Ophthalmic compositions containing latanoprost for use in treating eye diseases

Abstract

The present invention provides a pharmaceutical composition for use in the prevention or treatment of glaucoma, elevated intraocular pressure, ocular hypertension and / or symptoms related thereto, comprising: latanoprost and a liquid vehicle comprising a semi-fluorinated alkane; administered to a subject's eye; and the amount of latanoprost administered in a single dose per eye is in the range of approximately 0.5 to 1.4 μg. [Selection diagram] None

Description

[Technical Field]

[0001] The present invention relates to the field of medical therapy. More specifically, the present invention relates to the treatment of diseases and conditions affecting the eye, such as glaucoma, elevated intraocular pressure, ocular hypertension and / or symptoms related thereto. [Background technology]

[0002] Elevated intraocular pressure is a frequent disorder of the eye, often accompanied by optic nerve damage, in which case the disease is called glaucoma. In the absence of optic nerve damage, the condition is called ocular hypertension.

[0003] Normal intraocular pressure is usually defined as a range of 10–21 mmHg. Pressure results primarily from the balance between the eye's aqueous humor production and drainage rates. This is further influenced by corneal thickness and stiffness. Intraocular pressure typically fluctuates around 15–16 mmHg, with an amplitude of up to 6 mmHg. For example, intraocular pressure typically decreases at night due to decreased aqueous humor production. Intraocular pressure also responds to various physiological factors, such as exercise, heart rate, breathing, water intake, and certain systemic or topical medications.

[0004] Aqueous humor is produced by the ciliary body of the eye and flows into the posterior chamber. Its composition is very similar to that of plasma, but differs from plasma in that it has a lower protein content. Its main components are water (99%), electrolytes (inorganic ions that maintain physiological pH), small amounts of albumin and beta-globulin, ascorbate, glucose, lactate, and amino acids.

[0005] Aqueous humor is distributed from the posterior chamber of the eye through the pupil of the iris to the anterior chamber. From here, aqueous humor flows through the trabecular meshwork, a spongy tissue region lined by trabeculocytes whose primary function is to drain aqueous humor into a series of canals called Schlemm's canal, where it enters the blood circulation. Aqueous humor flow from the trabecular meshwork to Schlemm's canal occurs via two distinct routes: directly via aqueous veins to episcleral veins, or indirectly via collector channels via intrascleral plexuses to episcleral veins. This trabecular outflow route accounts for the majority of drained aqueous humor. Furthermore, there is a second major drainage route, the uveoscleral outflow, which is relatively independent of intraocular pressure and typically accounts for only 5–10% of aqueous humor drainage in healthy individuals.

[0006] Various prostanoid receptors have been found in both the trabecular meshwork and uveoscleral tissues, indicating that prostanoids are involved in regulating aqueous humor production and / or drainage, thereby affecting intraocular pressure. Genes encoding the EP, FP, IP, DP, and TP receptor families are expressed in the trabecular meshwork, whereas the EP and FP receptor families predominate in the uveoscleral tissues (Toris et al., Surv Ophthalmol. 2008;53, Suppl. 1, S107-S120).

[0007] Prostanoids are physiological fatty acid derivatives that represent a subclass of eicosanoids. They include prostaglandins, prostamides, thromboxanes, and prostacyclins, all of which are mediators involved in numerous physiological processes. PGF 2αNatural prostaglandins, such as PGE2, PGD2, and PGI2, exhibit specific affinity for their respective receptors (FP, EP, DP, IP), but also have some nonselective affinity for other prostaglandin receptors (ibid.). Prostaglandins also have direct effects on matrix metalloproteinases, which are neutral proteinases expressed in the trabecular meshwork and play a role in regulating aqueous humor outflow resistance by degrading the extracellular matrix.

[0008] Several prostaglandin analogues, such as latanoprost, bimatoprost, tafluprost, travoprost, and unoprostone, have been shown to be effective topically in reducing intraocular pressure. Some experts consider bimatoprost to be a prostamide rather than a prostaglandin derivative.

[0009] Latanoprost, travoprost, tafluprost, and possibly bimatoprost are also potent and selective PGF 2α These drugs are agonists. Their net effect is a reduction in intraocular pressure, primarily due to a substantial increase in aqueous humor drainage via the uveoscleral pathway. Presumably, they also increase trabecular outflow to some extent.

[0010] Various eye drop formulations containing prostaglandin analogs have been developed and are commercially available. Latanoprost and travoprost are provided as buffered, isotonic, and preserved aqueous solutions in multidose bottles with strengths of 50 μg / mL (0.005%) and 40 μg / mL (0.004%), respectively. Tafluprost is available in a similar preserved formulation as well as a non-preserved formulation in a single-dose container. Tafluprost formulations have a strength of 15 μg / mL (0.0015%) and further contain the surfactant polysorbate 80. Bimatoprost is also commercially available as a buffered, isotonic, and preserved aqueous solution; its strength is 0.3 mg / mL (0.03%). The commercially available unoprostone formulation has a strength of 1.5 mg / mL (0.15%) and contains a buffer, preservative, isotonicity agent, and polysorbate 80.

[0011] However, preserved aqueous ophthalmic formulations have the disadvantage of potentially causing irritation or hypersensitivity reactions, especially with long-term use, such as in glaucoma treatment. The most common preservative in these formulations is benzalkonium chloride, a quaternary ammonium compound associated with frequent irritant toxic reactions. Non-preserved single-use containers avoid this drawback but are expensive. Not only do they require a separate container for each single dose, but they also require overfilling of the formulation (meaning a significant portion, if not most, of the actual medication remains in the container and is excreted as waste). Considering the medication actually administered to the eye, only a portion is effective due to the limited volume capacity of the lacrimal sac: a significant portion of the administered fluid volume is expelled by blinking of the eyelid, and another portion is absorbed systemically via the nasolacrimal duct, potentially resulting in adverse drug reactions.

[0012] Despite the preservatives contained in currently available latanoprost formulations, there have been reports of bacterial keratitis caused by microbiological contamination of the product, likely by the patient, suggesting that the microbiological safety of the product is only relative.

[0013] Xalatan® (latanoprost) 0.005% ophthalmic solution and related names have been approved in several EU member states since 1996 for the relief of elevated intraocular pressure in adult patients with open-angle glaucoma and ocular hypertension. Xalatan is a sterile, isotonic, buffered aqueous solution of latanoprost at a concentration of 50 μg / mL. Each drop of the solution contains approximately 1.5 μg of latanoprost and is intended for topical administration to the eye. Xalatan is supplied in a 5 mL plastic ophthalmic dispenser bottle containing 2.5 mL of Xalatan, equivalent to approximately 80 drops of solution. Each mL of Xalatan contains 50 μg of latanoprost and also contains water for injection and benzalkonium chloride as a preservative. The recommended daily dose for adults is one drop (equivalent to approximately 1.5 μg of latanoprost) administered to one or both affected eyes, with optimal efficacy achieved when administered at night.

[0014] WO 2011 / 113855 discloses a pharmaceutical composition for treating elevated intraocular pressure based on semifluorinated alkanes, which are useful as carriers for a wide range of active ingredients. Preferred active ingredients include poorly water-soluble prostaglandin analogs, such as latanoprost, bimatoprost, tafluprost, travoprost, and unoprostone. The composition can be administered topically to the eye.

[0015] It is an object of the present invention to provide novel pharmaceutical compositions useful in methods for preventing or treating glaucoma, elevated intraocular pressure, ocular hypertension, or related conditions, which overcome at least one of the limitations or drawbacks associated with prior art formulations. In a specific embodiment, it is an object of the present invention to provide ophthalmic compositions capable of incorporating significant amounts of poorly water-soluble active ingredients 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]

[0016] [Patent Document 1] International Publication No. 2011 / 113855 Brochure [Non-patent literature]

[0017] [Non-Patent Document 1] Toris et al.,Surv Ophthalmol.2008;53,Suppl.1,S107-S120 Summary of the Invention

[0018] 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 conditions related thereto, comprising: comprising latanoprost and a liquid vehicle comprising a semi-fluorinated alkane; -Administered to the subject's eye; The amount of latanoprost administered in a single dose per eye ranges from approximately 0.5 to 1.4 μg. It relates to a composition. In a further aspect, the present invention provides a kit comprising a pharmaceutical composition for use according to the first aspect of the invention, the kit comprising a container for holding the pharmaceutical composition and a drop dispenser for administering the composition. [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 shows the results of two experimental animal studies (dogs), further outlined below, that investigated the pharmacodynamics of latanoprost on intraocular pressure (IOP) following repeated topical ocular administration. [Figure 2] FIG. 1 shows the results of a head-to-head comparison of a composition comprising latanoprost in F6H8 administered to the right eye (OD) of a test animal with Xalatan® administered to the left eye (OS) of the same test animal. DETAILED DESCRIPTION OF THE INVENTION

[0020] 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 conditions related thereto, comprising: comprising latanoprost and a liquid vehicle comprising a semi-fluorinated alkane; -Administered to the subject's eye; The amount of latanoprost administered in a single dose per eye ranges from approximately 0.5 to 1.4 μg. It relates to a composition.

