EA043904B1 - OPHTHALMOLOGICAL COMPOSITION CONTAINING BILASTINE, BETA-CYCLODEXTRIN AND AT LEAST ONE GELATINATING SUBSTANCE - Google Patents

Description

Field of invention

The present invention relates to aqueous pharmaceutical compositions containing high concentrations of bilastine suitable for once daily administration, as well as their use as antihistamine and antiallergic ophthalmic pharmaceutical compositions.

State of the art

It has long been known that histamine plays a very important role in allergic diseases such as allergic rhinitis, conjunctivitis, rhinoconjunctivitis, dermatitis, urticaria and asthma. Antihistamine compounds acting at the level of histamine _H1 receptors are used to treat such conditions.

In cases where allergic symptoms are primarily ocular, topical treatment is probably preferable to systemic treatment. Topical agents are superior, with a faster onset of action (within minutes) than systemic agents, and are thus easily able to control the allergic reaction. In direct comparisons, several studies using an antigen-stimulated conjunctival model have demonstrated superiority of topical agents over systemic antihistamines in the treatment of allergic conjunctivitis. Oral antihistamines can help relieve allergy symptoms other than just the eye ones, but have a delayed onset of action compared to topical eye medications. Topical antihistamines also have fewer side effects than systemic antihistamines due to the lower doses required to penetrate the conjunctiva and negligible serum levels when applied topically.

Although currently available topical medications are effective for the treatment of allergic conjunctivitis, patients experiencing incomplete symptom relief will likely benefit from a medication that provides symptomatic relief throughout the day with the convenience of once-daily dosing. Avoiding more frequent dosing is more convenient for patients, as once-daily dosing is cost-effective, helps ensure better patient compliance, and, more importantly, improves their quality of life.

EP 0818454 A1 and EP 0580541 A1 describe benzimidazole compounds with H ₁ receptor-selective antihistamine activity and without arrhythmogenic effects. Patent application EP 3040334 A1 also describes benzimidazole compounds having strong H ₁ receptor-selective antihistamine activity, without activity against the central nervous system and the cardiovascular system.

A particular compound with the above properties is 2-[4-(2-{4-[1-(2-ethoxyethyl)-1Hbenzimidazol-2-yl]-1-piperidinyl}ethyl)phenyl]-2-methylpropanoic acid, also known as bilastine, having the formula

and developed by Faes Farma, Spain. Bilastine is a benzimidazole compound that is an _H1 receptor antagonist and does not cause sedative side effects, cardiotoxic effects, or hepatic metabolism. In addition, bilastine has been effective for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria.

Bilastine was first described in January 1999, and since then a variety of ophthalmic solutions containing antihistamines have been described and are commercially available, for example EP 2709610 B1 describes a topical ophthalmic solution containing a high concentration of olopatadine, with the Office of The Food and Drug Administration (FDA) recently approved a new formulation of olopatadine hydrochloride 0.77% ophthalmic solution. However, no description is known from the prior art sufficient to reproduce the agent related to an ophthalmic pharmaceutical composition containing a high concentration of bilastine and suitable for administration once a day.

Patent application WO 9413299 A1 describes ophthalmic solutions of 1-(2-ethoxyethyl)-2-(4methyl-1-homopiperazinyl)benzimidazole, also known as emedastine. Despite the structural similarity to bilastine (emedastine is a benzimidazole derivative containing an ethoxyethyl chain linked to the nitrogen atom of the imidazole ring), the solubility of emedastine in water is much higher than that of bilastine, which allows the preparation of ophthalmic solutions containing emedastine (at concentrations of about 8 mg/day). ml) and with the usual excipients known to the skilled person, such as EDTA, NaCl, hydroxypropyl methylcellulose (HPMC) and pH adjusters NaOH/HCl and tris(hydroxymethyl)aminomethane.

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The only knowledge in this area that relates to the treatment of allergic ocular symptoms by administering bilastine relates entirely to orally administered bilastine, highlighting the difficulty of producing ophthalmic solutions of this molecule. For example Horak F, et al. Inflammation Research, 2010, (59) 391-398 or J Bartra et al., J. Investig. Allergol. Clin. Immunol., 2011, Vol.

21, Suppl.3: 24-33, describe only bilastine tablets.

US 2007265247 describes a topical composition containing bilastine.

WO 03089425 A1 describes that bilastine can be used for ophthalmic solutions, but does not provide any technical details regarding how to successfully prepare these solutions. WO 2007047253 A2 describes methods for increasing the water solubility of an antifungal azole using hydroxybutenylcyclodextrin. WO 2009003199 A1 describes compositions in the form of aqueous solutions containing a corticosteroid, an antihistamine and cyclodextrin sulfoalkyl ether derivatives for nasal and ocular tissues.

This problem becomes apparent when considering that not only is there no prior art that provides an ophthalmic pharmaceutical composition with a high concentration of bilastine, but also the prior art clearly indicates the use of olopatadine, as opposed to bilastine, for daily relief allergic signs and symptoms. Beauregard C. et al., ARVO Annual Meeting Abstract May 2008, even provide information that bilastine does not match the antihistamine activity or duration of action of olopatadine in vivo.

Accordingly, there is a need in the art for an ophthalmic solution suitable for once daily administration that includes high concentrations of these benzimidazole compounds.

Brief description of the invention

The inventors of the present invention have unexpectedly discovered that the ophthalmic compositions of the invention which contain bilastine provide an unexpected increase in the duration of effectiveness of the ophthalmic compound. These findings are particularly surprising given the fact that this increase in efficacy was not observed in preclinical studies using bilastine and the comparative antihistamine compounds olopatadine and azelastine. Thus, the present invention provides for the first time an ophthalmic composition containing bilastine for once daily use.

Therefore, in a first aspect, the invention relates to an ophthalmic pharmaceutical composition containing:

a) at least 0.4% w/v. bilastine or a pharmaceutically acceptable salt or solvate thereof, wherein bilastine or a salt or solvate thereof is completely dissolved in the aqueous ophthalmic pharmaceutical composition;

b) at least one β-cyclodextrin selected from the group consisting of alkyl-β-cyclodextrin, hydroxyalkyl-β-cyclodextrin, carboxyalkyl-β-cyclodextrin, carbonyl-β-cyclodextrin, β-cyclodextrin sulfoalkyl ether and mixtures thereof; And

c) at least one pharmaceutically acceptable water-soluble gelling agent or an acceptable salt thereof selected from the group consisting of hyaluronic acid, gellan gum, guar gum, locust bean gum, alginic acid, povidone, kappa-carrageenan, alginate gum, dextran, sulfate dextran, chitosan and mixtures thereof;

and wherein the pH of the composition is from 4 to 9, including both lower and upper limits of the range.

In a second aspect, the present invention relates to the above-described aqueous ophthalmic pharmaceutical composition for use as a medicine.

In a third aspect, the present invention relates to the above-described aqueous ophthalmic pharmaceutical composition for use in the treatment and/or prevention of a disorder or disease that is ameliorated by histamine H ₁ receptor antagonism.

Another aspect of the present invention relates to the aqueous ophthalmic pharmaceutical composition described above and an additional pharmaceutically acceptable carrier, adjuvant or excipient.

Another aspect of the present invention relates to the use of the above-described aqueous ophthalmic pharmaceutical composition in the manufacture of a medicament for the treatment and/or prevention of a disorder or disease that is ameliorated by histamine H1 receptor antagonism.

Another aspect of the present invention relates to a method of treating and/or preventing a disorder or disease that is ameliorated by histamine H ₁ receptor antagonism, the method comprising administering to a subject in need of such treatment and/or prophylaxis a therapeutically effective amount of bilastine in an aqueous ophthalmic pharmaceutical compositions as defined above.

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These aspects and their preferred embodiments are also further described below in the description and defined in the claims.

Brief description of drawings

In fig. 1 shows the stability of bilastine solutions at concentrations above 6.5 mg/ml in the presence of 9% w/v. five β-cyclodextrins in different pH environments at t ₀ ;

in fig. Figure 2 shows the stability of bilastine solutions at concentrations above 6.5 mg/ml in the presence of 9% w/v. five β-cyclodextrins in different pH environments at t1;

In fig. 3 shows the average ocular retention times (ART) for compositions of the invention comprising bilastine 0.4% w/v. and HBP 9% w/v. AH is sodium hyaluronate, GG is gellan gum and MC is methylcellulose;

in fig. 4 shows the effect of the ophthalmic compositions of the invention on histamine-induced conjunctivitis in a guinea pig;

in fig. Figure 5 shows treatment differences as represented by the mean ocular itch score defined as the active carrier using least squares means (LSMeans) measured for three concentrations of bilastine (bilastine 0.2% w/v, bilastine 0.4% w/v and bilastine 0.6% w/v) at different time points (minutes) after conjunctival allergization (CAC®): at the beginning of the study, after 16, 8 hours and 15 minutes;

Figure 6 shows the mean ocular itching scores (on a scale of 0 to 4) given at different time points (minutes) after CAC®: at baseline, 16 hours, 8 hours and 15 minutes.

Detailed Description of the Invention

The inventors of the present invention have unexpectedly discovered that the combination of bilastine with at least β-cyclodextrin and at least one pharmaceutically acceptable water-soluble gelling agent or an acceptable salt thereof is optimal for ophthalmic applications, demonstrating excellent prolonged action in the eye, allowing the use of ophthalmic a composition containing bilastine once a day. Surprisingly, these results were not observed in preclinical studies, as shown in the examples relating to preclinical and clinical studies.

