Ophthalmic preparations and methods of use

Abstract

The invention relates to ophthalmic compositions comprising thiol drugs, such as cysteamine, for the prevention and / or treatment of ocular conditions related to the hardening and / or opacification of the crystalline lens of the eye; for instance, ocular conditions such as cataracts and presbyopia.

Description

[0001] OPHTHALMIC PREPARATIONS AND METHODS OF USE

[0002] FIELD OF THE INVENTION

[0003] The invention relates to ophthalmic preparations comprising thiol drugs, such as cysteamine, for the prevention and / or treatment of ocular conditions related to the hardening and / or opacification of the crystalline lens of the eye; for instance, ocular conditions such as cataracts and presbyopia.

[0004] BACKGROUND OF THE INVENTION

[0005] The crystalline lens of the eyes (e.g., human eyes) is a transparent biconvex structure in the eye that, along with the cornea, helps to refract light to be focused on the retina. In its healthy, physiological state, the lens is clear, flexible, and curved in nature. It is controlled by ciliary muscles through the zonules. By changing the curvature of the lens, one can focus the eye on objects at different distances. This process is called accommodation.

[0006] So-called crystallins of the lens compose over 90 % of the lens protein. The three main crystallin types found in the human eye are a-, p-, and y-crystallins. Crystallins tend to form soluble, high-molecular weight aggregates that pack tightly in lens fibers, thus increasing the index of refraction of the lens while maintaining its transparency.

[0007] However, the crystalline lens is subject to various changes over a lifetime; the lens gradually hardens and loses its flexibility and transparency. The most known ocular conditions related to said hardening of the lens and loss of its transparency are presbyopia and cataract.

[0008] Presbyopia is a condition associated with the hardening of the lens that results in progressively worsening ability to focus clearly on close objects. Symptoms include difficulty reading small print, having to hold reading material farther away, headaches, and eyestrain. People over the age of forty are at risk for developing presbyopia, and typically all people become affected to some degree over their lifespan. Treatment of presbyopia is typically with eyeglasses or contact lenses, or, as of recently, with miotic pilocarpine eye drops. However, all these options are just treating the symptoms of presbyopia and cannot slow its progression, let alone reverse it. Other than aging, people who are hyperopic (farsighted) typically tend to experience the onset of presbyopia earlier than their emmetropic (normal vision) counterparts. Morbidities such as cardiovascular disease, diabetes and multiple sclerosis have also been implicated in the earlier onset of presbyopia.

[0009] Over time, the crystalline lens transparency loss leads to cataract formation. A cataract is a clouding of the normally clear lens of the eye, or in other words, a loss of its physiological transparency. If left untreated, cataracts can lead to blindness. With currently no approved eye drop option available for the treatment of cataracts, the only treatment is surgery to remove the lens and replace it with an artificial intraocular lens.

[0010] Other than aging, smoking, UV-radiation from sunlight, diabetes mellitus and use of corticosteroid are the known risk factors for the formation of cataract.

[0011] SUMMARY OF THE INVENTION

[0012] In a first aspect, the present invention provides a composition for the prevention and / or treatment of ocular conditions related to the hardening and / or opacification of a crystalline lens of an eye, wherein the composition is a topical ophthalmic composition for direct administration to the eye, and wherein the composition comprises at least one thiol drug or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0013] In a second aspect, the present invention provides a method for the prevention and / or treatment of ocular conditions related to the hardening and / or opacification of a crystalline lens of an eye, said method comprising a step of topically administering directly to the eye(s) of a subject in need thereof one or more doses of an ophthalmic composition comprising at least one thiol drug or a pharmaceutically acceptable salt thereof.

[0014] Further features and embodiments of the invention, as well as their advantages and / or areas of application, will become apparent from the following description, examples and claims. DETAILED DESCRIPTION OF THE INVENTION

[0015] In a first aspect, the present invention provides a composition for the prevention and / or treatment of ocular conditions related to the hardening and / or opacification of a crystalline lens of an eye, wherein the composition is a topical ophthalmic composition for direct administration to the eye, and wherein the composition comprises at least one thiol drug or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0016] In this context, the expression "for direct administration to the eye” as used herein means that the composition can be administered topically directly onto any surface of the eye and / or the eye socket, e.g., sclera, cornea, conjunctiva, conjunctival sac, and the like.

[0017] In one embodiment, the composition is used for the prevention and / or treatment of presbyopia. In a specific embodiment, the composition is used for the treatment of presbyopia.

[0018] In one embodiment, the composition is used for the prevention and / or treatment of cataracts. In a specific embodiment, the composition is used for the treatment of cataracts.

