NZ619229B2 - Topical ophthalmological pharmaceutical composition containing regorafenib - Google Patents

Abstract

Disclosed is a topical ophthalmological pharmaceutical composition containing regorafenib, a hydrate, solvate or pharmaceutically acceptable salt thereof or a polymorph thereof, wherein the regorafenib is suspended in a non-aqueous vehicle. Also disclosed is its process of preparation and its use for treating ophthalmological disorders such as age-related macular degeneration and retinopathy. r treating ophthalmological disorders such as age-related macular degeneration and retinopathy.

Description

Topical Ophthalmological Pharmaceutical Composition containing Regorafenib The present invention relates to topical ophthalmological pharmaceutical compositions containing regorafenib, a hydrate, e or pharmaceutically acceptable salt thereof or a polymorph thereof and its process of preparation and its use for treating ophthalmological disorders.

Regorafenib which is 4{4-[3-(4-chlorotrifluoromethylphenyl)-ureido]fluorophenoxy}- pyridine-Z-carboxylic acid methylamide, a compound of formula (I) CF3 0 Cl\©\ O CH o \ N/ 3 A H N N H H is a potent anti-cancer and anti-angiogenic agent that possesses various activities including inhibitory activity on the VEGFR, PDGFR, raf, p38, and/or fit-3 kinase signalling molecules and it can be used in treating various diseases and conditions like hyper-proliferative ers such as cancers, tumors, lymphomas, sarcomas and leukemias as described in WO 09961.

Furthermore salts of the compound of formula (I) such as its hydrochloride, mesylate and phenylsulfonate are mentioned in WC 05/009961. The monohydrate of the compound of formula (I) is mentioned in W0 08/043446.

Age-related macular degeneration (AMD) is a leading cause dness in the elderly population and is ized as dry and wet AMD (Expert Opin. Ther. Patents (2010), 20(1), 103 , 11). The dry, or nonexudative, form involves both atrophic and hypertrophic s of the retinal pigment epithelium (RPE). The dry form is characterized by macular drusen which are pigmented areas containing dead cells and lic products that distort the retina and eventually cause loss of acute vision. ts with nonexudative AMD (dry form) can ss to the wet, or exudative or neovascular, AMD, in which pathologic choroidal neovascular membranes (CNVM) develop under the , leak fluid and blood, and, ultimately, cause a centrally blinding disciform scar over a vely short time frame if left untreated. Choroidal neovascularization (CNV), the growth of new blood vessels from the choroid capillary network across the Bruch’s membrane/RPE interface [‘0 LII into the neural retina, results in retinal detachment, subretinal and intraretinal edema, and scarring.

Access to the d which is between the sclera and the retina other than via the blood is difficult. The eye is ed of three major anatomic compartments, the anterior chamber, posterior chamber, and vitreous cavity, that have limited physiological interaction with each other.

The retina is located in the back of the us cavity, and is protected from the outside by the sclera which is the white, tough, eable wall of the eye. Choroidal blood flow is the usual method of carrying substances to the choroid and requires e.g. oral or intravenous stration of the drug. Most drugs cannot be red to the choroid by eye drops or a depot in vicinity to the eye. Some drugs have been delivered to the retina and thus to the d by injection into the vitreous r of the eye. The treatment of posterior eye diseases (back of the eye) by easily able topical eye formulations like eye drops is still an unsolved problem.

VEGF (vascular endothelial growth factor) is a key cytokine in the pment of normal blood vessels as well as the development of vessels in tumors and other tissues undergoing abnormal enesis and appears to play a central role in the pathogenesis of CNV formation t Opin.

Ther. Patents (2010), 20(1), 103-118, Expert Opin. Ther. Patents (2009), 18(10), 1573-1580, J.

Clin. Invest. (2010), 120(9), 3033-3041, J. Cell. Physiol. (2008), 216, 29-37, New Engl. J. Med. 2006, 355, 485, , ). Drugs which block the effects of VEGF are described for treating wet AMD such as aptamers like pegaptanib (New Engl. J. Med. 2004, 351, 2805-2816), or VEGF antibodies like ranibizumab (New Engl. J. Med. 2006, 355, 1419- 1431) or bevacizumab (Ophthalmology, 2006, 113, 363-372). However, said drugs have to be administered intravitreally by injection into the eye. Sorafenib, a VEGF inhibitior as well, is bed for treating CNV by oral administration (Clinical and Experimental Ophthalmology, 2010, 38, 718-726). Pazopanib, a VEGF inhibitior as well, is described for treating AMD by topical administration of eye drops containing an aqueous solution of Pazopanib (WO 2011/009016). describes compounds for the treatment of CNV by topical administration of liposomal ations. , US2006257487 describe aqueous ophthalmological formulations for topical administration. describes emulsions for topical administration to the eye.

It is general expert knowledge that usually topical eye drops do not deliver therapeutic levels of drug molecules to the target tissues present at the back of the eye in order to treat posterior eye es (U.B. Kompella and HF. Edelhauser, "Drug Product Development for the Back of the Eye", aapspress Springer, 2011, page 449).

Despite the progress described in the art there remains a need for improved medicines for the treatment of ophthalmological disorders like AMD. In particular, there s a need for topical ophthalmological pharmaceutical compositions like eye drops which can be stered easily and therefore would increase the patient’s compliance. Furthermore there is still the need of applicable topical ophthalmological pharmaceutical compositions for compounds having for example a low solubility which cannot be formulated in a simple on, emulsion, as a complex or in a liposomal formulation. The topical ophthalmological pharmaceutical composition has to e a concentration of the active agent in the eye which is sufficient for an effective therapy.

This is dependent on the solubility and the release behavior of the active agent. In the case of a liquid formulation the dissolution ties and chemical stability of the active agent are of importance. In order to support a high compliance the topical ophthalmological ceutical composition should not have to be taken in more than 5 times a day, the less the better. Type and amount of the excipients in combination with the process of preparation of the pharmaceutical ition are essential for release properties, bioavailability of the active agent in the eye, in ular in the back of the eye (e.g. in the area of the retina, Bruch’s membrane and choroid), stability, compatibility, efficacy and the industrial applicability of the manufacturing process for the topical ophthalmological pharmaceutical composition.

The problem to be solved by the present invention is to e a topical ophthalmological pharmaceutical composition comprising regorafenib as active agent which has a sufficient stability and compatibility and which achieves an effective concentration of regorafenib in the eye, in particular in the back of the eye for the treatment of ophthalmological disorders with sufficient efficacy by avoiding an intravenous or oral administration or injection into or close to the eye (e.g. intravitreal or other injections). r problem to be solved by the present invention is to provide a topical ophthalmological pharmaceutical composition for the treatment of a posterior eye disease.

Regorafenib monohydrate has a limited solubility profile. The thermodynamic solubility of fenib monohydrate in different solvents is shown in table 1: Table 1: Solvent Solubility (mg/ml) Water < 0.] Ligth liquid paraffin Ethanol Polyethylenglycol (PEG) 400 HPB—Cyclodextrin/water (10 : 90) PEG 400/water (30:70) Oleoylpolyethylenglycol ides 3.6 Surprisingly the pharmaceutical composition according to the invention provides by topical administration a sufficient amount of the active agent into the eye which is ive for ng ophthalmological disorders. In particular, the pharmaceutical composition according to the invention provides the active agent in a sufficient amount into the back of the eye, i.e. that the pharmaceutical ition according to the invention effects the transportation of the active agent from the front of the eye to the back of the eye. Furthermore the pharmaceutical composition according to the invention has a sufficient ity without any meaningful degradation of the active agent and is compatible with the eye.

The present invention pertains to a topical ophthalmological pharmaceutical ition comprising regorafenib, the compound of the formula (I), CF3 O Cl O CH O N 3 N N H H F (I) a hydrate, solvate or pharmaceutically acceptable salt of regorafenib, or a polymorph f and at least one pharmaceutically acceptable vehicle and optionally at least one pharmaceutically acceptable excipient.

Preference is given to a topical ophthalmological pharmaceutical composition comprising regorafenib, a e, solvate or pharmaceutically acceptable salt of regorafenib or a polymorph thereof as active agent and at least one pharmaceutically acceptable vehicle and optionally at least one pharmaceutically acceptable ent wherein the composition is a suspension comprising the active agent suspended in the applicable pharmaceutically acceptable vehicle.

A pharmaceutically acceptable vehicle or excipient is any vehicle or excipient which is vely non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active agent so that any side s ascribable to the vehicle or excipient do not vitiate the beneficial s of the active agent. 3_1 (GHMatters) P95703.NZ JENNYP - 4a - The present invention as claimed herein is described in the ing items 1 to 17: 1. A topical lmological pharmaceutical ition comprising regorafenib, a hydrate, solvate or pharmaceutically able salt of regorafenib, or a polymorph thereof as active agent and at least one ceutically able vehicle wherein the composition is a suspension comprising the active agent suspended in the applicable pharmaceutically acceptable vehicle and said vehicle is non-aqueous. 2. The pharmaceutical composition of item 1 containing fenib monohydrate as active agent. 3. The pharmaceutical composition of any of items 1 to 2 wherein the active agent is in a solid form. 4. The pharmaceutical composition of any of items 1 to 3 wherein the active agent is in a crystalline form.

