阅读说明：本技术 包含比拉斯汀、β-环糊精和至少一种胶凝剂的眼用组合物 (Ophthalmic composition comprising bilastine, beta-cyclodextrin and at least one gelling agent ) 是由 贡萨洛·埃尔南德斯·埃雷尔 安那·贡萨洛·戈罗斯蒂萨 卡帕夫洛·莫兰·波拉杜拉 阿图罗·扎齐· 于 2019-01-09 设计创作，主要内容包括：本发明涉及一种水性眼用药物组合物,其包含：a)至少0.4％w/v的式(I)比拉斯汀或其药学上可接受的盐或其溶剂化物,其中所述比拉斯汀盐或其溶剂化物完全溶解在所述药物组合物中；b)至少一种β-环糊精；c)至少一种药学上可接受的水溶性胶凝剂；其中pH在4至9之间。以及其在治疗和/或预防由H<Sub>1</Sub>组胺受体介导的病症(例如过敏性病症或疾病)中的用途。本发明涉及过敏性结膜炎的治疗和/或预防。<Image he="439" wi="700" file="DDA0002592646070000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention relates to an aqueous ophthalmic pharmaceutical composition comprising a) at least 0.4% w/v of a bilastine of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the bilastine salt or solvate thereof is completely dissolved in the pharmaceutical composition, b) at least one β -cyclodextrin, c) at least one pharmaceutically acceptable water-soluble gelling agent, wherein the pH is between 4 and 9, and its use in the treatment and/or prevention of inflammation by H 1 Use in a histamine receptor mediated condition (e.g. an allergic condition or disease). The present invention relates to the treatment and/or prevention of allergic conjunctivitis.)

1. An aqueous ophthalmic pharmaceutical composition, characterized in that it comprises:

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

b) at least one beta-cyclodextrin selected from one or more of alkyl-beta-cyclodextrin, hydroxyalkyl-beta-cyclodextrin, carboxyalkyl-beta-cyclodextrin, carbonyl-beta-cyclodextrin, sulfoalkylether beta-cyclodextrin and mixtures thereof; and

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

wherein the composition has a pH in the range of from 4 to 9, including the lower and upper limits of this range.

2. The ophthalmic pharmaceutical composition according to claim 1, characterized in that it comprises at least 0.6% w/v of bilastine or a pharmaceutically acceptable salt or solvate thereof, wherein said bilastine or salt or solvate thereof is completely dissolved in said aqueous ophthalmic pharmaceutical composition.

3. The ophthalmic pharmaceutical composition according to claim 1 or 2, wherein the at least one pharmaceutically acceptable water-soluble gelling agent is hyaluronic acid, gellan gum, or an acceptable salt thereof.

4. An ophthalmic pharmaceutical composition according to any one of claims 1 to 3, characterized in that it comprises:

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

b) at least one beta-cyclodextrin selected from one or more of alkyl-beta-cyclodextrin, hydroxyalkyl-beta-cyclodextrin, carboxyalkyl-beta-cyclodextrin, carbonyl-beta-cyclodextrin, sulfoalkylether beta-cyclodextrin and mixtures thereof; wherein the concentration of the beta-cyclodextrin is at least 5% w/v but no greater 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.

5. The ophthalmic pharmaceutical composition according to any one of claims 1 to 4, wherein the β -cyclodextrin is hydroxyalkyl β -cyclodextrin.

6. The ophthalmic pharmaceutical composition according to any one of claims 1 to 5, wherein the hyaluronic acid or pharmaceutically acceptable salt thereof has a molecular weight of not more than 600000 Da.

7. The ophthalmic pharmaceutical composition according to any one of claims 1 to 6, wherein the pH is between 5 and 8, including the lower and upper limits of this range.

8. The ophthalmic pharmaceutical composition of any one of claims 1-7, wherein the composition has an osmolarity between about 250mOsm/kg and about 600 mOsm/kg.

9. The ophthalmic pharmaceutical composition according to any one of claims 1 to 8, further comprising a tonicity agent selected from one or more of glycerol, sorbitol, mannitol, erythritol, arabitol, xylitol, ribitol, galactitol, maltitol, polyethylene glycol, lactitol, and mixtures thereof.

10. An ophthalmic pharmaceutical composition according to any one of claims 1 to 9, characterized in that it comprises:

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

b) at least one hydroxyalkyl beta-cyclodextrin, wherein the concentration of the beta-cyclodextrin is at least 5% w/v but no greater than 15% w/v;

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 no more than 1% w/v;

d) from 0.001% w/v to 15% w/v of at least one pharmaceutically acceptable water soluble polymer selected from: one or more of cellulose ether derivatives, polyethylene glycol, polyvinyl alcohol and mixtures thereof; and

e) from 0.05% w/v to 5% w/v of at least one tonicity agent selected from the group consisting of: one or more of glycerol, sorbitol, mannitol, erythritol, arabitol, xylitol, ribitol, galactitol, maltitol, polyethylene glycol, lactitol, and mixtures thereof.