[0021] The pharmaceutical compositions according to the present invention are useful for treating or preventing glaucoma and / or symptoms associated therewith, such as those described below. Glaucoma, as understood herein, is a term for an eye condition that can damage the optic nerve and lead to blindness. The main division in classifying different types of glaucoma is open-angle glaucoma and angle-closure (or angle-closure) glaucoma. Open-angle refers to an angle where the iris meets the cornea that is wide and open, as it should be, allowing fluid to drain from the inside of the eye, thereby relieving internal pressure. If this angle is narrowed or closed, pressure increases, which can ultimately damage the optic nerve and lead to blindness.

[0022] The pharmaceutical composition according to the present invention is also useful for treating or preventing elevated 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 primary cause of damage to the optic nerve and is characterized by excessive fluid pressure within the eye, which can be due to a variety of reasons, including blockage of the drainage canal and narrowing or closure of the angle between the iris and the cornea. Elevated IOP is a major risk factor for visual field loss due to glaucoma. The higher the IOP level, the greater the likelihood of optic nerve damage and visual field loss.

[0023] Furthermore, the pharmaceutical compositions according to the present invention are useful for treating or preventing ocular hypertension and / or symptoms associated therewith, such as those described below. The term ocular hypertension, as understood herein, refers to the presence of elevated fluid pressure within the eye, usually without optic nerve damage or visual field loss. Elevated intraocular pressure is a significant risk factor for glaucoma. For most people, the normal range of intraocular pressure is 10 mmHg to 21 mmHg. Therefore, most people with consistently elevated intraocular pressure above 21 mmHg, especially in the presence of other risk factors, are typically treated to prevent ongoing glaucoma-related blindness that may result from ocular hypertension. Ocular hypertension can be considered the result of an imbalance between fluid entering the eye through the ciliary body and fluid exiting the eye through the trabecular meshwork.

[0024] The composition for use according to the present invention comprises a compound of empirical formula C 26 H 40 It contains the active ingredient latanoprost, which has an O5 and molecular weight of 432.593 g / mol (CAS number 130209-82-4). Latanoprost is an ester prodrug that is activated to the free acid in the cornea. It is a prostaglandin F2α analog, more specifically, a prostanoid-selective FP receptor agonist that is thought to reduce intraocular pressure (IOP) by increasing aqueous humor outflow. Animal and human studies suggest that the primary mechanism of action is increased uveoscleral outflow.

[0025] In a preferred embodiment, the pharmaceutical composition for use according to the invention comprises about 0.005% to about 0.015% (w / v) latanoprost, more preferably about 0.008% to about 0.015% (w / v), and most preferably about 0.008% to about 0.012% (w / v) of the active compound latanoprost. In another preferred embodiment, the pharmaceutical composition for use according to the invention comprises about 0.010% (w / v) of the active ingredient latanoprost.

[0026] Unless otherwise indicated, the term "% (w / v)" used throughout this specification in connection with the pharmaceutical composition refers to the amount of a component of the composition (e.g., latanoprost, etc.) as a weight percent relative to the total volume of the composition ("w" refers to weight, and "v" refers to volume). For example, 0.05% (w / v) can be understood to relate to 0.5 mg of a component in 1 mL of the composition, and 0.1% (w / v) would correspond to 1.0 mg of a component in 1 mL of the composition. Unless otherwise indicated, the term "% (w / w)" refers to the amount of a component of the composition as a weight percent relative to the total weight of the composition ("w" refers to weight).

[0027] The term "about" as used herein and in relation to parameters such as, for example, the concentration of latanoprost dissolved in a composition or the amount of latanoprost characterized in a single dose of the composition, includes the exact value defined as well as any value that falls within the degree of variation normally observed when measuring or determining these parameters using standard techniques and equipment known in the art and in the field.

[0028] The pharmaceutical composition according to the present invention further comprises a liquid vehicle containing a semi-fluorinated alkane. The active ingredient latanoprost can be dissolved or suspended, preferably dissolved, in a liquid vehicle containing the semi-fluorinated alkane described below. The terms "semi-fluorinated alkane" or "SFA", which are used interchangeably throughout this specification, refer to a compound consisting of a perfluorocarbon segment linked to a non-fluorinated hydrocarbon segment. Both segments may be branched or linear. However, preferably, both segments are unbranched linear segments.

[0029] In a preferred embodiment, the liquid vehicle of the pharmaceutical composition comprises a semi-fluorinated alkane or a mixture of two or more different semi-fluorinated alkanes, however, preferably the liquid vehicle of the pharmaceutical composition comprises only one semi-fluorinated alkane.

[0030] In the present invention, preferred semi-fluorinated alkanes are those of the general formula (I): CF3(CF2) n (CH2) m CH3(I), (wherein the formula, the coefficient n is an integer selected from 3 to 5, and m is an integer selected from 4 to 7) It is of the type.

[0031] Alternative nomenclature for certain semi-fluorinated alkanes, shown below in parentheses and which may be used further herein, is based on the general formula FHm, where F denotes a linear perfluorinated hydrocarbon segment, H denotes a linear non-fluorinated hydrocarbon segment, and n and m are the number of carbon atoms in each segment. For example, FHs may be used to denote 1-perfluorobutyl-pentane or CF(CF)-(CH)CH (alternatively, it may also be represented by the formula F(CF)(CH)H), which has a linear perfluorinated segment F with four carbons (n=4) and a linear non-fluorinated hydrocarbon segment with five carbons (m=5). Additionally, F6H8 can be used to represent 1-perfluorohexyl-octane or CF3(CF2)5-(CH2)7CH3 (alternatively, it can also be represented by the formula F(CF2)6(CH2)8H), which has a linear perfluorinated segment F with six carbons (n=6) and a linear non-fluorinated hydrocarbon segment with eight carbons (m=8).

[0032] Thus, the semi-fluorinated alkanes used in the compositions of the present invention are 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), CF3(CF2)4-(CH2) More preferably, the semi-fluorinated alkane may be selected from CF(CF)-(CH)CH(F4H5) and CF(CF)-(CH)CH(F6H8).

[0033] In a preferred embodiment, the pharmaceutical composition for use according to the invention comprises a semi-fluorinated alkane of formula (I) selected from 1-perfluorohexyl-octane (CF(CF)-(CH)CH(FH)) and 1-perfluorobutyl-pentane (CF(CF)-(CH)CH(FH)). In a particularly preferred embodiment of the invention, the semi-fluorinated alkane of formula (I) is 1-perfluorohexyl-octane (CF(CF)(CH)CH,(FH)).

[0034] The liquid SFAs mentioned above are chemically and physiologically inert, colorless, and stable. Their typical density is 1.1-1.7 g / cm. 3 and their surface tensions can be as low as 19 mN / m. FnHm-type SFAs are insoluble in water but are also somewhat amphiphilic, with increasing lipophilicity correlating with increasing size of the non-fluorinated segment.

[0035] The present inventors have discovered that SFA is particularly suitable as a carrier or vehicle for ophthalmic compositions.This is based on the fact that SFA is unexpectedly well tolerated by the eye, as shown in preclinical studies.This is very surprising, because organic solvents or non-aqueous solvents, except perhaps oily compounds, are typically very irritating or even very harmful when administered to the eye.

[0036] A pharmaceutical composition or liquid vehicle of the present invention comprising "a" semi-fluorinated alkane should be understood herein to comprise at least one semi-fluorinated alkane of formula (I) above. However, in some cases, the composition or liquid vehicle may comprise two or more, e.g., two or more semi-fluorinated alkanes of formula (I), i.e., a mixture of any one of the above semi-fluorinated alkane species.