Accordingly, in a first aspect, the invention provides an ophthalmic pharmaceutical composition comprising:

a) at least 0.4% w/v. bilastine or a pharmaceutically acceptable salt or solvate thereof, wherein bilastine or a salt or solvate thereof is completely dissolved in the aqueous ophthalmic pharmaceutical composition;

b) at least one β-cyclodextrin selected from the group consisting of alkyl-β-cyclodextrin, hydroxyalkyl-β-cyclodextrin, carboxyalkyl-β-cyclodextrin, carbonyl-β-cyclodextrin, β-cyclodextrin sulfoalkyl ether and mixtures thereof; And

c) at least one pharmaceutically acceptable water-soluble gelling agent, or an acceptable salt thereof, selected from the group consisting of hyaluronic acid, gellan gum, guar gum, locust bean gum, alginic acid, povidone, kappa-carrageenan, alginate gum, dextran, dextran sulfate, chitosan and mixtures thereof;

and wherein the pH of the composition is from 4 to 9, including both lower and upper limits of the range.

Bilastine

The aqueous ophthalmic pharmaceutical composition according to the invention contains bilastine of the formula

OEt or a pharmaceutically acceptable salt or solvate thereof. This compound, which is 2[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl}ethyl)phenyl]-2-methylpropanoic acid, is also known like bilastine. The synthesis of bilastine has been described in EP 0818454 A1, EP 0580541 A1 and EP 3040334 A1.

Bilastine may be in the form of a salt or solvate, preferably pharmaceutically acceptable salts or solvates.

The invention also relates to salts of the compounds described herein. By way of illustration, these salts may be acid addition salts, base addition salts or metal salts and can be synthesized from starting compounds containing a basic or acid moiety by conventional chemical processes known to those skilled in the art. Such salts are typically prepared, for example, by reacting the free acid or base form of the compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof. Non-aqueous media such as ether,

- 3 043904 ethyl acetate, ethanol, acetone, isopropanol or acetonitrile are generally preferred. Illustrative examples of acid addition salts include inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc., organic acid addition salts, such as, for example, acetate, maleate, fumarate, citrate , oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, camphorsulfonate, etc. Illustrative examples of base addition salts include inorganic base salts such as, for example, ammonium salts and organic base salts, such as, for example, ethylenediamine, ethanolamine, K,K-dialkylene-ethanolamine, triethanolamine, glutamine, basic amino acid salts, etc. Illustrative examples of metal salts include, for example, sodium, potassium, calcium, magnesium, aluminum and lithium salts.

The term solvate in accordance with the present invention should be understood to mean any form of the active compound in accordance with the invention that has another molecule (most likely a polar solvent) attached to it through a non-covalent bond. Examples of solvates include hydrates and alcoholates. Solvation methods are well known in the art.

The compounds of the invention also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention, other than replacing hydrogen with deuterium or tritium, or replacing carbon with ¹³ C- or ¹⁴ C-rich carbon, or nitrogen with ¹⁵ K-rich nitrogen, are included within the scope of the present invention.

Concentration of at least 0.4% w/v. means that more than 4 mg of bilastine completely dissolves, that is, without any significant signs of precipitation, in only 1 ml of water. In the present invention, unless otherwise indicated, all percentages are given in mass-to-volume units. In another embodiment, bilastine is completely dissolved in the pharmaceutical composition of the invention at a concentration of at least 0.6% w/v, preferably at least 0.7% w/v. In another embodiment, bilastine is completely dissolved in the pharmaceutical composition of the invention at a concentration of at least 0.6% w/v, but not more than 1.0% w/v. In a specific embodiment, the pharmaceutical composition contains at least 0.4% w/v, at least 0.6% w/v, at least 0.7% w/v, at least 0 .8% w/v, at least 0.9% w/v. or at least 0.6%, but not more than 1.0% w/v. bilastine, and bilastine is completely dissolved. In another specific embodiment, the pharmaceutical composition contains at least 0.4% w/v, at least 0.6% w/v, at least 0.7% w/v, at least 0.8% w/v, at least 0.9% w/v or at least 0.6%, but not more than 1.0% w/v. bilastine, and bilastine is completely dissolved. In a preferred embodiment, bilastine is completely dissolved in the pharmaceutical composition of the invention at a concentration of at least 0.6% w/v, but not more than 1.0% w/v.

Cyclodextrins

In the context of the present invention, cyclodextrin (CD) is a cyclic structure consisting of 5 or more e-D-glucopyranose units linked at the 1,4 positions, typically having 6 (α-cyclodextrin), 7 (β-cyclodextrin), 8 (γ- cyclodextrin) or 9 (δ-cyclodextrin) sugar units in one cyclodextrin molecule.

The MS (mean molar degree of substitution) value is the average number of moles of substituent groups per mole of glucopyranose. For example, in the case of β-cyclodextrins, the average number of substituents per β-cyclodextrin core can be calculated by multiplying the MS value by 7 (βcyclodextrin contains 7 sugar units per cyclodextrin molecule). The specific designation for this value corresponds to DS (degree of substitution).

Both amorphous and crystalline cyclodextrins are included within the scope of this application. As used herein, the term cyclodextrin may refer to cyclodextrin or a cyclodextrin derivative. Cyclodextrins are commercially available or can be synthesized by methods well known in the art. Examples of cyclodextrins include, but are not limited to, modified or unmodified α-, β-, γ- and δ-cyclodextrins. The cyclodextrins of the present invention are β-cyclodextrins. The derivatives of cyclodextrins and, in particular, β-cyclodextrins according to the invention include cyclodextrins in which some or all of the OH groups are converted to OR groups. These derivatives include derivatives with A ₆ alkyl groups, for example, methylated, ethylated, propylated and butylated cyclodextrins, where R represents a methyl, ethyl, propyl or butyl group; derivatives with hydroxyalkyl-substituted groups, such as, for example, hydroxypropylcyclodextrins or hydroxyethylcyclodextrins, where R represents a group -CH2CH(OH)CH ₃ or CH2CH2OH; branched cyclodextrins such as maltose-linked cyclodextrins; cationic cyclodextrins; quaternary ammonium; anionic cyclodextrins such as carboxymethylcyclodextrins, cyclodextrin sulfates and cyclodextrin succinates; amphoteric cyclodext

- 4 043904 rins such as carboxymethylcyclodextrin and quaternary ammonium cyclodextrin. Other specific modifications include one or more hydroxyalkyl ether (eg, R is C ₁ . ₆ alkylene hydrox) moieties; one or more sulfoalkyl ethers (for example, R is C ₂ . ₆ alkylene SO ₃ ); carboxyalkyl (eg, R is C(O) _C1-6 alkyl) moieties; substituted phenoxy moieties; tryptophan fragments; or mixtures thereof. The total number of OR groups per cyclodextrin molecule is defined as the degree of substitution/modification.

In the present invention, the cyclodextrin of the ophthalmic pharmaceutical composition is β-cyclodextrin. In a preferred embodiment, the β-cyclodextrin is selected from the group consisting of alkyl-β-cyclodextrin, hydroxyalkyl-β-cyclodextrin, carboxyalkyl-β-cyclodextrin, carbonyl-β-cyclodextrin, β-cyclodextrin sulfoalkyl ether, and mixtures thereof.

In one embodiment, the β-cyclodextrin is an alkyl β-cyclodextrin. Preferred alkyl-β-cyclodextrins include methyl-β-cyclodextrin; dimethyl-b-cyclodextrin; trimethyl-b-cyclodextrin; ethyl-b-cyclodextrin; diethyl-b-cyclodextrin; propyl-to-cyclodextrin; and butyl-b-cyclodextrin. In a more preferred embodiment, the β-cyclodextrin is selected from the group consisting of methyl-β-cyclodextrin or dimethyl-β-cyclodextrin. In the context of the present invention, when the term alkyl-β-cyclodextrin is used, it is intended to include β-cyclodextrins wherein the alkyl group is optionally substituted, with the exception of hydroxyalkyl-β-cyclodextrins.

The alkyl-b-cyclodextrin derivatives preferably have a degree of substitution/modification of from about 1 to about 18, from about 3 to about 16, from about 4 to about 14, from about 4 to about 12.6, and more preferably from about 4 to 6.

In a specific embodiment, the β-cyclodextrin is not an alkenyl-β-cyclodextrin, in particular, the β-cyclodextrin is not a hydroxybutenyl-β-cyclodextrin.

In another embodiment, the cyclodextrin is a hydroxyalkyl-b cyclodextrin. Preferred hydroxyalkyl-b-cyclodextrins include hydroxyethyl-b-cyclodextrin; hydroxypropyl-β-cyclodextrin (which corresponds to 2-hydroxypropyl-β-cyclodextrin) and 2-hydroxybutyl-β-cyclodextrin. In a more preferred embodiment, the cyclodextrin is hydroxypropyl-in-cyclodextrin (HPBCD or HP-in-CD).

Hydroxyalkylcyclodextrin derivatives, and in particular hydroxypropyl-β-cyclodextrin, preferably have a degree of substitution/modification of from about 1 to about 14, more preferably from about 4 to about 8.

In another embodiment, the cyclodextrin is a carboxyalkyl-b-cyclodextrin. Preferred carboxyalkyl-β-cyclodextrins for use herein include carboxymethyl-β-cyclodextrin and (2-carboxyethyl)-β-cyclodextrin.

In another embodiment, the cyclodextrin is a sulfoalkyl ester of cyclodextrin. The preferred β-cyclodextrin sulfoalkyl ether for use herein is β-cyclodextrin sulfobutyl ether.

The β-cyclodextrin sulfoalkyl ether derivatives preferably have a degree of substitution/modification of from about 1 to about 14, preferably from about 1 to about 7.

In a preferred embodiment, the cyclodextrin is a β-cyclodextrin selected from the group consisting of alkyl-β-cyclodextrin, hydroxyalkyl-β-cyclodextrin, carboxyalkyl-β-cyclodextrin, β-cyclodextrin sulfoalkyl ether, and mixtures thereof.

