Ophthalmic composition

Abstract

The present invention provides an aqueous liquid composition for ophthalmic administration comprising a therapeutically effective amount of a ketorolac compound and a corticosteroid, wherein the ketorolac compound is present in essentially dissolved form and the corticosteroid is present in the form of suspended particles, and the composition exhibits an acidic pH of about 6.5 or less. The present invention further provides the compositions disclosed herein for use in preventing or treating ocular inflammation, and methods of preventing or treating ocular inflammation in a subject.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of International Application No. PCT / US2021 / 017519, filed February 11, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Ophthalmic compositions containing the nonsteroidal anti-inflammatory drug (NSAID) ketorolac tromethamine are commercially available to treat eye irritation caused by allergies and inflammation occurring after cataract surgery. Similarly, ophthalmic compositions containing corticosteroid drugs are commercially available to treat certain eye conditions resulting from inflammation, injury, or surgery. Some patients use both drugs to treat irritation or inflammation symptoms. Combining and administering both types of active ingredients in one stable composition is more convenient for patients and increases patient compliance. However, combining both types of active ingredients in a single composition is known to be difficult. Chemical incompatibility, stability, safety, and / or efficacy are often adversely affected, and the results are unpredictable.

[0003] US Patent Application Publication No. 2013 / 0217657 discloses a composition for topical ophthalmic application comprising an aqueous mixture of steroidal and nonsteroidal anti-inflammatory agents in a flowable mucoadhesive polymer for treating ocular inflammation and inflammatory conditions. The composition has a viscosity in the range of about 1,000 to about 30,000 centipoise (cps) or millipascal seconds (mPa·s) and gels within the eye after contact with the tear fluid of the eye, and therefore remains in place for an extended period of time to provide sustained release of the ophthalmic medication. The disclosure emphasizes that a viscosity substantially lower than about 1,000 cps or mPa·s prevents the ability to gel upon contact with tear fluid and reduce ocular retention. However, highly viscous compositions can cause undesirable visual impairments, including optical aberrations such as blurring the patient's vision, and can prevent uniform suspension and / or resuspension of solids present in the composition, resulting in inaccurate dosing. Furthermore, preparation of certain compositions of U.S. Patent Application Publication No. 2013 / 0217657 demonstrates the formation of insoluble precipitates of ketorolac tromethamine and chitosan, potentially reducing the bioavailability of ketorolac tromethamine and the accuracy of ketorolac tromethamine dosing in such highly viscous compositions.

[0004] It is therefore an object of the present invention to provide a composition comprising a ketorolac compound and a corticosteroid that is chemically and physically storage stable at room temperature. Such a composition has a low viscosity and the ketorolac compound is essentially present in dissolved form. Further objects of the present invention will become apparent based on the following description, examples, and claims of the invention. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] US Patent Application Publication No. 2013 / 0217657 Summary of the Invention

[0006] In a first aspect, the present invention relates to an aqueous liquid composition for ophthalmic administration comprising a therapeutically effective amount of a ketorolac compound and a corticosteroid, wherein the ketorolac compound is present essentially in dissolved form and the corticosteroid is present in the form of suspended particles, and the composition exhibits an acidic pH of about 6.5 or less.

[0007] In a further aspect, the present invention provides a composition as disclosed herein for use in the prevention or treatment of ocular inflammation.

[0008] In yet a further aspect, the present invention provides a method of preventing or treating ocular inflammation in a subject, comprising topically administering to the eye of the subject any of the compositions disclosed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The object is solved by the subject matter of the independent claims. Advantageous embodiments are set forth in the dependent claims and the subsequent description.

[0010] definition We first provide definitions of some of the terms used throughout this specification and the claims. The definitions should be used to determine the meaning of each expression, unless the context requires a different meaning.

[0011] The term "a" or "an" does not exclude a plurality, i.e., the singular forms "a," "an," and "the" should be understood to include plural referents unless the context clearly indicates or requires otherwise. In other words, all references to singular features or limitations in this disclosure shall include the corresponding plural features or limitations, and vice versa, unless expressly specified otherwise or clearly indicated otherwise by the context in which the reference is made. Thus, the terms "a," "an," and "the" have the same meaning as "at least one" or "one or more," unless otherwise defined. For example, reference to a "component" includes a mixture of components, and the like.