. The pharmaceutical composition of any of items 1 to 4 wherein the active agent is in a microcrystalline form. 6. The pharmaceutical composition of any of items 1 to 5 wherein the concentration of the active agent in the pharmaceutical composition is from 0.01 to 10% by weight of the total amount of the composition. 7. The pharmaceutical composition of any of items 1 to 6 wherein the pharmaceutically acceptable vehicle is selected from the group comprising oleoyl hyleneglycol gylcerides, linoleoyl polyethyleneglycol gylcerides, lauroyl polyethyleneglycol gylcerides, liquid paraffin, light liquid paraffin, soft paraffin (vaseline), hard paraffin, castor oil, peanut oil, sesame oil, middle chain cerides, cetylstearylalcohols, wool fat, glycerol, propylene glycol, polyethyleneglycols (PEG) or a mixture of those. 8. The pharmaceutical composition of any of items 1 to 7 based on a hydrophobic vehicle. 9. The pharmaceutical composition of any of items 1 to 8 wherein the pharmaceutically acceptable vehicle is selected from the group comprising liquid paraffin, light liquid paraffin or a mixture thereof. 3_1 (GHMatters) P95703.NZ JENNYP - 4b - . The pharmaceutical composition of any of items 1 to 9 comprising further pharmaceutically acceptable excipients like stabilizers, surfactants, polymer base carriers like gelling agents, organic co-solvents, pH active ents, osmotic active components and preservatives. 11. The pharmaceutical composition of item 10 n the stabilizer is a hydrophobic silica. 12. The pharmaceutical composition of item 11 comprising hydrophobic silica in an amount of 0.1 % to 10 % by weight of the total composition. 13. A process for manufacturing a ceutical ition according to any of items 1 to 12 n the active agent is suspended in an applicable pharmaceutically acceptable vehicle which is non-aqueous optionally in the presence of further one or more pharmaceutically acceptable excipients and the suspension is homogenized. 14. The pharmaceutical composition of any of items 1 to 12 for the use of treating or preventing an ophthalmological disorder selected from the group comprising age-related macular ration (AMD), choroidal neovascularization (CNV), choroidal cular ne (CNVM), cystoid macula edema (CME), epi-retinal membrane (ERM) and r hole, myopia-associated choroidal neovascularisation, vascular streaks, retinal detachment, diabetic retinopathy, diabetic macular edema (DME), atrophic changes of the retinal pigment epithelium (RPE), hypertrophic changes of the retinal pigment epithelium (RPE), retinal vein ion, choroidal l vein ion, macular edema, macular edema due to retinal vein occlusion, tis tosa, Stargardt’s disease, glaucoma, inflammatory conditions, cataract, refractory anomalies, ceratoconus, retinopathy of prematurity, angiogenesis in the front of the eye, corneal angiogenesis ing keratitis, corneal transplantation or keratoplasty, corneal enesis due to hypoxia (extensive contact lens wearing), pterygium conjunctivae, subretinal edema and intraretinal edema.

. The pharmaceutical composition of item 14 for the use of treating or preventing an ophthalmological disorder selected from the group comprising dry AMD, wet AMD or choroidal neovascularization (CNV). 16. Use of a pharmaceutical composition of any of items 1 to 12, 14 and 15 in the preparation of a medicament for treating or preventing an ophthalmological disorder selected from the group comprising age-related macular degeneration (AMD), choroidal neovascularization 7259893_1 (GHMatters) P95703.NZ JENNYP - 4c - (CNV), choroidal neovascular membrane (CNVM), cystoid macula edema (CME), epiretinal membrane (ERM) and macular hole, myopia-associated choroidal neovascularisation, vascular streaks, retinal detachment, diabetic retinopathy, diabetic r edema (DME), atrophic changes of the retinal pigment epithelium (RPE), hypertrophic s of the retinal pigment epithelium (RPE), l vein ion, choroidal retinal vein ion, macular edema, macular edema due to retinal vein occlusion, retinitis pigmentosa, Stargardt’s disease, glaucoma, inflammatory conditions, cataract, refractory ies, ceratoconus, retinopathy of prematurity, angiogenesis in the front of the eye, corneal enesis following keratitis, corneal transplantation or keratoplasty, corneal angiogenesis due to hypoxia (extensive contact lens wearing), ium conjunctivae, subretinal edema and intraretinal edema. 17. Use of a pharmaceutical composition of any of items 1 to 12, 14 and 15 in the preparation of a ment for treating or preventing an ophthalmological disorder selected from the group comprising dry AMD, wet AMD or choroidal neovascularization (CNV).

The term "the compound of formula (I)" or "regorafenib" refer to 4-{4-[({[4-chloro uoromethyl)phenyl]amino}carbonyl)amino]fluorophenoxy}-N-methylpyridine carboxamide as depicted in formula (I).

The term "compound of the invention" or "active agent" refer to regorafenib, a hydrate, solvate or pharmaceutically acceptable salt of regorafenib, or a polymorph thereof.

Solvates for the purposes of the invention are those forms of the compounds or their salts where solvent molecules form a stoichiometric complex in the solid state and include, but are not limited to for example ethanol and methanol. 7259893_1 (GHMatters) P95703.NZ JENNYP Hydrates are a specific form of solvates, where the solvent molecule is water. Hydrates of the nds of the invention or their salts are stoichiometiic compositions of the compounds or salts with water, such as, for example, hemi-, mono- or dihydrates. Preference is given to the monohydrate of regorafenib.

Sa_lts for the purposes of the present invention are preferably pharmaceutically acceptable salts of the compounds according to the invention. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include salts of inorganic and organic acids, such as hydrochloric acid, romic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid (tosylate salt), 1- naphthalenesulfonic acid, Z-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts e salts of inorganic bases, such as salts ning alkaline cations (e.g., Li+ Na+ or KT), alkaline earth s (e.g., Mg+2 Ca+2 or , the um cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and nary ammonium cations, such as those arising from protonation or peralkylation of triethylamine, NN—diethylamine, NN—dicyclohexylamine, lysine, ne, NN—dimethylaminopyridine (DMAP), 1,4- diazabiclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]nonene (DBN) and 1,8- diazabicyclo[5.4.0]undecene (DBU). Preference is given to the hydrochloride, mesylate or phenylsulfonate salt of regorafenib.

Preferred are regorafenib and the monohydrate of regorafenib, most preferred is regorafenib monohydrate as compounds ofthe present invention.

Due to the low solubility of regorafenib, in particular of regorafenib monohydrate (see table 1) standard solutions are not able. Also ons containing tolerable amounts of emulsifiers, solubilising agents, complex forming excipients etc. are not available to provide for example sufficient ity of regorafenib.

The topical ophthalmological pharmaceutical composition according to the invention comprises the compound ofthe invention, preferably regorafenib, more preferably regorafenib monohydrate in a solid form, preferably in a crystalline form, more preferably in a microcrystalline form. ization can be achieved by standard g methods, preferably by air jet milling, known to a skilled person. The microcrystalline form can have a mean particle size of from 0.5 to 10 um, preferably from 1 to 6 um, more preferably from 1 to 3 um. The indicated particle size is the mean of the particle size distribution measured by laser diffraction known to a skilled person (measuring device: HELOS, Sympatec).

The minimum concentration of the compound ofthe ion, preferably regorafenib, more preferably regorafenib monohydrate in the topical ophthalmological pharmaceutical composition is 0.0] %, preferably 0.2 % by weight of the total amount of the composition. The maximum concentration of the compound of the ion, preferably regorafenib, more preferably regorafenib monohydrate in the topical ophthalmological pharmaceutical composition is 10 %, ably 5 %, more preferably 4 "/0 by weight ofthe total amount ofthe composition.

Preference is given to a concentration of the compound of the present invention in the ceutical composition from 0.1 to 100 mg/ml, preferably from 1 to 50 mg/ml, more preferably from 2 to 40 mg/ml.

Particular preference is given to a concentration ofregorafenib in the pharmaceutical composition from 0.] to 100 mg/ml, preferably from 1 to 50 mg/ml, more preferably from 2 to 40 mg/ml.

Particular preference is given to a pharmaceutical composition resulting from addition of regorafenib monohydrate in amounts from 0.1 to 100 mg/ml, preferably from 1 to 50 mg/ml, more preferably from 2 to 40 mg/ml.

The topical ophthalmological pharmaceutical composition according to the invention includes but is not d to eye drops, gels, ointments, dispersions or suspensions.

Preference is given to a l ophthalmological ceutical composition which is a suspension.

The compound of the invention, preferably regorafenib, more preferably regorafenib monohydrate is used ably in a micronized form.

Micronization can be achieved by standard milling methods, preferably by air jet milling, known to a skilled person. The micronized form can have a mean particle size of from 0.5 to 10 um, preferably from 1 to 6 um, more preferably from 2 to 3 urn. The indicated particle size is the mean of the particle size distribution measured by laser diffraction known to a skilled person ring device: HELO S, Sympatec).

One embodiment of the t invention is a topical ophthalmological ceutical composition which is a suspension sing the compound of the invention, preferably regorafenib, more preferably regorafenib monohydrate in a solid form, preferably in a crystalline form, more preferably in a microfine crystalline form suspended in an applicable pharmaceutically able vehicle, and optionally further comprising one or more pharmaceutically acceptable excipients.

Preference is given to a suspension based on a non—aqueous e, more preferably to a suspension based on a hydrophobic vehicle.

Suitable pharmaceutically acceptable vehicles according to the present invention include but are not limited to oleoyl polyethyleneglycol gylcerides, linoleoyl hyleneglycol gylcerides, lauroyl polyethyleneglycol gylcerides, hydrocarbon vehicles like liquid paraffin (Paraffinum liquidum, mineral oil), light liquid paraffin (low viscosity paraffin, Paraffinum perliquidum, light mineral oil), soft paraffin (vaseline), hard paraffin, vegetable fatty oils like castor oil, peanut oil or sesame oil, synthetic fatty oils like middle chain trigylcerides (MCT, triglycerides with saturated fatty acids, preferably octanoic and decanoic acid), isopropyl myristate, caprylocaproyl macrogol-8 glyceride, caprylocaproyl polyoxyl-8 glycerides, wool alcohols like tearylalcohols, wool fat, glycerol, propylene glycol, propylene glycol diesters of caprylic/capric acid, polyethyleneglycols (PEG), water like an aqueous isotonic sodium chloride solution or a e ofthereof.