[0019] In one embodiment, the composition is used for the prevention and / or treatment of presbyopia and cataracts. In a specific embodiment, the composition is used for the treatment of presbyopia and cataracts.

[0020] The invention is thus based, in parts, on the discovery that the hardening and / or opacification of the crystalline lens of the eye can be prevented, slowed down, and even reversed by thiol drugs, such as cysteamine, provided in the form of topical ophthalmic compositions, as illustrated in the experimental section. This is surprising and advantageous insofar as many prior art studies aimed at these indications showed only preventive, or prophylactic, effects and / or required systemic routes of application such as oral application, injections, or implants.

[0021] In one embodiment, the eye subjected to the composition is a human eye.

[0022] In this context, it should be understood that in order to for the composition to be effective for the prevention and / or treatment of the above ocular conditions, it needs to contain an effective amount of the active principle(s). Hence, unless where expressly specified otherwise, all composition shall contain, and all methods performed with, an effective amount of the thiol drug, and - where present - an effective amount of active principles in addition to the at least one thiol drug.

[0023] In one embodiment, the composition is an aqueous composition, meaning that the at least one thiol drug or its pharmaceutically acceptable salt are provided in an aqueous vehicle; or, in other words, that the composition contains water as a primary component. In a specific embodiment, the composition is an aqueous liquid, or a viscous aqueous liquid (such as eye drops or eye gels, respectively). In a further specific embodiment, the composition is provided in the form of an aqueous liquid, such as eye drops. For the purpose of instilling, or dropping, the said aqueous liquid into the eye, it may have a dynamic viscosity in the range of 1-60 cP, or l-50cP, or 1-20 cP, for instance, a dynamic viscosity of less than 5 cP. In embodiments where the composition is provided in the form of a viscous aqueous liquid, for instance, as an eye-gel formulation, the dynamic viscosity is in the range of 20-100 cP, or 50-100 cP, or 60-100 cP.

[0024] As used herein, the term 'dynamic viscosity’ refers to the dynamic viscosity at room temperature (20 ± 5 °C) as determined by, or measured using, a Brookfield rotating spindle viscometer which measures the force to turn the spindle in a test sample at a given rotation rate. The test sample is stored at room temperature for about 2 h prior to testing and then placed on the measurement chamber with a pipette. Then a proper rotation speed is selected for the spindle according to the expected viscosity of the test solution. Furthermore, it is also preferred if the composition is isotonic, or essentially isotonic, with lacrimal fluid (tear fluid).

[0025] The composition may further comprise metal ions to stabilize the thiol drug, for instance in the form of a metal ion-thiol drug complex which is soluble in the composition. In one embodiment, the composition is an aqueous composition, and the composition further comprises at least one pharmaceutically acceptable metal ion selected from zinc (Zn) or a pharmaceutically acceptable salt thereof, magnesium (Mg) or a pharmaceutically acceptable salt thereof, calcium (Ca) or a pharmaceutically acceptable salt thereof, or a combination of any two or more thereof. In a specific embodiment, the at least one pharmaceutically acceptable metal ion is provided in the form of zinc bromide, zinc chloride, zinc gluconate, zinc acetate, zinc phosphate, magnesium bromide, magnesium gluconate, magnesium acetate, magnesium phosphate, calcium bromide, calcium chloride, calcium gluconate, calcium acetate, or a combination of any two or more thereof. In a more specific embodiment, the at least one pharmaceutically acceptable metal ion is provided in the form of zinc chloride. Zinc, or a zinc salt, such as zinc chloride, for forming the complex with the thiol drug, may be present in any suitable amount. For example, in liquid compositions like topical ophthalmic liquids (e.g., eye drops), zinc, or the salt thereof (e.g., zinc chloride), may be present in a concentration of about 0.01-5.0 %, or about 0.05-2.0 %, or about 0.1-1.0 %. In a yet more specific embodiment, the at least one pharmaceutically acceptable metal ion is provided in the form of zinc chloride in a concentration of about 0.1-1.0 %, such as 0.41 %.

[0026] In one embodiment, the thiol drug, or the pharmaceutically acceptable salt thereof, is present in the composition in the form of a complex with the above-mentioned metal ion(s), or the pharmaceutically acceptable salt(s) thereof, and the complex is soluble in the composition.

[0027] In one embodiment, the concentration of the thiol drug is in the range of about 0.1-10.0 %, preferably in the range of about 0.5-5.0 %, more preferably in the range of about 0.3-3.0 %. Unless expressly indicated otherwise, all ingredient concentrations provided herein are presented in units of % weight / volume (i.e., "% w / v”, or occasionally shorter "%”)■

[0028] In one embodiment, the thiol drug is cysteamine, or a pharmaceutically acceptable salt thereof. Unless where explicitly specified otherwise, the term cysteamine is taken to mean the free base form, salt forms such as hydrochlorides or tartrates, or mixtures of the free base form and salt forms. In a specific embodiment, the thiol drug is cysteamine hydrochloride (cysteamine HC1). In a more specific embodiment, the concentration of cysteamine is in the range of about 0.1-10.0 %, or about 0.5-5.0 %, or about 0.3-3.0 %, such as about 2.0 %.