In another preferred embodiment, the cyclodextrin is a β-cyclodextrin selected from the group consisting of hydroxyalkyl-β-cyclodextrin, carboxyalkyl β-cyclodextrin, β-cyclodextrin sulfoalkyl ether, and mixtures thereof.

In the most preferred embodiment, the cyclodextrin is a β-cyclodextrin selected from the group consisting of hydroxyalkyl-β-cyclodextrins, sulfoalkyl ether β-cyclodextrins, and mixtures thereof.

Examples of the present invention use the following β-cyclodextrins:

β-CD: β-cyclodextrin (Sigma-Aldrich Ref.: C4767-25G).

HP-β-CD: 2-hydroxypropyl-β-cyclodextrin with degree of substitution 5.6 (Sigma-Aldrich Ref.: 332607-5G).

HPB: 2-hydroxypropyl-b-cyclodextrin, degree of substitution 4.5 (KleptoseTM Roquette Pharma).

CM-β-CD: sodium salt of carboxymethyl-β-cyclodextrin with degree of substitution 3 (SigmaAldrich Ref.: 21906-5G).

DM-β-CD: heptakis(2,6-di-O-methyl)-β-cyclodextrin (Sigma-Aldrich Ref: H0513-5G).

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SBE-e-CD: sodium salt of β-cyclodextrin sulfobutyl ether - according to USP (United States Pharmacopoeia) with degree of substitution 6.2-6.9 (Carbosynth Ref: SBECD).

In a preferred embodiment, the cyclodextrin is a pharmaceutically acceptable cyclodextrin.

In a specific embodiment, the cyclodextrin is present in the composition in an amount of from about 0.1 to about 50% w/v. In this case, wt./vol. means percentage concentration - the ratio of weight to volume (g/100 ml), for example, when cyclodextrin is present in the composition in an amount of from about 0.1 to about 50%, means that it is present in an amount from about 1 to about 500 mg/ml . In the present invention, all percentages are given in mass-to-volume units unless otherwise indicated. In specific embodiments, the cyclodextrin is present in an amount of from about 0.25 to about 30%, from about 0.5 to about 25%, from about 1 to about 20%, from about 2 to about 15%, or from about 3 to about 10% w/v In a preferred embodiment, the cyclodextrin of the pharmaceutical composition according to the invention is at a concentration of at least 5% w/v, but not more than 15% w/v, that is, about 50-150 mg/ml. More preferably, the cyclodextrin is present in an amount of at least 8%, but not more than 10% w/v. In another preferred embodiment, the composition of the invention contains 9% w/v. cyclodextrin.

Gelatinating agent

Water-soluble gelling agents refer to substances that can increase the viscosity of an aqueous solution, such as the ophthalmic pharmaceutical composition of the invention, without significantly changing its other properties, but which form a gel when dissolved in the liquid phase in the form of a colloidal mixture that forms a structure with a weak cohesion. In a preferred embodiment, the at least one gelling agent is a pharmaceutically acceptable gelling agent for ophthalmic purposes.

In a preferred embodiment, at least one gelling agent of the ophthalmic pharmaceutical composition of the invention, or an acceptable salt thereof, is selected from the group consisting of hyaluronic acid, gellan gum, guar gum, locust bean gum, alginic acid, povidone, kappa-carrageenan, alginate gum, dextran, dextran sulfate, chitosan and mixtures thereof.

In a preferred embodiment, at least one pharmaceutically acceptable water-soluble gelling agent, or an acceptable salt thereof, is selected from hyaluronic acid, gellan gum, and mixtures thereof.

Accordingly, in a preferred embodiment, the at least one pharmaceutically acceptable water-soluble gelling agent is hyaluronic acid or an acceptable salt thereof.

In a specific embodiment, the gelling agent or a suitable salt thereof is present in the aqueous composition of the invention in an amount of from about 0.001 to about 2% w/v, preferably from about 0.003 to about 1% w/v. In specific embodiments, the gelling agent is present in the aqueous composition of the invention in an amount of about 0.05%, about 0.1%, about 0.25%, about 0.50%, about 0.75%, about 1%, about 1 .5% or about 2%. All percentages are given in mass to volume units unless otherwise noted. In a preferred embodiment, the gelling agent is present in the aqueous composition of the invention in an amount of at least 0.05% w/v, but not more than 1% w/v, most preferably 0.1% w/v .

In a preferred embodiment, the ophthalmic pharmaceutical composition according to the invention contains:

a) at least 0.6% w/v but not more than 1.0% w/v. bilastine or a pharmaceutically acceptable salt or solvate thereof, wherein bilastine or a salt or solvate thereof is completely dissolved in the aqueous ophthalmic pharmaceutical composition;

b) at least one β-cyclodextrin selected from the group consisting of alkyl-β-cyclodextrin, hydroxyalkyl-β-cyclodextrin, carboxyalkyl-β-cyclodextrin, carbonyl-β-cyclodextrin, β-cyclodextrin sulfoalkyl ether and mixtures thereof, wherein the concentration of said β-cyclodextrin cyclodextrin is at least 5% w/v, but not more than 15% w/v; And

c) hyaluronic acid or a pharmaceutically acceptable salt thereof, wherein the concentration of hyaluronic acid or a pharmaceutically acceptable salt thereof is at least 0.05% w/v but not more than 1% w/v.

In a specific embodiment, the gelling agent is hyaluronic acid or a pharmaceutically acceptable salt thereof and has a molecular weight of no more than 600,000 Da. The molecular weight of the gelling agent can be measured according to methods known in the art. Preferably, but not limited to, the average molecular weight of hyaluronic acid or a pharmaceutically acceptable salt thereof can be determined by gel permeation chromatography coupled with multi-angle laser light scattering (SEC-MALLS).

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Alternatively, the average molecular weight of hyaluronic acid or a pharmaceutically acceptable salt thereof can also be determined using true viscosity and the Mark Hoovink equation.

Other embodiments

In a specific embodiment, the ophthalmic pharmaceutical composition of the invention further comprises at least one pharmaceutically acceptable water-soluble polymer as a viscosity control component selected from the group consisting of cellulose ether derivative, polyethylene glycol, polyvinyl alcohol and mixtures thereof.

Water-soluble polymers refer to hydrophilic polymers that are at least partially soluble in water. In a preferred embodiment, the at least one water-soluble polymer is a pharmaceutically acceptable water-soluble polymer.

In a preferred embodiment, the at least one water-soluble polymer is a cellulose ether derivative, most preferably methylcellulose. In another embodiment, the at least one water-soluble polymer is polyethylene glycol.

In a specific embodiment, the water-soluble polymer is present in the aqueous composition of the invention in an amount of from about 0.001 to about 15% w/v, preferably from about 0.01 to about 15% w/v. In specific embodiments, the water-soluble polymer is present in the aqueous composition of the invention in an amount of about 0.01%, about 0.05%, about 0.1%, about 0.25%, about 0.50%, about 0.75%, about 1%, about 3%, about 5%, about 7%, about 10%, about 13% or about 15%. All percentages are given in mass to volume units unless otherwise noted.

Cellulose ether derivatives

In one embodiment, the water-soluble polymer is a cellulose ether derivative. Cellulose ether derivative refers to cellulose, where the hydroxyl groups of cellulose have been partially or completely replaced to produce cellulose ethers (OR). In one embodiment, the cellulose ether derivative is selected from the group consisting of alkylcelluloses, hydroxyalkylcelluloses, carboxyalkylcelluloses, and mixtures thereof.

In a preferred embodiment, the cellulose ether derivative is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, carboxyalkylcellulose, and mixtures thereof.

In one embodiment, the cellulose ether derivative is an alkylcellulose. Preferred alkylcelluloses used herein include methylcellulose (MC), ethylcellulose, ethylmethylcellulose, and mixtures thereof.

In one embodiment, the cellulose ether derivative is hydroxyalkylcellulose. Preferred hydroxyalkylcelluloses for use herein include hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) and ethylhydroxyethylcellulose.

In one embodiment, the cellulose ether derivative is carboxyalkylcellulose. Preferred carboxyalkylcelluloses used herein include carboxymethylcellulose (CMC). CMC and sodium carboxymethylcellulose (CMCNa) are equivalent.

Polyethylene glycol (PEG)

PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE). In one preferred embodiment, the PEG is a low molecular weight PEG, that is, a PEG having a molecular weight of 300 to 1000 g/mol. The molecular weight of PEG is more preferably from 300 to 500 g/mol. In a preferred embodiment, the molecular weight is 400 g/mol, which corresponds to PEG400.

In a specific embodiment, the composition has an osmolality of from about 200 to about 640 mOsm/kg, preferably from about 250 to about 600 mOsm/kg. In a preferred embodiment, the osmolality is from about 240 to about 340 mOsm/kg. The osmolality of the ophthalmic pharmaceutical solution of the invention can be determined by standard methods well known in the art. Preferably, but not limited to, the osmolality of the ophthalmic pharmaceutical solution of the invention can be determined by measuring the freezing point depression of the solution using an osmometer.

In a specific embodiment, the composition of the invention may further comprise osmolal or tonicity agents selected from glycerol, sorbitol, mannitol, erythriol, arabitol, xylitol, adonitol, galactitol, maltitol, macrogol, lactitol, and mixtures thereof. If present, said osmolar or tonicity adjusting agents are present in the aqueous composition of the invention in an amount of about 0.05%, about 0.1%, about 0.25%, about 0.50%, about 0.75% , about 1%, about 1.5%, about 1.6%, about 2%, about 3%, about 5%, about 7%, about 10%, about 13% or about 15%. In an embodiment consistent with the foregoing, said osmolar or tonicity agents are present in the aqueous composition of the invention in an amount of less than 15, 13, 10, 7, 5, 3 or 2%. All percentages are given in mass to volume units unless otherwise noted.