[0037] In yet another embodiment, the liquid vehicle of the pharmaceutical composition may consist of a semi-fluorinated alkane of formula (I) as specified above. In this context, the term "a" semi-fluorinated alkane should be understood as at least one semi-fluorinated alkane, but may also include two or more, or multiple, semi-fluorinated alkane compound options. Thus, in one embodiment, the liquid vehicle may consist of two or more semi-fluorinated alkanes of formula (I) as specified above.

[0038] As used herein, the term "consists of" and related terms such as "consisting of" or "consist" should be understood to mean the absence of other features other than those preceded by the term. In the context of a composition, if other components or ingredients other than those preceded by such terms are present in the composition, they will be present only in trace or residual amounts that do not confer any technical advantage or relevance for the purposes of the present invention, and may be further understood, for example, by the terms "essentially" or "substantially" used in conjunction with these terms (e.g., "essentially consisting of"). It should be understood that isomeric or olefinic impurities that originate from the synthesis of the semifluorinated alkane and cannot be quantitatively removed during purification and therefore are present only in trace or residual amounts and that do not confer any technical advantage or relevance for the purposes of the present invention fall within the above definition of such other components or ingredients. In contrast, the term "comprising" or related terms such as "comprises" or "comprise" in the context of the present compositions should be understood to mean that other features may be present in the composition besides the one preceded by the term.

[0039] In a further embodiment, the liquid vehicle of the pharmaceutical composition defined in any of the preceding embodiments preferably comprises a semi-fluorinated alkane, or optionally a mixture of semi-fluorinated alkanes, in an amount of at least 70% (w / w), 75% (w / w), 85% (w / w), 90% (w / w), 95% (w / w), 98% (w / w), 98.5% (w / w), 99% (w / w), 99.5% (w / w), 99.8% (w / w), or at least 99.9% (w / w) based on the total weight of the liquid vehicle. In a preferred embodiment of the invention, the liquid vehicle comprises at least 97.5% (w / w) of a semi-fluorinated alkane based on the total weight of the liquid vehicle.

[0040] As used herein, unless otherwise indicated, the term "% (w / w)" refers to the amount of a component of the composition as a weight percentage relative to the total weight of the liquid vehicle of the pharmaceutical composition (where "w" indicates weight).

[0041] In yet further embodiments of the present invention, the liquid vehicle preferably comprises a semi-fluorinated alkane, or optionally a mixture of the above semi-fluorinated alkanes, in an amount of about 90% (w / w) to about 99.9% (w / w), more preferably about 95% (w / w), 97% (w / w), or 97.5% (w / w) to about 99.5% (w / w), based on the total weight of the liquid vehicle. In the most preferred embodiments of the present invention, the liquid vehicle comprises a semi-fluorinated alkane in an amount of about 97.5% (w / w) to about 99.5% (w / w), based on the total weight of the liquid vehicle.

[0042] In a further embodiment, the pharmaceutical composition, more particularly the liquid vehicle of the pharmaceutical composition, may further comprise a solubilizing agent.The term "solubilizing agent" as used herein refers to a compound or a combination of compounds that enhances or promotes the solubility of the active ingredient latanoprost in a selected liquid vehicle, including the above-mentioned semi-fluorinated alkane.In a preferred embodiment, as already mentioned above, latanoprost is completely dissolved in a liquid vehicle, including the semi-fluorinated alkane and optionally a solubilizing agent.

[0043] The solubilizer, which may optionally be included in the liquid vehicle of the pharmaceutical composition, may be present in an amount of preferably up to 3% (w / w), or preferably up to 2.5% (w / w), based on the total weight of the liquid vehicle. In a preferred embodiment, the liquid vehicle contains a low amount of solubilizer, up to 1% (w / w), preferably up to 0.5% (w / w), based on the total weight of the liquid vehicle. In another preferred embodiment, the liquid vehicle further contains a solubilizer in an amount of about 2.5% to 0.5% (w / w), preferably about 1% to 0.5% (w / w), based on the weight of the liquid vehicle.

[0044] In some embodiments, the solubilizer may be a liquid excipient such as an organic cosolvent and / or oil selected from, for example, glyceride oils, liquid waxes and liquid paraffins, or an organic solvent that exhibits a high degree of biocompatibility.

[0045] Examples of potentially useful liquid excipients include oily excipients that can be used in combination with one or more SFAs, including triglyceride oils, mineral oils, medium-chain triglycerides (MCTs), oily fatty acid isopropyl myristate, oily fatty alcohols, esters of sorbitol and fatty acids, oily sucrose esters, or any other substance physiologically acceptable to the eye. In a preferred embodiment, the liquid vehicle contains a solubilizer in the form of a liquid excipient. In this case, it is even more preferred that the liquid excipient is MCT, preferably at a concentration of up to 3% (w / w), more preferably up to 2.5% (w / w), based on the total weight of the liquid vehicle.

[0046] Another example of a potentially useful solubilizer used herein is an organic solvent.Preferred organic solvents include glycerol, propylene glycol, polyethylene glycol and ethanol.In a preferred embodiment, the liquid vehicle of the composition can contain diethylene glycol monoethyl ether (DEGEE) as a solubilizer, preferably in an amount of up to 1.5% (w / w), more preferably up to 1% (w / w) based on the weight of the liquid vehicle of the pharmaceutical composition.

[0047] In an even more preferred embodiment, the liquid vehicle of the pharmaceutical composition may comprise ethanol as a solubilizing agent, preferably in an amount of up to 1% (w / w), more preferably up to 0.8% (w / w), and most preferably up to 0.5% (w / w) by weight of the liquid vehicle of the pharmaceutical composition.

[0048] Therefore, in a preferred embodiment, the liquid vehicle of the pharmaceutical composition further comprises a solubilizer, preferably selected from ethanol, MCT, and DEGEE.

[0049] Pharmaceutical compositions for use according to the invention may or may not contain further excipients such as, for example, preservatives, more particularly preservatives and / or surfactants, however, in a preferred embodiment, the pharmaceutical compositions according to the invention are substantially free of preservatives.

[0050] In a preferred embodiment, the pharmaceutical composition for use according to the present invention is substantially free of water. As understood herein, the terms "substantially free" or "essentially free" in relation to a composition component refer to the presence of no more than trace amounts of said component, whereby when present in trace amounts, the component does not technically contribute to the composition.

[0051] In a still further preferred embodiment, the pharmaceutical composition for use according to the invention is substantially free of water and preservatives.

[0052] In a particularly preferred embodiment, the pharmaceutical composition for use according to the present invention comprises latanoprost dissolved in a liquid vehicle consisting essentially of at least 99% (w / w) 1-perfluorobutyl-pentane (CF3(CF2)3-(CH2)4CH3(F4H5)) or 1-perfluorohexyl-octane (CF3(CF2)5-(CH2)7CH3(F6H8)) and up to 1% (w / w) ethanol based on the total weight of the liquid vehicle.

[0053] In a further preferred embodiment, the pharmaceutical composition for use according to the present invention comprises latanoprost dissolved in a liquid vehicle consisting essentially of at least 99.5% (w / w) 1-perfluorobutyl-pentane (CF3(CF2)3-(CH2)4CH3(F4H5)) or 1-perfluorohexyl-octane (CF3(CF2)5-(CH2)7CH3(F6H8)) and up to 0.5% (w / w) ethanol based on the total weight of the liquid vehicle.

[0054] In a further preferred embodiment, the pharmaceutical composition for use according to the present invention comprises latanoprost dissolved in a liquid vehicle consisting essentially of at least 99.5% (w / w) 1-perfluorohexyl-octane (CF3(CF2)5-(CH2)7CH3(F6H8)) and up to 0.5% (w / w) ethanol based on the total weight of the liquid vehicle.

[0055] In a more preferred embodiment, the pharmaceutical composition for use according to the present invention consists essentially of latanoprost dissolved in a liquid vehicle consisting essentially of at least 99.5% (w / w) 1-perfluorohexyl-octane (CF3(CF2)5-(CH2)7CH3(F6H8)) and up to 0.5% (w / w) ethanol based on the total weight of the liquid vehicle.

[0056] As outlined above, the composition for use according to the present invention is preferably provided as a clear solution in which latanoprost is completely dissolved in the selected liquid vehicle.Furthermore, the composition for use according to the present invention is preferably provided in a sterile form.