[0012] The term "about" or "ca." compensates for variability accepted in the pharmaceutical industry and inherent in pharmaceutical products, such as differences in content due to manufacturing variations and / or product degradation over time. The term allows for any variation that, in pharmaceutical practice, allows for the product being evaluated to be considered bioequivalent in the stated strength of the claimed product.

[0013] The terms "active agent," "therapeutic agent," "active pharmaceutical ingredient (API)," "active ingredient," "drug," and "bioactive agent" are used interchangeably and refer to a compound or combination of compounds that is pharmacologic active against an undesirable condition.

[0014] The term "composition" refers to any type of composition in which a particular component may be optionally incorporated along with any additional components.

[0015] The term "compound" refers to a chemical substance that is a material made up of molecules that have essentially the same chemical structure and properties. In the case of small molecule compounds, the molecules are typically identical in terms of their atomic composition and structural makeup. In the case of macromolecular or polymeric compounds, the molecules of the compound are very similar, although not all of them are necessarily identical.

[0016] The terms "comprise", "comprises" and "comprising" and similar expressions are to be interpreted in an open and inclusive sense, including but not limited to.

[0017] The term "corticosteroids" refers to steroid hormones produced in the adrenal cortex of vertebrates and synthetic analogs of these steroid hormones. The term also includes any salts, esters, acetonides or other hydrolyzable prodrugs of corticosteroids. Corticosteroids include drugs that reduce inflammation or reduce immune system activity.

[0018] Terms such as "essentially," "about," "approximately," "substantially," and the like, in connection with an attribute or value include the exact attribute or exact value, as well as any attribute or value that would normally be considered to be within a normal range or variability accepted in the relevant art. For example, "essentially water-free" means that water is not intentionally included in the composition, but does not exclude the presence of residual moisture.

[0019] The term "consisting essentially of" refers to a composition or dosage form to which no additional ingredients other than those listed have been added. Nevertheless, very small amounts of other ingredients, such as impurities inherent in the material, may be present. Furthermore, for example, when referring to "consisting essentially of A, B, C, and optionally D," this means that no additional ingredients other than A, B, C, and D have been added to the composition or dosage form, and D is an optional ingredient (i.e., not required) in that composition or dosage form.

[0020] The term "essentially free" refers to a composition that contains less than a functional amount of each component, including 0 wt%, typically less than 1 wt%, preferably less than 0.1 wt% or even less than 0.01 wt% of each component.

[0021] The terms "hydroxypropyl cellulose" and "HPC" refer to cellulose ethers in which some of the hydroxyl groups in the glucose units are replaced with hydroxypropyl groups.

[0022] The terms "hydroxypropyl methylcellulose" and "HPMC" refer to a cellulose ether in which some of the hydroxyl groups in the glucose units are replaced with methyl groups and others are replaced with hydroxypropyl groups.

[0023] The term "ketorolac compound" refers to the compound with the chemical name 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylic acid and Chemical Abstracts Service (CAS) number [74103-06-3]. The term "ketorolac compound" also includes any salts, solvates, esters or other hydrolyzable prodrugs thereof. Ketorolac has a molecular weight of 255.27 g / mol and the following structure: [ka]

[0024] The term "ketorolac tromethamine" refers to the compound ketorolac having the chemical name 2-amino-2-(hydroxymethyl)propane-1,3-diol; 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylic acid and CAS number [74103-07-4]. The term "ketorolac tromethamine" also includes any salts, solvates, esters or other hydrolyzable prodrugs thereof. Ketorolac tromethamine has a molecular weight of 376.4 g / mol and the following structure: [ka]

[0025] The term "loteprednol compound" refers to a compound having the chemical name chloromethyl (8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17-carboxylate and CAS number [129260-79-3]. The term "loteprednol compound" also includes any salts, solvates, esters or other hydrolyzable prodrugs thereof. Loteprednol has a molecular weight of 394.9 g / mol and the following structure: [ka]

[0026] The term "loteprednol etabonate" refers to the compound loteprednol having the chemical name chloromethyl (8S,9S,10R,11S,13S,14S,17R)-17-ethoxycarbonyloxy-11-hydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17-carboxylate and CAS number [82034-46-6]. The term "loteprednol etabonate" also includes any salts, solvates, esters or other hydrolyzable prodrugs thereof. Loteprednol etabonate has a molecular weight of 466.9 g / mol and the following structure: [ka]

[0027] The term "low molecular weight polyol" refers to an organic compound that contains multiple hydroxyl (-OH) groups and has a molecular weight of about 45 g / mol to about 450 g / mol.