11. An ophthalmic pharmaceutical composition according to any one of claims 1 to 10, characterized in that it comprises:

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

b) at least one hydroxyalkyl beta-cyclodextrin, wherein the concentration of the beta-cyclodextrin is at least 5% w/v but no greater than 15% w/v;

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 no more than 1% w/v;

d) from 0.001% w/v to 15% w/v of a cellulose ether derivative; and

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

12. An ophthalmic pharmaceutical composition according to any one of claims 1 to 11, characterized in that it comprises:

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

b) at least one hydroxyalkyl beta-cyclodextrin, wherein the concentration of the beta-cyclodextrin is at least 5% w/v but no greater than 15% w/v;

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 no more than 1% w/v;

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

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

13. The ophthalmic pharmaceutical composition according to any one of claims 1 to 12, characterized in that it is a once daily ophthalmic pharmaceutical composition.

14. An aqueous ophthalmic pharmaceutical composition according to any one of claims 1 to 13 for use as a medicament.

15. An aqueous ophthalmic pharmaceutical composition according to any one of claims 1 to 13 for the treatment and/or prevention of H proneness₁Disorders or diseases ameliorated by antagonism of the histamine receptor.

16. Aqueous ophthalmic pharmaceutical composition according to claim 15, characterized in that it isWherein said is easily passed through H₁The condition or disease ameliorated by antagonism of the histamine receptor is an ocular allergic condition, allergic disease or allergic symptom.

17. The aqueous ophthalmic pharmaceutical composition according to claim 15 or 16, wherein the readily passable H is₁The condition or disease ameliorated by antagonism of the histamine receptor is rhinitis, rhinoconjunctivitis, allergic conjunctivitis, vernal keratoconjunctivitis, ectopic keratoconjunctivitis, giant papillary conjunctivitis, ocular irritation, itching, redness, tearing, conjunctival edema, keratosicca or dysfunctional tear syndrome.

Technical Field

The present invention relates to aqueous pharmaceutical compositions containing a high concentration of bilastine suitable for once daily administration and their use as ophthalmic pharmaceutical compositions of antihistamines and antiallergic agents.

Background

It has long been known that histamine is responsible for allergic diseases (such as allergic rhinitis, conjunctivitis, rhinoconjunctivitis, dermatitis)Urticaria and asthma) play a very important role. Act on H₁Antihistamine compounds that receptor histamine levels are useful for treating such diseases.

Local treatment appears to be superior to systemic treatment if the allergic symptoms are predominantly ocular. Topical formulations are superior because they have a faster onset of action (within a few minutes) than systemic formulations, and therefore, are able to easily delay allergic reactions. In a head-to-head comparison, several studies using a conjunctival antigen challenge model have shown that topical agents are superior to systemic antihistamines in the treatment of allergic conjunctivitis. Oral antihistamines can relieve other allergic symptoms in addition to the eye, but have a slower onset compared to topical ophthalmic agents. Topical antihistamines also have fewer side effects than systemic antihistamines because the dosage required to penetrate the conjunctiva is lower and serum levels from topical use are negligible.

Although current topical products have efficacy in treating allergic conjunctivitis, partial patient relief of symptoms may be through convenient once-a-day dosing to relieve symptoms throughout the day. Avoiding more frequent dosing is more convenient for the patient, since once daily dosing saves costs, helps to ensure better patient compliance, and more importantly, represents an improvement in the quality of life of the patient.

Documents EP0818454A1 and EP0580541A1 disclose that benzimidazoles have a selectivity H₁Has antihistaminic activity and no arrhythmia effect. Patent application EP3040334A1 also discloses H having a high selectivity₁A benzimidazole compound having antihistaminic activity which is devoid of activity on the central nervous system and cardiovascular system.

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

the compound is prepared from SpainDeveloped by Faes Farma. Bilastine is H without sedative side effects, cardiotoxicity, hepatic metabolism₁An antagonist benzimidazole compound. In addition, bilastine has been shown to be effective in treating the symptoms of allergic rhinoconjunctivitis and urticaria.

Bilastine was first disclosed in 1 month 1999, since which a number of ophthalmic solutions containing antihistamines were disclosed and commercially available, for example EP2709610B1 discloses a topical ophthalmic solution containing high concentrations of olopatadine (olopatadine), the U.S. Food and Drug Administration (FDA) recently approved a new formulation for an ophthalmic solution of olopatadine hydrochloride at 0.77%. However, there is no single disclosure in the prior art that provides ophthalmic pharmaceutical compositions containing bilastine at high concentrations suitable for once-daily administration.

Patent application WO9413299a1 discloses ophthalmic solutions of 1- (2-ethoxyethyl) -2- (4-methyl-1-homopiperazinyl) -benzimidazole (also known as emedastine). Despite being structurally similar to bilastine, a benzimidazole derivative containing an ethoxyethyl chain attached to the nitrogen atom of the imidazole ring, emedastine is much more water soluble than bilastine, which makes it possible to provide ophthalmic solutions containing emedastine (at a concentration of about 8 mg/mL) and the usual excipients known to the person skilled in the art, such as EDTA, NaCl, Hydroxypropylmethylcellulose (HPMC) and the pH regulators NaOH/HCl and tris (hydroxymethyl) aminomethane.