[0057] The pharmaceutical composition for use according to the present invention, comprising latanoprost and a liquid vehicle comprising a semi-fluorinated alkane, may be administered to the eye of a subject either topically or by subconjunctival injection. However, in a preferred embodiment, the pharmaceutical composition for use according to the present invention is administered to the eye of a subject topically.

[0058] The term "topically administered" as used herein includes all possible administration methods that allow the liquid pharmaceutical composition to contact the surface of a subject's eye. Typically, the pharmaceutical composition can be administered to the subject's eye in the form of one or more drops or droplets. The droplets can be administered to the surface of the eye, preferably any surface area or tissue of the eye that is accessible to topical administration or instillation, such as the cornea or conjunctiva. The droplets or droplets of the composition can be instilled directly onto the surface of the eye, such as the corneal surface of the eye, or into the space, i.e., the capsule or pocket, formed by slowly pulling down the lower eyelid of the eye.

[0059] The term "subconjunctival injection" as used herein refers to any form of injection of the pharmaceutical composition of the present invention under the conjunctiva of the subject's eye. This may include injection of the pharmaceutical composition using a suitable syringe. The term subconjunctival injection may also include injection using a medical device or insert inserted under the conjunctiva, for example, through an opening created in the conjunctiva.

[0060] As used herein, the term "administration to an eye" or "per eye" refers to a given administration, e.g., a single administration, of a pharmaceutical composition for use according to the present invention to each individual eye of a subject. However, it should be understood that the treatment of ocular diseases, i.e., glaucoma, elevated intraocular pressure, ocular hypertension and / or symptoms associated therewith, described herein is not limited to treatment of one eye in a subject, but also includes therapy involving administration of a composition for use according to the present invention to each eye, i.e., both eyes, of a subject suffering from said disease.

[0061] As used herein, the term "subject" refers to a human or animal suffering from, diagnosed with, or at risk of developing glaucoma, elevated intraocular pressure, ocular hypertension, and / or their associated conditions, but preferably a human.

[0062] The pharmaceutical composition for use according to the present invention, comprising latanoprost and a liquid vehicle comprising a semi-fluorinated alkane, is further characterized in that the amount of latanoprost administered in a single dose per eye is in the range of about 0.5 to 1.4 μg. However, in a preferred embodiment, the amount of latanoprost administered in a single dose per eye is in the range of about 0.7 to 1.4 μg, preferably about 1.0 to 1.2 μg, and even more preferably about 1.1 μg.

[0063] Pharmaceutical compositions for use according to the present invention form small droplets (droplets). In a preferred embodiment of the present invention, the volume of composition administered in a single dose per eye, referred to herein as the "target dose volume per eye" of the composition, when administered from a suitable droplet dispenser, is in the range of about 6 to 28 μl, more preferably about 6 to 24 μl, and most preferably about 6 to 15 μl. In another preferred embodiment of the present invention, 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 about 9 to 14 μl, and most preferably about 10 to 12 μl. In a 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 latanoprost compositions, such as Xalatan, which are characterized by a droplet size of about 30 μl.

[0064] Thus, in a preferred embodiment, there is provided a pharmaceutical composition for use in the prevention or treatment of glaucoma, elevated intraocular pressure, ocular hypertension, and / or symptoms related thereto, the composition comprising latanoprost and a liquid vehicle containing a semi-fluorinated alkane; administered to a subject's eye; the amount of latanoprost administered in a single dose per eye is in the range of about 0.5 to 1.4 μg; and the amount of latanoprost administered in a single dose per eye is provided in a defined volume of the pharmaceutical composition (hereinafter referred to as the "target administration volume per eye of the composition"). In a further preferred embodiment, the target administration volume per eye of the composition (containing the amount of latanoprost administered in a single dose per eye) is 30 μl or less, preferably less than 25 μl, and more preferably less than 15 μl.

[0065] In a preferred embodiment of the present invention, a pharmaceutical composition for use according to the present invention comprises about 0.005% to 0.015% (w / v) latanoprost and a liquid vehicle comprising a semi-fluorinated alkane; the composition is administered to a subject's eye; and the amount of latanoprost administered in a single dose per eye is in the range of about 1.0 to 1.2 μg.

[0066] In another preferred embodiment of the present invention, a pharmaceutical composition for use according to the present invention comprises about 0.008% to 0.015% (w / v) latanoprost and a liquid vehicle comprising a semi-fluorinated alkane; the composition is administered to an eye of a subject; and the amount of latanoprost administered in a single dose per eye is in the range of about 1.0 to 1.2 μg.

[0067] In another preferred embodiment of the present invention, a pharmaceutical composition for use according to the present invention comprises about 0.008% to 0.012% (w / v) latanoprost and a liquid vehicle comprising a semi-fluorinated alkane; the composition is administered to an eye of a subject; and the amount of latanoprost administered in a single dose per eye is in the range of about 1.0 to 1.2 μg.

[0068] In a particularly preferred embodiment, the pharmaceutical composition for use according to the invention comprises about 0.008% to about 0.012% (w / v) latanoprost, with about 1.1 μg of latanoprost administered per eye in a single dose.

[0069] In another preferred embodiment, a pharmaceutical composition for use according to the present invention comprises about 0.010% (w / v) latanoprost and a liquid vehicle comprising a semi-fluorinated alkane, wherein the composition is administered to the subject's eye(s), wherein the amount of latanoprost administered per eye is about 1.1 μg and the target administration volume per eye is about 11 μl.

[0070] In a most preferred embodiment, a pharmaceutical composition for use according to the present invention comprises latanoprost and a liquid vehicle comprising a semi-fluorinated alkane, and the composition is administered to a subject's eye such that the amount of latanoprost administered in a single dose per eye ranges from about 1.0 to about 1.2 μg, and the target dose volume per eye ranges from about 6 to 24 μl, preferably about 6 to 15 μl, more preferably about 8 to 15 μl, even more preferably about 10 to 12 μl, and most preferably 11 μl.

[0071] Thus, in a preferred embodiment, the pharmaceutical composition for use according to the invention is administered once daily. In a more preferred embodiment, a single dose of the pharmaceutical composition for use according to the invention is administered as a single drop into the subject's eye.

[0072] Surprisingly, it has been found that the presence of the above-mentioned SFA as a component of the liquid vehicle allows the preparation of this pharmaceutical composition, which has a beneficial combination of a single dose of latanoprost and a target administration volume of the composition that is more advantageous than the above-mentioned known aqueous compositions.Specifically, it is possible to achieve a reduction in intraocular pressure comparable to that achieved by administering the commercially available composition Xalatan, which features a target administration of 1.5 μg per eye and a target administration volume of 30 μl per eye.As shown in Figure 2, for example, a composition with a target administration of 1.1 μg per eye shows a reduction in intraocular pressure comparable to that of Xalatan.In addition, another advantage of the pharmaceutical composition for use according to the present invention is that the composition can be administered at a target administration volume that is significantly lower than that of Xalatan.

[0073] By way of example, in a preferred embodiment, the pharmaceutical composition for use according to the present invention is characterized by a fairly low volume of composition administered in a single dose per eye (target administration volume of the composition), such as from about 8 μl to about 15 μl, preferably from about 10 μl to about 12 μl, and more preferably about 11 μl.

[0074] Furthermore, one of the complications associated with the administration of aqueous compositions with significantly large droplet sizes is that usually only a small portion of the amount of aqueous composition topically administered to the ocular surface actually remains there.In many cases, a portion of the relatively large amount of aqueous composition immediately leaks from the ocular surface and is often wiped off.Therefore, to ensure that a therapeutically effective amount of latanoprost actually reaches the eye, an excess of composition is usually required.

[0075] On this basis, the pharmaceutical compositions for use of the present invention allow for a significant reduction in droplet size and the associated target administration volume, and therefore a significant reduction in the total daily amount of latanoprost administered for use in treating glaucoma, elevated intraocular pressure, ocular hypertension and / or conditions related thereto, as outlined above.

[0076] In a second aspect, the present invention provides a pharmaceutical composition according to the first aspect of the invention, namely for use in the prevention or treatment of glaucoma, elevated intraocular pressure, ocular hypertension and / or conditions related thereto, comprising: comprising latanoprost and a liquid vehicle comprising a semi-fluorinated alkane; -Administered to the subject's eye; The amount of latanoprost administered per eye in a single dose ranges from approximately 0.5 to 1.4 μg. The composition comprises: A kit is provided that includes a container for holding the pharmaceutical composition and a drop dispenser for administering the composition.