Preference is given to non-aqueous pharmaceutically acceptable vehicles which include but are not limited to middle chain trigylcerides (MCT, triglycerides with saturated fatty acids, preferably octanoic and decanoic acid, isopropyl myristate, caprylocaproyl macrogol-8 glyceride, caprylocaproyl polyoxyl-8 glycerides, oleoyl polyethyleneglycol ides, oleoyl macrogol-6 glycerides (Labrafil M 1944 CS), linoleoyl macrogol-6 glycerides (Labrafil M2125 CS = linoleoyl polyoxyl-6 glycerides), lauroyl macrogol-6 glycerides (Labrafil M 2130 CS = lauroyl polyoxyl-6 glycerides», hydrocarbon vehicles, fatty oils like castor oil or a mixture of thereof. Most preferably hydrophobic es are used like hydrocarbon es which include but are not limited to liquid paraffin or light liquid paraffin or a mixture thereof.

Very surprisingly the ceutical composition according to the present invention comprising a lipophilic vehicle like liquid or light liquid paraffin provides by topical administration a sufficient amount of the active agent into the eye which is ive for ng ophthalmological disorders, although the solubility of fenib monohydrate in lipophilic es is very low.

The pharmaceutically acceptable vehicle is the basis of the topical ophthalmological pharmaceutical composition according to the present invention and is t in the composition in a minimum concentration of 75%, preferably 80%, more ably 85% and in a m concentration of 999%, preferably 99%, more preferably 98% by weight ofthe total amount ofthe composition.

The pharmaceutical composition according to the present invention may have different viscosities, so that in principle a range from low-viscosity system to pastes is vable. Preference is given to fluid systems which e low-viscosity and also higher-viscosity systems as long as they still flow under their own weight.

Suitable further pharmaceutically acceptable excipients used in the topical ophthalmological pharmaceutical composition according to the present invention include but are not d to stabilizers, surfactants, polymer based carriers like gelling agents, organic co-solvents, pH active components, osmotic active components and preservatives.

Suitable stabilizers used in the topical ophthalmological pharmaceutical composition according to the present invention include but are not d to colloidal silica, hydrophilic and hydrophobic silicas.

Preference is given to hydrophobic silicas which are silicas which are not wetted by water; this means that they float on the water surface. Likewise suitable are hydrophobicized mixed oxides of n dioxide and um oxide, but hydrophobic pure silicas are preferred. They are produced by mixing hydrophilic silica with silanes (halosilanes, alkoxysilanes, silazanes, siloxanes). This entails silanol groups being alkylated by alkyl groups preferably having one up to 1 8 carbon atoms, particularly preferably having one up to 8 carbon atoms, very particularly preferably having one up to 4 carbon atoms, ally by methyl groups. Examples of silanes used in the production of hydrophobic silicas are thyldisilazane or, preferably, dimethyldichlorosilane. The appropriate hydrophobic silicas may be d from precipitated, dal, precompacted or pyrogenic silicas, with ence for pyrogenic silicas. For example, reaction of a hydrophilic silica with dimethyldichlorosilane s in hydrophobic Aerosil having the proprietary name Aerosil® R 972; this has a degree of methylation of 66% to 75% (determined by titration of the remaining silanol groups).

The hydrophobic silica is ed in the formulations typically in a proportion of 0.1 to 10% by weight, preferably employed with 0.5 to 5%, for e with 2 %, by weight of the total composition.Further suitable stabilizing and/ or gelling agents used in the topical lmic pharmaceutical composition according to the present ion include but are not limited to ene glycol monopalmitostearate, glyceryl monostearate, glyceryl dibehenate, glyceryl distearate, hard fat, nylpyrrolidon, polyethylene, glycerol, polyoxyethylene stearates, sorbitan fatty acid esters, cholesterol, macrogol-20—glycerolmonostearat, poloxamer 124, isopropyl myristate, pyl palmitate, colloidal silica, hydrophobic colloidal silica, magnesium stearate, zinc stearate, ium stearate, lanolin alcohols, organoclays, petrolatum, polyoxyl 6 stearate, Suitable surfactants used in the topical ophthalmological pharmaceutical composition according to the present invention include but are not limited to lipids such as phospholipids, phosphatidylcholines, lecithin, cardiolipins, fatty acids, phosphatidylethanolamines, phosphatides, tyloxapol, polyethylenglycols and derivatives like PEG 400, PEG 1500, PEG 2000, poloxamer 407, poloxamer 188, polysorbate 80, rbate 20, sorbitan laurate, sorbitan stearate, an palmitate or a mixture thereof, preferably polysorbate 80.

Suitable polymer base carriers like gelling agents used in the l ophthalmological pharmaceutical composition according to the present invention include but are not limited to cellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), carboxymethyl cellulose (CMC), methylcellulose (MC), hydroxyethylcellulose (HEC), amylase and derivatives, amylopectins and derivatives, dextran and derivatives, polyvinylpyrrolidone (PVP), polyvinyl l (PVA), and acrylic polymers such as derivatives of polyacrylic or polymethacrylic acid like HEMA, carbopol and derivatives of the before mentioned or a mixture thereof.

Suitable organic co-solvents used in the pharmaceutical composition according to the invention include but are not d to ethylene glycol, propylene glycol, yl pyrrolidone, 2- pyrrolidone, 3-pyrrolidinol, 1,4-butanediol, ylglycol monomethylether, diethyleneglycol monomethylether, solketal, glycerol, polyethylene glycol, polypropylene .

Suitable pH active components such as buffering agents or pH-adjusting agents used in the pharmaceutical composition according to the invention include but are not limited to disodium phosphate, monosodium phosphate, boric acid, sodium , sodium citrate, hydrochloric acid, sodium hydroxide.

The pH active components are chosen based on the target pH for the composition which generally ranges from pH 4 — 9. le osmotic active components used in the pharmaceutical composition according to the invention include but are not limited to sodium chloride, mannitol, ol.

Preservatives used in the pharmaceutical composition according to the invention include but are not limited to benzalkonium chloride, alkyldimethylbenzylammonium chloride, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzethonium chloride, thiomersal, chlorobutanol, benzyl l, phenoxethanol, phenylethyl alcohol, sorbic acid, methyl and propyl parabens, chlorhexidine digluconate, EDTA or mixtures thereof.

Gelling agents, pH active agents and c active agents are preferably used in the case of an aqueous pharmaceutically acceptable e.

The amount of the suitable further pharmaceutically acceptable ent in the suspension according to the t invention can be from 0.1 to 15 %, preferably from 0.5 to 10 %, more preferably from 1 to 5 % by the total weight ofthe suspension.

Preferably the amount of hydroxypropylmethylcellulose in the suspension ing to the present invention can be from 0.05 to 15 %, preferably from 0.1 to 10 %, more preferably from 1 to 5 % by the total weight of the suspension.

Preferably the amount of polysorbate 80 in the suspension according to the present invention can be from 0.05 to 10 %, preferably from 0.1 to 7 %, more ably from 0.5 to 4 % by the total weight of the suspension.

Preference is given to a topical ophthalmological pharmaceutical composition comprising crystalline regorafenib monohydrate, more preferably microcrystalline regorafenib monohydrate in a concentration of for example 0.01 to 10 %, more preferably 0.2 to 5 % weight of the total amount ofthe ition ded in a pharmaceutically acceptable vehicle selected from the group comprising liquid paraffin, light liquid paraffin or a mixture thereof optionally containing hydrophobic silica as stabilizer in an amount of 0.1 % to 10 %, preferably 0.5 to 5 %, for example with 2 %, by weight of the total composition.

Preference is also given to a topical ophthalmological pharmaceutical composition comprising lline fenib monohydrate, more preferably microfine crystalline regorafenib monohydrate in a concentration of for example 0.1 to 10 %, more preferably 0.2 to 5 % weight of the total amount of the composition suspended in oleoyl polyethyleneglycol glyceride as pharmaceutically acceptable vehicle optionally containing hydrophobic silica as stabilizer in an amount of 0.1 % to 10 %, preferably 0.5 to 5 %, for example with 2 %, by weight of the total composition.

The total amount of the active agent to be administered via the l route into the eye using the pharmaceutical composition of the present invention will generally range from about 0.01 to 50 mg, preferably 0.02 to 10 mg, more preferably 0.05 to 5 mg per administration and per eye. Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of ophthalmological disorders, by standard pharmacological assays for the determination of ent of the ions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the pharmaceutical compositions of this invention can readily be determined by those skilled in the art.

The amount of the administered active ingredient can vary Widely according to such considerations as the particular compound and dosage unit employed, the mode and time of stration, the period of ent, the age, sex, and general ion of the patient treated, the nature and extent of the condition treated, the rate of drug metabolism and excretion, the potential drug combinations and drug-drug interactions, and the like.

The pharmaceutical ition according to the ion is administered one or more, preferably up to 5, more preferably up to 3 times per day.

The typical method of administration of the pharmaceutical composition ing to the invention is the topical delivery into the eye.

Nevertheless, it may in some cases be advantageous to deviate from the amounts specified, depending on individual response to the active ingredient, type of preparation and time or al over which the administration is effected. For instance, less than the aforementioned minimum s may be sufficient in some cases, while the upper limit specified has to be exceeded in other cases. In the case of administration of vely large amounts, it may be advisable to divide these into several individual doses over the day.

This ceutical composition will be utilized to e the desired pharmacological effect by preferably topical administration into the eye to a t in need thereof, and will have advantageous properties in terms of drug release, bioavailability, and/or compliance in mammals. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease.

The pharmaceutical composition according to the invention is chemically stable for more than 18 months, preferably more than 24 months. Chemically stable according the present invention means that the active agent does not e significantly (< 1 %) during storage.