Disclosure of Invention

The inventors of the present invention surprisingly found that: the ophthalmic formulations of the present invention comprising Bilastine (Bilastine) unexpectedly increase the duration of ocular efficacy of the compound. These findings are particularly surprising when it is considered that such an increase in the duration of efficacy was not observed in preclinical studies involving bilastine and the comparative antihistamine compounds olopatadine and azelastine (azelastine). Accordingly, the present invention provides for the first time an ophthalmic formulation comprising bilastine for once daily administration.

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

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

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

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

the pH of the composition is comprised between 4 and 9, including the lower and upper limits of this range.

In a second aspect, the present invention relates to the use of the above-mentioned aqueous ophthalmic pharmaceutical composition as a medicament.

In a third aspect, the present invention relates to the use of an aqueous ophthalmic pharmaceutical composition as described above for the treatment and/or prevention of ocular diseases susceptible to H passage₁Use of a condition or disease that is alleviated by histamine receptor antagonism.

Another aspect of the present invention relates to the above aqueous ophthalmic pharmaceutical composition and a pharmaceutically acceptable carrier, adjuvant or solvent.

Another aspect of the present invention relates to the use of an aqueous ophthalmic pharmaceutical composition as described above for the preparation of a medicament for the treatment and/or prevention of the ocular diseases susceptible to H passage₁Use of a medicament for a condition or disease in which antagonism of the histamine receptor is ameliorated.

Another aspect of the invention relates to a method for treating and/or preventing the predisposition to pass H₁A method for a condition or disease ameliorated by antagonism of the histamine receptor, which method comprises administering to a subject in need of such treatment and/or prevention a therapeutically effective amount of an aqueous ophthalmic pharmaceutical composition as described above of bilastine.

These aspects and preferred embodiments thereof are additionally also further described in the following description and defined in the claims.

Drawings

FIG. 1 shows bilastine solutions at concentrations above 6.5mg/mL in the presence of 9% w/v of 5 β -cyclodextrins at different pH media at t₀Stability in time.

FIG. 2 shows bilastine solutions at concentrations above 6.5mg/mL in the presence of 9% w/v of 5 β -cyclodextrins at different pH media₁Stability in time.

FIG. 3 shows the average ocular retention time (ART) of a composition of the invention comprising 0.4% w/v bilastine and 9% w/v HPB. AH is sodium hyaluronate, GG is gellan gum, and MC is methylcellulose.

Figure 4 shows the effect of the ophthalmic formulation of the present invention on histamine-induced conjunctivitis in guinea pigs.

FIG. 5 shows the calculation of the average ocular itching score for the activity-control using the least squares method (LSmeans) to represent the treatment difference, allergen challenge after conjunctivaDifferent times (minutes): treatment differences were measured at three bilastine concentrations (0.2% w/v bilastine, 0.4% w/v bilastine and 0.6% w/v bilastine) at baseline, 16 hours, 8 hours and 15 minutes.

FIG. 6 showsDifferent times (minutes) thereafter: average eye itch scores (0-4 scores) measured (baseline, 16 hours, 8 hours, and 15 minutes).

Detailed Description

The inventors have surprisingly found that the combination of bilastine with at least one beta-cyclodextrin and at least one pharmaceutically acceptable water-soluble gelling agent, or an acceptable salt thereof, is optimal for ophthalmic use, showing an excellent long-term effect in the eye, which makes it possible to provide once daily ophthalmic formulations comprising bilastine. Surprisingly, these results were not observed in preclinical trials, as shown in the examples relating to preclinical and clinical studies. Accordingly, in a first aspect, the present invention provides an ophthalmic pharmaceutical composition comprising:

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

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

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

the pH of the composition is comprised between 4 and 9, including the lower and upper limits of this range.

Bilastine

The aqueous ophthalmic pharmaceutical composition of the present invention comprises bilastine of the formula:

or a pharmaceutically acceptable salt or solvate thereof. The compound is 2- [4- (2- {4- [1- (2-ethoxyethyl) ] -1H-benzimidazol-2-yl ] -1-piperidinyl } ethyl) phenyl ] -2-methylpropionic acid, also known as bilastine (bilastine). The synthesis of bilastine is described in documents EP0818454a1, EP0580541a1 and EP3040334a 1.

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

The invention also provides "salts" of the compounds described herein. For example, the salts can be acid addition salts, base addition salts, or metal salts, and can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods known to those skilled in the art. Such salts are typically prepared, for example, by reacting the free acid or base form of the compound with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Nonaqueous media such as diethyl ether, ethyl acetate, ethanol, acetone, isopropanol or acetonitrile are generally preferred. Illustrative examples of the acid addition salts include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate and the like; organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, camphorsulfonate and the like. Illustrative examples of base addition salts include inorganic base salts such as ammonium salts and organic base salts, such as ethylenediamine, ethanolamine, N-dialkylenethanolamine, triethanolamine, glutamine, amino acid basic salts, and the like. Illustrative examples of the metal salt include, for example, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, and lithium salt.

