms, wherein the amount of tafluprost administered in a single dose per eye is about 0.30 μg to about 0.35 μg, the method reduces the amount of tafluprost per total daily dose by up to about 34%, and the method is at least as therapeutically effective in the treatment of glaucoma, elevated intraocular pressure, ocular hypertension and / or related symptoms as administering one drop of an aqueous solution containing 0.0015% (w / v) tafluprost per eye daily.

[0090] It should be understood that all embodiments described in detail above in relation to pharmaceutical compositions for use according to the first aspect of the present invention may be applied to methods according to the third to sixth aspects of the present invention. Detailed description of the drawing

[0091] Figure 1 shows the results of a direct comparison between a composition containing 0.0030% (w / v) tafluprost in F6H8 administered to the right eye (OD) of test animals and taflotane® administered to the left eye (OS) of the same test animals, as will be further outlined below. The graph shows the change in mean intraocular pressure (IOP) over time in mmHg. Figure 2 shows the results of a direct comparison between a composition containing 0.0030% (w / v) tafluprost in F6H8 administered to the right eye (OD) of test animals and taflotane® administered to the left eye (OS) of the same test animals, as will be further outlined below. The graph shows the mean percentage change from baseline in intraocular pressure (IOP) in mmHg over time.

[0092] The following numbered list of items represents embodiments included in the present invention. 1. A pharmaceutical composition comprising tafluprost and a partially fluorinated alkane for use in a method of treating glaucoma, elevated intraocular pressure, ocular hypertension and / or related conditions. 2. The pharmaceutical composition for use according to item 1, wherein the partially fluorinated alkane is selected from 1-perfluorohexyloctane or 1-perfluorobutylpentane, preferably 1-perfluorohexyloctane. 3. A pharmaceutical composition for use according to item 1 or 2, wherein the target dose of tafluprost per eye is in the range of about 0.20 μg to 0.55 μg, preferably in the range of about 0.30 μg to 0.50 μg, and more preferably in the range of 0.30 μg to 0.45 μg. 4. A pharmaceutical composition for use according to any one of items 1 to 3, wherein the concentration of tafluprost is in the range of 0.002 to 0.005% w / v. 5. A pharmaceutical composition for use according to any one of items 1 to 4, wherein tafluprost is dissolved in the partially fluorinated alkane. 6. A pharmaceutical composition for use according to any one of items 1 to 5, further comprising a solubilizing agent. 7. The pharmaceutical composition for use according to item 6, wherein the solubilizer is present at a concentration of about 0.2 to about 1.5% v / v, preferably about 0.5 to 1.4% v / v, and more preferably about 0.5 to 1% v / v. 8. A pharmaceutical composition for use as described in any one of items 1 to 7, which is administered to the target eye. 9.1 A pharmaceutical composition for use as described in item 8, administered in a dose volume of 8 to 15 μl per eye, preferably about 10 to 12 μl. 10. A pharmaceutical composition for use according to any one of items 1 to 9, to be administered once daily to the target eye. 11.1 A pharmaceutical composition for use according to any one of items 1 to 10, administered in a dose volume of 11 μl per eye. 12. A pharmaceutical composition for use according to any one of items 1 to 11, which is administered to the target eye by local administration or subconjunctival injection. 13. A pharmaceutical composition for use according to any one of items 1 to 12, substantially free of water and / or preservatives and / or surfactants, preferably free of water and / or preservatives and surfactants, and more preferably free of water and preservatives and surfactants. 14. A pharmaceutical composition for use as described in any one of items 1 to 13, comprising approximately 0.0030 to 0.0045% (w / v) of tafluprost. 15. a) a pharmaceutical composition for use according to any one of items 1 to 14, comprising at least 99% (w / w) of 1-perfluorobutyl-pentane (CF3(CF2)3-(CH2)4CH3(F4H5)) and / or 1-perfluorohexyl-octane (CF3(CF2)5-(CH2)7CH3(F6H8)) based on the total weight of the composition, and b) tafluprost dissolved in a liquid vehicle containing a solubilizer, preferably ethanol. 16. a) a pharmaceutical composition for use according to any one of items 1 to 15, comprising at least 99% (w / w) of 1-perfluorohexyl-octane (CF3(CF2)5-(CH2)7CH3(F6H8)) based on the total weight of the composition, and b) tafluprost dissolved in a liquid vehicle, preferably essentially ethanol, as a solubilizer. 17. A pharmaceutical composition for use in methods of preventing or treating glaucoma, elevated intraocular pressure, ocular hypertension, or related symptoms, comprising tafluprost and a partially fluorinated alkane. 18.1 The composition for use according to item 17, wherein the amount of tafluprost administered in a single dose per eye is in the range of about 0.20 to about 0.55 μg, preferably in the range of about 0.25 to 0.35 μg, and more preferably in the range of about 0.30 to 0.35 μg. 19.1 A composition for use as described in item 17 or 18, wherein the target dose volume per eye is about 8 to about 15 μl, preferably about 10 to 12 μl. 20. A composition for use according to any one of items 17 to 19, further comprising a solubilizer, preferably ethanol. 21. The composition for use according to item 20, wherein the solubilizer is contained in an amount of up to 1.5% (v / v) relative to the total volume of the composition, preferably up to 1.0% (v / v) relative to the total volume of the composition. 