In this connection the topical ophthalmological pharmaceutical composition according to the invention contains 4-(4-aminofluorophenoxy)pyridinecarboxylic acid methylamide : 4-(4-aminofluorophen0xy)-N—methylpyridinecarboxamide) (AFP—PMA) in an amount of equal or less than 0.05%, that means from 0.001% to a maximum of 0.05%, preferably in an amount of equal or less than 0.025%, that means from 0.001% to a maximum of 0.025%, most preferably in an amount of equal or less than 0.01%, that means from 0.001% to a maximum of 0.01% by weight based on the amount of the compound of the formula (1).

Process for cturing Various methods can be used to prepare the ophthalmological pharmaceutical ition according to the invention. First the pharmaceutically acceptable vehicle is prepared by optionally mixing the applicable vehicle or mixture of vehicles with the pharmaceutically acceptable excipients. Thereafter the active agent is dispersed or suspended into said mixture. The process may also include sterilization e.g. by sterile precipitation, gamma irradiation, sterile ion, heat sterilization, aseptic filling, or a combination of such optional steps.

The t invention also relates to a process for the manufacturing of a topical ophthalmological ceutical composition according to the invention, wherein the compound of the present 1.1 invention is suspended in an applicable pharmaceutically acceptable vehicle optionally in the presence of further one or more pharmaceutically able ents and the suspension is homogenized.

Preference is given to a process for the manufacturing of a topical ophthalmological pharmaceutical composition according to the invention, wherein a) the applicable pharmaceutically acceptable vehicle or a mixture ofapplicable pharmaceutically acceptable vehicles is prepared by mixing the vehicles ally in the presence of a further one or more ceutically able excipients, b) the compound of the present invention, preferably regorafenib, more preferably regorafenib monohydrate, is suspended into said applicable pharmaceutically acceptable vehicle or mixture for example at room temperature, optionally in the ce of a further one or more pharmaceutically acceptable excipients, c) the suspension is homogenized by stirring, shaking or vortexing, preferably stirring, at room temperature, (1) the suspension is ided into single units and filled into applicable vials, container, tube, flask, dropper and/or syringe.

Optionally in step a) the further one or more ceutically acceptable excipients are added to the applicable pharmaceutically acceptable vehicle at elevated temperatures for example of 40 to 700C.

Method of treating ophthalmological disorders The t invention also relates to a use of the pharmaceutical composition according to the invention to treat or t ophthalmological disorders.

Furthermore the present invention also relates to a method for treating or preventing an ophthalmological disorder comprising administering a pharmaceutical composition containing a pharmaceutically effective amount of an active agent according to the present invention.

Examples of ophthalmological disorders according to the invention include but are not d to age-related macular degeneration (AMD), choroidal neovascularization (CNV), choroidal neovascular ne (CNVM), cystoid macula edema (CME), epi-retinal membrane (ERM) and macular hole, myopia-associated choroidal cularisation, ar streaks, retinal detachment, diabetic retinopathy, diabetic macular edema (DME), atrophic changes of the retinal pigment epithelium (RPE), hypertrophic changes of the retinal pigment epithelium (RPE), retinal vein occlusion, choroidal retinal vein occlusion, r edema, macular edema due to retinal vein occlusion, retinitis pigmentosa, Stargardt’s disease, glaucoma, atory conditions of the eye such as e.g. uveitis, scleritis or endophthalmitis, cataract, refractory anomalies such as e.g. , hyperopia or astigmatism and ceratoconus and retinopathy of prematurity. In addition, examples include but are not limited to angiogenesis in the front of the eye like corneal angiogenesis following e.g. keratitis, corneal transplantation or keratoplasty, corneal angiogenesis due to hypoxia (extensive contact lens wearing), pterygium conjunctivae, subretinal edema and intraretinal edema.Examples of age-related macular degeneration (AMD) include but are not limited to dry or nonexudative AMD, or wet or exudative or neovascular AMD.

Preference is given to age-related macular ration (AMD) like dry AMD, wet AMD or choroidal neovascularization (CNV).

Another embodiment or the present invention is a topical ophthalmological pharmaceutical composition for the treatment or prevention of a posterior eye disease n the composition is a suspension comprising an active agent applicable for the treatment or prevention of a posterior eye disease ded in a applicable pharmaceutically acceptable vehicle. ence is given to a sion based on a non-aqueous vehicle, more preferably to a suspension based on a hydrophobic e.

Examples of ior eye diseases include but are not limited to age-related macular degeneration (AMD), choroidal neovascularization (CNV), choroidal cular membrane (CNVM), d macula edema (CME), epi-retinal membrane (ERM) and macular hole, myopia-associated choroidal neovascularisation, vascular streaks, retinal detachment, ic retinopathy, diabetic macular edema (DME), atrophic s of the retinal pigment epithelium (RPE), hypertrophic changes of the retinal pigment epithelium (RPE), retinal vein occlusion, choroidal retinal vein occlusion, macular edema, macular edema due to retinal vein occlusion, retinitis tosa, Stargardt’s disease and retinopathy of prematurity.

Preferred posterior eye es include age-related macular degeneration (AMD) like dry AMD, wet AMD or choroidal cularization (CNV).

Examples of age-related macular degeneration (AMD) include but are not limited to dry or nonexudative AMD, or wet or exudative or neovascular AMD, Active agents applicable for the treatment or prevention of a ior eye disease according to the present invention e but are not limited to signal transduction inhibitors targeting receptor kinases of the domain families of e.g. VEGFR, PDGFR, FGFR and their respective ligands or other pathway inhibitors like VEGF-Trap rcept), pegaptanib, ranibizumab, pazopanib, bevasiranib, KH-902, mecamylamine, PF-04523655, E-10030, ACU—4429, volociximab, sirolismus, fenretinide, disulfiram, sonepcizumab, regorafenib, sorafenib and/or tandospirone. These agents include, by no way of limitation, antibodies such as Avastin (bevacizumab). These agents also include, by no way of limitation, small-molecule inhibitors such as STI-571 / Gleevec (Zvelebil, Curr. Opin. Oncol, Endocr.

Metab. Invest. Drugs 2000, 2(1), 74-82), PTK-787 (Wood et al., Cancer Res. 2000, 60(8), 2178-2189), SU-11248 (Demetri et al., dings of the American y for Clinical Oncology 2004, 23, ct 3001), ZD-6474 quin et al., 92nd AACR Meeting, New Orleans, March 24-28, 2001, abstract 3152), AG-13736 (Herbst et al., Clin. Cancer Res. 2003, 9, 16 (suppl 1), ct C253), KRN- 951 (Taguchi et al., 95th AACR Meeting, Orlando, FL, 2004, abstract 2575), CP-547,632 (Beebe et al., Cancer Res. 2003, 63, 7301-7309), CP-673,451 (Roberts et al., dings of the American Association of Cancer Research 2004, 45, abstract 3989), CHIR-258 (Lee et al., dings of the American Association of Cancer ch 2004, 45, ct 2130), MLN—S 18 (Shen et al., Blood 2003, 102, 11, abstract 476), and AZD-2171 (Hennequin et al., dings of the American Association of Cancer Research 2004, 45, abstract 4539), PKC412, nepafenac.

Preference is given to regorafenib, bevacizumab, afiibercept, pegaptanib, ranibizumab, pazopanib and/or bevasiranib.

Suitable pharmaceutically acceptable vehicles according to the present invention include but are not limited to oleoyl polyethyleneglycol gylcerides, linoleoyl polyethyleneglycol gylcerides, lauroyl polyethyleneglycol ides, hydrocarbon vehicles like liquid paraffin (Paraffinum liquidum, mineral oil), light liquid paraffin (low viscosity paraffin, Paraffinum perliquidum, light mineral oil), soft paraffin ine), hard paraffin, vegetable fatty oils like castor oil, peanut oil or sesame oil, synthetic fatty oils like middle chain trigylcerides (MCT, triglycerides with saturated fatty acids, preferably octanoic and decanoic acid), isopropyl myristate, caprylocaproyl macrogol-8 glyceride, caprylocaproyl polyoxyl-8 glycerides, wool alcohols like cetylstearylalcohols, wool fat, glycerol, propylene glycol, propylene glycol diesters of caprylic/capric acid, polyethyleneglycols (PEG) or a mixture of thereof.

Preference is given to non-aqueous pharmaceutically acceptable vehicles which include but are not limited to middle chain trigylcerides (MCT, triglycerides with saturated fatty acids, preferably octanoic and decanoic acid, isopropyl myristate, caprylocaproyl macrogol-8 glyceride, ocaproyl polyoxyl-8 glycerides, oleoyl polyethyleneglycol glycerides, oleoyl macrogol-6 glycerides (Labrafil M 1944 CS), linoleoyl macrogol-6 glycerides (Labrafil M2125 CS = oyl polyoxyl-6 glycerides), lauroyl macrogol-6 glycerides (Labrafil M 2130 CS = l polyoxyl-6 glycerides)), hydrocarbon vehicles, fatty oils like castor oil or a e of thereof. Most ably hydrophobic vehicles are used like hydrocarbon vehicles which include but are not limited to liquid paraffin or light liquid n or a mixture thereof.

Very surprisingly the suspension according to the present invention comprising a lipophilic vehicle like liquid or light liquid paraffin es by topical administration a sufficient amount of the active agent to the back of the eye which is effective for treating a posterior eye disease.

Suitable r pharmaceutically acceptable excipients used in the topical ophthalmological ceutical composition according to the present invention include but are not limited to stabilizers, surfactants, polymer based carriers like gelling , organic co-solvents, pH active components, osmotic active components and preservatives.

Suitable stabilizers used in the topical ophthalmological pharmaceutical composition according to the present invention include but are not limited to colloidal silica, hydrophilic and hydrophobic silicas.

Preference is given to hydrophobic silicas.