According to the invention, the term "solvate" is understood to mean any form of the active compound according to the invention having another molecule bound by non-covalent bonds, most likely a polar solvent. Examples of solvates include hydrates and alcoholates. Solvation processes are generally known in the art.

The compounds of the present invention should also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacement of hydrogen by deuterium or tritium, or by¹³C-or¹⁴C is enriched in carbon instead of carbon, or¹⁵Except that N is enriched in nitrogen instead of nitrogen, compounds having the structure of the present invention are within the scope of the present invention.

A concentration of at least 0.4% w/v means that more than 4mg of bilastine is completely dissolved in 1mL of water, i.e., without any obvious sign of precipitation. In the present invention, all percentages are in w/v unless otherwise indicated. 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 comprises 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 of bilastine, wherein the bilastine is fully dissolved. In another specific embodiment, the pharmaceutical composition comprises 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 of bilastine, wherein the bilastine is fully 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.

Cyclodextrin

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

The MS value (average molar degree of substitution) is the average number of moles of substituent per mole of glucopyranose. For example, in the case of β -cyclodextrin, the average number of substituents per β -cyclodextrin nucleus can be calculated by multiplying the MS value by 7(β -cyclodextrin contains 7 saccharide units per cyclodextrin molecule). A clear indication of this value is DS (degree of substitution).

As used herein, the term "cyclodextrin" may refer to cyclodextrins OR cyclodextrin derivatives.Cyclodextrins are commercially available OR may 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-cyclodextrins_1-6Those derivatives of alkyl groups, such as methylated, ethylated, propylated and butylated cyclodextrins, wherein R is methyl, ethyl, propyl or butyl; those having hydroxyalkyl substituents, e.g. hydroxypropyl or hydroxyethyl cyclodextrins, in which R is-CH₂CH(OH)CH₃Or CH₂CH₂An OH group; branched cyclodextrins, such as maltose-bonded cyclodextrins; a cationic cyclodextrin; a quaternary ammonium salt; anionic cyclodextrins, such as carboxymethyl cyclodextrins, cyclodextrin sulfates (cyclodextrin sulfates), and cyclodextrin succinates (cyclodextrin succinates); amphoteric ringDextrins, such as carboxymethyl/quaternary ammonium cyclodextrins. Other specific modifications include one or more hydroxyalkyl ethers (e.g., R is C)_1-6Alkylene hydroxy) moieties; one or more sulfoalkyl ethers (e.g. R is C)_2-6Alkylene SO₃ ^-) A moiety; carboxyalkyl (e.g. R is C (O) C_1-6Alkyl) moieties; a substituted phenoxy moiety; a tryptophan moiety; 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 beta-cyclodextrin is selected from the group consisting of: one or more of alkyl-beta-cyclodextrin, hydroxyalkyl beta-cyclodextrin, carboxyalkyl-beta-cyclodextrin, carbonyl beta-cyclodextrin, sulfoalkyl ether beta-cyclodextrin, and mixtures thereof.

In one embodiment, the beta-cyclodextrin is an alkyl-beta-cyclodextrin. Preferred alkyl- β -cyclodextrins include methyl β -cyclodextrin; dimethyl-beta-cyclodextrin; trimethyl-beta-cyclodextrin; ethyl-beta-cyclodextrin; diethyl-beta-cyclodextrin; propyl-beta-cyclodextrin; and butyl-beta-cyclodextrin. In a more preferred embodiment, the beta-cyclodextrin is selected from methyl-beta-cyclodextrin or dimethyl-beta-cyclodextrin. In the context of the present invention, when the term "alkyl- β -cyclodextrin" is used, it is meant to include β -cyclodextrins in which the alkyl moiety is optionally substituted but which do not include hydroxyalkyl β -cyclodextrins.

The degree of substitution/modification of the alkyl β -cyclodextrin derivative is preferably 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 particular embodiment, the beta-cyclodextrin is not alkenyl-beta-cyclodextrin, in particular, the beta-cyclodextrin is not hydroxybutenyl-beta-cyclodextrin.

In another embodiment, the cyclodextrin is hydroxyalkyl- β -cyclodextrin. Preferred hydroxyalkyl- β -cyclodextrins include hydroxyethyl- β -cyclodextrin; hydroxypropyl-beta-cyclodextrin (equivalent to 2-hydroxypropyl-beta-cyclodextrin) and 2-hydroxybutyl-beta-cyclodextrin. In a more preferred embodiment, the cyclodextrin is hydroxypropyl- β -cyclodextrin (HPBCD or HR- β -CD).

Hydroxyalkyl cyclodextrin derivatives, particularly 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- β -cyclodextrin. Preferred herein are carboxyalkyl- β -cyclodextrins, including carboxymethyl- β -cyclodextrin and (2-carboxyethyl) - β -cyclodextrin.