[0077] It should be understood that all of the embodiments detailed above in relation to the pharmaceutical composition for use according to the first aspect of the invention may be included in a kit according to this second aspect of the invention.

[0078] As understood herein, a droplet dispenser may be a dispenser or applicator means that can be attached to, secured to, or connected to a container for holding a pharmaceutical composition. Preferably, the droplet dispenser is adapted to dispense a single dose in the form of one drop of a pharmaceutical composition according to the first aspect of the present invention. More preferably, the droplet dispenser is adapted to dispense a single dose of about 8 μl to about 15 μl volume, preferably about 10 μl to about 12 μl volume, and even more preferably a single dose of about 11 μl volume.

[0079] Containers for holding pharmaceutical compositions as understood herein are preferably of a volume capable of holding a single dose, but more preferably of a volume capable of holding multiple or multiple doses of the composition.

[0080] The container and / or the droplet dispenser may preferably be made from a thermoplastic material or polymer. In one embodiment, the container and / or the droplet dispenser is made from a thermoplastic material selected from polyethylene and polypropylene.

[0081] In one particular embodiment, the droplet dispenser is made of a polyethylene material, preferably selected from low-density polyethylene and high-density polyethylene, more preferably high-density polyethylene. In another embodiment, the container is made of a polypropylene or polyethylene material, more preferably polypropylene.

[0082] 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 a further embodiment, 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 fill volume, i.e., the volume of the pharmaceutical composition held in the container. For example, in a kit including a container with a total volume of 3.0 ml, the container preferably 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 would be about 0.7.

[0083] Such kits provided by these embodiments may improve the storage and dispensability (ie ease and consistency of dispensing) of pharmaceutical compositions according to the first aspect of the invention.

[0084] In a third aspect, the present invention refers to a method for treating or preventing glaucoma, elevated intraocular pressure, ocular hypertension and / or conditions related thereto, comprising the step of administering a composition comprising latanoprost and a liquid vehicle comprising a semi-fluorinated alkane to an eye of a subject, preferably a human having glaucoma, elevated intraocular pressure, ocular hypertension or conditions related thereto, wherein the amount of latanoprost administered in a single dose per eye is about 0.5 to 1.4 μg, and the method is therapeutically effective in treating glaucoma, elevated intraocular pressure, ocular hypertension and / or conditions related thereto.

[0085] In a fourth aspect, the present invention provides a pharmaceutical composition for use in a method for preventing or treating glaucoma, elevated intraocular pressure, ocular hypertension and / or conditions related thereto, the composition comprising latanoprost and a liquid vehicle comprising a semi-fluorinated alkane, the composition being therapeutically effective in treating or preventing glaucoma, elevated intraocular pressure, ocular hypertension and / or conditions related thereto when administered in a single dose of about 0.5 to 1.4 μg latanoprost per eye.

[0086] In a fifth aspect, the present invention relates to a method for reducing the total daily dose of latanoprost administered to a human being for treating glaucoma, elevated intraocular pressure, ocular hypertension and / or symptoms related thereto, comprising the step of administering to the human's eye once daily a composition comprising latanoprost and a liquid vehicle comprising a semi-fluorinated alkane, preferably latanoprost dissolved in an SFA, wherein the amount of latanoprost administered in a single dose per eye is about 0.5 to 1.4 μg, resulting in a reduction of the amount of latanoprost per total daily dose by about 67% to 7%, and wherein the amount of latanoprost administered in a single dose per eye is at least equally therapeutically effective in treating glaucoma, elevated intraocular pressure, ocular hypertension and / or symptoms related thereto compared to the daily administration of one drop per eye of an aqueous solution containing 0.005% (w / v) latanoprost.

[0087] In a preferred embodiment of the method according to this fifth aspect of the invention, one drop of said composition has a drop volume of about 11 μl and one drop of said 0.005% (w / v) aqueous latanoprost solution has a drop volume of about 30 μl.

[0088] In a further preferred embodiment of the method according to this fifth aspect of the invention, systemic exposure to latanoprost is reduced compared to the daily administration of one drop of a 0.005% (w / v) aqueous solution of latanoprost.

[0089] In an even more preferred embodiment of the method according to this fifth aspect of the invention, one or more adverse effects are reduced compared to the daily administration of one drop of a 0.005% (w / v) aqueous solution of latanoprost. The term "adverse effects" as used herein, according to its general meaning, refers to undesirable and harmful effects resulting from a drug, and in this particular case due to topical ocular administration of latanoprost, for example, blurred vision, burning and stinging, conjunctival injection, foreign body sensation, itching, increased pigmentation (brownness) of the iris causing (heterochromia), elongation and thickening of the eyelashes, punctate epithelial keratopathy, cold or upper respiratory tract infection, flu-like syndrome, dry eyes, excessive tearing, eye pain, eyelid crusting, eyelid edema, eyelid erythema (redness), eyelid pain, photophobia, chest pain, allergic skin reactions, joint pain, back pain, muscle pain, asthma, herpes keratitis, iritis, keratitis, retinal artery embolism, retinal detachment, toxic epidermal necrolysis, uveitis, vitreous hemorrhage due to diabetic retinopathy, and / or keratoconus.

[0090] In a sixth aspect, the present invention provides a method for reducing the total daily dose of latanoprost administered to a human being for treating glaucoma, elevated intraocular pressure, ocular hypertension, and / or symptoms related thereto, comprising the step of administering once daily to an eye of a human being having glaucoma, elevated intraocular pressure, ocular hypertension, and / or symptoms related thereto, a composition comprising about 0.01% (w / v) latanoprost dissolved in one drop of F6H8 or F4H5, wherein the composition is substantially free of water and substantially free of preservatives, and the amount of latanoprost administered in a single dose per eye is about 1.1 μg, resulting in an approximately 27% reduction in the amount of latanoprost per total daily dose and being at least equally therapeutically effective in treating glaucoma, elevated intraocular pressure, ocular hypertension, and / or symptoms related thereto, compared to the once-daily administration of one drop per eye of an aqueous solution comprising 0.005% (w / v) latanoprost.

[0091] It should be understood that all embodiments detailed above in relation to the pharmaceutical composition for use according to the first aspect of the invention may be applied to the methods according to the third to seventh aspects of the invention. Detailed Description of the Drawings

[0092] Figure 1 shows the results of an experimental animal study (dogs), further outlined below, which investigated the pharmacodynamics of intraocular pressure (IOP) following repeated topical ocular administration of latanoprost (0.005% (w / v)) in F4H5 or F6H8 and the corresponding semi-fluorinated alkane alone. The graph shows the evolution of mean intraocular pressure (IOP) (mmHg) over time.

[0093] Figure 2 shows the results of a direct comparison of a composition comprising latanoprost (0.01% w / v) in F6H8 administered to the right eye (OD) of a test animal with Xalatan® administered to the left eye (OS) of the same test animal, as further outlined below. The graph shows the progress of mean intraocular pressure (IOP) (mmHg) over time.

[0094] The following numbered list of embodiments encompassed by the present invention: 1. A pharmaceutical composition for use in the prevention or treatment of glaucoma, elevated intraocular pressure, ocular hypertension and / or conditions related thereto, comprising: comprising latanoprost and a liquid vehicle comprising a semi-fluorinated alkane; -Administered to the subject's eye; The amount of latanoprost administered in a single dose per eye ranges from approximately 0.5 to 1.4 μg. composition.

[0095] 2. The composition for use according to item 1, wherein the semi-fluorinated alkane is selected from F6H8 and F4H5.

[0096] 3. The composition for use according to item 1 or 2, wherein the semi-fluorinated alkane is F6H8.

[0097] 4. The composition for use according to any one of the preceding items, which is administered topically or by subconjunctival injection to the subject's eye.

[0098] 5. The composition for use according to any one of the preceding items, which is administered topically to the eye of a subject.

[0099] 6. The composition for use according to any one of items 1 to 4, which is administered to the subject's eye by subconjunctival injection.

[0100] 7. A composition for use according to any one of the preceding items, further comprising a solubilizer.

[0101] 8. The composition for use according to item 7, wherein the solubilizer is selected from ethanol, MCT and DEGEE.

[0102] 9. The composition for use according to item 7 or 8, wherein the solubilizer is contained in an amount of up to 2.5% (w / w) relative to the total weight of the liquid vehicle.