[0029] In one embodiment, the thiol drug, or its pharmaceutically acceptable salt, (e.g., cysteamine, or cysteamine HC1) is the sole active principle, or the only drug, effective in the prevention and / or treatment of ocular conditions related to the hardening and / or opacification of a crystalline lens of an eye (e.g., presbyopia and / or cataract). Providing the thiol drug, or its pharmaceutically acceptable salt, in the form of a soluble complex with metal ion(s) selected as outlined above, is advantageous in particular for instable thiol drugs, such as cysteamine, which otherwise would require storage in either frozen state and / or refrigerated. For instance, cysteamine containing eye drops Cystaran® must be kept frozen during long term storage, and once opened under refrigerated condition for max. one week before they must be discarded. As shown by the inventors in US20210369648A1, formulating instable thiol drugs such as cysteamine into soluble complexes with metal ions, or metal ion salts such as zinc chloride, improves the stability of the thiol drug, and thereby allows for less cumbersome storage options.

[0030] In other words, in one embodiment, the thiol drug, or the pharmaceutically acceptable salt thereof, is present in the composition in the form of a soluble, metal-ion stabilized complex, wherein the metal ion selected from zinc (Zn) or a pharmaceutically acceptable salt thereof, magnesium (Mg) or a pharmaceutically acceptable salt thereof, calcium (Ca) or a pharmaceutically acceptable salt thereof, or a combination of any two or more thereof; or more specifically from zinc bromide, zinc chloride, zinc gluconate, zinc acetate, zinc phosphate, magnesium bromide, magnesium gluconate, magnesium acetate, magnesium phosphate, calcium bromide, calcium chloride, calcium gluconate, calcium acetate, or a combination of any two or more thereof.

[0031] Said metal-ion stabilized, soluble thiol drug complex is further advantageous in ophthalmic compositions for direct application to the eye because it reduces the irritation risk, for instance reducing any scratching sensations, or similar foreign-body sensations. Both easier storage of the drug composition and reduced irritation risk are expected to improve patient compliance since it increases patient comfort.

[0032] Since the composition is intended for direct application to the eye, it is understood that the composition is sterile, especially when intended for - though not only then - for instillation into the eye. In one embodiment, the composition is subjected to sterile filtration, for instance, by passing it through a 0.22 pm filter.

[0033] Moreover, as mentioned above, the composition comprises at least one pharmaceutically acceptable excipient; for instance, an aqueous vehicle containing one or more pharmaceutically acceptable excipients. These excipients are typically selected from, tonicity-adjusting agents (also referred to as tonicity modifiers), pH-adjusting agents (e.g., acids, bases, and / or buffering agents), stabilizing agents, surfactants, solubilizers, viscosity-modifying agents (usually viscosity-enhancing agents), antioxidants, preservatives, chelating agents, or a combination of any two or more thereof.

[0034] Examples of tonicity-adjusting agents include, but are not limited to mannitol, sorbitol, potassium chloride, sodium chloride, xylitol, glycerin, trehalose, taurine, erythritol, combinations thereof, and the like. In a specific embodiment, the tonicity-adjusting agent is sodium chloride. In a more specific embodiment, the tonicity-adjusting agent in the composition is sodium chloride in a concentration of about 0.1-1.0 %, such as 0.36 %.

[0035] Since the compositions according to the invention are intended for direct administration to the eye, the amount of tonicity-adjusting agent in the composition will be the amount required to render the composition approximately isotonic with lacrimal fluid (i.e., tear fluid).

[0036] In one embodiment, the composition exhibits a tonicity (osmolality) in the range of about 200-450 mOsm / kg, or about 240-420 mOsm / kg, or about 240-360 mOsm / kg, or about 270-350 mOsm / kg, or about 280-300 mOsm / kg.