22. A composition for use according to any one of items 17 to 21, wherein the partially fluorinated alkane is selected from 1-perfluorohexyl-octane and 1-perfluorobutyl-pentane, preferably 1-perfluorohexyl-octane. 23. A composition for use according to any one of items 17 to 22, administered once daily. 24. A composition for use according to any one of items 17 to 23, substantially free of water and / or preservatives and / or surfactants, preferably free of water and / or preservatives and surfactants, and more preferably free of water and preservatives and surfactants. 25. A kit comprising a pharmaceutical composition for use as described in any one of items 1 to 24, the kit comprising a container for holding the pharmaceutical composition and a drop dispenser for administering the composition. 26. The kit according to item 25, wherein the container and drop dispenser for holding the pharmaceutical composition are adapted to administer the composition in a volume of about 8 to 15 μl per drop, preferably 10 to 12 μl per drop, and more preferably 11 μl per drop. 27. A method for treating glaucoma, elevated intraocular pressure, ocular hypertension, or related symptoms, comprising administering a composition comprising tafluprost and a partially fluorinated alkane to the eye of a subject having glaucoma, elevated intraocular pressure, ocular hypertension, or related symptoms, wherein the tafluprost is preferably dissolved in the partially fluorinated alkane, and the method is therapeutically effective in treating glaucoma, elevated intraocular pressure, ocular hypertension, or related symptoms. 28.1 The method according to item 27, wherein the amount of tafluprost administered as a single dose per eye is about 0.20 to about 0.55 μg, preferably about 0.30 to about 0.50 μg, and more preferably about 0.30 to about 0.45 μg. 29. The method according to item 27 or 28, wherein the composition comprises tafluprost at a concentration of about 0.0020 to 0.0050% (w / v), preferably about 0.0030 to 0.0045% (w / v), and more preferably about 0.0030 to about 0.0040% (w / v). 30. The method according to any one of items 27 to 29, wherein the target dose volume per eye of the composition is about 10 to about 12 μl, preferably about 11 μl. 31. The method according to any one of items 27 to 30, wherein the composition further comprises a solubilizer, preferably ethanol as a solubilizer. 32. The method according to item 31, wherein the solubilizer is present in an amount of up to 1.5% (v / v) of the total volume of the composition, preferably up to 1% (v / v) of the total volume of the composition. 33.1 The method according to any one of items 27 to 32, wherein the tafluprost administered as a single dose per eye is about 0.30 to 0.35 μg, preferably 0.33 μg. 34. The method according to any one of items 27 to 33, wherein the partially fluorinated alkane is selected from 1-perfluorohexyl-octane and 1-perfluorobutyl-pentane, preferably 1-perfluorohexyl-octane. 35. The method according to any one of items 27 to 34, wherein the composition is administered once daily. 36. The method according to any one of items 27 to 35, wherein the pharmaceutical composition comprises tafluprost dissolved in a solution of about 99% (v / v) 1-perfluorohexyl-octane and about 1% (v / v) ethanol. 37. The method according to any one of items 27 to 36, wherein the pharmaceutical composition comprises tafluprost dissolved in a solution of about 99% (v / v) 1-perfluorohexyl-octane and up to 1% (v / v) ethanol. 38. The method according to any one of items 27 to 37, wherein the target dose volume per eye of the composition is 11 μl. 39. A method for reducing the total daily dose of tafluprost administered to a human for the treatment of glaucoma, elevated intraocular pressure, ocular hypertension, or related conditions, comprising administering to the human eye once daily a composition comprising tafluprost and a partially fluorinated alkane, wherein the amount of tafluprost administered in a single dose per eye is about 0.30 to 0.40 μg, the method reduces the amount of tafluprost per total daily dose by up to about 34%, and is at least as therapeutically effective as administering one drop of 0.0015% (w / v) aqueous tafluprost solution per eye daily in the treatment of glaucoma, elevated intraocular pressure, ocular hypertension, or related conditions. 40. A method for reducing the total daily dose of tafluprost administered to a human for the treatment of glaucoma, elevated intraocular pressure, ocular hypertension or related conditions, as described in item 39, wherein one drop of the composition has a drop volume of about 11 μl, and one drop of the 0.0015% (w / v) tafluprost aqueous solution has a drop volume of about 30 μl. 41. A method for reducing the total daily dose of tafluprost administered to a human for the treatment of glaucoma, elevated intraocular pressure, ocular hypertension or related conditions, as described in item 39 or 40, which reduces systemic exposure to tafluprost compared to daily administration of one drop of 0.0015% (w / v) tafluprost aqueous solution. 42. The kit according to item 25 or 26, wherein the container and the drop dispenser are adapted to administer a single dose or multiple doses of the pharmaceutical composition. 43. The kit according to item 42, wherein the drop dispenser is adapted to administer a single dose of the pharmaceutical composition. 44. The kit according to item 42 or 43, wherein the container is adapted to hold multiple doses of the pharmaceutical composition.