[0028] The terms "one embodiment," "an embodiment," "a specific embodiment," and the like mean that the particular feature, characteristic or characteristic, or particular grouping or combination of features, characteristics or characteristics, referenced in combination with the respective expression is present in at least one embodiment of the invention. The appearances of these expressions in various places throughout this specification do not necessarily refer to the same embodiment. Furthermore, the particular features, characteristics or characteristics may be combined in any suitable manner in one or more embodiments.

[0029] The term "pharmaceutical acceptable" refers to a compound or mixture that is useful for preparing pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and includes compounds or mixtures that are acceptable for human pharmaceutical use.

[0030] The term "poloxamer" refers to a nonionic triblock copolymer having a central hydrophobic chain of poly(propylene oxide) flanked by two hydrophilic chains of poly(ethylene oxide). Poloxamers have the following general structure: [ka]

[0031] The term "polymeric thickener" refers to a polymer that increases or decreases the viscosity of a liquid composition.

[0032] The terms "polyvinylpyrrolidone" and "povidone" refer to the homopolymer of vinylpyrrolidone, also known as PVP, polyvidone, and 1-ethenyl-2-pyrrolidone homopolymer.

[0033] The term "preservative" refers to a compound or agent used to prevent bacterial contamination and / or growth in a pharmaceutical composition.

[0034] The term "prophylaxis" refers to the prevention of a disease, condition or symptom, as well as the prevention of recurrence or further growth and spread of the disease, condition or symptom following an initial amelioration or initial elimination of the cause of the disease, condition or symptom.

[0035] The term "prodrug" refers to a derivative of an active ingredient that is converted into the active ingredient in the body. For example, compounds containing hydroxy or carboxy substituents can form physiologically hydrolyzable and acceptable esters as prodrug compounds.

[0036] The term "room temperature" refers to a temperature in the range of 15°C to 25°C, as defined, for example, by the European Pharmacopoeia or the WHO guidance 'Guidelines for the Storage of Essential Medicines and Other Health Commodities' (2003).

[0037] The term "subject" typically refers to a human. However, the invention is not limited to humans and may be used in animals as appropriate.

[0038] The term "surfactant" refers to an amphiphilic compound or agent that helps to solubilize a therapeutically active agent or other insoluble components of the composition or helps to stabilize the suspensions described herein.

[0039] The term "therapeutically effective amount" refers to the amount that, when administered to a subject for treating or preventing a disease, is sufficient to effect such treatment or prevention of the disease.

[0040] The term "treatment" refers to a therapeutic intervention that can result in a cure of a disease, condition or symptom, but also includes amelioration, alleviation, control, control of progression, prevention of progression, prevention of recurrence, and the like.

[0041] The term "tyloxapol" refers to a nonionic surfactant that is a copolymer of 4-(1,1,3,3-tetramethylbutyl)phenol, formaldehyde, and oxirane having CAS number [25301-02-4] and a monomer molecular weight of 280.4 g / mol.

[0042] Particle size distribution was determined by laser diffraction and reported as D 10 , D 50 and D. 90 Values ​​are based on volume distribution. D 10 , D 50 Or D 90 Values ​​of 0.01 indicate that 10, 50 or 90% respectively of the particle volume is contained in particles smaller than these values.

[0043] composition The present invention provides an aqueous liquid composition for ophthalmic administration that is a homogeneous suspension upon shaking and before administration. The composition has a suitable viscosity for ocular comfort and exhibits physical and chemical stability during storage. Polymers can increase the viscosity of the eye drops and enhance adhesion to the lacrimal mucus layer. In practice, the optimal viscosity of eye drops is often a compromise between comfort and visual requirements. Increasing viscosity increases retention time but causes undesirable visual impairments, including optical aberrations.