[0037] Examples of pH-adjusting agents include alkaline agents, acidic agents, and buffering agents. Examples of suitable alkaline agents include, but are not limited to, sodium hydroxide (NaOH), potassium hydroxide (KOH), tromethamine, monoethanolamine, sodium bicarbonate (NaHCOs) and other organic and inorganic bases. Examples of suitable acidic agents include, but are not limited to, hydrochloric acid (HC1), citric acid, tartaric acid, lactic acid, acetic acid, and other organic and inorganic acids, and mixtures thereof. Examples of suitable buffering agents include, but are not limited to, phosphate salt, borate salt, citrate salt, acetate salt, carbonate salt, bicarbonate salt, borate-polyol complexes, boric acid, sodium acetate, amino acid, Tris, bicarbonate, BIS-Tris, or salt thereof, combinations thereof and the like. The buffering agent(s) can be present in the composition in an amount ranging from about 5-200 mM, or about 10-100 mM. In a specific embodiment, the pH-adjusting agents are sodium hydroxide (NaOH) and / or hydrochloric acid (HC1) quantum satis (q.s.), i.e., as required for the intended pH-value.

[0038] In one embodiment, the ophthalmic composition of present invention has a pH in the range of about 4-9, preferably in the range of about 4.5-7.5, more preferably in the range of about 5.0-6.5, such as about 5.0, about 5.4, about 5.5, or about 5.6. In a specific embodiment, the ophthalmic composition exhibits an osmolality in the range of about 200-450 mOsm / L and a pH in the range of about 4-9. In a more specific embodiment, the ophthalmic composition exhibits an osmolality in the range of about 240-420 mOsm / L and a pH in the range of about 4.5-7.5. In a yet more specific embodiment, the ophthalmic composition exhibits an osmolality in the range of about 240-360 mOsm / L and a pH in the range of about 5.0-6.5.

[0039] Examples of suitable surfactants include, but are not limited to poloxamers, tyloxapol, polysorbates such as polysorbate 80 or polysorbate 20, polyoxyethylene castor oil derivatives, sorbitan esters, and combinations thereof. The composition typically comprises less than 5 %, less than 2 % or less than 1 % of surfactants]. In one embodiment, the composition may be free, or essentially free, of surfactants (s). For instance, the exemplary cysteamine HC1 solution described in Example 1 as EY-6_F30 does not contain a surfactant.

[0040] Examples of suitable solubilizers include, but are not limited to, Solutol, Soluplus, cyclodextrin(s), vegetable oils, combinations thereof, and the like. The composition typically comprises less than 5 %, less than 2 % or less than 1 % of solubilizer (s). In one embodiment, the composition may be free, or essentially free, of solubilizer(s). For instance, the exemplary cysteamine HC1 solution described in Example 1 as EY-6_F30 does not contain a solubilizer.

[0041] Viscosity-modifying agents, or viscosity-enhancing agents, are hydrophilic polymers that are commonly added to topical ophthalmic compositions for two main reasons: (1) to control the rate at which the drop flows out of the container (and thus enhance ease of application); and, more importantly, (2) to control the residence time of the composition within the precorneal environment. Examples of suitable viscosity-modifying / enhancing agents include, but are not limited to, cellulose ether such as hydroxypropyl methylcellulose (HPMC), hydroxpropylcellulose (HPC), hydroxyethyl cellulose (HEC), or carboxymethylcellulose, hyaluronic acid, chondroitin sulfate, polyvinyl alcohol, polylysine, polyacrylic acid, polyacrylamides, N-(2-Hydroxypropyl) methacrylamide (H PM A), xanthan gum, pectins, chitosan, dextran, carrageenan, guar gum, polyoxyl stearate 40, polyvinyl pyrrolidone, polyethylene glycol (PEG), propylene glycol (PG), and combinations of any two or more thereof. In one embodiment, the viscosity-enhancing agent is selected from cellulose ethers, such as hydroxypropyl methylcellulose (HPMC), hydroxpropylcellulose (HPC), hydroxyethyl cellulose (HEC), or carboxymethylcellulose, polyvinyl alcohol, or polyacrylic acid. In a specific embodiment selected from hydroxypropyl methylcellulose (HPMC), hydroxpropylcellulose (HPC), hydroxyethyl cellulose (HEC), or carboxymethylcellulose. In a more specific embodiment, the viscosityenhancing agent in the composition is hydroxypropyl methylcellulose (HPMC). In a yet more specific embodiment, the viscosity-enhancing agent is an HPMC E4M grade. In a more specific embodiment, the viscosity-enhancing agent in the composition is an HPMC E4M grade in a concentration of about 0.01-0.5 %, such as 0.05 %.

[0042] HPMC is a partially methylated and 0-(2-hydroxypropylated) cellulose derivative. In aqueous ocular formulations HPMC is used in the concentration of 0.45-1.0 % w / v (the actual concentration being dependent on the molecular weight of polymer used).

[0043] Poly(vinyl alcohol). This is a water-soluble vinyl polymer that is available in three grades: (1) high-viscosity (average molecular weight 200 000 g / mol); (2) medium-viscosity (average molecular weight 130 000 g / mol); and (3) low-viscosity (average molecular weight 20 000 g / mol). It is used to enhance the viscosity of ocular formulations in concentrations ranging from 0.25% to 3.00% w / w (the actual concentration being dependent on the molecular weight of polymer used).