In a preferred embodiment, if present, the osmolar or tonicity adjusting agents are present in the aqueous composition of the invention in an amount of from 0.05 to 5% w/v.

In a particular embodiment, the inventors have surprisingly discovered that the composition of the invention is stable and advantageously does not require the addition of preservatives such as benzalkonium chloride, imidazolidinyl urea, methylparaben, propylparaben, phenoxyethanol, disodium EDTA, thimerosal, chlorobutanol and sorbic acid, which are known to cause dry eyes and eye irritation. Thus, in a particular embodiment, the ophthalmic pharmaceutical composition of the invention does not contain preservatives.

In a specific embodiment, the composition of the invention contains glycerin. Glycerol is a synonym for glycerol. Preferably, glycerin is present in the aqueous composition of the invention in an amount of 0.05 to 5% w/v, more preferably 0.05 to 3% w/v. In a preferred embodiment, glycerol is present as a tonicity agent at a concentration of no more than 2.5%. In another preferred embodiment, the composition of the invention contains glycerol in an amount of about 1.6%, preferably 1.61%. All percentages are given in mass to volume units unless otherwise noted.

PH

The aqueous pharmaceutical composition of the invention has preferably been developed for ophthalmic use and/or administration, that is, the aqueous ophthalmic pharmaceutical composition is adapted for these purposes. It is known that the physiological pH of the eye, in particular the human eye, is in the range of about 6.5-8.0.

In a preferred embodiment, the pharmaceutical composition has a pH value ranging from 4 to 9, including both lower and upper limits. In some embodiments, the pH value of the aqueous ophthalmic pharmaceutical composition of the present invention is 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4 , 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5 ,7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 , 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8 ,2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3 or 9.4 .

Regarding pH values, it should be noted that a pH value of 4 can also be defined as corresponding to a pH value range from 3.6 to 4.4. Likewise, a pH value of 9 can also be defined as corresponding to a pH range of 8.6 to 9.4. In another preferred embodiment, the pH value of the pharmaceutical composition is 4.0, 5.5, 7.4, 8.0 or 9.0.

In one embodiment, a pH adjusting agent selected from the group consisting of hydrochloric acid, boric acid, acetic acid, sodium hydroxide, potassium hydroxide, or a combination thereof is present.

In one embodiment, a buffer substance selected from the group consisting of an acetate buffer, a citrate buffer, a phosphate buffer, a borate buffer, or a combination thereof is present.

In another embodiment, the composition has a pH in the range that maintains the chemical, physical and/or physiological stability of bilastine and is well tolerated by the eye.

Applications

Bilastine has been found to be an H ₁ -histamine receptor antagonist and, therefore, can be used in the treatment and/or prevention of diseases that are known to be reduced in intensity by H ₁ -histamine receptor antagonism.

Accordingly, an aspect of the invention relates to an aqueous ophthalmic pharmaceutical composition as defined above for use as a medicament.

Another aspect of the invention relates to an aqueous ophthalmic pharmaceutical composition as defined above for use in the treatment and/or prevention of a disorder or disease that is ameliorated by histamine H ₁ receptor antagonism. Such diseases are, for example, allergic diseases or disorders, or symptoms caused by allergies.

In a preferred embodiment, the invention relates to an aqueous ophthalmic pharmaceutical composition as defined above for use in the treatment and/or prevention of an allergic eye disorder, allergic disease or allergic symptoms. Preferably, the allergic disease, disorder or symptom is selected from rhinitis, rhinoconjunctivitis, allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, giant papillary conjunctivitis, eye irritation, itching, redness, lacrimation, chemosis, dry eye syndrome, keratoconjunctivitis sicca or lacrimal syndrome dysfunction. In a preferred embodiment, the allergic disease or disorder is selected from rhinitis,

- 8 043904 rhinoconjunctivitis, allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, giant papillary conjunctivitis and chemosis. In another preferred embodiment, the allergic symptom is selected from eye irritation, itching, redness, lacrimation, dry eye syndrome, keratoconjunctivitis sicca or tear dysfunction syndrome. In the context of the present invention, dry eye syndrome includes sicca keratitis, sicca keratoconjunctivitis or lacrimal dysfunction syndrome.

Preferably, the invention relates to an aqueous ophthalmic pharmaceutical composition as defined above for use in the treatment and/or prevention of allergic conjunctivitis. In another preferred embodiment, the invention relates to an aqueous ophthalmic pharmaceutical composition, as defined above, for use in the treatment and/or prevention of dry eye syndrome. In a more preferred embodiment, the invention relates to an aqueous ophthalmic pharmaceutical composition as defined above for use in the simultaneous treatment and/or prevention of allergic conjunctivitis and dry eye syndrome.

The term treat or treat, as used herein, means administering a compound or drug of the invention to alleviate or eliminate a disease or one or more symptoms associated with said disease. Treatment also includes reducing the intensity or eliminating the physiological effects of the disease.

The term reduction in intensity in the context of the present invention is understood to mean any improvement in the condition of the patient being treated.

The term prophylaxis or prevent as used herein means the administration of a compound or composition according to the invention to reduce the risk of acquiring or developing a disease or one or more symptoms associated with said disease.

Pharmaceutical composition

The expression aqueous ophthalmic pharmaceutical composition refers to a liquid pharmaceutical composition containing water suitable for ophthalmic use.

In one embodiment, bilastine is completely dissolved in the aqueous ophthalmic pharmaceutical composition of the invention at a concentration of at least 0.4% w/v. In another embodiment, bilastine is completely dissolved in the aqueous ophthalmic pharmaceutical composition of the invention at a concentration of at least 0.6% w/v, preferably at least 0.7%. In another embodiment, bilastine is completely dissolved in the aqueous ophthalmic pharmaceutical composition of the invention at a concentration of 0.6 to 1.0% w/v, preferably at a concentration of 0.6 to 0.9% w/v, more preferably at a concentration of 0.6 to 0.8%. Preferably, bilastine is completely dissolved in the aqueous ophthalmic pharmaceutical composition of the invention at a concentration of 0.6% w/v. In this case, % wt./vol. means percentage concentration - ratio of weight to volume (g/100 ml), for example, when bilastine is present in the composition in an amount of from about 0.6 to about 1.0%, means that it is present in an amount from about 6 to about 10 mg /ml. In the present invention, all percentages are given in weight/volume units unless otherwise noted.

In one embodiment, the amount of bilastine in the pharmaceutical composition of the invention is preferably greater than 4500 μg/ml, preferably greater than 6000 μg/ml, preferably greater than 6500 μg/ml, preferably greater than 7000 μg/ml, preferably greater than 7500 μg/ml, preferably greater than 8000 µg/ml, preferably greater than 8500 µg/ml, preferably greater than 9000 µg/ml and more preferably greater than 9500 µg/ml. In a preferred embodiment, the amount of bilastine in the pharmaceutical composition of the invention is less than 10,500 μg/ml.

In a specific embodiment, the aqueous ophthalmic pharmaceutical composition contains bilastine, β-cyclodextrin and hyaluronic acid or an acceptable salt thereof, wherein bilastine is completely dissolved in the aqueous ophthalmic pharmaceutical composition. In another specific embodiment, the aqueous ophthalmic pharmaceutical composition contains bilastine, hydroxypropyl-β-cyclodextrin and hyaluronic acid or an acceptable salt thereof, wherein bilastine is completely soluble in the aqueous ophthalmic pharmaceutical composition.

The expression "therapeutically effective amount" means that amount of a drug which, when administered, provides an amount of one or more pharmaceutically active substances contained therein to provide a therapeutic effect in the treatment or therapy of a disease or disease state.

In a preferred embodiment, the pharmaceutical composition of the invention contains a therapeutically effective amount of bilastine.

The aqueous ophthalmic pharmaceutical composition of the invention may contain additional pharmaceutically acceptable excipients.

The expression pharmaceutically acceptable excipient refers to a carrier, once

- 9 043904 additive or adjuvant, which is administered with the active ingredient. Such pharmaceutical excipients may be sterile liquids such as water and oils, including petroleum-based oils, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. As carriers, in particular for injection solutions, aqueous or saline aqueous solutions and aqueous solutions of dextrose and glycerol are preferably used. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, E.W. Martin, 21st edition, 2005.

The excipients and excipients necessary to produce the desired dosage form for administration of the pharmaceutical composition of the invention will depend, among other factors, on the chosen route of administration of the dosage form. Said dosage forms for administering a pharmaceutical composition will be prepared in accordance with conventional methods known to one skilled in the art. An overview of the different methods of administration of active ingredients, the excipients used and the methods for their preparation can be found in Tratado de Farmacia Galenica, C. Fauli i Trillo, Luzan 5, S.A. de Ediciones, 1993.

The expression pharmaceutically acceptable refers to compositions and molecular substances that are physiologically tolerable and do not typically cause an allergic reaction or similar adverse reaction, such as gastric upset, dizziness, and the like, when administered to a human or animal. Preferably, the term pharmaceutically acceptable means that the substance is approved by a state or federal regulatory agency or included in the US Pharmacopoeia or other generally accepted pharmacopoeia for use in animals and, more specifically, in humans.

The compositions described herein also optionally further contain one or more ophthalmic excipients. Ophthalmic excipients include, but are not limited to, at least one selected from a mucoadhesive, a preservative, a pH-regulating agent, a tonicity-regulating agent, a buffering agent, an antioxidant, a chelating agent, an antimicrobial preservative, a chemical preservative, a viscosity control, or a combination thereof. In a specific embodiment, the ophthalmic composition further comprises a water-soluble polymer as defined above.