[0044] In a first aspect, the present invention provides an aqueous liquid composition for ophthalmic administration comprising a therapeutically effective amount of a ketorolac compound and a corticosteroid, wherein the ketorolac compound is present essentially in dissolved form, the corticosteroid is present in the form of suspended particles, and the composition exhibits an acidic pH of about 6.5 or less. In some embodiments, an aqueous liquid composition for ophthalmic administration comprises a therapeutically effective amount of a ketorolac compound and a corticosteroid, wherein the ketorolac compound is present essentially in dissolved form, the corticosteroid is present in the form of suspended particles, the composition exhibits an acidic pH of about 6.5 or less, and the viscosity of the aqueous liquid composition ranges from about 1 to about 60 centipoise (cps) or millipascal seconds (mPa·s). A composition having such a low viscosity allows for uniform suspension of the suspended particles of the corticosteroid, reducing undesirable visual impairments, including optical aberrations such as blurred vision. In some embodiments, the ketorolac compound is ketorolac tromethamine. In some embodiments, the corticosteroid is a compound selected from dexamethasone, prednisolone, fluorometholone, betamethasone, difluprednate, triamcinolone, remexolone, loteprednol, and clobetasol. In some particular embodiments, the corticosteroid is a loteprednol compound. In other particular embodiments, the loteprednol compound is loteprednol etabonate. In other particular embodiments, the ketorolac compound is ketorolac tromethamine and the corticosteroid is loteprednol etabonate. In other particular embodiments, the composition includes, where applicable, any salt, solvate, ester, acetonide, or other hydrolyzable prodrug of any compound present in the composition. Pharmaceutically acceptable analogs of such salts, solvates, esters, acetonides, or other prodrugs are also contemplated.

[0045] In some embodiments, the concentration of ketorolac tromethamine in the composition is about 0.2% to about 1.0% by weight, preferably about 0.3% to about 0.6% by weight. In other embodiments, the concentration of ketorolac tromethamine is about 0.45%, 0.5% or about 1.0% by weight. In some embodiments, the concentration of loteprednol etabonate in the composition is about 0.1% to about 1.2% by weight, about 0.3% to about 1.2% by weight, and about 0.5% or about 1.0% by weight. In other embodiments, the concentration of loteprednol etabonate in the composition is preferably about 0.5% or about 1.0% by weight.

[0046] As used herein, compositions may be prepared in either weight % or w / v %, and units may be used interchangeably, for example, in tables disclosed herein, unless otherwise specified. For example, if a range is expressed as "about 0.2 wt % to about 1.0 wt %, the range may also be expressed as "about 0.2 w / v % to about 1.0 w / v %". However, in tables where a reference point is used, the units are specifically specified in the first row of the table, for example, Tables 1-3 include values ​​in weight %, and Tables 4 and 7-8 include values ​​in w / v %.

[0047] In some embodiments, the composition exhibits an acidic pH of about 6.5 or less. In other embodiments, the composition exhibits a pH of about 6.0 or less. In other embodiments, the composition exhibits a pH of about 5.5 or less. In yet other embodiments, the composition exhibits a pH of about 5-6. In other particular embodiments, the composition exhibits a pH of about 5.5. Conventionally known stable compositions containing ketorolac compounds are typically formulated at higher pH, such as about 7.0 to about 7.4. However, loteprednol compounds are typically unstable at higher pH levels, above 6.5. Despite this apparent pH incompatibility, the present inventors have unexpectedly found that it is possible to formulate compositions containing ketorolac compounds and loteprednol compounds at lower pH values, below about 6.5.

[0048] In some embodiments, the composition is essentially free of a buffer system. Buffer systems are well known in the art and are solutions that resist changes in pH when acid or base is added. Generally, buffers contain a mixture of a weak acid and its conjugate base or a weak base and its conjugate acid. Common buffer systems used in ophthalmic compositions include citrate, phosphate, Tris-HCl (Tris) and borate buffers.

[0049] In other embodiments, the composition is essentially free of sodium chloride.

[0050] In yet other embodiments, the composition is essentially free of poloxamer.

[0051] In yet another embodiment, the composition is essentially free of crosslinked carboxy-containing polymers. Such polymers include polycarbophil. The inclusion of crosslinked carboxy-containing polymers leads to highly viscous gel compositions that may prevent uniform suspension of solid particles and result in inaccurate dosing. Furthermore, viscous gels may cause undesirable visual disturbances, including optical aberrations such as blurred vision.