[0103] 10. The composition for use according to any one of items 7 to 9, wherein the solubilizing agent is ethanol.

[0104] 11. The composition for use according to item 10, wherein the amount of ethanol is at most 0.5% (w / w) relative to the total weight of the liquid vehicle.

[0105] 12. A composition for use according to any one of the preceding items, which is substantially free of water and preservatives.

[0106] 13. A composition for use according to any one of the preceding items, wherein the target administration volume of the composition per eye is about 8 to 15 μl.

[0107] 14. A composition for use according to any one of the preceding items, wherein the target administration volume of the composition per eye is about 10 to 12 μl.

[0108] 15. A composition for use according to any one of the preceding items, comprising about 0.005 to 0.015% (w / v), preferably about 0.008 to 0.012% (w / v) of latanoprost.

[0109] 16. The composition for use according to any one of the preceding items, wherein the amount of latanoprost administered in a single dose per eye is in the range of about 1.0 to 1.2 μg.

[0110] 17. A composition for use according to any one of the preceding items, comprising about 0.01% (w / v) latanoprost, wherein the amount of latanoprost administered in a single dose per eye is about 1.1 μg, and the target dose volume of the composition per eye is about 11 μl.

[0111] 18. A pharmaceutical composition for use according to any one of the preceding items, consisting essentially of latanoprost dissolved in a liquid vehicle consisting essentially of at least 99% (w / w) 1-perfluorobutyl-pentane (CF3(CF2)3-(CH2)4CH3(F4H5)) and / or 1-perfluorohexyl-octane (CF3(CF2)5-(CH2)7CH3(F6H8)) and up to 1% (w / w) ethanol based on the total weight of the liquid vehicle.

[0112] 19. A composition for use according to any one of the preceding items, which is administered once daily.

[0113] 20. The pharmaceutical composition for use according to any one of the preceding items, wherein a single dose of the composition is administered as one drop into the subject's eye.

[0114] 21. A pharmaceutical composition for use in a method for preventing or treating glaucoma, elevated intraocular pressure, ocular hypertension, or symptoms related thereto, comprising latanoprost dissolved in a liquid vehicle comprising a semi-fluorinated alkane, wherein the amount of latanoprost administered in a single dose per eye is in the range of about 0.5 to 1.4 μg.

[0115] 22. The composition for use according to item 21, wherein the target administration volume of the composition per eye is about 8 to about 15 μl.

[0116] 23. A composition for use according to item 21 or 22, comprising about 0.005 to 0.015% (w / v), preferably about 0.008 to 0.012% (w / v) of latanoprost.

[0117] 24. The composition for use according to any one of items 21 to 23, wherein the amount of latanoprost administered in a single dose per eye is about 1.0 to 1.2 μg.

[0118] 25. The composition for use according to any one of items 21 to 24, wherein the target administration volume of the composition per eye is about 10 to 12 μl.

[0119] 26. The composition for use according to any one of items 21 to 25, further comprising a solubilizer, preferably selected from ethanol, MCT and DEGEE.

[0120] 27. The composition for use according to item 26, wherein the solubilizer is contained in an amount of up to 2.5% (w / w) relative to the total weight of the liquid vehicle.

[0121] 28. The composition for use according to item 26, wherein the solubilizing agent is ethanol.

[0122] 29. The composition for use according to item 28, wherein the amount of ethanol is at most 1.0% (w / w), preferably at most 0.5% (w / w), relative to the total weight of the liquid vehicle.

[0123] 30. The composition for use according to any one of items 21 to 29, comprising about 0.01% (w / v) latanoprost; the latanoprost administered in a single dose per eye is about 1.1 μg, and the target dose volume per eye is about 11 μl.

[0124] 31. A composition for use according to any one of items 21 to 30, wherein the SFA is selected from F6H8 and F4H5.

[0125] 32. The composition for use according to item 31, wherein the SFA is F6H8.

[0126] 33. A composition for use according to any one of items 21 to 32, which is administered once a day.

[0127] 34. A composition for use according to any one of items 21 to 33, which is substantially free of water and preservatives.

[0128] 35. A kit comprising a pharmaceutical composition for use according to any one of the preceding items, the kit comprising a container for holding the pharmaceutical composition and a drop dispenser for administering the composition.

[0129] 36. The kit according to item 35, wherein the container for holding the pharmaceutical composition and the droplet dispenser are adapted to administer a volume of about 8 to 15 μl of the composition per drop, preferably a volume of 10 to 12 μl of the composition per drop, more preferably a volume of 11 μl of the composition per drop.

[0130] 37. A method for treating glaucoma, elevated intraocular pressure, ocular hypertension, or a condition related thereto, comprising the step of administering to the eye of a human having glaucoma, elevated intraocular pressure, ocular hypertension, or a condition related thereto a composition comprising latanoprost and a liquid vehicle comprising a semi-fluorinated alkane, wherein the latanoprost is preferably dissolved in the liquid vehicle, and the amount of latanoprost administered in a single dose per eye is about 0.5 to about 1.4 μg, which method is therapeutically effective in treating glaucoma, elevated intraocular pressure, ocular hypertension, or a condition related thereto.

[0131] 38. The method according to item 37, wherein the target administration volume of the composition per eye is about 8 to about 15 μl.

[0132] 39. The method according to item 37 or 38, wherein the composition comprises about 0.005 to 0.015% (w / v), preferably about 0.008 to 0.012% (w / v) of latanoprost.

[0133] 40. The method of any one of items 37 to 39, wherein the amount of latanoprost administered in a single dose per eye is about 1.0 to 1.2 μg.

[0134] 41. The method according to any one of items 37 to 40, wherein the target administration volume of the composition per eye is about 10 to about 12 μl, preferably about 11 μl.

[0135] 42. The method according to any one of items 37 to 41, wherein the composition further comprises a solubilizer, preferably selected from ethanol, MCT and DEGEE.

[0136] 43. The method according to any one of items 37 to 42, wherein the solubilizer is contained in an amount of up to 2.5% (w / w) relative to the total weight of the liquid vehicle.

[0137] 44. The method according to item 42, wherein the solubilizing agent is ethanol.

[0138] 45. The method according to item 44, wherein the amount of ethanol is at most 1% (w / w), preferably at most 0.5% (w / w), relative to the total weight of the liquid vehicle.

[0139] 46. ​​The method of any one of items 37 to 45, wherein the composition comprises about 0.01% w / v latanoprost; the amount of latanoprost administered in a single dose per eye is about 1.1 μg, and the target dose volume per eye is about 11 μl.

[0140] 47. The method according to any one of items 37 to 46, wherein the semi-fluorinated alkane is selected from F6H8 and F4H5.

[0141] 48. The method according to item 47, wherein the semi-fluorinated alkane is F6H8.

[0142] 49. The method of any one of items 37 to 48, wherein the composition is administered once a day.

[0143] 50. The method of any one of items 37 to 49, wherein the composition is substantially free of water and preservatives.

[0144] 51. The method of claim 37, wherein the composition further comprises up to about 1% (w / w) ethanol.

[0145] 52. The method of claim 37, wherein the composition consists of latanoprost dissolved in a solution of about 99% (w / w) F4H5 or F6H8 and about 1% (w / w) ethanol.

[0146] 53. The method of claim 37, wherein the composition consists of latanoprost dissolved in a solution of at least about 99% (w / w) F4H5 or F6H8 and up to about 1% (w / w) ethanol.

[0147] 54. The method of claim 37, wherein the composition further comprises up to about 0.5% (w / w) ethanol.

[0148] 55. The method of claim 37, wherein the composition consists of latanoprost dissolved in a solution of about 99.5% (w / w) F4H5 or F6H8 and about 0.5% (w / w) ethanol.

[0149] 56. The method of item 37, wherein the composition consists of latanoprost dissolved in a solution of at least about 99.5% (w / w) F4H5 or F6H8 and up to about 0.5% (w / w) ethanol.

[0150] 57. A pharmaceutical composition for use in a method for preventing or treating glaucoma, elevated intraocular pressure, ocular hypertension, or a condition related thereto, comprising latanoprost and a liquid vehicle comprising a semi-fluorinated alkane, wherein the latanoprost is preferably dissolved in the semi-fluorinated alkane, and the composition is therapeutically effective in treating or preventing glaucoma, elevated intraocular pressure, ocular hypertension, or a condition related thereto when administered in a single dose of about 0.5 to 1.4 μg latanoprost per eye.