[0044] Poly(acrylic acid). This is a water-soluble acrylate polymer that is cross-linked with either allyl sucrose or allyl ethers of pentaerythritol. It is predominantly used in ocular aqueous formulations for the treatment of dry-eye syndrome. However, it may be used to increase the viscosity of ocular formulations that contain a therapeutic agent.

[0045] As mentioned above, antioxidant(s) may be added to the ophthalmic composition. As used herein, the term "antioxidant" is intended to mean an agent that inhibits oxidation of the composition, and thus is used to prevent the deterioration or spoiling thereof by oxidative processes. These antioxidant(s) are thus meant to be separate from, or in addition to, the thiol drug(s), such as cysteamine, which are the active principle(s) of the compositions according to the invention and which may also exhibit antioxidative properties. Exemplary antioxidants include, but are not limited to, ascorbic acid, malic acid, citric acid, or their respective salts such as sodium citrate, butylated hydroxyanisole, butylated hydroxytoluene (BHT), propyl gallate, sodium ascorbate, sodium metabisulfite, sodium bisulfite, amino acids, ascorbyl palmitate, hypophosphorous acid, monothioglycerol, propyl gallate, sodium formaldehyde sulfoxylate, and other materials known to one of ordinary skill in the art and mixtures thereof. If present, the amount (concentration) of antioxidant will be sufficient to minimize oxidative degradation of the one or more active ingredients. In a specific embodiment, the antioxidant in the composition is citric acid, or citric acid monohydrate. In a more specific embodiment, e antioxidant in the composition is citric acid monohydrate in a concentration of about 0.01-0.5 %, such as 0.13 %.

[0046] Examples of suitable preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, p-oxybenzoates such as methyl- or ethyl p-oxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid or salts thereof, citric acid or salts thereof, thimerosal, chlorobutanol, quaternary amine, chlorhexidine gluconate, stabilized oxychloro complex, combinations thereof, and the like. The preservative, if included, will be present in an amount required to pass USP and / or Ph. Eur. antimicrobial preservative effective test required for eye drops. For instance, benzalkonium chlorides can be used in ophthalmic solutions or suspensions at a concentration of about 0.002-0.02 % (typically 0.005-0.01 %), it is customary to include 0.01-0.1 % disodium edetate in ophthalmic compositions in which benzalkonium chloride is used. Benzethonium chloride, unlike benzalkonium chloride, is a pure compound (and not a mixture of compounds). It is commonly used in ophthalmic compositions in a concentration of about 0.01-0.02 % (although it has been reported to exhibit lower antimicrobial activity than benzalkonium chloride). Esters of parahydroxybenzoates (parabens), such as mixtures of methyl- and propyl-esters of parahydroxybenzoic acid are used in ophthalmic compositions typically at a combined concentration of 0.2 % w / w. Non-irritating, specifically not eye -irritating, organic alcohols such as chlorobutanol and phenylethyl alcohol can also be used as preservatives for ophthalmic formulations. Chlorobutanol is used in ophthalmic compositions at a concentration of about 0.5 %. Phenylethyl alcohol has similar properties to chlorobutanol and is used in ophthalmic compositions at typical concentrations of about 0.25-0.50 % w / v. Typical concentration of preservative is within an effective amount required to pass USP and / or Ph. Eur. antimicrobial preservative effective test for eye drops.

[0047] In a specific embodiment, the preservative in the composition is benzalkonium chloride. In a more specific embodiment, the preservative in the composition is benzalkonium chloride in a concentration of about 0.002-0.02 %, or about 0.005-0.01 %, such as 0.01 %. Examples of chelating agents include, but are not limited to disodium edetate (EDTA, ethylenediaminetetraacetic acid salt), sodium citrate, condensed sodium phosphate, combinations thereof and the like. The amount of chelating agent(s) typically ranges from about 0.01-0.2 %. In a specific embodiment, the chelating agent in the composition is disodium edetate. In a more specific embodiment, the chelating agent is disodium edetate in a concentration of about 0.01-0.1 %, such as 0.10 %.

[0048] As mentioned above, the thiol drug, or its pharmaceutically acceptable salt, (e.g., cysteamine, or cysteamine HC1) can be the sole active principle, or the only drug, effective in the prevention and / or treatment of ocular conditions related to the hardening and / or opacification of a crystalline lens of an eye (e.g., presbyopia and / or cataract).