[0052] In yet another embodiment, the composition is essentially free of chitosan.Compositions containing both chitosan and ketorolac form insoluble precipitates because positively charged chitosan forms an insoluble salt complex with negatively charged ketorolac compound, as shown in Examples 5 and 6 disclosed herein.The inclusion of chitosan in the compositions disclosed herein may reduce the bioavailability of ketorolac compound and the accuracy of administration of ketorolac compound due to the formation of insoluble precipitates.

[0053] In some embodiments, the composition is further characterized as exhibiting a surface tension in the range of about 20-70 dynes per centimeter (dyn / cm) or about 0.020-0.070 Newtons per meter (N / m), a zeta potential in the range of about + / -10 to + / -40 millivolts (mV), and / or a viscosity in the range of about 1 to 60 centipoise (cps) or millipascal seconds (mPa·s). In other embodiments, the composition is further characterized as exhibiting a surface tension in the range of about 20-70 dynes per centimeter (dyn / cm) or about 0.020-0.070 Newtons per meter (N / m), and / or a zeta potential in the range of about + / -10 to + / -40 millivolts (mV). In yet other embodiments, the composition is further characterized as exhibiting a viscosity in the range of about 1 to about 60 centipoise (cps) or millipascal seconds (mPa·s). As used herein, viscosity refers to viscosity measured by a Brookfield viscometer. Generally, the test solution is stored at room temperature for about 2 hours before testing. A pipette is used to place the test solution into the measurement chamber, and an appropriate speed is selected for the spindle depending on the expected viscosity of the sample. The Brookfield viscometer determines viscosity by measuring the force required to rotate a spindle in the solution at a given speed.

[0054] In some embodiments, the composition comprises: (a) a polymeric thickener; (b) a non-ionic surfactant; and / or (c) Low molecular weight polyol Includes.

[0055] In some embodiments, the polymeric thickener is a non-ionic water-soluble polymer, preferably selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP). In some specific embodiments, the polymeric thickener is polyvinylpyrrolidone. In other specific embodiments, the weight ratio of ketorolac tromethamine to polyvinylpyrrolidone is about 1:10 to about 10:1, about 1:10 to about 5:1, and about 1:3 to about 2:1. In other specific embodiments, the weight ratio of ketorolac tromethamine to polyvinylpyrrolidone is about 1:10 to about 5:1, preferably about 1:3 to about 2:1. In other embodiments, the weight ratio of ketorolac tromethamine to polyvinylpyrrolidone is about 1:1 to about 1:2.

[0056] In some embodiments, the nonionic surfactant is tyloxapol and the concentration of tyloxapol in the composition is from about 0.1% to about 1.2% by weight, preferably from greater than about 0.2% to less than about 1.0% by weight.

[0057] In some embodiments, the low molecular weight polyol is glycerol and the concentration of glycerol in the composition is about 0.5% to about 2.5% by weight, in other embodiments, the concentration of glycerol in the composition is about 1.0% to about 2.0% by weight.

[0058] In some embodiments, the composition comprises an additional polymeric thickener, which is an anionic carbohydrate, including any salt thereof, preferably selected from hyaluronic acid, gellan gum, or carboxymethylcellulose. In some particular embodiments, the anionic carbohydrate is at least partially neutralized carboxymethylcellulose. In other particular embodiments, the carboxymethylcellulose is sodium carboxymethylcellulose (NaCMC), and the weight ratio of sodium carboxymethylcellulose to polyvinylpyrrolidone is about 1:10 to about 10:1, about 1:10 to about 5:1, and about 1:2 to about 2:1. In other particular embodiments, the weight ratio of sodium carboxymethylcellulose to polyvinylpyrrolidone is about 1:10 to about 5:1, preferably about 1:2 to about 2:1.

[0059] In some embodiments, the composition further comprises a cyclodextrin, preferably 2-hydroxypropyl-β-cyclodextrin or sulfobutylether-β-cyclodextrin, and the molar ratio of the cyclodextrin to ketorolac tromethamine is about 1:85 to about 6:1, preferably about 1:25 to about 1:2. In some specific embodiments, the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin. In other specific embodiments, the cyclodextrin is sulfobutylether-β-cyclodextrin.