[0151] 58. The composition for use according to item 57, wherein the target administration volume of the composition per eye is 8 to about 15 μl.

[0152] 59. The composition for use according to item 57, comprising about 0.005 to 0.015% (w / v), preferably about 0.008 to 0.012% (w / v) of latanoprost.

[0153] 60. The composition for use according to item 57, wherein the amount of latanoprost administered in a single dose per eye is about 1.0 to 1.2 μg.

[0154] 61. The composition for use according to item 57, wherein the target administration volume of the composition per eye is about 10 to 12 μl.

[0155] 62. The composition for use according to item 57, comprising up to about 0.5% (w / w) ethanol.

[0156] 63. The composition for use according to item 57, consisting of latanoprost dissolved in a solution of about 99.5% (w / w) F4H5 or F6H8 and about 0.5% (w / w) ethanol.

[0157] 64. The composition for use according to item 57, comprising latanoprost dissolved in a solution of at least about 99.5% (w / w) F4H5 or F6H8 and up to about 0.5% (w / w) ethanol.

[0158] 65. The composition for use according to item 57, further comprising up to about 1% (w / w) ethanol.

[0159] 66. The composition for use according to item 57, consisting of latanoprost dissolved in a solution of about 99% (w / w) F4H5 or F6H8 and about 1% (w / w) ethanol.

[0160] 67. The composition for use according to item 57, comprising latanoprost dissolved in a solution of at least about 99% (w / w) F4H5 or F6H8 and up to about 1% (w / w) ethanol.

[0161] 68. The composition for use according to item 57, wherein the latanoprost is contained in a concentration of about 0.008% to 0.012% (w / v), the single dose per eye is about 1.0 to 1.2 μg, preferably 1.1 μg, of latanoprost, and the composition is substantially free of water and substantially free of preservatives.

[0162] 69. The composition for use according to item 68, comprising up to about 0.5% (w / w) ethanol.

[0163] 70. The composition for use according to item 68, consisting of latanoprost dissolved in a solution of about 99.5% (w / w) F4H5 or F6H8 and about 0.5% (w / w) ethanol.

[0164] 71. The composition for use according to item 68, comprising latanoprost dissolved in a solution of at least about 99.5% (w / w) F4H5 or F6H8 and up to about 0.5% (w / w) ethanol.

[0165] 72. The composition for use according to item 68, further comprising up to about 1% (w / w) ethanol.

[0166] 73. The composition for use according to item 68, consisting of latanoprost dissolved in a solution of about 99% (w / w) F4H5 or F6H8 and about 1% (w / w) ethanol.

[0167] 74. The composition for use according to item 68, comprising latanoprost dissolved in a solution of at least about 99% (w / w) F4H5 or F6H8 and up to about 1% (w / w) ethanol.

[0168] 75. A method for reducing the total daily dose of latanoprost administered to a human being for treating glaucoma, elevated intraocular pressure, ocular hypertension, or a condition related thereto, comprising the step of administering to the human's eye once daily a composition comprising latanoprost dissolved in a liquid vehicle comprising a semi-fluorinated alkane, wherein the amount of latanoprost administered in a single dose per eye is about 0.5 to 1.4 μg, resulting in a reduction of the amount of latanoprost per total daily dose by about 67% to 7%, and being at least equally therapeutically effective in treating glaucoma, elevated intraocular pressure, ocular hypertension, or a condition related thereto, compared to the daily administration of one drop per eye of a 0.005% (w / v) aqueous solution of latanoprost.

[0169] 76. The method of reducing the total daily dose of latanoprost administered to a human being for treating glaucoma, elevated intraocular pressure, ocular hypertension or symptoms related thereto according to item 75, wherein one drop of the composition has a drop volume of about 11 μl and one drop of the 0.005% (w / v) aqueous latanoprost solution has a drop volume of about 30 μl.

[0170] 77. A method for reducing the total daily dose of latanoprost administered to a human for treating glaucoma, elevated intraocular pressure, ocular hypertension or symptoms related thereto according to item 75 or 76, wherein systemic exposure to latanoprost is reduced compared to daily administration of one drop of a 0.005% (w / v) aqueous solution of latanoprost.

[0171] 78. A method for reducing the total daily dose of latanoprost administered to a human to treat glaucoma, elevated intraocular pressure, ocular hypertension or a condition related thereto, according to any one of items 75 to 77, wherein one or more adverse effects are reduced compared to the daily administration of one drop of a 0.005% (w / v) aqueous solution of latanoprost.

[0172] 79. The method for reducing the total daily dose of latanoprost administered to a human for treating glaucoma, elevated intraocular pressure, ocular hypertension, or conditions related thereto, according to item 78, wherein the one or more adverse effects are selected from the group of adverse effects consisting of blurred vision, burning and stinging, conjunctival injection, foreign body sensation, itching, increased pigmentation (brown) of the iris causing (heterochromia), elongation and thickening of the eyelashes, punctate epithelial keratopathy, cold or upper respiratory tract infection, flu-like syndrome, dry eye, excessive tearing, eye pain, eyelid crusting, eyelid edema, eyelid erythema (redness), eyelid pain, photophobia, chest pain, allergic skin reactions, joint pain, back pain, muscle pain, asthma, herpes keratitis, iritis, keratitis, retinal artery embolism, retinal detachment, toxic epidermal necrolysis, uveitis, vitreous hemorrhage due to diabetic retinopathy, and keratoconus.

[0173] 80. A method for reducing the total daily dose of latanoprost administered to a human being for treating glaucoma, elevated intraocular pressure, ocular hypertension, or a condition related thereto, comprising the step of administering once daily to an eye of a human being having glaucoma, elevated intraocular pressure, ocular hypertension, or a condition related thereto, a composition comprising about 0.01% (w / v) latanoprost dissolved in one drop of F6H8 or F4H5, wherein the composition is substantially free of water and substantially free of preservatives, and the amount of latanoprost administered in a single dose per eye is about 1.1 μg of latanoprost, resulting in an approximately 27% reduction in the amount of latanoprost per total daily dose and being at least equally therapeutically effective in treating glaucoma, elevated intraocular pressure, ocular hypertension, or a condition related thereto, compared to administration of one drop per eye once daily of a 0.005% (w / v) aqueous solution of latanoprost.

[0174] The following examples serve to illustrate the present invention but should not be understood as limiting the scope of the invention. [Example]

[0175] Example 1 The following studies were performed to evaluate the pharmacodynamics (intraocular pressure, IOP) of latanoprost after repeated topical ocular administration of latanoprost in perfluorobutylpentane (F4H5) and perfluorohexyloctane (F6H8) in normotensive dogs, and to evaluate the pharmacokinetics of latanoprost acid in aqueous humor. Dogs are a suitable species for evaluating the ocular distribution and pharmacodynamics of prostaglandin analogs; this model can also provide quantitative pharmacokinetic data.

[0176] Test Setup Animals were selected for study participation based on general health, body weight, ophthalmic examination results, response to IOP challenge, and the following criteria: - Healthy and normal ocular surface; - No invasive ophthalmic procedures, particularly procedures generally involving the cornea or anterior segment, at least 1 month prior to the study; - No topical or systemic corticosteroid treatment for at least 1 month; - Withdrawal from previous topical ophthalmic study medication consistent with the typical withdrawal period used in clinical trials (at least 1 week).

[0177] Study Design: The study was performed according to the schedule summarized in Table 1 below. Topical ocular doses (11 or 30 μl, respectively) were administered via a micropipette to the central or superior cornea and allowed to spread over the entire surface of the eye. After administration, the eyes were allowed to close naturally. Each animal was restrained for approximately 1 minute to prevent eye rubbing.

[0178] [Table 1] d number of days IOP intraocular pressure OD right eye OS left eye PBS Phosphate-buffered saline QD Once a day a There was a washout period of at least 7 days between each phase, including the pre-test. b Collected from 4 eyes / time point.

[0179] The pharmaceutical compositions used in Phases 1 to 14 were prepared by dissolving latanoprost in a liquid vehicle containing a semi-fluorinated alkane.