[0049] Alternatively, in one of the optional embodiments, the composition may further comprise a muscarinic receptor agonist (MRA), i.e., drugs causing miosis. Unless specified otherwise, the term MRA is taken to mean the free base form, salt forms, or mixtures of the free base form and salt forms; this applies to all MRAs listed. In a specific embodiment, the composition may further comprise an MRA selected from the group consisting of pilocarpine, aceclidine, carbachol, talsaclidine, sabcomeline, cevimeline, arecoline, acetylcholine, bethanechol, oxotremorine, or the respective pharmaceutically acceptable salts thereof. In a more specific embodiment, the composition further comprises an MRA selected from the group consisting of pilocarpine, carbachol, aceclidine, and cevimeline. For instance, in one embodiment, the concentration of the thiol drug is in the range of about 0.1-10.0 % and the concentration of pilocarpine is in the range of about 0.1-2.0 %. In an alternative embodiment, the concentration of the thiol drug is in the range of about 0.1-10.0 % and the concentration of cevimeline is in the range of about 0.1-6.0 %. In more specific embodiments, the concentration of cysteamine is in the range of about 0.1-10.0 % and the concentration of pilocarpine is in the range of about 0.1-2.0 %; or the concentration of cysteamine is in the range of about 0.1-10.0 % and the concentration of cevimeline is in the range of about 0.1-6.0 %.

[0050] In one embodiment, the invention provides an aqueous topical ophthalmic composition comprising about 0.1-10%, or about 0.5-5 %, or about 0.3-3 %, of cysteamine or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients for the prophylaxis and / or treatment of ocular conditions related to the hardening and / or opacification of the crystalline lens of the eye, such as presbyopia and / or cataract.

[0051] In a second aspect, the invention provides a method for the prevention and / or treatment of ocular conditions related to the hardening and / or opacification of a crystalline lens of an eye, said method comprising a step of topically administering directly to the eye(s) of a subject in need thereof one or more doses of an ophthalmic composition comprising at least one thiol drug or a pharmaceutically acceptable salt thereof. Said composition can be the composition according to the first aspect of the invention as outlined above. Accordingly, any embodiments disclosed herein in connection with the composition according to the first aspect of the invention, may be applied to the method according to this second aspect of the invention.

[0052] For instance, in one embodiment of the method, the composition is administered for the prevention and / or treatment of presbyopia. In a specific embodiment of the method, the composition is administered for treatment of presbyopia.

[0053] In one embodiment of the method, the composition is administered for the prevention and / or treatment of cataracts. In a specific embodiment of the method, the composition is administered for treatment of cataracts.

[0054] In one embodiment of the method, the composition is administered for the prevention and / or treatment of presbyopia and cataracts. In a specific embodiment of the method, the composition is administered for treatment of presbyopia and cataracts.

[0055] In one embodiment of the method, the eye to which the composition is administered is a human eye.

[0056] In one embodiment of the method, the administered composition is an aqueous composition; for instance, an aqueous liquid, or a viscous aqueous liquid (such as eye drops or eye gels, respectively).

[0057] The administered composition may further comprise metal ions to stabilize the thiol drug, for instance in the form of a metal ion-thiol drug complex which is soluble in the composition. In one embodiment of the method, the administered composition is an aqueous composition, and the composition further comprises at least one pharmaceutically acceptable metal ion selected from zinc or a pharmaceutically acceptable salt thereof, magnesium or a pharmaceutically acceptable salt thereof, calcium or a pharmaceutically acceptable salt thereof, or a combination of any two or more thereof. In a specific embodiment, the at least one pharmaceutically acceptable metal ion is provided in the form of zinc bromide, zinc chloride, zinc gluconate, zinc acetate, zinc phosphate, magnesium bromide, magnesium gluconate, magnesium acetate, magnesium phosphate, calcium bromide, calcium chloride, calcium gluconate, calcium acetate, or a combination of any two or more thereof. In a more specific embodiment, the at least one pharmaceutically acceptable metal ion is provided in the form of zinc chloride. In a yet more specific embodiment, the at least one pharmaceutically acceptable metal ion is provided in the form of zinc chloride in a concentration of about 0.1-1.0 %, such as 0.41 %.

[0058] In one embodiment of the method, the thiol drug, or the pharmaceutically acceptable salt thereof, is present in the administered composition in the form of a complex with the above-mentioned metal ion(s), or the pharmaceutically acceptable salt(s) thereof, and the complex is soluble in the composition.

[0059] In one embodiment of the method, the thiol drug is cysteamine, or a pharmaceutically acceptable salt thereof. In a specific embodiment, the thiol drug is cysteamine hydrochloride (cysteamine HC1). In other words, in one embodiment, the method comprises a step of topically administering directly to the eye(s) of a subject in need thereof one or more doses of an ophthalmic composition comprising cysteamine, or a pharmaceutically acceptable salt thereof; preferably, an ophthalmic composition comprising a metal ion stabilized complex of cysteamine, or a pharmaceutically acceptable salt thereof.