The pharmaceutically acceptable vehicle is the basis of the topical ophthalmological pharmaceutical ition ing to the present invention and is present in the composition in a minimum concentration of 75%, preferably 80%, more preferably 85% and in a maximum concentration of 999%, preferably 99%, more preferably 98% by weight of the total amount of the itionThe active ingredient used in the topical ophthalmological pharmaceutical composition is used preferably in a micronized form. ization can be achieved by rd milling methods, preferably by air jet g, known to a skilled person. The micronized form can have a mean particle size of from 0.5 to 10 um, preferably from 1 to 6 pm, more preferably from 2 to 3 urn. The indicated particle size is the mean of the le size distribution measured by laser diffraction known to a skilled person (measuring device: HELO S, Sympatec).

The concentration ofthe active ingredient in the ceutical composition is from 0.1 to 100 mg/ml, preferably from 1 to 50 mg/ml, more preferably from 2 to 40 mg/ml.

The pharmaceutical ition according to the invention can be administered as the sole pharmaceutical composition or in combination with one or more other pharmaceutical compositions or active agents where the combination causes no unacceptable adverse effects.

"Combination" means for the purposes of the invention not only a dosage form which contains all the active agents (so-called fixed combinations), and combination packs ning the active agents separate from one another, but also active agents which are administered simultaneously or sequentially, as long as they are employed for the prophylaxis or treatment of the same disease.

Since the combination according to the ion is well tolerated and is potentially effective even in low dosages, a Wide range of formulation variants is possible. Thus, one possibility is to formulate the individual active ingredients of the combination ing to the invention separately. In this case, it is not absolutely necessary for the individual active ingredients to be taken at the same time; on the contrary, sequential intake may be advantageous to e optimal effects. It is appropriate with such separate administration to combine the formulations of the individual active ingredients simultaneously er in a suitable primary packaging. The active ingredients are present in the primary packaging in each case in separate containers which may be, for e, tubes, bottles or blister packs. Such separate packaging of the components in the joint primary packaging is also ed to as a kit.

In one embodiment, the pharmaceutical compositions of the present invention can be combined with other ophthalmological agents. Examples of such agents include but are not d to carotenoids like lycopene, lutein, zeaxanthin, phytoene, phytofluene, carnosic acid and derivatives thereof like ol, 6,7-dehydrocarnosic acid 7-ketocarnosic acid, a zink source like zinc oxide or a zinc salt like its chloride, acetate, ate, ate, sulphate, borate, nitrate or silicate salt, copper oxide, vitamin A, n C, vitamin E and/or B-carotene.

In another embodiment, the pharmaceutical itions of the present invention can be combined with other signal transduction tors targeting receptor kinases of the domain families of e.g.

VEGFR, PDGFR, FGFR and their respective ligands or other pathway inhibitors like VEGF-Trap (aflibercept), pegaptanib, ranibizumab, pazopanib, bevasiranib, KH-902, mecamylamine, PF- 04523655, E-10030, 29, volociximab, sirolismus, fenretinide, disulfiram, sonepcizumab and/or tandospirone. These agents include, by no way of limitation, dies such as Avastin (bevacizumab).

These agents also e, by no way of limitation, small-molecule inhibitors such as STI-571 / Gleevec (Zvelebil, Curr. Opin. Oncol, Endocr. Metab. Invest. Drugs 2000, 2(1), 74-82), PTK-787 (Wood et al., Cancer Res. 2000, 60(8), 2178—2189), SU—11248 (Demetri et al., Proceedings of the an Society for Clinical Oncology 2004, 23, abstract 3001), ZD-6474 (Hennequin et al., 92nd AACR Meeting, New Orleans, March 24-28, 2001, abstract 3152), AG-13736 (Herbst et al., Clin.

Cancer Res. 2003, 9, 16 (suppl 1), abstract C253), KRN—951 (Taguchi et al., 95th AACR Meeting, Orlando, FL, 2004, abstract 2575), CP-547,632 (Beebe et al., Cancer Res. 2003, 63, 7301-7309), CP- 673,451 (Roberts et al., Proceedings of the American Association of Cancer Research 2004, 45, abstract 3989), CHIR-258 (Lee et al., Proceedings of the American Association of Cancer Research 2004, 45, ct 2130), MLN—5 18 (Shen et al., Blood 2003, 102, 11, abstract 476), and AZD-2171 (Hennequin et al., Proceedings of the American Association of Cancer Research 2004, 45, abstract 4539), PKC412, nepafenac.

Preference is given to a ation with zumab, aflibercept, pegaptanib, zumab, pazopanib and/or bevasiranib.

Generally, the use of the other ophthalmological agents in combination with the pharmaceutical compositions ofthe present invention will serve to: (1) yield better efficacy as compared to administration of either agent alone, (2) e for the administration of lesser amounts of the administered agents, (3) provide for treating a broader spectrum ofmammals, especially humans, (4) provide for a higher response rate among treated patients, (5) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other agent combinations produce antagonistic effects. It is believed that one skilled in the art, using the preceding information and information available in the art, can utilize the present invention to its t extent.

It should be apparent to one of ordinary skill in the art that changes and modifications can be made to this invention without ing from the spirit or scope of the invention as it is set forth herein.

All ations, applications and patents cited above and below are orated herein by reference.

The weight data are, unless stated otherwise, percentages by weight and parts are parts by weight.

HPLC Methods: Two separate HPLC methods were developed for the determination of regorafenib content, unidentified degradation products and unidentified secondary components, as well as for the determination of the specific degradation product 4-(4-aminofluor0phenoxy)pyridine carboxylic acid methylamide (AFP-PMA), respectively, within pharmaceutical formulations. 1) HPLC method for the determination of regorafenib content, unidentified secondary components, and unidentified ation products: Samples were prepared by dilution of drawn formulation aliquots with water/acetonitrile (25/75) to a final regorafenib concentration of ml. 10u1 of each sample were injected into an Agilent 1100 HPLC system (Agilent, Waldbronn, y), and samples were run on a heated (400C) Symmetry C18 column (150 x 4,6mm - 3,5um particle size, Waters, Eschborn, Germany) applying a flow rate of 1ml/min. The mobile phase consisted of a e of potassium phosphate buffer pH 2.4 (A) and acetonitrile/ethanol (6/4) (B). The following gradient was applied: minute 0: A, 60% / B, 40%; minute 12: A, 20% / B, 80%; minute 16: A, 20% / B, 80%; minute 16.5: A, 60% / B, 40%; minute 20: A, 60% / B, 40%. Regorafenib, unidentified secondary components, and unidentified degradation products were fied using a DAD detector at a wavelength of 265 nm. Regorafenib content (column 3 in tables below) within formulations was quantified by using an external t calibration straight line. Unidentified secondary ents and unidentified degradation products (columns 5-7 in tables below) are described as % of summarized sample-related peak areas. Precision of the system was ined with each sample set run, by six times injection of a 100% regorafenib standard (e.g. 100ug/ml), coefficient of variation of peak areas resulting from these six injections was always below 2%.

Relative Y-axis intercept of a 2-point (e.g. 5 011g/ml, 100ug/ml) calibration straight line was always below 3% (referring to 100% fenib standard). The regorafenib peak appears at 11.5 minutes.

Alternatively (examples 3 - 5), the content of regorafenib and its degradation products is determined by a different but similar HPLC method, using 100 mm x 4.6 mm reversed phase columns (YMC Pack Pro RS C18, 3 pm particle size). Samples of 5 ul with a nominal t of 0.16 mg/ml were ed and eluted with a mobile phase gradient consisting of trifluoro acetic acid (2 ml per liter of water) (A) and acetonitrile (B) at a flow rate of 1.0 ml/min. The following gradient conditions were applied: 0 - 1 min 75% A / 25 % B; until 3.5 min d to 50 % A / 50 % B; until 11.5 min changed to 43 % A / 57 % B; until 13 min changed to 15 % A / 85 % B and kept until 16 min at 15 % A / 85 % B, followed by re-equilibration to 75% A /’ 25 % B. The column temperature was 40°C and the detection ngth was 260 nm (using diode array detection). The quantitation of regorafenib was done via external standard with 3-point calibration. The degradation products are quantified using the same calibration on obtained with fenib reference standard. This HPLC method is fully validated for a solid oral dosage for containing regorafenib and meets all requirements with respect to selectivity, precision, ity and robustness. The elution time for the regorafenib peak is about the same as for the method described above 2) HPLC method for the ination of the specific degradation product 4-(4-amino fluorophenoxy)pyridinecarboxylic acid methylamide (IUPAC: 4-(4-aminofluorophenoxy)-N— methylpyridinecarboxamide) (AFP-PMA). Samples were prepared by dilution of drawn formulation aliquots with aceton to a final regorafenib concentration of 3000ug/ml. 15 ul of each sample were injected into an Agilent 1100 HPLC system (Agilent, Waldbronn, Germany), and samples kept at 100 in the autosampler were run on a Symmetry C18 column (150 x 4,6mm - 3,5um particle size, Waters, Eschbom, Germany) held at 200C with a flow rate of 1ml/min. The mobile phase consisted of a mixture of potassium phosphate buffer pH 2.4 (A) and acetonitrile/ethanol (6/4) (B). The ing gradient was applied: minute 0: A, 62% / B, 38%; minute 5: A, 44% / B, 56%; minute 5.01: A, 15% / B, 85%; minute 9: A, 15% /’ B, 85%; minute 9.01: A, 62% / B, 38%; minute 12: A, 62% / B, 38%, 4-(4-amino—3-fluorophenoxy)pyridine carboxylic acid methylamide (column 4 in tables below) was quantified using a DAD detector at a wavelength of 232 nm, referring to an external 3-point (e.g. 0.04ug/ml, 0.1ug/ml, lug/ml) calibration straight line. The 4-(4-aminofluorophenoxy)pyridinecarboxylic acid amide peak appears at 3.9 minutes, Limit of detection (LOD) and limit of fication (LOQ) of 4-(4— amino-3 ophenoxy)pyridinecarboxylic acid methylamide were determined for two different matrices (water and paraffin), and were: LOD: 4ppm = 0,0004% (water), 13ppm = 0,0013% (paraffin); LOQ: 13ppm = 0,0013% (water) and 43ppm = 0,0043% fin).