In another embodiment, the cyclodextrin is a sulfoalkyl ether β -cyclodextrin. Preferred sulfoalkyl ether- β -cyclodextrin herein is sulfobutyl ether- β -cyclodextrin.

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

In a preferred embodiment, the cyclodextrin is a β -cyclodextrin selected from the group consisting of: one or more of alkyl-beta-cyclodextrin, hydroxyalkyl-beta-cyclodextrin, carboxyalkyl-beta-cyclodextrin, sulfoalkylether-beta-cyclodextrin, and mixtures thereof.

In another preferred embodiment, the cyclodextrin is a β -cyclodextrin selected from the group consisting of: one or more of hydroxyalkyl-beta-cyclodextrin, carboxyalkyl-beta-cyclodextrin, sulfoalkylether-beta-cyclodextrin and mixtures thereof.

In a most preferred embodiment, the cyclodextrin is a β -cyclodextrin selected from the group consisting of: one or more of hydroxyalkyl-beta-cyclodextrin, sulfoalkyl ether-beta-cyclodextrin, and mixtures thereof.

In the examples of the present invention, the following β -cyclodextrins were used:

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

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

2-hydroxypropyl- β -Cyclodextrin with a degree of substitution of 4.5, (Klepotase; (HPB)^TMRoquette Pharma)。

-CM- β -CD: carboxymethyl- β -cyclodextrin sodium salt with a degree of substitution of 3 (Sigma-Aldrich ref.: 21906-5G).

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

-SBE- β -CD: beta-cyclodextrin sulfobutyl ether sodium salt (USP) having a degree of substitution of 6.2 to 6.9 (Carbosynthref.: 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 about 0.1% to about 50% w/v. Herein, w/v refers to the weight/volume percent concentration (g/100mL), for example, when cyclodextrin is present in the composition in an amount of about 0.1% to about 50%, it is present in an amount of about 1mg/mL to about 500 mg/mL. In the present invention, all percentages are expressed in w/v units unless otherwise indicated. In particular embodiments, the cyclodextrin is present in an amount of about 0.25% to about 30%, about 0.5% to about 25%, about 1% to about 20%, about 2% to about 15%, or about 3% to about 10% w/v. In a preferred embodiment, the concentration of cyclodextrin in the pharmaceutical composition of the invention is at least 5% w/v, but not more than 15% w/v, i.e. about 50 to 150 mg/mL. More preferably, the cyclodextrin is present in an amount of at least 8% but no more than 10% w/v. In another preferred embodiment, the composition of the invention comprises 9% w/v cyclodextrin.

Gelling agent

A water-soluble gelling agent refers to a substance that can increase the viscosity of an aqueous solution (e.g., an ophthalmic pharmaceutical composition of the present invention) without substantially changing its other properties, but forms a gel that dissolves in the liquid phase to form a colloidal mixture having a weakly viscous internal structure. In a preferred embodiment, the at least one gelling agent is a pharmaceutically acceptable gelling agent for ophthalmic purposes.

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

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

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

In a particular embodiment, the gelling agent or an acceptable salt thereof is present in the aqueous composition of the present invention in an amount of from about 0.001% w/v to about 2% w/v, preferably from about 0.003% w/v to about 1% w/v. In a particular embodiment, the gelling agent is present in the aqueous composition of the present 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 expressed in w/v units unless otherwise indicated. 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 of the present invention comprises:

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

b) at least one beta-cyclodextrin selected from the group consisting of: one or more of alkyl-beta-cyclodextrin, hydroxyalkyl beta-cyclodextrin, carboxyalkyl beta-cyclodextrin, carbonyl-beta-cyclodextrin, sulfoalkyl ether beta-cyclodextrin, and mixtures thereof; wherein the concentration of the beta-cyclodextrin is at least 5% w/v but no 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 particular embodiment, the gelling agent is hyaluronic acid or a pharmaceutically acceptable salt thereof, and has a molecular weight of no more than 600000 Da. The molecular weight of the gelling agent can be measured according to techniques known in the art. Preferably, but not limited to, the average molecular weight of the hyaluronic acid or pharmaceutically acceptable salt thereof may be determined using size exclusion chromatography coupled with multi-angle laser light scattering (SEC-MALLS). Alternatively, the average molecular weight of the hyaluronic acid or pharmaceutically acceptable salt thereof may also be determined using the intrinsic viscosity and Mark-Houwink relationship.

Further embodiments

In a particular embodiment, the ophthalmic pharmaceutical composition of the present invention further comprises at least one pharmaceutically acceptable water-soluble polymer as viscosity-increasing agent selected from the group consisting of: one or more of ether derivatives of cellulose, polyethylene glycol, polyvinyl alcohol and mixtures thereof.

Water-soluble polymer refers to a hydrophilic polymer that is 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 an ether derivative of cellulose, most preferably methylcellulose. In another embodiment, the at least one water soluble polymer is polyethylene glycol.