[0060] In one embodiment of the method, the thiol drug, or its pharmaceutically acceptable salt, (e.g., cysteamine, or cysteamine H Cl) is the sole active principle, or the only drug, effective in the prevention and / or treatment of ocular conditions related to the hardening and / or opacification of a crystalline lens of an eye (e.g., presbyopia and / or cataract).

[0061] Alternatively, the administered composition may further comprise a muscarinic receptor agonist (MRA), i.e., drugs causing miosis. In a specific embodiment, the administered composition further comprises an MRA selected from the group consisting of pilocarpine, aceclidine, carbachol, talsaclidine, sabcomeline, cevimeline, arecoline, acetylcholine, bethanechol, oxotremorine, or the pharmaceutically acceptable salts thereof. In a more specific embodiment, the composition further comprises an MRA selected from the group consisting of pilocarpine and cevimeline.

[0062] EXAMPLES

[0063] Example 1 - Ex-vivo prevention / prophylaxis tests with cysteamine and porcine lenses In order to evaluate the protective effects of cysteamine against oxidation stress, and thus the preventive, or prophylactic effects of cysteamine against presbyopia and / or cataract, extracted lenses from pig eyes were first tested for their flexibility, or rigidity, using a texture analyzer (TA.XT.plus).

[0064] Thereafter the lenses were incubated for 1 day (24 h) in two different solutions (labeled group I and group II) based on saline (0.9 %NaCl) as the culture medium. The culture medium was supplemented with either a placebo solution EY-6_F32 with the addition of hydrogen peroxide (H2O2) as an oxidative stress agent (Group I), and an exemplary cysteamine solution EY-6_F30, also with the addition of H2O2 (Group II). In other words, group I represents the placebo / control group, and group II the verum / treatment group. The respective components of the cysteamine solution (EY-6_F30) and the placebo solution(EY-6_F32) are found in Table 1 below. The respective components of the incubation solutions of Groups I and II are found Table 2 below.

[0065] Table 1 Composition of placebo and cysteamine solution

[0066] Table 2 Composition of incubation solutions for ex vivo pig lens experiment

[0067] Figures 1 and 2 below depict the appearance of lenses before and after the one-day incubation, respectively. Prior to incubation, lenses of both tested groups looked equally clear. After just one day, the lenses in the placebo group (group I) had turned opaque, while the lenses incubated with cysteamine (group II) exhibited far less opacity, indicating that cysteamine protected the lens from oxidative stress (i.e., prevention).

[0068] Figures 3 and 4 below depict the lenses’ rigidity before and after the one-day incubation as both force-displacement curves (i.e., force required to deform the lens), and lens modulus, respectively; with the lens modulus / rigidity being obtained from the slope of the semilogarithmic force-displacement curve. The rigidity of lenses incubated with cysteamine (group II) remained unchanged, while pronounced rigidity increases were seen for the lenses of the placebo group (group I), thus indicating that cysteamine-treated lenses are more resistant to oxidative stress and retain their initial flexibility even under oxidative stress.

[0069] Example 2 - Ex-vivo treatment / healing tests with cysteamine and porcine lenses

[0070] In order to evaluate the healing effects of cysteamine on the lenses resulting from Example 1 after their exposure to oxidation stress (i.e., whether cysteamine can restore the elasticity, or flexibility, thereof), and thus the suitability of cysteamine as a treatment against presbyopia and / or cataract, the extracted, pre-incubated and thus pre-stressed lenses of Example 1 (groups I and II) were further incubated for another 5 days in a cysteamine HC1 containing solution (same mixture consisting of 2000 pL saline and 1000 pL of the cysteamine solution EY-6_F30), and then tested once more for their flexibility, or rigidity, using a texture analyzer (TA.XT.plus). Figure 5 depicts the appearance of lenses after the five-day "healing incubation” of the ex vivo pig lenses pre-incubated in groups I, and II (placebo and verum) according to Example 1. Prior to the 5 -day incubation, all lenses had shown signs of opacification, even though significantly less so for the lenses incubated in the presence of the drug cysteamine. After the five-day "healing incubation”, the lenses of both groups I and II showed visibly less opacity, suggesting that cysteamine can not only protect the lens from oxidative stress in a prophylactic manner (i.e., prevention), but also that the opacification that occurs over time as a result of the oxidative stress can actually be reduced and reversed in a therapeutic manner (i.e., treatment).