Example 1: Ophthalmological suspension comprising regorafenib monohydrate in oleoyl polyethyleneglycol glyceride (20 mg/ml) 200 mg of micronized regorafenib monohydrate was suspended in oleoyl polyethyleneglycol glyceride (10 ml). The suspension was homogenized by stirring at room temperature for 15 minutes.

Stability of regorafenib in oleoyl polyethyleneglycol glyceride was tested at a concentration of 3 mg/ml over 4 weeks at 250C, 60% relative humidity (r.h,) and 400C, 75% r,h,, Regorafenib content ranged between 95 .0-101% of theoretical concentration, t unidentified degradation product ranged from 0.3 to 0.7%. 4-(4-aminofluorophenoxy)pyridinecarboxylic acid methylamide (AFP-PMA) content was below < 13 ppm = 0,0013% (< LOD determined for paraffin based formulation, Table 2). For analytical details see HPLC Method section above.

Table 2. Content and stability of regorafenib within oleoyl polyethyleneglycol glyceride based formulation : e regorafenib AFP-PMA Largest t Largest condition content (% t (% unidentified unidentified unidentified of referring to ary secondary degradation theoretical), Regorafenib) component component product in via external via external in rd in sample , sample (% ation calibration (% of (% of of summarized summarized summarized peak areas) peak areas) peak areas) 0.04 °C/ 60% r.h. 250C/ . 0.04 60%r.h. 40°C/ . 0.04 75%r.h.

Example 2: Ophthalmological suspension comprising regorafenib monohydrate in liquid paraffin (20 mg/ml) 400 mg of micronized regorafenib monohydrate was suspended in 20 ml of light liquid paraffin.

The suspension was homogenized by stirring at room temperature for 15 minutes. ity of the sion was tested at a concentration of l over 13 weeks at 250C, 60% relative humidity (r.h.) and 40°C, 75% r.h.. Regorafenib content ranged between 74.8-99.6% of theoretical concentration. The observed fluctuation is most likely due to inhomogeneity of the sample after manual shaking of the suspension. No unidentified ation product was observed in chromatograms. AFP—PMA content was below < 43 ppm = 0.0043% (< LOQ determined for paraffin based formulation, Table 3). For analytical s see Analytics section above.

Table 3. t and stability ofregorafenib within paraffin based formulation.

Storage regorafenib AFP-PMA Largest Largest t condition content (% content (% unidentified unidentified unidentified of referring to secondary secondary degradation theoretical), Regorafenib) component component product in via external via external in standard in sample , sample (9/0 calibration calibration (% of (% of of summarized summarized summarized peak areas) peak areas) peak areas) 0.04 0.04 %r.h. 4 weeks 40°C/75 %r.h. %r.h. 40°C/75 %r.h.

Example 3: Ophthalmological suspension comprising regorafenib monohydrate and 0.5% hydrophobic dal silica in liquid paraffin (20 mg/ml) 0.25 g of hydrophobic colloidal silica (Aerosil® R972) was dispersed in light liquid paraffin (50 ml) by stirring at room temperature to prepare the suspending vehicle (0.5% (W/v) hydrophobic colloidal silica in light liquid paraffin). 200 mg of regorafenib monohydrate was added to an aliquot of the suspending vehicle (10 ml) and the suspension was homogenized for 45 min. using a vibration mill at a frequency of 9.1 s].

Afterwards, the suspension was filled into glass vials (approximately 6 ml per vial) and the vials were closed with rubber stoppers and sealed with aluminium crimp caps.

Stability of the sion was tested over 4 weeks at 4°C, room temperature (approx. 25°C) and 40°C/ 75% relative humidity (see Table 4). The variation and apparent higher concentrations relating to the nominal content en 100 and 125 %) is most likely due to an artefact in sample ation for analytics. The mode of sample preparation of silica-containing sions has been optimized subsequently as bed in example 4 b).

Table 4. Content and stability of Regorafenib within Example 3 formulation Content Degradation Content AFP-PMA Degradation RegorafenibI product/ I I _ Storage conditionI fenib1 content products/ (% of max. single (g/1) 0%)) Sum (04)) nominal). (%) 21.07 109.3 0.05 <0.005 0.05 24.13 125.2 0.05 40°C/ 75 % r.h. 19.41 100.7 <0.05 1 based on anhydrous drug substance Example 4: Ophthalmological suspension comprising regorafenib monohydrate and 2% hydrophobic dal silica in liquid paraffin (20 mg/ml) 1 g of hydrophobic colloidal silica il® R972) was dispersed in light liquid paraffin (50 mL) by stirring at room temperature to prepare the suspending vehicle (2% (w/v) hydrophobic dal silica in light liquid paraffin). 200 mg of regorafenib monohydrate was added to an aliquot of the suspending e (10 mL) and the suspension was homogenized for 45 min. using a vibration mill at a ncy of 9.1 s'].

Afterwards, the suspension was filled into glass vials (approximately 6 mL per vial) and the vials were closed with rubber stoppers and sealed with aluminium crimp caps.

Stability of the suspension was tested over 4 weeks at 4°C, room temperature (approx. 250C) and 40°C/ 75% relative ty (see Table 5). The variation and apparent higher concentrations relating to the nominal content (between 104 and 118 %) is most likely due to an ct in sample preparation for analytics. The mode of sample preparation of silica-containing suspensions has been optimized subsequently as described in example 4 b).

Table 5. Content and stability of fenib within Example 4 a) formulation Content Degradation Content AFP-PMA Degradation Storage RegorafembI product/ Regorafenib1. content products/ ion. I (% of I max. Single (g/I) sum (%> nominal). (%) 4°C 20.01 103.8 <0.05 <0.05 21.84 113.3 0.05 0.05 40°C/ 75 % 117.6 0.05 0.05 r.h. 1 based on anhydrous drug substance g of hydrophobic colloidal silica (Aerosil® R972) was dispersed in light liquid paraffin (500 mL) at room temperature for 15 minutes using a high shear mixer (10230 rpm) to prepare the suspending vehicle (2% (w/v) hydrophobic colloidal silica in light liquid paraffin). 9 g of regorafenib monohydrate was added to an aliquot of the suspending vehicle (450 mL) and the suspension was homogenized for 45 minutes using a high shear mixer (10230 rpm).

The suspension was filled into glass vials (5 mL per vial) and the vials were closed with rubber stoppers and sealed with aluminium crimp caps. Afterwards, the vials were ated by gamma- radiation at an effective dose of 27.9 kGy.

Stability of the radiated suspension was tested over 4 weeks at 40°C/ 75% relative humidity (see Table 6). The mode of sample preparation of silica-containing suspensions was optimized at this time point. The content of Regorafenib ranged between 98 and 103 % of the nominal t. AFP— PMA content was below 0.005 % (50 ppm).

Table 6. Content and stability of Regorafenib within Example 4 b) formulation Gamma Content Deg radatio AFP- Storage Content Degradatio radiatio Regorafeni n prod uct/ PMA conditio Regorafenib n products/ n (27.9 b (% of max. single content 1 (9") sum (%) kGy) l) (%) (%) 0.05 <0.005 0.05 0.05 <0.005 0.05 <0.005 1 based on anhydrous drug substance Example 5: Ophthalmological suspension comprising fenib monohydrate and 5% hydrophobic colloidal silica in liquid paraffin (20 mg/ml) 2.5 g of hydrophobic dal silica (Aerosil® R972) was dispersed in light liquid paraffin (50 mL) by stirring at room temperature to prepare the suspending vehicle (5% (w/v) hydrophobic colloidal silica in light liquid paraffin). 200 mg of regorafenib monohydrate was added to an aliquot of the suspending vehicle (10 mL) and the suspension was homogenized for 45 min. using a vibration mill at a frequency of 9.] s'l.

Afterwards, the suspension was filled into glass vials (approximately 6 mL per vial) and the vials were closed with rubber stoppers and sealed with aluminium crimp caps.

Stability of the suspension was tested over 4 weeks at 4°C, room temperature (approx. 250C) and 40°C/ 75% relative humidity (see Table 7). The variation in the content en 99 and 97 %) is most likely due to an artefact in sample preparation for analytics. The mode of sample preparation of silica-containing suspensions has been optimized subsequently as described in e 4 b).

Table 7. Content and stability of Regorafenib within Example 5 ation Content Degradation Content AFP-PMA Degradation.

Regorafenib. product/ e condition fenib1 content products/ (% of max. single (gm (%) sum (%) nominal) (%) RT 18.55 96.2 <0.05 <0.005 <0.05 40°C/ 75 % r.h. 18.76 97.3 <0.05 <0.005 <0.05 J 1 based on anhydrous drug substance Example 6: Ophthalmological suspension comprising regorafenib monohydrate in water based vehicle (20 mg/ml) 1.7 g of ypropymethylcellulose 15 cp (HPMC) was dispersed in isotonic sodium chloride on (48 g, 0.9% NaCl in water) at 700C. The mixture was cooled down to room temperature while stirring. At room temperature ated water, and subsequently polysorbate 80 (0.5 g) was added and dissolved under moderate stirring. 518 mg of regorafenib monohydrate was added to an aliquot of the prepared e (245g) and the suspension was homogenized by gently stirring at room temperature for 15 minutes.

Stability of the suspension was tested at a concentration of 10 mg/ml over 13 weeks at 25°C, 60% relative humidity (r.h.) and 40°C, 75% r.h.. fenib content ranged between 2% of theoretical concentration. The observed fluctuation is most likely due to inhomogeneity of the sample after manual shaking of the suspension. Largest unidentified degradation product was < 0.1% of summarized sample related peak areas. Amount of A was determined only after 9 weeks storage.