In a specific embodiment, the composition of the invention does not contain a corticosteroid.

In a preferred embodiment, the ophthalmic pharmaceutical composition contains:

a) at least 0.6% w/v but not more than 1.0% w/v. bilastine or a pharmaceutically acceptable salt or solvate thereof, wherein bilastine or a salt or solvate thereof is completely dissolved in the aqueous ophthalmic pharmaceutical composition;

b) at least one hydroxyalkyl β-cyclodextrin, wherein the concentration of said β-cyclodextrin is at least 5% w/v but not more than 15% w/v.

c) hyaluronic acid or a pharmaceutically acceptable salt thereof, wherein the concentration of said hyaluronic acid or a pharmaceutically acceptable salt thereof is at least 0.05% w/v but not more than 1% w/v.

d) from 0.001 to 15% w/v. at least one pharmaceutically acceptable water-soluble polymer selected from the group consisting of cellulose ether derivative, polyethylene glycol, polyvinyl alcohol and mixtures thereof; And

e) from 0.05 to 5% w/v. at least one tonicity adjusting agent selected from the group consisting of glycerol, sorbitol, mannitol, erythriol, arabitol, xylitol, ribitol, galactitol, maltitol, macrogol, lactitol, and mixtures thereof.

In another preferred embodiment, the ophthalmic pharmaceutical composition contains:

a) at least 0.6% w/v but not more than 1.0% w/v. bilastine or a pharmaceutically acceptable salt or solvate thereof, wherein bilastine or a salt or solvate thereof is completely dissolved in the aqueous ophthalmic pharmaceutical composition;

b) at least one hydroxyalkyl β-cyclodextrin, wherein the concentration of said β-cyclodextrin is at least 5% w/v but not more than 15% w/v.

c) hyaluronic acid or a pharmaceutically acceptable salt thereof, wherein the concentration of said hyaluronic acid or a pharmaceutically acceptable salt thereof is at least 0.05% w/v but not more than 1% w/v.

d) from 0.001% to 15% w/v. cellulose ether derivative and

e) from 0.05 to 5% w/v. glycerin.

In a more preferred embodiment, the ophthalmic pharmaceutical composition contains:

a) at least 0.6% w/v but not more than 1.0% w/v. bilastine or its pharmaceutical

- 10 043904 a highly acceptable salt or solvate, wherein bilastine or a salt or solvate thereof is completely dissolved in an aqueous ophthalmic pharmaceutical composition;

b) at least one hydroxyalkyl β-cyclodextrin, wherein the concentration of said β-cyclodextrin is at least 5% w/v but not more than 15% w/v.

c) hyaluronic acid or a pharmaceutically acceptable salt thereof, wherein the concentration of said hyaluronic acid or a pharmaceutically acceptable salt thereof is at least 0.05% w/v but not more than 1% w/v.

d) from 0.005 to 0.1% w/v. methylcellulose and

e) from 0.5 to 2% w/v. glycerin.

In the table below. 1 provides a list of typical ingredients suitable for a typical preferred composition of the ophthalmic composition of the present invention, and the required weight-volume percentages for these ingredients. Please note that the following table. 1 is provided by way of example and that certain ingredients may be added or removed from the table and the concentrations of certain ingredients may be changed, but the composition may remain within the scope of the present invention unless specifically stated otherwise.

Table 1. Example of the preferred composition of the ophthalmic composition of the present invention and the required weight-volume percentages for these ingredients

Ingredient Mass/Volume % Bilastine 0.6 β-cyclodextrin (hydroxypropyl-βcyclodextrin) 9.0 Gelatinating agent (sodium hyaluronate) OD Tonicity regulating agent (glycerin) 1.61 Viscosity control agent (methylcellulose) 0.01 pH adjusting agent (NaOH or HC1) Sufficient to achieve pH=7.4 Purified water Enough to reach 100%

Dosage forms

Examples of pharmaceutical compositions include any liquid composition for topical administration to the eye. Liquid forms are solutions, suspensions or emulsions.

Examples of suitable preparations for topical administration to the eye include ophthalmic drops (ie, eye drops or artificial tears), ophthalmic emulsions, and ophthalmic ointments. In a specific embodiment, the compositions of the present invention are in the form of ophthalmic preparations in the form of ophthalmic drops. Ophthalmic preparations may include a suitable antimicrobial agent. In a preferred embodiment, the ophthalmic preparations do not include a preservative. In a more preferred embodiment, the ophthalmic preparations do not include a preservative selected from benzalkonium chloride, imidazolidinyl urea, methylparaben, propylparaben, phenoxyethanol, disodium EDTA, thimerosal, chlorobutanol and sorbic acid.

The present invention relates to an ophthalmic pharmaceutical composition as defined above. In a preferred embodiment, said ophthalmic pharmaceutical composition is a pharmaceutical composition for once daily use.

The following examples are merely illustrative of some embodiments of the invention and should not be construed as limiting the same in any way.

Examples Substances and methods

The following substances were used: bilastine (supplied by Sai Life Sciences, lot 5000011325); cyclodextrins described above as β-CD, HP-e-CD, HPB, CM-e-CD, DM-e-CD and SBE-βCD; methylcellulose 1500 (MC1500) (Acofarma); gellan gum (GG) (Kelcogel CG-LA, CPKelco), sodium hyaluronate (Caref), and glycerin (Merck-Millipore). The water used in the following examples was purified water obtained using the Elix® water purification system from Merck-Millipore.

Example 1. Stability above 6.5 mg/ml bilastine at 25°C, in the presence of 9% various β-cyclodextrins in aqueous solutions at different pH values

This example demonstrates the stability of solutions of bilastine at concentrations above 6.5 mg/ml (0.65% w/v) in the presence of 9.0% w/v. five cyclodextrins β-CD, HP-β-CD, CM-β-CD, DM-β-CD and SBE-β-CD in aqueous solutions at different pH values. Each pH value was obtained by adjusting starting from the stock solution as follows.

Bilastine in non-buffered solutions (pH adjustment)

a) Solution of bilastine 7 mg/ml in basic medium: 70 mg of bilastine was added to a 10 ml volumetric vessel. Approximately 5 ml of deionized water was added and then 1 M NaOH was added dropwise while shaking the mixture until all of the bilastine had dissolved. 900 mg of the appropriate cyclodextrin was then added and the mixture was shaken until the cyclodextrin was completely solubilized (except in the specific example using β-CD, which did not result in complete solubilization). Then the volume was adjusted to 10 ml.

b) 900 μl of each of the five bilastine + cyclodextrin solutions obtained in step a were transferred into separate Eppendorf tubes.

c) If necessary, the pH of each Eppendorf tube was adjusted to the desired value by careful addition of 50% AcOH, 1M HCl or 1M NaOH.

t ₀ =0 days

The solutions were kept under stirring at 30°C for 1 hour, after which the concentration of bilastine was measured.

t ₁ =7 days

After analysis at t ₀ , the solutions were kept for 7 days in a thermostated room at a temperature of 22 ± 2°C without stirring and repeated analysis was carried out.

Each Eppendorf tube was placed in an incubator (VWR® shaker incubator) with constant stirring (100 rpm) and incubated at 30°C for 1 hour. Then, 1.5 ml samples from each Eppendorf tube were centrifuged for 0. 5 hours at 12500 rpm (thermostated centrifuge SIGMA 2-16P) to remove solid bilastine particles. Supernatant samples were appropriately diluted (1:100) to determine bilastine concentration. Bilastine concentration was measured using a Hewlett Packard 8452A diode array spectrophotometer. Assays were performed in triplicate. The results are presented below.

Table 2. Concentration of bilastine (target value 7 mg/ml) in the presence of 9% w/v. various cyclodextrins in unbuffered aqueous solutions at different pH values at _____________________ time t ₀ ______________________

pH 4.0 5.5 7.4 8.0 9.0 β-CD 7.0 7.0 6.9 7.0 6.9 ΗΡ-β-CD 6.4 6.6 6.6 6.6 6.7 CM^-CD 6.5 6.6 6.7 6.7 6.8 ϋΜ-β-CD 6.7 6.8 6.8 6.7 6.8 ΞΒΕ-β-ϋϋ 6.6 6.8 6.9 6.7 6.8

The deviation from 7 mg/ml in bilastine concentration values is due to the dilution effect after the pH adjustment step.

Table 3. Concentration of bilastine (target value 7 mg/ml) in the presence of 9% w/v. various cyclodextrins in an unbuffered aqueous solution at different pH values ________________________at time t1 (7 days) ___________________

pH 4 5.5 7.4 8 9 β-CD 7.2 7.3 7.2 7.1 7.2 ΗΡ-β-CD 6.7 6.8 6.8 6.9 6.8 CM-β-CD 6.6 6.8 6.8 6.8 6.9 ϋΜ-β-CD 6.7 6.9 6.8 6.9 6.9 SBE-β-CD 6.6 6.8 6.9 6.8 6.8

After 1 week, values were still greater than 6.5 mg/mL. Compared to the results at time _t0 , there is a small but overall increase in bilastine concentration, which is caused by slight evaporation of the solvent.

This example shows that bilastine at concentrations above 6.5 mg/ml is stable in unbuffered solutions after 1 hour at 30°C and after 7 days at 22°C for a pH range of 4.0 to 9.0. These results are presented in Fig. 1 (t ₀ ) and Fig. 2( _t1 ).

Example 2. Bioadhesion to the ocular surface of bilastine 0.4% w/v. and HPB 9% in various compositions

Bioadhesion of bilastine 0.4% w/v. and HPB 9% of the compositions in the eye of animals (rat) were measured using positron emission tomography (PET). The compositions differed in viscosity and content of agents that regulate tonicity: methylcellulose and glycerin; and gelling agent: sodium hyaluronate and/or gellan gum. The addition of the positron-emitting tracer 18FDG made it possible to measure the average retention time of each composition in rat eye tissue.