[0060] In some embodiments, the composition further comprises ethylenediaminetetraacetic acid (EDTA), preferably at a concentration of about 0.1% by weight or less, hi some particular embodiments, the EDTA is sodium ethylenediaminetetraacetate (NaEDTA).

[0061] In other embodiments, the composition further comprises a preservative. Preservatives used in ophthalmic preparations are known in the art, such as, for example, benzalkonium chloride (BAK), chlorobutanol, sodium perborate, and stabilized oxychloro complexes. In some specific embodiments, the preservative is benzalkonium chloride (BAK).

[0062] In some embodiments, the carboxymethylcellulose is sodium carboxymethylcellulose and the composition comprises: (a) ketorolac tromethamine, preferably from about 0.3% to about 0.6% by weight; (b) corticosteroids; (c) preferably about 0.2% to about 1% by weight of tyloxapol; (d) preferably about 0.4% to about 0.8% by weight of polyvinylpyrrolidone; (e) preferably about 0.4% to about 0.8% by weight of sodium carboxymethylcellulose; (f) glycerol, preferably from about 0.5% to about 2.5% by weight; (g) EDTA, preferably from about 0.01% to about 0.1% by weight; (h) benzalkonium chloride, preferably from about 0.005% to about 0.02% by weight; (i) water; and, optionally, (k) preferably about 0.1% to about 0.8% by weight of 2-hydroxypropyl-β-cyclodextrin; and / or an acid or base to adjust the pH of the composition to about 5-6. It essentially consists of:

[0063] In some embodiments of the compositions described herein, the suspended particles of the corticosteroid have a D of less than about 20 μm, less than about 10 μm, or less than about 5 μm. 90 In other embodiments of the compositions described herein, the suspended particles of corticosteroid have a D of less than about 3 μm, less than about 1 μm, or less than about 0.5 μm. 90 In still other embodiments of the compositions described herein, the suspended particles have a D of less than about 1 μm. 50In some embodiments, the compositions described herein comprise particles in the submicron size range. In other embodiments, the compositions described herein comprise particles in the nanometer size range. In general, smaller particle sizes promote better bioavailability of the corticosteroid.

[0064] Use and Method In a second aspect, the present invention provides uses and methods of preventing or treating ocular conditions using the compositions disclosed herein.

[0065] In some embodiments, the present invention provides a composition for use in the prevention or treatment of ocular inflammation. In other embodiments, the ocular inflammation is associated with or occurs after cataract surgery. In other embodiments, the ocular inflammation is associated with seasonal allergic conjunctivitis. In some embodiments, the use comprises once-daily, twice-daily, or three-times-daily ophthalmic administration of the composition.

[0066] In some embodiments, the present invention provides a method for preventing or treating ocular inflammation in a subject, the method comprising topically administering any of the compositions disclosed herein to the eye of the subject. In some embodiments, the ocular inflammation is associated with or occurs after cataract surgery. In other embodiments, the ocular inflammation is associated with seasonal allergic conjunctivitis. In yet other embodiments, administration of the composition is once daily, twice daily, or three times daily.

[0067] The following examples serve to illustrate the invention but should not be understood as limiting its scope. EXAMPLES

[0068] Materials and Methods The following materials were used to prepare the exemplary ophthalmic compositions described herein: ketorolac tromethamine, loteprednol etabonate, tyloxapol, poloxamer, carbomer, polyvinylpyrrolidone (povidone), ethylenediaminetetraacetic acid (EDTA), sodium ethylenediaminetetraacetate (NaEDTA), glycerol, benzalkonium chloride (BAK), sodium carboxymethylcellulose (NaCMC), 2-hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, hydrochloric acid, sodium hydroxide, and purified water.

[0069] Viscosity is measured using a Brookfield Viscometer. The test solution is stored at room temperature for approximately 2 hours before testing. A pipette is used to place the test solution into the measurement chamber and an appropriate speed is selected for the spindle depending on the expected viscosity of the sample. The Brookfield Viscometer determines viscosity by measuring the force required to rotate a spindle in the solution at a given speed.