[0180] As an example of the preparation of the composition used in Phase 14, the preparation of a composition containing 0.005% (w / v) latanoprost in F6H8 containing 0.5% (w / w) ethanol is described herein: 1,625 g of ethanol (Seccosolv, Merck, maximum 0.01% HO) is mixed with 324.3 g of F6H8 (99.888%, Lomapharm, GmbH) to obtain a solution containing 0.5% (w / w) ethanol. Then, 2.558 mg of latanoprost (99.5%, Yonsung, Korea) is dissolved in 50 mL of F6H8 solution containing 0.5% (w / w) ethanol to obtain a solution containing 0.005% (w / v) latanoprost.

[0181] The pre-test and compositions administered in each phase are described herein: Pre-test 1: OD: 0.005% (w / v) latanoprost solution; OS: Phosphate-buffered saline (PBS) Pre-test 2: OD: 0.005% (w / v) latanoprost solution; OS: 0.005% (w / v) latanoprost solution; Phase 1: OD: perfluorobutylpentane containing 0.5% (w / w) ethanol OS:PBS Phase 2: OD: in perfluorobutylpentane containing 0.5% (w / w) ethanol 0.00125% (w / v) latanoprost OS: perfluorobutylpentane containing 0.5% (w / w) ethanol Phase 3: OD: perfluorobutylpentane containing 0.5% (w / w) ethanol OS: 0.0025% (w / v) latanoprost in perfluorobutylpentane containing 0.5% (w / w) ethanol Phase 4: OD: perfluorobutylpentane containing 0.5% (w / w) ethanol OS: 0.005% (w / v) latanoprost in perfluorobutylpentane containing 0.5% (w / w) ethanol Phase 5: OD: in perfluorohexyl octane containing 0.5% (w / w) ethanol 0.005% (w / v) latanoprost OS: perfluorohexyl octane containing 0.5% (w / w) ethanol Phase 6: OD: perfluorohexyl octane containing 0.5% (w / w) ethanol OS:PBS Phase 7: OD: in perfluorobutylpentane containing 0.5% (w / w) ethanol 0.005% (w / v) latanoprost OS: perfluorobutylpentane containing 0.5% (w / w) ethanol Phase 8: OD: in perfluorohexyl octane containing 0.5% (w / w) ethanol 0.010% (w / v) latanoprost OS: perfluorohexyl octane containing 0.5% (w / w) ethanol Phase 9: OD: perfluorohexyl octane containing 0.5% (w / w) ethanol OS: in perfluorohexyl octane containing 0.5% (w / w) ethanol 0.015% (w / v) latanoprost Phase 10: OD: in perfluorohexyl octane containing 2.5% (w / w) medium chain triglycerides (MCT) 0.010% (w / v) latanoprost OS: Perfluorohexyl octane containing 2.5% (w / w) MCT Phase 11: OD: Perfluorohexyl octane containing 2.5% (w / w) MCT OS:PBS Phase 12: OD: in perfluorohexyl octane containing 0.5% (w / w) ethanol 0.010% (w / v) latanoprost OS: Xalatan [0.005% (w / v) latanoprost solution] Phase 13: OD: in perfluorohexyl octane containing 0.5% (w / w) ethanol 0.010% (w / v) latanoprost OS: in perfluorohexyl octane containing 0.5% (w / w) ethanol 0.010% (w / v) latanoprost Phase 14: OD: Contains 1.0% (w / w) 2-(2-ethoxyethoxy)ethanol (DEGEE) Perfluorohexyl octane OS: Contains 1.0% (w / w) 2-(2-ethoxyethoxy)ethanol 0.010% (w / v) latanoprost in perfluorohexyl octane

[0182] Two weeks prior to Phase 1, in intraocular efficacy pre-study 1 (see Table 1, Pre-study 1), each animal received a single 30 μl dose of 0.005% (w / v) latanoprost ophthalmic solution in the right eye (OD) and phosphate-buffered saline (PBS) in the left eye (OS) for intraocular efficacy challenge. The resulting IOP was measured using a TonoVet tonometer at -1, 0 (immediately before dosing), 1, 2, 4, 6, 24, and 48 hours post-dose.

[0183] One week prior to Phase 1, a single dose of 30 μl of 0.005% (w / v) latanoprost ophthalmic solution was administered to both eyes of each animal at pre-study intraocular efficacy load 2 (see Table 1, Pre-study 2). Corresponding IOP was measured using TonoVet at −1, 0 (just before dosing), 4, and 6 hours post-dose.

[0184] Pretests 1 and 2 were conducted to assess IOP response (Pretest 1) and similarity between eyes (Pretest 2). Animals that were IOP responsive and showed similarity in response to treatment in both eyes, as outlined in Table 1, were selected for the 14 phases of the study. Additional criteria for animal selection were a baseline intraocular pressure of at least 13 mmHg, a response of at least a 15% reduction in IOP from baseline after treatment with Xalatan®, and animal behavior during IOP measurements.

[0185] After two pre-study efficacy phases, animals were subjected to 14 phases of the study, as described in Table 1. Intraocular pressure measurements during Phases 1-14 were taken on Days 1, 2, 3, and 6 at 0 (just before dosing), 4, and 6 hours post-dose, and on Day 7 at -1, 0 (just before dosing), 1, 2, 4, 6, 24, and 48 hours post-dose. Three readings / eye were taken using the TonoVet.

[0186] Ocular irritation scoring during Phases 1-14 was performed pre-dose (up to 2 days prior to dosing), on Days 1, 2, 3, and 6, followed by IOP measurements at 0 (just before dosing), 4, and 6 hours post-dose; and on Day 7, followed by IOP measurements at 0 (just before dosing), 4, 6, 24, and 48 hours post-dose. Both eyes were scored / graded using a modified Hackett-McDonald scale following IOP measurements. Sporadic findings of irritation were present during dosing sessions; however, there were no apparent differences between treatment groups or phases.

[0187] Test Analysis: Administration of latanoprost solutions in F4H5 and F6H8, respectively, reduced intraocular pressure, as shown in Figure 1. The latanoprost solutions in F4H5 and F6H8 further contained 0.5% (w / w) ethanol.

[0188] Figure 2, referring to Phase 12 of the study outlined in Table 1, shows a direct comparison of a composition containing latanoprost in F6H8 with Xalatan®, in which administration of a solution of latanoprost in F6H8 with a target dose level of 1.1 μg / eye and a target dose volume of 11 μl / eye demonstrates IOP reduction comparable to that achieved by instillation of Xalatan® with a target dose level of 1.5 μg / eye and a target dose volume of 30 μl / eye. The experimental data demonstrate that by using a composition according to the present invention, it is possible to achieve IOP reduction comparable to that of the gold standard Xalatan®, even using a lower target dose of the active ingredient. Furthermore, the lower target dose can be administered, for example, in a volume of 11 μl, i.e., significantly lower than 30 μl, thereby reducing the amount of composition excreted or taken up systemically.

Claims

1. A pharmaceutical composition for use in the prevention or treatment of elevated intraocular pressure, comprising: - Latanoprost and 1-perfluorohexyl-octane (CF ３ (CF ２ ) ５ - (CH ２ ) ７ CH ３ (F6H8)) and 0.5% (w / w) ethanol based on the total weight of the liquid vehicle; containing 0.010% (w / v) latanoprost; - administered topically to the subject's eye; - the amount of latanoprost administered in a single dose per eye is 1.1 μg and the target dose volume of the composition per eye is 11 μl; - administered once a day; - substantially free of water, composition.

2. 10. The composition of claim 1, wherein a single dose of the composition is administered as one drop to the eye of a subject.

3. 3. The composition of claim 1, which is substantially free of preservatives.

4. 4. The composition of any one of claims 1 to 3, comprising latanoprost dissolved in a liquid vehicle consisting essentially of at least 99.5% (w / w) 1-perfluorohexyl-octane (CF 3 (CF 2 ) 5 —(CH 2 ) 7 CH 3 (F6H8)) and 0.5% (w / w) ethanol, based on the total weight of the liquid vehicle.

5. 5. The composition of any one of claims 1 to 4, consisting essentially of latanoprost dissolved in a liquid vehicle consisting essentially of at least 99.5% (w / w) 1-perfluorohexyl-octane (CF 3 (CF 2 ) 5 —(CH 2 ) 7 CH 3 (F6H8)) and 0.5% (w / w) ethanol, based on the total weight of the liquid vehicle.

6. 6. A kit comprising the composition of any one of claims 1 to 5, the kit comprising a container for holding the composition, and a drop dispenser for administering the composition.

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