- 12 043904

Table 4. Average ocular retention time (ART) of compositions according to the invention, __________ containing bilastine 0.4% w/v. and HPB 9%________

Glycerol Methylcellulose Gellanovaya gum Sodium hyaluronate ART/min — — — 80.8 1.61% 0.01% — — 59.9 — 0.2% — 99.7 1.61% 0.01% 0.2% — 108.7 — — 0.1% 110.4 1.61% 0.01% — 0.1% 105.7 — 0.2% 0.1% 111.3 1.61% 0.01% 0.2% 0.1% 107.2

In table 4 shows that the greatest retention time or bioadhesion on the ocular mucosa is achieved when sodium hyaluronate (HA), gellan gum (GG) or a mixture of AH and GG are used in combination with bilastine and cyclodextrin HPB with or without methylcellulose (MC) and glycerol . Accordingly, the results indicate that at least GG or HA are useful for increasing the ocular retention time of a composition containing bilastine and HPB, and optionally MC and glycerol. The results are presented in Fig. 3.

Example 3. Preclinical effectiveness of ophthalmic compositions in vivo

Animal model

Male Dunkin-Hartley guinea pigs weighing 300-349 g upon receipt (Harlan Laboratories Inc./Envigo) and kept under standard conditions (2 animals per cage) were used. Animals (6-10 per group) were reused after a washout period of at least 4 days between two consecutive uses to ensure complete recovery of the conjunctiva.

Experimental procedure

Two aqueous ophthalmic compositions of bilastine were prepared with bilastine concentrations of 0.4% and 0.6% w/v. Both formulations also contained HPB at a concentration of 90 mg/ml, methylcellulose at a concentration of 0.1 mg/ml, sodium hyaluronate at a concentration of 1 mg/ml and glycerol at a concentration of 16.1 mg/ml.

Ophthalmic drugs were administered by instillation into the right eye (25 μl), keeping the animal motionless for 2-3 min to ensure retention of the product in the conjunctival sac. The left eye was then injected with a similar volume of the appropriate vehicle or 0.9% NaCl for commercially available eye drops. Each animal had its own positive control.

After a set time (it can range from 10 minutes to 24 hours), acute conjunctivitis was induced by introducing a solution of histamine dihydrochloride (5% in NaCl 0.9%, 25 μl/eye) into each eye, keeping the animal immobile for 2- 3 min. The response to histamine was assessed 30 minutes after its application.

The following parameters were assessed for each eye: degree of edema (conjunctival chemosis), conjunctival redness and vascular injection (conjunctival hyperemia), and tear secretion (epiphora). Severity was assessed according to a subjective scale from 0 to 4 (OECD Test Guideline No. 405: 0=normal; 1=minimal; 2=moderate; 3=intense; 4=severe). The result of adding the individual scores of each parameter in each eye (total score from 0 to 12) was considered as the average value of the overall degree of conjunctivitis.

Statistical research

Compositions that did not reach statistical significance or compositions that achieved statistical significance but that antagonized the action of histamine in a percentage of <30% were considered inactive. For each treatment, the mean total scores were determined for the control eye (left) and the antihistamine-treated eye (right). In addition, the percentage of inhibition (average pharmacological effect) was calculated using the following formula:

Inhibition(%)=[(control score-treatment score)/control score]x100

Statistical analyzes included the use of nonparametric Wilcoxon signed rank tests (paired data) and Mann-Whitney U tests (for independent data) to compare each treatment with the corresponding control and determine differences between treatments, respectively. Statistically significant differences were considered at a p value of <0.05.

The effect of commercial compositions

Azelastine 0.5 mg/ml (Afluon®) was active 9 hours after administration (38.4% inhibition of histamine-induced effects) but not 12 hours (19.2% inhibition). Olopatadine dose 1

- 13 043904 mg/ml (Opatanol®) provided much longer-lasting activity, since its inhibitory activity was observed 24 hours after administration (inhibition 38.0%). The observed differences between azelastine and olopatadine in this model (see Fig. 4) are consistent with previous data comparing the duration of antihistamine activity of commercial drugs for the topical treatment of seasonal allergic conjunctivitis using the guinea pig model of histamine-induced conjunctival vascular permeability. (Beauregard C, Stephens D, Roberts L, Gamache D and Yanni J. Duration of action of topical antiallergy drugs in a Guinea pig model of histamine-induced conjunctival vascular permeability. J Ocul Pharmacol Ther. 2007, 23: 315-20). It is noteworthy that human clinical studies have confirmed the prolonged duration of action of olopatadine 0.2% in this animal model of histamine-induced extravasation (Vogelson CT, Abelson MB, Pasquine T, Stephens DM, Gamache DA, Gross RD, Robertson SM, Yanni JM. Preclinical and clinical antiallergic effect of olopatadine 0.2% solution 24 hours after topical ocular administration. Allergy Asthma Proc. 2004, 25: 69-75).

Effect of bilastine concentrations

The bilastine 4 mg/ml (0.4% w/v) composition described above was prepared and the duration of action was determined. Similar to azelastine at a concentration of 0.5 mg/ml, the activity obtained with this composition against histamine-induced conjunctivitis in guinea pigs remained significant up to 9 hours after its application (36.4% inhibition, Fig. 4).

The 6 mg/mL bilastine (0.6% w/v) formulation described above was also prepared and its activity was compared with that of 4 mg/mL bilastine. The results obtained indicate a slight improvement in terms of percent inhibition with the highest concentration of bilastine at both 9 hours (40.5 and 36.4% inhibition) and 12 hours dosing (29.0 and 20.4% inhibition). No statistical differences were found at any time point. Olopatadine at a concentration of 1 mg/mL demonstrated significant activity (inhibition of 75.9 and 63.9% at 9 and 12 hours after dosing, respectively) at the same time intervals. It was concluded that increasing the concentration of bilastine did not produce a noticeable improvement in terms of efficacy and duration of effect.

Effect of methylcellulose

The effectiveness of equivalent compositions of bilastine 0.4% w/v was compared. with and without methylcellulose 0.1 mg/ml. Both formulations also contained HPB 100 mg/ml, sodium hyaluronate 1 mg/ml and gellan gum 2 mg/ml. At 9 hours post-dose, both drugs were clearly active (44.7 vs. 47.4% antagonism of histamine-induced effects, respectively). These results indicate that methylcellulose does not have a corresponding effect on the duration of activity of bilastine 0.4% w/v.

Effect of glycerin

The effectiveness of equivalent compositions of bilastine 0.4% w/v was compared. with and without glycerol 16.1 mg/ml. Both formulations also contained HPB 100 mg/ml, methylcellulose 0.1 mg/ml, sodium hyaluronate 1 mg/ml and gellan gum 2 mg/ml. 9 hours after dosing, both drugs were active (33.5 vs. 45.8% inhibition for formulations with and without glycerol, respectively). 12 hours after dosing, both drugs were clearly inactive (24.5 vs. 26.7% antagonism, respectively). No statistical differences were found at any time point. These results indicate that glycerol does not have a corresponding effect on the duration of activity of the bilastine 0.4% w/v composition.

Example 4. Clinical efficacy of ophthalmic compositions in vivo

In this example, as well as in table. 5-6 and in Fig. 5-6 show the results of a single-center, double-blind, randomized, placebo-controlled, dose-ranging phase 2 study evaluating the efficacy of bilastine ophthalmic solution (0.2% w/v, 0.4% w/v, and 0.6% w/v). ./vol.) compared to the vehicle for the treatment of allergic conjunctivitis in the conjunctival allergization model (ORA-CAC®).

Aqueous ophthalmic preparations of bilastine were prepared at bilastine concentrations of 0.2% w/v, 0.4% and 0.6% w/v. The carrier composition did not contain bilastine. Excipients were as indicated above in the table. 1, that is, HPB 90 mg/ml, methylcellulose 0.1 mg/ml, sodium hyaluronate 1 mg/ml and glycerol 16.1 mg/ml were also included.

The CAC® is a standardized model for studying treatments for allergic eye disease. CAC® produces signs and symptoms of allergic eye disease (eg, red eyes, swollen watery eyes, and itchy eyes) by directly introducing the allergen into the conjunctiva.

A single dose (one drop per eye) of the assigned study drug was administered 15 minutes, 8, or 16 hours before the CAC® study and assessment of signs and symptoms of allergic conjunctivitis. The study consisted of eight visits over approximately six to ten weeks. Efficacy was assessed using the CAC® model performed by ORA, Inc., Andover, Massachusetts, United States, 01810. The CAC® model includes a screening, treatment, and follow-up period.

During the screening period, at Visit 1, subjects signed an informed consent and underwent an allergy skin test. At Visit 2, each subject underwent bilateral CAC® titration using an allergen to which the subjects had a positive skin test reaction. Subjects testing positive after CAC® underwent CAC® confirmation at Visit 3 using the same allergen with which they qualified at Visit 2.

The treatment period began at visit 4a after subjects were randomized. At this visit, subjects received an outpatient dose of medication to which patients were randomized. Approximately 16 hours after study drug instillation, subjects underwent CAC® at Visit 4b. At visit 5a, subjects received an outpatient dose of the same study drug. Approximately 8 hours after study drug instillation, subjects received CAC® at Visit 5b. Subjects received their final dose of study drug at Visit 6 approximately 15 minutes before CAC®.

During the observation period, on day 29 (±3), all patients were monitored by telephone. In table 5 provides a brief description of the visit schedule.