In a particular embodiment, the water soluble polymer is present in the aqueous composition of the present invention in an amount of from about 0.001% w/v to about 15% w/v, preferably from about 0.01% w/v to about 15% w/v. In particular embodiments, the water-soluble polymer is present in the aqueous composition of the present 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 expressed in w/v units unless otherwise indicated.

Cellulose ether derivatives

In one embodiment, the water soluble polymer is an ether derivative of cellulose. Cellulose ether derivatives refer to cellulose in which the hydroxyl groups in the cellulose have been partially OR completely substituted to form a cellulose ether (-OR). In one embodiment, the ether derivative of cellulose is selected from: one or more of alkyl cellulose, hydroxyalkyl cellulose, carboxyalkyl cellulose and mixtures thereof.

In a preferred embodiment, the ether derivative of cellulose is selected from: one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose, carboxyalkyl cellulose and mixtures thereof.

In one embodiment, the cellulose ether derivative is an alkyl cellulose. Alkyl celluloses preferred for use herein include Methyl Cellulose (MC), ethyl cellulose, ethyl methyl cellulose, and mixtures thereof.

In one embodiment, the cellulose ether derivative is a hydroxyalkyl cellulose. Preferred hydroxyalkyl celluloses for use herein include hydroxymethyl cellulose (HMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC) and ethyl hydroxyethyl cellulose.

In one embodiment, the cellulose ether derivative is a carboxyalkyl cellulose. Preferred carboxyalkyl celluloses for use herein include carboxymethyl cellulose (CMC). CMC and sodium carboxymethyl cellulose (CMCNa) are equivalent.

Polyethylene glycol (PEG)

PEG is also known as polyethylene oxide (PEO) or Polyoxyethylene (POE). In a preferred embodiment, PEG is a low molecular weight PEG, which means a PEG with a molecular weight between 300-1000 g/mol. The molecular weight of PEG is more preferably between 300 and 500 g/mol. In a preferred embodiment, the molecular weight is 400g/mol, i.e. PEG 400.

In a particular embodiment, the osmolality (osmolality) of the composition is comprised between about 200 and about 640, preferably about 250 to about 600 mOsm/kg. In a preferred embodiment, the osmolality is from about 240mOsm/kg to about 340 mOsm/kg. The osmolarity of the ophthalmic drug solutions of the present invention can be measured using standard methods known in the art. Preferably, but not limited to, the osmolarity of an ophthalmic drug solution of the present invention can be determined by measuring the freezing point depression of the solution with an osmometer.

In a particular embodiment, the composition of the invention may further comprise an osmotic or tonicity agent selected from the group consisting of: one or more of glycerol, sorbitol, mannitol, erythritol, arabitol, xylitol, ribitol, galactitol, maltitol, polyethylene glycol, lactitol, and mixtures thereof. When present, the osmotic or tonicity agent is present in the aqueous composition of the present 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 embodiments compatible with the former, the amount of the osmotic or tonicity agent in the aqueous composition of the present invention is less than 15%, 13%, 10%, 7%, 5%, 3%, or 2%. All percentages are expressed in w/v units unless otherwise indicated.

In a preferred embodiment, the amount of said osmotic or tonicity agent, when present, in the aqueous composition of the present invention is between 0.05% and 5% w/v.

In a particular embodiment, the inventors have surprisingly found that the compositions of the present invention are stable and do not require the addition of preservatives that cause dry eye and eye irritation, such as benzalkonium chloride, imidazolidinyl urea, methylparaben, propylparaben, phenoxyethanol, disodium EDTA, thimerosal, chlorobutanol and sorbic acid. Thus, in a particular embodiment, the ophthalmic pharmaceutical composition of the present invention is free of preservatives.

In a particular embodiment, the composition of the invention comprises glycerol. Glycerol (glycerol) is a synonym for glycerol (glycerol) or glycerol (glycerol). Preferably, the amount of glycerol in the aqueous composition of the invention is between 0.05% and 5% w/v, more preferably between 0.05% and 3% w/v. In a preferred embodiment, the 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 comprises about 1.6%, preferably 1.61% glycerol. All percentages are expressed in w/v units unless otherwise indicated.

pH value

The aqueous pharmaceutical compositions of the present invention are preferably for ophthalmic use and/or administration, i.e. aqueous ophthalmic pharmaceutical compositions suitable for these purposes. The physiological pH of the eye, particularly the human eye, is known to be between about 6.5-8.0.

In a preferred embodiment, the pH of the pharmaceutical composition is between 4 and 9, including lower and upper limits. In some embodiments, the aqueous ophthalmic pharmaceutical composition of the present invention has a pH of 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, 8.9, 9.0, 9.9, 9.2, 9.4, 9.9.9, or 1.2.

With respect to pH, it is readily understood that a pH of 4 may also be considered to correspond to a pH range of 3.6 to 4.4. Similarly, a pH of 9 may also be considered to correspond to a pH range of 8.6 to 9.4. In another preferred embodiment, the pH of the pharmaceutical composition is 4.0, 5.5, 7.4, 8.0 or 9.0.