[0071] Figures 6 and 7 depict the lenses’ rigidity after the five-day incubation as both forcedisplacement curves in (i.e., the force required to deform the lens), and lens modulus, respectively; with the lens modulus / rigidity being obtained from the slope of the semilogarithmic force-displacement curve. As can be seen from these figures, after a 5-day incubation in the presence of cysteamine, the rigidity of the "H2O2 stress-hardened” lenses of group I was reduced, while the lenses of group II (the verum group whose rigidity remained unchanged in the experiment of Example 1) showed no changes in rigidity.

[0072] The results thus indicate that thiol drugs, such as cysteamine, can reverse the effects of oxidative stress by restoring elasticity and appearance, but in particular elasticity, in lenses hardened and opacified due to oxidative stress. At the same time, healthy lenses (i.e., clear and with natural flexibility) as well as those prevented from oxidative stress by the prophylactic use of thiol drugs like cysteamine, are not softened further or otherwise affected negatively.

[0073] This renders thiol drugs, and in particular as shown herein cysteamine, suitable drug candidates not only for the prevention but also the treatment of ocular conditions related to the hardening and / or opacification of a crystalline lens of an eye (e.g., presbyopia and / or cataract).

Claims

CLAIMS1. A composition for the prevention and / or treatment of ocular conditions related to the hardening and / or opacification of a crystalline lens of an eye, wherein the composition is a topical ophthalmic composition for direct administration to the eye, and wherein the composition comprises at least one thiol drug or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

2. The composition of claim 1, wherein the composition is used for the prevention and / or treatment of presbyopia.

3. The composition of claim 1, wherein the composition is used for the prevention and / or treatment of cataracts.

4. The composition of claim 1, wherein the composition is an aqueous composition, optionally an aqueous liquid.

5. The composition of claim 1, wherein the composition is an aqueous composition, and wherein the composition further comprises at least one pharmaceutically acceptable metal ion selected from zinc or a pharmaceutically acceptable salt thereof, magnesium or a pharmaceutically acceptable salt thereof, calcium or a pharmaceutically acceptable salt thereof, or a combination of any two or more thereof.

6. The composition of claim 5, wherein the at least one pharmaceutically acceptable metal ion is provided in the form of zinc bromide, zinc chloride, zinc gluconate, zinc acetate, zinc phosphate, magnesium bromide, magnesium gluconate, magnesium acetate, magnesium phosphate, calcium bromide, calcium chloride, calcium gluconate, calcium acetate, or a combination of any two or more thereof.

7. The composition of claim 5, wherein the at least one pharmaceutically acceptable metal ion is provided in the form of zinc chloride.

8. The composition of claim 5, wherein the thiol drug, or the pharmaceutically acceptable salt thereof, is present in the composition in the form of a complex with the metal ion, or the pharmaceutically acceptable salt thereof, and wherein the complex is soluble in the composition.

9. The composition of claim 1, wherein the thiol drug is cysteamine, or a pharmaceutically acceptable salt thereof.

10. The composition of claim 1, further comprising a muscarinic receptor agonist (MRA).

11. A method for the prevention and / or treatment of ocular conditions related to the hardening and / or opacification of a crystalline lens of an eye, said method comprising a step of topically administering directly to the eye(s) of a subject in need thereof one or more doses of an ophthalmic composition comprising at least one thiol drug or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the composition is administered for the prevention and / or treatment of presbyopia.

13. The method of claim 11, wherein the composition is administered for the prevention and / or treatment of cataracts.

14. The method of claim 11, wherein the composition is an aqueous composition, optionally an aqueous liquid.

15. The method of claim 11, wherein the composition is an aqueous composition, and wherein the composition further comprises at least one pharmaceutically acceptable metal ion selected from zinc or a pharmaceutically acceptable salt thereof, magnesium or a pharmaceutically acceptable salt thereof, calcium or a pharmaceutically acceptable salt thereof, or a combination of any two or more thereof.

16. The method of claim 15, wherein the at least one pharmaceutically acceptable metal ion is provided in the form of zinc bromide, zinc chloride, zinc gluconate, zinc acetate, zinc phosphate, magnesium bromide, magnesium gluconate, magnesium acetate, magnesium phosphate, calcium bromide, calcium chloride, calcium gluconate, calcium acetate, or a combination of any two or more thereof.

17. The method of claim 15, wherein the at least one pharmaceutically acceptable metal ion is provided in the form of zinc chloride.

18. The method of claim 15, wherein the thiol drug, or the pharmaceutically acceptable salt thereof, is present in the composition in the form of a complex with the metal ion, or the pharmaceutically acceptable salt thereof, and wherein the complex is soluble in the composition.

19. The method of claim 11, wherein the thiol drug is cysteamine, or a pharmaceutically acceptable salt thereof.

20. The method of claim 11, further comprising a muscarinic receptor agonist (MRA).

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