[0093] The following examples illustrate the present invention, but should not be understood as limiting the scope of the invention. [Examples]

[0094] (Example 1) The studies described below were conducted to assess the pharmacokinetics of tafluprost (intraocular pressure, IOP) and to evaluate the pharmacokinetics of tafluprost in aqueous humor after repeated topical ocular administration of tafluprost in 1-perfluorohexyloctane (F6H8) in dogs with normal blood pressure. Dogs are a suitable species for evaluating the intraocular distribution and pharmacokinetics of prostaglandin analogs, and this model can also provide quantitative pharmacokinetic data.

[0095] Research setup: Animals were selected to participate in the study based on their overall health status, weight, ophthalmic examination results, response to IOP loading, and the following criteria. - A healthy and normal surface of the eyeball; - No invasive procedures on the eyeball have been performed for at least one month prior to the study; in particular, procedures that generally involve the cornea or anterior segment of the eye; - No topical or systemic corticosteroid treatment has been administered for at least one month; - Washout from previous topical ophthalmic investigational agents, commensurate with a typical washout period (at least one week) used in clinical trials.

[0096] Research design: The study was conducted according to the plan outlined in Table 1 below. A local ocular dose (11 or 30 μl, respectively) was administered via micropipette to the central or upper part of the cornea and spread across the entire surface of the eye. After administration, the animals were allowed to close their eyes naturally. Each animal was restrained for approximately one minute to prevent eye rubbing.

[0097] Table 1: JPEG0007855312000001.jpg37164d Day IOP (Intraocular Pressure) OD right eye OS left eye QD once a day

[0098] The preparation of a composition containing 0.0030% (w / v) tafluprost in F6H8 containing 1% (v / v) ethanol, as used in the test of Example 1, is described herein. 0.030 mg of tafluprost (CAS number: 209860-87-7, manufactured by Yonsung Fine Chemicals Co.) is dissolved in 0.00791 g of ethanol (99.9%) mixed with 1.3221 g of F6H8 to obtain a solution with a tafluprost concentration of 0.0030% (w / v).

[0099] Intraocular pressure was measured in all animals at 0 (immediately before administration), 2, 4, and 6 hours after administration on days 1, 2, 3, 6, and 7, and at -1, 0 (immediately before administration), 1, 2, 4, 6, 24, and 48 hours after administration on day 8. Three readings were taken per eye using TonoVet.

[0100] Research analysis: As shown in Figures 1 and 2, in a direct comparison of tafluprost at 30 μg / ml in 1% (v / v) ethanol and F6H8 with taflotane®, administration of a tafluprost F6H8 solution (target dose level 0.33 μg / eye, target dose volume 11 μl / eye) showed an IOP reduction comparable to that achieved by instilling taflotane® (target dose level 0.45 μg / eye, target dose volume 30 μl / eye). The experimental data demonstrate that by using the composition according to the present invention, it is possible to achieve an IOP reduction comparable to that of the gold standard taflotane®, even when using a lower target dose of the active ingredient. By using the pharmaceutical composition according to the present invention, for example, it is possible to reduce the amount of tafluprost instilled into the eye by up to approximately 27%. Furthermore, since a smaller target dose can be administered, for example in a volume of 11 μl, that is, a volume considerably smaller than 30 μl, the amount of composition that is excreted or taken up systemically can be reduced.

Claims

1. A pharmaceutical composition for use in a method of treating glaucoma, elevated intraocular pressure, and / or ocular hypertension, comprising 0.0030% (w / v) tafluprost dissolved in a liquid vehicle essentially consisting of at least 99% (w / w) 1-perfluorohexyloctane and a solubilizer, wherein a single dose of 0.30 μg to 0.35 μg of tafluprost per eye is administered to the target eye once daily, the solubilizer being ethanol, and the pharmaceutical composition containing neither water nor preservatives.

2. The pharmaceutical composition for use according to claim 1, wherein the pharmaceutical composition is administered to the eye of a patient in a single dose of 0.33 μg of tafluprost per eye.

3. The pharmaceutical composition for use according to claim 1 or 2, wherein the pharmaceutical composition is administered in a dose volume of 11 μl per eye.

4. A kit for use in a method for treating glaucoma, elevated intraocular pressure, and / or ocular hypertension, comprising a pharmaceutical composition according to any one of claims 1 to 3, the kit comprising a container for holding the pharmaceutical composition and a drop dispenser adapted for dispensing 9 to 14 μl of the pharmaceutical composition per drop.

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