Table 5. Brief description of visit schedule

Visit 1 (day -50 to -22): Screening/Informed Consent/Skin Test Visit 2 (day -21 ± 3): Titration of SAS® Visit 3 (day -14 ± 3): CAC® confirmation Visit 4a (day 1): Inclusion in Study/Randomization/Outpatient instillation Visit 4b (Day 1; 16 hours after 16 hour duration of action visits 4a): CAC® Visit 5a (day 15 ± 3): Outpatient instillation Visit 5b (Day 15 ± 3; 8 hours 8 hour duration of action after visiting 5 a): CAC® Visit 6 (day 22 ± 3): Outpatient instillation/onset of action SAS® within 15 minutes Day 29 (±3): Telephone communication to monitor the patient

A total of 220 subjects were recruited to enroll approximately 120 subjects at one (1) study site. The primary objective was to measure ocular itching as the main symptom of allergic conjunctivitis.

In the CAC® model, each patient was administered drug or vehicle and exposed to the allergen at specific challenge time points. The challenge times in the study were 15 minutes, 8 and 16 hours post-dose. Pruritus was then measured at time points 3, 5, and 7 minutes postchallenge at Visits 4b (16 hours after study drug instillation), 5b (8 hours after study drug instillation), and 6 (15 minutes after study drug instillation). Patients were asked to rate ocular itching on a scale of 0 to 4 (in half-unit increments) to obtain itching scores, and in each rating, 0 was the lowest and 4 was the highest. Thus, patients received three doses of drug or vehicle, and each dose was followed by an allergen challenge, and then the subject assessed ocular itching in the manner described above.

Treatment success was defined as at least one concentration of bilastine ophthalmic solution demonstrating a clinical benefit over vehicle of at least 0.5 units for all 3 time points post-CAC® and at least 1 unit for most time points post-CAC ®. The results of these studies at these time points are presented in Table. 6, and these data are plotted in FIG. 5 and 6.

- 15 043904

Table 6. Differences in mean treatment scores for itchy eyes defined as Active SubstanceCarrier using least squares method (LSMeans).

Visit Visit 4b (Duration 16 hours) Visit 5b (Duration 8 hours) Visit 6 (Duration 15 min) Reference time (min) 5 7 5 7 3 5 7 Bilastine 0.2% w/v. -0.776* -0.861* -0.742* -1.097 -1.118 -1.205 -1.859 -1.657 -1.463 Bilastine 0.4% w/v. -0.857* -0.926* -0.843* -1.340 -1.206 -1.152 -1.812 -1.459 -1.283 Bilastine 0.6% w/v. -1.444 -1.649 -1.546 -1.694 -1.685 -1.762 -2.137 -1.984 -1.831

*No clinical significance of treatment differences.

Bilastine at a concentration of 0.6% w/v. had clinically significant differences in the improvement of ocular itching at 15 minutes (Visits 6b), 8 hours (Visits 5b), and 16 hours (Visits 4b) after instillation of study drug. Bilastine 0.2% w/v. and 0.4% w/v. had clinically significant differences in the treatment of itchy eyes 15 minutes (visits 6) and 8 hours (visits 5b) after instillation of the study drug. All concentrations of bilastine showed statistically significant differences from vehicle in the treatment of ocular itching at all visits.

As can be seen from table. 6 and fig. 5-6, bilastine at a concentration of 0.6% w/v. had the only analytical concentration that was clinically and statistically effective when administered 16 hours before CAC® (Visit 4b), for the treatment of itchy eyes. These data are particularly surprising because prior to this CAC® study there was no indication that the 0.6% w/v bilastine formulation. will be highly effective in relieving itchy eyes 16 hours after instillation.

In previous preclinical studies (for example, in the previous example), which evaluated the in vivo effectiveness of ophthalmic compositions of bilastine at a concentration of 4 mg/ml (0.4% wt./vol.) and 6 mg/ml (0.6% wt. /vol.) on a model of acute conjunctivitis in a guinea pig, it was concluded that increasing the concentration of bilastine from 0.4 to 0.6% wt./vol. did not lead to a noticeable improvement in terms of effectiveness and duration of effect. Bilastine 0.6% w/v. was considered active 9 hours after dosing, but not 12 hours. It was also confirmed that 1 mg/ml olopatadine (Opatanol®) provides much longer-lasting activity, since its inhibitory activity is observed 24 hours after dosing. Interestingly, prior art data support in human clinical studies the long duration of action of olopatadine 0.2% solution in this animal model of histamine-induced extravasation. (Vogelson CT, Abelson MB, Pasquine T, Stephens DM, Gamache DA, Gross RD, Robertson SM, Yanni JM. Preclinical and clinical antiallergic effect of olopatadine 0.2% solution 24 hours after topical ocular administration. Allergy Asthma Proc. 2004, 25: 69-75). In another clinical study, the relief of ocular itching provided by olopatadine 0.77% was maintained for 24 hours (Torkildsen G., Narvekar A., Bergmann M. Efficacy and safety of olopatadine hydrochloride 0.77% in patients with allergic conjunctivitis using a conjunctival allergen-challenge model. Clinical Ophthalmology 2015:9 1703-1713).

In another study, the antihistamine effects of bilastine and olopatadine were compared in a guinea pig model of histamine-induced conjunctival vascular permeability. To determine in vivo antihistamine activity, guinea pigs were given a subconjunctival histamine challenge after pretreatment with topical drug or vehicle and intravenous injection of Evans blue dye. When bilastine was administered 2-8 hours before the histamine challenge, 50% efficacy was not achieved, whereas olopatadine maintained the ED ₅₀ value below 0.1%. (May 2008, Volume 49, Issue 13, ARVO Annual Meeting Abstract, Comparative Effects of Olopatadine, Bepotastine, and Bilastine on Conjunctival Mast Cell Stabilization and Histamine-Induced Vascular Permeability, C. Beauregard; DJ Stephens; ST Miller; L. Roberts; DA Gamache; JM Yanni). Accordingly, it is clear to date from the prior art that bilastine is unable to match the potency or duration of the antihistamine action of olopatadine in vivo.

However, it is unexpected that the data presented in table. 6 and FIG. 5-6 show that bilastine at a concentration of 0.6% wt./vol. provides statistically significant relief of eye itching after 16 hours

- 16 043904 compared to vehicle, determined using the CAC® model, providing a once-daily dose of a drug containing bilastine greater than 0.4% w/v. in the treatment of itching in the eye associated with allergic conjunctivitis.

Limitations related to currently available medications, such as the need for multiple daily doses and ocular side effects, may lead to poor adherence or treatment discontinuation, particularly if the negative impact on quality of life is perceived as a burden that exceeds the self-imposed allergic conjunctivitis. In addition, once-daily dosing regimens have been shown to significantly improve patient adherence, reduce the risk of missed doses, and likely improve treatment outcomes and symptom control.

Thus, patients who have difficulty treating their symptoms of allergic conjunctivitis with a single dose of their antiallergy eye drops and therefore require a second dose may benefit from the increased convenience of a once-daily dosing regimen of a composition containing at least 0.0 bilastine. 4% w/v

Example 5. Biodistribution of ophthalmic compositions in vivo in the eye

This example confirms the results of Example 4, showing that the bilastine in the ophthalmic compositions of the invention, when administered to the eyes of a rabbit, is found primarily in the conjunctiva, compared to the tissues of the cornea, iris, retina and lens.

Aqueous ophthalmic compositions of bilastine were prepared at a bilastine concentration of 0.6% w/v. Excipients were as indicated above in the table. 1, that is, they also contained HPB 90 mg/ml, methylcellulose 0.1 mg/ml, sodium hyaluronate 1 mg/ml and glycerol 16.1 mg/ml.

The results of this example were obtained in accordance with the following good laboratory practices:

Real Decreto (Royal Decree) 1369/2000 of 19 July (Spain)

OECD Principles of Good Laboratory Practice (Revised 1997), ENV/MC/CHEM (98) 17;

Commission Directive 2004/10/EC of the European Economic Community of 11 February 2004;

Arre ^A te du 14 Mars 2000 (France), 2004/10/EC

OECD ENV/JM/MONO (2002) 9, 25 June 2002

US Food and Drug Administration (FDA) Industry Guidance - Bioanalytical Method Validation - May 2018 and

European Medicines Agency (EMA) Guidelines for the Validation of Bioanalytical Methods EMEA/CHMP/EWP/192217/2009 Rev 1 Corr 2 - July 2011

The subjects were 42 Dutch rabbits aged 4-5 months. The weight of the animals at the beginning of treatment ranged from 1.6 to 2.1 kg.

Animal care and living conditions

Acclimatization 12-14 days Veterinary examination Upon arrival and before treatment, the animals were examined by a veterinarian. conditions Optimal hygienic conditions behind the barrier system. Air conditioners with 14-16 air changes per hour and a constantly controlled environment with room temperature ranges of 19-21°C and humidity ranges from 50 to 85%. 12 hours daylight/12 hours darkness. Accommodation Individual polyphenylene oxide cells (65.3 x 65.3 x 47 cm). Diet Standard granulated food for rabbits Teklad 203OS in unlimited quantities (supplied by Envigo RMS, S.L.). Water Unlimited bottled tap water Environmental enrichment program Various types of species-specific substances have been supplied to reduce stress, improve well-being and improve behavior.

The animals were injected once with 30 μl of the ophthalmic composition into each eye. The ophthalmic composition was applied directly to both eyes of each animal using an automatic pipette. A new pipette tip was used for each eye.

The eyes of the studied animals were not washed after instillation. Animals were weighed before administration and observed after administration to record any possible clinical manifestations.