In one embodiment, there is a pH adjusting agent selected from hydrochloric acid, boric acid, acetic acid, sodium hydroxide, potassium hydroxide, or combinations thereof.

In one embodiment, there is a buffer selected from an acetate buffer, a citrate buffer, a phosphate buffer, a borate buffer, or a combination thereof.

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

Use of

Bilastine has been found to be histamine H₁Antagonists of the receptor, and are therefore useful in the treatment and/or prevention of histamine H, a known predisposition to histamine₁The disease is relieved by the antagonism of the receptor.

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

Another aspect of the invention relates to a method for treating and/or preventing the predisposition to pass H₁An aqueous ophthalmic pharmaceutical composition as defined above for a condition or disease ameliorated by antagonism of the histamine receptor. The disease is, for example, an allergic disease or disorder, or a symptom derived from an allergy.

In a preferred embodiment, the present invention relates to an aqueous ophthalmic pharmaceutical composition as defined above for the treatment and/or prevention of an ocular allergic disorder, allergic disease or allergic symptoms. Preferably, the allergic disease, disorder or condition is selected from rhinitis, rhinoconjunctivitis, allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, giant papillary conjunctivitis, ocular irritability, itching, redness, lacrimation, conjunctival edema, keratoconjunctivitis sicca or dysfunctional tear syndrome. In a preferred embodiment, the allergic disease or disorder is selected from rhinitis, rhinoconjunctivitis, allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, giant papillary conjunctivitis, and conjunctival edema. In another preferred embodiment, the allergic condition is selected from the group consisting of ocular irritation, itching, redness, tearing, keratoconjunctivitis sicca, and dysfunctional tear syndrome. In the context of the present invention, dry eye includes keratoconjunctivitis sicca, or dysfunctional tear syndrome.

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

In the context of the present specification, the term "treatment" refers to the administration of a compound or formulation according to the present invention to ameliorate or eliminate the disease or one or more symptoms associated with the disease. "treating" also includes ameliorating or eliminating the physiological sequelae of the disease.

In the context of the present invention, the term "improvement" is understood to mean any improvement in the condition of the patient being treated.

In the context of the present specification, the term "prevention" (or to prevention) refers to the administration of a compound or formulation according to the invention to reduce the risk of acquiring or developing the disease or one or more symptoms associated with the disease.

Pharmaceutical composition

The term "aqueous ophthalmic pharmaceutical composition" refers to a liquid pharmaceutical composition comprising water suitable for the eye.

In one embodiment, bilastine is completely dissolved in the aqueous ophthalmic pharmaceutical composition of the present 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 present 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 present invention at a concentration ranging between 0.6 and 1.0 w/v%, preferably at a concentration ranging between 0.6 and 0.9 w/v%, more preferably at a concentration ranging between 0.6 and 0.8 w/v%. Preferably, bilastine is completely dissolved in the aqueous ophthalmic pharmaceutical composition of the present invention at a concentration of 0.6% w/v. Herein, w/v% refers to the weight/volume percent concentration (g/100mL), for example, when bilastine is present in an amount of about 0.6% to about 1.0% in the composition, it refers to its presence in an amount of about 6mg/mL to about 10 mg/mL. In the present invention, all percentages are expressed in w/v units unless otherwise indicated.

In one embodiment, the amount of bilastine in the pharmaceutical composition of the invention is preferably greater than 4500 μ g/mL, preferably greater than 6000 μ g/mL, preferably greater than 6500 μ g/mL, preferably greater than 7000 μ g/mL, preferably greater than 7500 μ g/mL, preferably greater than 8000 μ g/mL, preferably greater than 8500 μ g/mL, preferably greater than 9000 μ g/mL, and more preferably greater than 9500 μ g/mL. In a preferred embodiment, the amount of bilastine in the pharmaceutical composition of the invention is less than 10500 μ g/mL.

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

The term "therapeutically effective amount" means that amount of a drug which, when administered, provides a therapeutic effect in the treatment or control of a disease or condition for which one or more pharmaceutically active agents contained therein is obtained.

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

The aqueous ophthalmic pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable excipient.

The term "pharmaceutically acceptable excipient" refers to a carrier, diluent or adjuvant with which the active ingredient is administered. The pharmaceutically acceptable excipient can be a sterile liquid, such as water and oil, including those from petroleum, animal, vegetable, or synthetic; such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water or saline solutions, and aqueous dextrose and glycerol solutions, are preferably employed as carriers, particularly for injectable solutions. Suitable Pharmaceutical carriers are described in e.w. martin, 2005, 21 st edition, "Remington's Pharmaceutical Sciences".

The excipients and auxiliary substances necessary to produce the pharmaceutical form required for administration of the pharmaceutical composition of the invention will depend, inter alia, on the selected pharmaceutical form to be administered. The pharmaceutical form of administration of the pharmaceutical composition will be manufactured according to conventional methods known to those skilled in the art. A review of the methods of administration of the different active ingredients, the excipients to be used and the methods of their production can be found in Tratado de pharmacia galenic, c.