Table 8. Content and Stability of Regorafenib within water based formulation. e regorafenib AFP-PMA Largest Largest Largest condition content (% content (% unidentified unidentified unidentified of referring to secondary secondary degradation tical), Regorafenib) component component product in via external via external in standard in sample , sample (% calibration calibration (% of (% of of summarized summarized summarized peak areas) peak areas) peak areas) In 103 0.04 0.04 °C/60 %r.h. 40°C/75 112 %r.h.

°C/60 %r.h. %r.h.

°C/60 %r.h. 40°C/75 %r.h.

In tables 2, 3 and 8 above column 5 describes the percental amount of the largest unidentified secondary ent in the standard used, in the HPLC method to be compared With the value of column 6 Which describes the percental amount of the same unidentified secondary component in the formulation. Column 7 describes the percental amount of the largest unidentified degradation product in the formulation which is not AFP-PMA. Said degradation product is not able in the rd but is formed in the formulation.

Example 7: Ophthalmological suspension comprising regorafenib monohydrate in middle chain triglycerides (MCT, miglyol) (20 mg/ml) Example 7 was prepared according to example 1.

Table 9. Content and stability of regorafenib Within MCT- based formulation. 1—!— 2 T 3 1—4 5 6 if] Storage Storage regorafenib AFP—PMA t Largest t con— content (% content (% unidentified unidentified unidentified dition of referring to secondary secondary degradation theoretical), Regorafenib) component component product in Via external Via external in standard in sample (% , sample (% of ation calibration (% of of summarized summarized summarized peak areas) peak areas) peak areas) °C/60 %r.h. 40°C/75 %r.h. %r.h. 40°C/75 %r.h.

Example 8: Ophthalmological suspension comprising regorafenib monohydrate in oculentum simplex (20 mg/g) 100 mg of micronized regorafenib monohydrate was suspended in 4900 mg oculentum x (composition: cholesterole 1%, liquid paraffin 42.5%, soft paraffin 56.5% by weight). The suspension was nized by stirring at room temperature in an Agate motar for approximately Example 9: Topical efficacy of different formulations containing regorafenib in the laser- induced choroidal neovascularization gCNYL model The aim of this study was to determine whether twice daily topical administration (eye drops) of the topical ophthalmological pharmaceutical compositions according to the invention results in a decrease of vascular e and/or choroidal neovascularization in a rat model of laser-induced choroidal neovascularisation (Dobi et al, Arch. Ophthalmol. 1989, , 264-269 or Frank et al, Curr. Eye Res. 1989 Mar, 8(3), 239-247) For this purpose, a total of 133 pigmented Brown-Norway rats with no visible sign of ocular defects were selected and randomly assigned to eight groups of six to eight animals each. On day 0, the animals were anaesthetized by an intraperitoneal injection (15 mg / kg xylazine and 80 mg / kg ne lved in water containing 5 mg/ml chlorobutanol hemihydrate and propylenglycol) After lation of one drop of 0.5 % atropin (dissolved in 0.9 % saline containing Benzalkoniumchloride) to dilate the pupils, choroidal neovascularisation was induced by burning six holes in the retina (disruption of Bruch’s membrane) of one eye per animal (lesion size: 50 um, laser intensity: 150 mW; stimulus duration: 100 ms) using a 532 nm argon laser.

The following formulations were included: a) 100 % oleoyl polyethyleneglycol glycerides as used in example 1 le l), b) Example 1 (20 mg/ml, suspension), n=8 c) 100 % light liquid paraffin as used in example 2 (vehicle control), n=8 (1) Example 2 (20 mg/ml, suspension), n=8 e) Water-based vehicle (Hydroxypropymethylcellulose 15 cp 3.5%, polysorbate 80 0.5%, isotonic NaCl solution 96% as used in example 6 (vehicle l), n=6 f) Example 6 (20 mg/ml, sion), n=6 g) 0.5 % hydrophobic colloidal silica in liquid paraffin as used in example 3 (vehicle control), n=10 11) Example 3 (20 mg/ml, suspension), n=10 i) 2.0% hydrophobic colloidal silica in liquid paraffin as used in example 4 (vehicle control), n=10 j) Example 4 (20 mg/ml, sion), n=10 k) 5.0% hydrophobic colloidal silica in liquid paraffin as used in example 5 (vehicle control), n=10 1) Example 5 (20 mg/ml, suspension), n=10 m) 100 % Miglyol as used in example 7 (vehicle control), n=8 n) Example 7 (20 mg/ml, suspension), n=7 0) 100 "/0 oculentum simplex as used in e 8 (vehicle control), n=8 p) Example 8 (20 mg/g, suspension), n=6 Of each formulation, 10 ul were applied to the ed eye twice daily at an 10:14 hour interval during the complete observation period of 23 days. The body weight of all animals was recorded before the start and once daily during the study. An angiography was performed on day 21 using a fluorescence fundus camera (Kowe Genesis Df, Japan). Here, after anesthesia and pupillary dilation, 10 % sodium cein (dye, ved in water) was subcutaneously ed and pictures were recorded approximately 2 min after dye injection. The vascular leakage of the fluorescein on the rams was evaluated by three different ers who were blinded for group allocation (examples 1 to 3 versus respective vehicle). Each lesion was scored with 0 (no leakage) to 3 (strongly stained), and a mean from all 6 lesions was used as the value for the respective animal. On day 23, s were sacrificed and eyes were harvested and fixed in 4% paraformaldehyde solution for 1 hour at room temperature. After washing, the retina was carefully peeled, and the sclera-choroid complex was washed, blocked and stained with a FITC-isolectine B4 antibody in order to visualize the vasculature. Then, the sclera-choroids were flat-mounted and examined under a fluorescence microscope (Keyence Biozero) at 488 nm excitation wavelength.

The area (in umz) of choroidal neovascularization was measured using ImageTool software.

Results: A) Efficacy ing vascular leakage (angiography scores day 21): Fig. 1: Angiography scores of vehicle (oleoyl polyethyleneglycol glycerides (Labrafil), formulation a) and regorafenib (example 1, formulation b) treated s at day 21. Data are presented as mean i SD, p—value according to . N=8 per group.

Table 10: Raw data of the histogram depicted in Fig. 1. Single values represent the means from three different observers blinded with respect to treatment.

Animal 100% oleoyl polyethyleneglycol glycerides Example 1 (formulation b) (formulation a) 1.80 Fig. 2: Angiography scores of vehicle (paraffin, formulation c) and regorafenib (example 2, formulation d) treated animals at day 21. Data are presented as mean :‘t SD, p-value according to t- test. N=8 per group.

Table 11: Raw data of the histogram depicted in Fig. 2. Single values represent the means from three different observers blinded with respect to treatment.

Animal 100% paraffin (formulation c) Example 2 (formulation (1) 1 2.33 2 1.77 3 1.50 4 1.91 2.21 6 2.06 \l 2.10 DO 2.54 Fig. 3: Angiography scores of vehicle (water based, formulation e) and regorafenib (example 3, formulation f) d s at day 21. Data are presented as mean i SD, p—value according to t- test. N=6 per group.

Table 12: Raw data of the histogram depicted in Fig. 3. Single values represent the means from three different observers d with respect to treatment.

I Animal Formulation e Example 3 (formulation 1) 1 1.61 1.78 2 1.78 1.60 3 1.93 1.34 4 2.27 2.00 1.49 0.80 6 2.10 2.20 B) Efficacy ing neovascularization (neovascular area day 23): Fig. 4: Neovascular area of e (oleoyl polyethyleneglycol glycerides (Labrafil), formulation a) and regorafenib (example 1, formulation b) treated animals at day 23. Data are presented as mean 2‘: SD, p-value according to t-test. N=8 per group.

Table 13: Raw data of the histogram depicted in Fig. 4. Single values represent the means from all six s. 100 "/0 oleoyl polyethyleneglycol Example 1 (formulation 1)) glycerides (formulation a) 134507 69696 103307 Fig. 5: Neovascular area of vehicle (paraffin, formulation 0) and regorafenib (example 2, formulation d) treated animals at day 23. Data are presented as mean i SD, p-value according to t- test. N=8 per group.

Table 14: Raw data of the histogram depicted in Fig. 5. Single values represent the means from all six lesions.

Animal 100 % paraffin (formulation e) Example 2 (formulation (1) 105910 81060 98735 85019 98071 101668 113797 Fig. 6: Neovascular area of vehicle (water based, formulation e)) and regorafenib (example 3, formulation f) treated animals at day 23. Data are ted as mean 2‘: SD, e according to t- test. N=5 per group.