At each control time point, two to three animals were sacrificed (0.5, 1, 2, 4, 6, 8, 12

- 17 043904 and 24 hours) and the following tissues were collected from both eyes: intraocular fluid, vitreous body, cornea, conjunctiva, iris/ciliary body, lens and retina. Immediately after sampling, all solid matrices were weighed (to the nearest 4 digits) to determine the amount of each tissue sampled.

Bilastine concentration was determined by LC-MS/MS.

Bilastine analyzes were performed according to the following analytical methods:

PKH/MOA/1022 for rabbit plasma,

PKH/MOA/1042 for rabbit intraocular fluid,

PKH/MOA/1043 for rabbit vitreous,

PKH/MOA/1028 for rabbit cornea homogenate,

PKH/MOA/1041 for rabbit iris/ciliary body homogenate (iridociliary zone),

PKH/MOA/1036 for rabbit conjunctival homogenate,

PKH/MOA/1032 for rabbit lens homogenate,

PKH/MOA/1029 for rabbit retinal/choroidal homogenate, which were previously developed and validated in Eurofins|ADME BIOANALYSES in accordance with the US Food and Drug Administration (FDA) Industry Guidelines - Validation of Bioanalytical Methods, May 2018. , and the European Medicines Agency (EMA) Guidelines EMEA/CHMP/EWP/192217/2009-21 July 2011, in studies 18-014A - 18-014H.

Analytical methods included plasma protein precipitation and dilution of other matrices followed by LC-MS/MS analysis using F21201RR (Bilastin-d6) as internal standard.

The results showed that 24 hours after administration, significant concentrations of bilastine were detected in the conjunctiva (mean value: 388.45 ng/g), while the rest of the ocular tissue contained lower concentrations of bilastine: cornea (mean value: 28.68 ng /g), iris/ciliary body (12.42 ng/g), retina/choroid (1.91 ng/g) and lens (0.12 ng/g).

Claims (16)

CLAIM 1. An aqueous ophthalmic pharmaceutical composition containing: a) at least 0.4% w/v but not more than 1.0% w/v. bilastine or a pharmaceutically acceptable salt or hydrate thereof, wherein bilastine or a salt or hydrate thereof is completely dissolved in the aqueous ophthalmic pharmaceutical composition; b) at least one β-cyclodextrin selected from the group consisting of unmodified β-cyclodextrin, C ₁ -C ₆ -alkyl-β-cyclodextrin, C ₁ -C ₆ -hydroxyalkyl-β-cyclodextrin, C1-C6carboxyalkyl-v -cyclodextrin, carbonyl-β-cyclodextrin, C ₂ -C ₆ -sulfoalkyl ether β-cyclodextrin and mixtures thereof; And c) at least one pharmaceutically acceptable water-soluble gelling agent or an acceptable salt thereof selected from the group consisting of hyaluronic acid, gellan gum and mixtures thereof; and wherein the pH of the composition is from 4 to 9, including both lower and upper limits of the range. 2. Ophthalmic pharmaceutical composition according to claim 1, characterized in that at least one β-cyclodextrin is selected from the group consisting of unmodified β-cyclodextrin, C ₁ -C ₆ -alkyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, 2hydroxybutyl-β-cyclodextrin, C ₁ -C ₆ -carboxyalkyl-β-cyclodextrin, carbonyl-β-cyclodextrin, C ₂ -C ₆ -sulfoalkyl ester β-cyclodextrin and mixtures thereof. 3. Ophthalmic pharmaceutical composition according to any one of claims 1 or 2, containing at least 0.6% w/v. bilastine or a pharmaceutically acceptable salt or hydrate thereof, wherein bilastine or a salt or hydrate thereof is completely dissolved in the aqueous ophthalmic pharmaceutical composition. 4. Ophthalmic pharmaceutical composition according to any one of claims 1-3, containing: a) at least 0.6% w/v but not more than 1.0% w/v. bilastine or a pharmaceutically acceptable salt or hydrate thereof, wherein bilastine or a salt or hydrate thereof is completely dissolved in the aqueous ophthalmic pharmaceutical composition; b) at least one β-cyclodextrin selected from the group consisting of unmodified β-cyclodextrin, C ₁ -C ₆ -alkyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, 2-hydroxybutyl-β -cyclodextrin, C ₁ -C ₆ -carboxyalkyl-β-cyclodextrin, carbonyl-β-cyclodextrin, C ₂ -C ₆ -sulfoalkyl ether β-cyclodextrin and mixtures thereof, wherein the concentration of said β-cyclodextrin is at least 5 wt.%. /vol., but not more than 15% wt./vol.; And - 18 043904 c) hyaluronic acid or a pharmaceutically acceptable salt thereof, wherein the concentration of said hyaluronic acid or a pharmaceutically acceptable salt thereof is at least 0.05% w/v but not more than 1% w/v. 5. Ophthalmic pharmaceutical composition according to claim 1 or 3, characterized in that the C1-C6 β-cyclodextrin is a hydroxyalkyl-β-cyclodextrin selected from the group consisting of hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclo dextrin and 2 -hydroxybutyl-cyclodextrin. 6. Ophthalmic pharmaceutical composition according to any one of claims 1 to 5, characterized in that hyaluronic acid or a pharmaceutically acceptable salt thereof has a molecular weight of not more than 600,000 Da. 7. Ophthalmic pharmaceutical composition according to any one of claims 1 to 6, characterized in that the pH value is from 5 to 8, including the lower and upper limits of the range. 8. Ophthalmic pharmaceutical composition according to any one of claims 1 to 7, characterized in that the composition has an osmolality of from about 250 to about 600 mOsm/kg. 9. Ophthalmic pharmaceutical composition according to any one of claims 1 to 8, further containing a tonicity regulating agent selected from the group consisting of glycerol, sorbitol, mannitol, erythriol, arabitol, xylitol, ribitol, galactitol, maltitol, macrogol, lactitol and their mixtures. 10. Ophthalmic pharmaceutical composition according to any one of claims 1 to 9, containing: a) at least 0.6% w/v, but not more than 1.0% w/v. bilastine or a pharmaceutically acceptable salt or hydrate thereof, wherein bilastine or a salt or hydrate thereof is completely dissolved in the aqueous ophthalmic pharmaceutical composition; b) at least one C ₁ -C ₆ -hydroxyalkyl-β-cyclodextrin, wherein the concentration of said β-cyclodextrin is at least 5% w/v but not more than 15% w/v. c) hyaluronic acid or a pharmaceutically acceptable salt thereof, wherein the concentration of said hyaluronic acid or a pharmaceutically acceptable salt thereof is at least 0.05% w/v but not more than 1% w/v. d) from 0.001 to 15% w/v. at least one pharmaceutically acceptable water-soluble polymer selected from the group consisting of cellulose ether derivative, polyethylene glycol, polyvinyl alcohol and mixtures thereof; And e) from 0.05 to 5% by weight of at least one tonicity adjusting agent selected from the group consisting of glycerol, sorbitol, mannitol, erythriol, arabitol, xylitol, ribitol, galactitol, maltitol, macrogol, lactitol and mixtures thereof . 11. Ophthalmic pharmaceutical composition according to any one of claims 1-10, containing: a) at least 0.6% w/v, but not more than 1.0% w/v. bilastine or a pharmaceutically acceptable salt or hydrate thereof, wherein bilastine or a salt or hydrate thereof is completely dissolved in the aqueous ophthalmic pharmaceutical composition; b) at least one C ₁ -C ₆ -hydroxyalkyl-β-cyclodextrin, wherein the concentration of said β-cyclodextrin is at least 5% w/v but not more than 15% w/v. c) hyaluronic acid or a pharmaceutically acceptable salt thereof, wherein the concentration of said hyaluronic acid or a pharmaceutically acceptable salt thereof is at least 0.05% w/v but not more than 1% w/v. d) from 0.001 to 15% w/v. cellulose ether derivative and e) from 0.05 to 5% w/v. glycerin. 12. Ophthalmic pharmaceutical composition according to any one of claims 1-11, containing: a) at least 0.6% w/v, but not more than 1.0% w/v. bilastine or a pharmaceutically acceptable salt or hydrate thereof, wherein bilastine or a salt or hydrate thereof is completely dissolved in the aqueous ophthalmic pharmaceutical composition; b) at least one C ₁ -C ₆ -hydroxyalkyl-β-cyclodextrin, wherein the concentration of said β-cyclodextrin is at least 5% w/v but not more than 15% w/v. c) hyaluronic acid or a pharmaceutically acceptable salt thereof, wherein the concentration of said hyaluronic acid or a pharmaceutically acceptable salt thereof is at least 0.05% w/v but not more than 1% w/v. d) from 0.005 to 0.1% w/v. methylcellulose and e) from 0.5 to 2% w/v. glycerin. 13. The use of an aqueous ophthalmic pharmaceutical composition according to any one of claims 1 to 12 as a medicinal product intended for the treatment and/or prevention of a disorder or disease, the intensity of which is reduced by antagonism of the H ₁ -histamine receptor, where said disorder or disease is an allergic disorder, allergic disease or allergic eye symptoms. 14. The use of an aqueous ophthalmic pharmaceutical composition according to any one of claims 1 to 12 for the treatment and/or prevention of a disorder or disease, the intensity of which decreases with - 19 043904 β-histamine receptor antagonism, where the specified disorder or disease is an allergic disorder, allergic disease or allergic eye symptoms. 15. Use according to claim 14, wherein said disorder or disease, the intensity of which is attenuated by H ₁ -histamine receptor antagonism, is rhinitis, rhinoconjunctivitis, allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, giant papillary conjunctivitis, eye irritation, itching, redness , lacrimation, chemosis, dry eye syndrome, keratoconjunctivitis sicca or tear dysfunction syndrome. 16. Use according to claim 14 or 15, where the aqueous ophthalmic pharmaceutical composition is administered once a day.