The term "pharmaceutically acceptable" refers to compositions and molecular entities that are physiologically tolerable and do not typically produce allergic or similar untoward reactions (e.g., gastric disorders, dizziness, and the like) when administered to a human or animal. Preferably, the term "pharmaceutically acceptable" means approved by a regulatory agency of the state or federal government or encompassed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

The formulations disclosed herein may also optionally further comprise one or more ophthalmic excipients. By way of non-limiting example, the ophthalmic excipient comprises at least one agent selected from the group consisting of a mucoadhesive, a preservative, a pH adjuster, a tonicity-adjusting agent, a buffering agent, an antioxidant, a chelating agent, an antimicrobial preservative, a chemical preservative, a viscosity enhancer, or a combination thereof. In a particular embodiment, the ophthalmic composition further comprises a water soluble polymer, as defined above.

In a particular embodiment, the composition of the invention does not comprise a corticosteroid.

In a preferred embodiment, the ophthalmic pharmaceutical composition comprises:

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

b) at least one hydroxyalkyl beta-cyclodextrin, wherein the concentration of the beta-cyclodextrin is at least 5% w/v but no greater than 15% w/v;

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 no more than 1% w/v;

d) from 0.001% w/v to 15% w/v of at least one pharmaceutically acceptable water soluble polymer selected from: one or more of cellulose ether derivatives, polyethylene glycol, polyvinyl alcohol and mixtures thereof; and

e) from 0.05% w/v to 5% w/v of at least one tonicity agent selected from the group consisting of: one or more of glycerol, sorbitol, mannitol, erythritol, arabitol, xylitol, ribitol, galactitol, maltitol, polyethylene glycol, lactitol, and mixtures thereof.

In another preferred embodiment, the ophthalmic pharmaceutical composition comprises:

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

b) at least one hydroxyalkyl beta-cyclodextrin, wherein the concentration of the beta-cyclodextrin is at least 5% w/v but no greater than 15% w/v;

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 no more than 1% w/v;

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

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

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

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

b) at least one hydroxyalkyl beta-cyclodextrin, wherein the concentration of the beta-cyclodextrin is at least 5% w/v but no greater than 15% w/v;

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 no more than 1% w/v;

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

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

Table 1 below provides a list of exemplary ingredients suitable for exemplary preferred formulations of the ophthalmic compositions of the present invention, and the desired weight/volume percentages of these ingredients. It is to be understood that, unless otherwise specifically noted, table 1 below is exemplary, that certain ingredients may be added or removed from the table and that the concentrations of certain ingredients may be varied, and that the formulations may remain within the scope of the invention.

Table 1 exemplary preferred formulations of ophthalmic compositions of the present invention and the desired weight/volume percentages of the ingredients

Composition (I)	w/v％
		Bilastine	0.6
β -Cyclodextrin (hydroxypropyl β -Cyclodextrin)	9.0
		Gelling agent (sodium hyaluronate)	0.1
Tension agent (Glycerol)	1.61
		Tackifier (methyl cellulose)	0.01
PH regulator (NaOH or HCl)	In an amount sufficient to achieve a pH of 7.4
		Purified water	Proper amount to 100

Pharmaceutical forms

Examples of pharmaceutical compositions include any liquid composition for topical administration to the eye. The liquid form is a solution, suspension or emulsion.

Examples of suitable formulations for topical administration to the eye include eye drops (i.e., eye drops or artificial tears), ophthalmic emulsions, and ophthalmic ointments. In a particular embodiment, the composition of the invention is in the form of an ophthalmic formulation such as an eye drop. The ophthalmic formulation may include a suitable antimicrobial agent. In a preferred embodiment, the ophthalmic formulation does not comprise a preservative. In a more preferred embodiment, the ophthalmic formulation does not comprise a preservative selected from the group consisting of: benzalkonium chloride (benzalkonium chloride), imidazolidinyl urea, methylparaben, propylparaben, phenoxyethanol, disodium EDTA, thimerosal, chlorobutanol, and sorbic acid.

The present invention provides an ophthalmic pharmaceutical composition as defined above. In a preferred embodiment, the ophthalmic pharmaceutical composition is a once daily pharmaceutical composition.

The following examples are merely illustrative of certain embodiments of the invention and are not to be considered as limiting in any way.

Examples

Materials and methods

The following materials have been used, bilastine (supplied by Sai Life Sciences, lot number 5000011325), the above-mentioned cyclodextrins such as β -CD, HP- β -CD, HPB, CM- β -CD, DM- β -CD and SBE- β -CD, methylcellulose 1500(MC1500) (Acofarma), Gellan Gum (GG) (Kelcogel CG-LA, CPKelco), sodium hyaluronate (Caref) and glycerol (Merck-Millipore). the water used in the following examples is water using Merck-MilliporePurified water obtained from the water purification system.