[0070] Example 1 Screening Experiment The compositions shown in Tables 1 and 2 were prepared with various surfactants and viscosity agents to evaluate the physicochemical stability of the combined suspension of loteprednol etabonate and ketorolac over time. Tyloxapol, poloxamer, and mixtures thereof were evaluated as surfactants. Polyvinylpyrrolidone, sodium carboxymethylcellulose, carbomer, and mixtures thereof were evaluated as viscosity agents.

[0071] [Table 1]

[0072] [Table 2]

[0073] The carbomer-containing formulations (F2, F4, F7 and F9) formed highly viscous gels that could not be resuspended to produce a homogenous composition, therefore the carbomer-containing compositions were not pursued further.

[0074] Compositions F2 and F3, which contained a mixture of 0.1% by weight tyloxapol and 0.6% by weight poloxamer, were physically unstable as evidenced by an increase in particle size over time, and therefore were not selected for further evaluation.

[0075] Composition F5, containing 0.3 wt% tyloxapol as a surfactant and 0.6 wt% poloxamer and a mixture of sodium carboxymethylcellulose (NaCMC or sodium CMC) as a viscosity agent, showed a significant decrease in loteprednol and ketorolac assay values ​​over time, and therefore these compositions were not selected for further evaluation.

[0076] Compositions F8 and F10, containing tyloxapol without the presence of poloxamer and a mixture of povidone and NaCMC as viscosity agents, achieved the desired physical and chemical stability, resuspensionability, and low viscosity. These compositions were further evaluated for optimization.

[0077] Example 2 Preparation of Exemplary Compositions Based on the screening experiments of Example 1, compositions containing the loteprednol compound, the ketorolac compound, tyloxapol, povidone, sodium carboxymethylcellulose, and additional ingredients were further optimized and evaluated.

[0078] A grinding aid solution was prepared by dissolving povidone, tyloxapol, glycerol and EDTA in purified water and filtering the solution using a 0.2 μm filter. Loteprednol etabonate powder was then dispersed in the grinding aid solution using high shear mixing with an ULTRA-TURRAX. The loteprednol etabonate dispersion was transferred to a grinding chamber (Dyno-Mill) and then filled with beads (zirconium oxide beads). The suspension slurry was milled for a specific time and discharged from the chamber. The suspension slurry was diluted with washing media during transfer to ensure complete transfer from the grinding chamber. The mixture of milled suspension slurry, beads, and washing media was collected and filtered using a dialysis membrane and a vacuum pump. Additional washing media was used to wash the grinding beads during the filtration process. The suspension slurry is typically sterilized by irradiation before further mixing with the remaining formulation ingredients. For micron-sized formulations, the milling step may not be necessary.

[0079] Ketorolac tromethamine stock solution was prepared by dissolving ketorolac tromethamine in the grinding aid solution. Carboxymethylcellulose sodium stock solution was prepared by dissolving carboxymethylcellulose sodium in the grinding aid solution. Benzalkonium chloride may be added to the ketorolac tromethamine stock solution. The carboxymethylcellulose sodium stock solution and the ketorolac tromethamine stock solution were filtered through a 0.2 μm filter and then mixed with the loteprednol etabonate suspension slurry until homogenous. The pH was adjusted with 0.1M HCl / 0.1M NaOH.

[0080] Specific exemplary compositions prepared as described above in Example 2 are summarized in Table 3 below.

[0081] Example 3 Preparation of an exemplary composition containing cyclodextrin Exemplary compositions further comprising cyclodextrin were prepared as described above in Example 2, with cyclodextrin added as an additional component in the grinding aid composition, or alternatively, cyclodextrin was added as a powder to the loteprednol etabonate suspension slurry after milling.

[0082] Specific exemplary compositions prepared as described above in Example 3 are summarized in Table 4 below.

[0083] [Table 3]

[0084] [Table 4]

[0085] Example 4 Stability Testing of Exemplary Compositions The stability of the exemplary compositions was investigated using gradient high performance liquid chromatography analysis at different storage time points of 1 month, 3 months, 6 months, 9 months, and 11 months. The amount of each active ingredient and associated degradants, pH, osmolality, particle size distribution, and viscosity were measured for each composition at each time point.

[0086] Ketorolac tromethamine (KT) was stable in all compositions. The decomposition of loteprednol etabonate (LE) was pH dependent, so pH was optimized for loteprednol etabonate stability.