Table 15: Raw data of the histogram depicted in Fig. 6. Single values represent the means from all six lesions. formulation e Example 3 (formulation f) 107547 117379 72404 107654 In both groups, one flatmount preparation each could not be scored due to poor tissue quality. sfor example 1: Table 16 (n=8 per group) Formulation A) Vascular leakage B) Choroidal [angiography score] neovaseularization lesion size a) 100% oleoyl polyethyleneglyeol 1.80 2‘: 0.25 92596 2‘: 20754 glycerides (vehicle control) b) Regorafenib (20 mg/ml) .26 56942i22025 suspension in 100% oleoyl hyleneglycol glycerides (example 1) p-value Resultsfor example 2: Table 17 (n=8 per group) Formulation A) Vascular leakage B) Choroidal [angiography score] neovascularization lesion size [umzl c) 100 % liquid n (vehicle 2.05 :‘c 0.33 97959 i 10580 control) d) Regorafenib (20 mg/ml) 1161—039 72824i11496 suspension in 100 % liquid paraffin (example 2) p-Value Resultsfor example 6: Table 18 (n=6 per group for leakage, 11:5 per group for neovascularization) Formulation A) Vascular leakage B) Choroidal [angiography score] neovascularization lesion size [11le e) Water-based vehicle control 1.86i0.30 90806:: 11414 1) Regorafenib (20 mg/ml) 1.62 4: 0.50 97736 i 17027 suspension in based vehicle (example 6) p-value 0.330 (n.s.) 0.471 (n.s.) Resultsfor example 7: Table 19 (n=8 fo vehicle, n=7 for regorafenib) Formulation A) Vascular leakage B) Choroidal [angiography score] neovascularization lesion size [umzl m) 100% middle chain 1.53 i 0.50 84971 :‘t 14882 triglycerides (Miglyol, vehicle control) n) Regorafenib (20 mg/ml) 1.40 i 0.27 68127 i 8954 suspension in miglyol p-value 0.567 (n.s.) Resultsfor example 8: Table 20 (n=8 for vehicle, n=6 for regorafenib) Formulation A) Vascular leakage B) dal [angiography score] neovascularization lesion size [umzl o) 100% Oculentum x 1.41i0.41 83301 :‘: 9729 (vehicle control) p) Regorafenib (20 mg/g) 1.1] i 0.36 60628 2‘: 17812 sion in tum simplex l_p-value B180 (n.s.) Resultsfor example 3, 4 and example 5: Table 21 (I1: 8 - 10 per group) Formulation A) Vascular leakage B) dal [angiography score] neovascularization lesion size [11ml] g) liquid Paraffin 0.5% Aerosil 1.65 i 0.15 78040 3‘: 21180 (vehicle control), n=10 h) Regorafenib (20 mg/ml) 1.14 2‘: 0.34 55364 i 8307 suspension in liquid Paraffin 0.5% Aerosil le 3), n=9 for A), n=10 for B) i) liquid Paraffin 2% Aerosil 1.63i0.16 82750z‘t12471 (vehicle l), n=10 j) Regorafenib (20 mg/ml) 1.11 d: 0.13 51209 2‘: 4463 suspension in liquid Paraffin 2% Aerosil (example 4), n=8 for A), n=10 for B) k) liquid Paraffin 5% Aerosil 1.70:‘c0.24 66389i8790 (vehicle control) 1) Regorafenib (20 mg/ml) 1.32 i 0.19 54984 i 9973 suspension in liquid n 5% Aerosil (example 5) p-value g vs h p-value i vs j p-value k vs 1 0.001 Example 10: Ocular pharmacokinetics: At day of experiment a defined dose of the test compound (regorafenib monohydrate l) as suspension in different vehicles is applied to each eye by the use of an Eppendorf pipet. In a period of 24 to 96 hours after application a sequence (8-12 time points) of animals were sacrificed to get the eyes of these animals . These eyes were rinsed in 1 ml of physiological saline solution at least 2 times and afterwards dried with a paper flies. To ine the total concentration of the test compound in the eye it is homogenized Within a defined amount of saline solution and an aliquot of the homogenate is spiked with Acetonitrile to precipitate proteins in the solution. After centrifugation, in the supernatant the test compound and its possible known osition products were quantified with appropriate LC/‘MS—MS methods. Are the concentrations of the test compound or its possible known decomposition products to be determined in some defined compartments of the eye, the eyes are dissected into the riate compartments and each compartment is homogenized, handled and measured as bed above.

In that way a concentration-time curve is determined; this is then used to calculate standard cokinetic parameters to assess the qualification of a n formulation (concentration maximum and half-life). The calculated rd pharmacokinetic parameters of the test compound or of the hereof released active pharmaceutical ingredient are: AUCmrm, Cmax, and MRT (mean residence time).

Pharmacokinetic parameters regarding regorafenib calculated from eye concentration-time curves for equal doses but with different formulations are shown in the table below.

Table 22: it PM [mg/L] AUCnorm [kg’l‘h/L] MRT [h] Labrafil (example 1) 23 40 Paraffin (example 2) 28 41 Water (example 6) 5.3 28 Miglyol (example 7) 12 30 Oculentum x (example 8) 1.7 4.8 28 B) Three unanaesthetized female rabbits were administered with a defined amount (30 11L) of suspension in Paraffin in the lower lacrimal sac of each eye. Using a glass capillary over a period of 60 min, several weight controlled samples (n=8) of tear fluid were collected. The determination of the concentration of the compound in the fluid and the tion of the pharmacokinetic parameters is the same as described above.

Table 23: AUCnorm [kg*h/L] Paraffin (example 2) The results show a surprisingly high residence time of the active agent in the tear fluid and on the (2011163..

Although the invention has been disclosed with nce to specific embodiments, it is apparent that other embodiments and variations of the invention may be devised by others skilled in the art Without departing from the true spirit and scope of the invention. The claims are intended to be construed to e all such embodiments and equivalent variations.

Claims (18)

What is claimed

1. A topical ophthalmological pharmaceutical ition comprising regorafenib, a hydrate, solvate or pharmaceutically acceptable salt of regorafenib, or a polymorph thereof as active agent and at least one pharmaceutically acceptable vehicle n the composition is a 5 suspension comprising the active agent suspended in the applicable pharmaceutically acceptable vehicle and said vehicle is non-aqueous.

2. The pharmaceutical composition of claim 1 containing regorafenib monohydrate as active agent.

3. The ceutical composition of any of claims 1 to 2 wherein the active agent is in a solid 10 form.

4. The pharmaceutical composition of any of claims 1 to 3 wherein the active agent is in a crystalline form.

5. The pharmaceutical composition of any of claims 1 to 4 wherein the active agent is in a microcrystalline form. 15

6. The pharmaceutical composition of any of claims 1 to 5 wherein the tration of the active agent in the pharmaceutical composition is from 0.01 to 10% by weight of the total amount of the composition.

7. The pharmaceutical composition of any of claims 1 to 6 wherein the pharmaceutically acceptable vehicle is selected from the group comprising oleoyl polyethyleneglycol gylcerides, 20 linoleoyl polyethyleneglycol gylcerides, l polyethyleneglycol gylcerides, liquid paraffin, light liquid paraffin, soft paraffin (vaseline), hard in, castor oil, peanut oil, sesame oil, middle chain trigylcerides, tearylalcohols, wool fat, glycerol, propylene glycol, polyethyleneglycols (PEG) or a mixture of those.

8. The pharmaceutical composition of any of claims 1 to 7 based on a hydrophobic vehicle. 25

9. The pharmaceutical composition of any of claims 1 to 8 wherein the pharmaceutically acceptable vehicle is selected from the group comprising liquid paraffin, light liquid paraffin or a e thereof. 3_1 (GHMatters) P95703.NZ JENNYP

10. The pharmaceutical composition of any of claims 1 to 9 comprising further pharmaceutically acceptable excipients like stabilizers, surfactants, polymer base carriers like gelling agents, organic vents, pH active components, osmotic active components and preservatives.

11. The pharmaceutical composition of claim 10 wherein the stabilizer is a hydrophobic silica. 5

12. The pharmaceutical composition of claim 11 comprising hydrophobic silica in an amount of 0.1 % to 10 % by weight of the total composition.

13. A s for manufacturing a pharmaceutical composition according to any of claims 1 to 12 wherein the active agent is suspended in an applicable pharmaceutically acceptable vehicle which is non-aqueous optionally in the presence of further one or more pharmaceutically 10 acceptable excipients and the sion is homogenized.

14. The pharmaceutical composition of any of claims 1 to 12 for the use of treating or preventing an ophthalmological disorder selected from the group comprising age-related macular degeneration (AMD), choroidal neovascularization (CNV), choroidal neovascular membrane , cystoid macula edema (CME), epi-retinal membrane (ERM) and 15 macular hole, myopia-associated choroidal neovascularisation, vascular streaks, l detachment, diabetic retinopathy, diabetic macular edema (DME), atrophic changes of the retinal pigment epithelium (RPE), hypertrophic s of the l pigment epithelium (RPE), retinal vein occlusion, choroidal retinal vein occlusion, macular edema, macular edema due to retinal vein occlusion, tis pigmentosa, Stargardt’s e, ma, 20 inflammatory conditions, cataract, refractory anomalies, ceratoconus, pathy of prematurity, angiogenesis in the front of the eye, corneal angiogenesis following tis, corneal transplantation or keratoplasty, corneal angiogenesis due to hypoxia (extensive contact lens wearing), pterygium conjunctivae, subretinal edema and intraretinal edema.

15. The ceutical composition of claim 14 for the use of treating or preventing an 25 ophthalmological er selected from the group comprising dry AMD, wet AMD or choroidal neovascularization (CNV).

16. Use of a pharmaceutical composition of any of claims 1 to 12, 14 and 15 in the ation of a medicament for treating or preventing an ophthalmological disorder selected from the group comprising age-related macular degeneration (AMD), choroidal neovascularization 7259893_1 (GHMatters) P95703.NZ JENNYP (CNV), dal neovascular membrane (CNVM), d macula edema (CME), epiretinal membrane (ERM) and macular hole, myopia-associated choroidal neovascularisation, vascular s, retinal detachment, diabetic retinopathy, ic macular edema (DME), atrophic changes of the retinal pigment epithelium (RPE), hypertrophic changes of the 5 retinal pigment epithelium (RPE), retinal vein occlusion, choroidal retinal vein occlusion, macular edema, macular edema due to retinal vein occlusion, retinitis pigmentosa, Stargardt’s disease, ma, inflammatory conditions, cataract, refractory anomalies, ceratoconus, retinopathy of prematurity, angiogenesis in the front of the eye, corneal angiogenesis following tis, corneal transplantation or keratoplasty, corneal 10 angiogenesis due to hypoxia (extensive contact lens wearing), pterygium conjunctivae, subretinal edema and intraretinal edema.

17. Use of a pharmaceutical composition of any of claims 1 to 12, 14 and 15 in the ation of a medicament for treating or preventing an ophthalmological disorder selected from the group comprising dry AMD, wet AMD or choroidal neovascularization (CNV). 15

18. The pharmaceutical composition of any of claims 1 to 12, 14 and 15, the s of claim 13, or the use of claim 16 or 17, ntially as herein described with reference to any one of the Examples. 7259893_1 (GHMatters) P95703.NZ JENNYP -