[0087] The results of Panel I stability testing of the compositions shown in Table 3 are summarized in Table 5. The suspension slurries were not sterilized by irradiation in the preparation of the Panel 1 formulations.

[0088] In Tables 5 and 6 below, the term "RS" refers to "Related Substances", "LOQ" refers to "Limit of Detection", "RRT" refers to "Relative Retention Time", and LR refers to "Loteprednol Etabonate Related".

[0089] [Table 5] JPEG2024507110000011.jpg226152JPEG2024507110000012.jpg169152

[0090] Loteprednol degradation occurred in the formulation as expected and within acceptable levels. Minimal degradation of ketorolac was achieved in this formulation, and all other test parameters such as pH, osmolality, viscosity, and particle size remained stable throughout the stability study.

[0091] The results of Panel II stability studies at accelerated conditions (40° C.) for the compositions shown in Table 4 are summarized in Table 6. Suspension slurries of Panel 2 formulations F7, F8 and F9 were sterilized by irradiation.

[0092] [Table 6] JPEG2024507110000014.jpg228152JPEG2024507110000015.jpg198152

[0093] Similar to the results of Panel 1 study, degradation of loteprednol occurred as expected in the formulation, minimal degradation of ketorolac was achieved in this formulation, and all other test parameters, including pH, osmolality, viscosity, surface tension, zeta potential, and particle size, remained stable throughout the stability study.

[0094] Example 5: Verification of chitosan as an additive In an exemplary embodiment of the composition disclosed herein, chitosan was investigated as an additive. The composition in this example included the following components:

[0095] [Table 7]

[0096] Given that chitosan is positively charged and the ketorolac compound, NaCMC, and NaEDTA are negatively charged in aqueous solution, it was hypothesized that chitosan may form an insoluble precipitate with one or more of these components due to the formation of an insoluble salt complex. In this exemplary embodiment, loteprednol etabonate was omitted to ensure visibility of any potential precipitates formed during preparation.

[0097] Two different approaches were investigated. In the first experiment, a solution of fully dissolved chitosan was added to a clear, colorless solution of NaCMC and NaEDTA, producing a solution with a white flocculant precipitate and a pH of 4.1. Chitosan is fully soluble at pH 4, suggesting incompatibility of chitosan with NaCMC and / or NaEDTA. In the second experiment, a solution of fully dissolved chitosan was added to a clear, colorless solution of glycerin, tyloxapol, PVP, HP-b-cyclodextrin, and ketorolac tromethamine with a pH of 5.1. Upon addition of the two solutions, white flocculants immediately formed, resulting in a solution with a pH of 3.8. When the pH 3.8 solution containing the white flocculants was pH adjusted to a final formulation of pH 5.5, the white flocculants persisted. When the preparation was repeated without ketorolac tromethamine, no precipitate formed. Furthermore, chitosan is fully soluble at pH 3.8. Thus, the observed white precipitate is a chitosan / ketorolac tromethamine insoluble complex. The formation of the precipitate reduces the bioavailability of ketorolac and the accuracy of ketorolac dosing, highlighting the incompatibility of chitosan in such compositions.

[0098] Example 6 Comparative test with chitosan-containing gel composition Chitosan-containing compositions of ketorolac tromethamine and loteprednol etabonate were prepared using the methods disclosed in US Patent Application Publication No. 2013 / 0217657, specifically compositions 7 and 8 in Table 6. The compositions contained the following ingredients:

[0099] [Table 8]

[0100] Compositions 7 and 8 were prepared by combining polycarbophil, sodium chloride, and sodium edetate in water and stirring for 0.5 hours. The compositions were autoclaved at 121°C for 45 minutes and cooled to room temperature to produce a white opaque suspension. An aqueous solution of chitosan was prepared using hydrochloric acid and added to the polycarbophil suspension to produce a free-flowing white opaque suspension. Mannitol, poloxamer 407, and ketorolac tromethamine were dissolved in water to form a clear, colorless solution, and loteprednol etabonate was added to the solution by dry particle addition to form a white suspension. The mannitol, poloxamer 407, ketorolac tromethamine, and loteprednol etabonate suspension were added to the polycarbophil, sodium chloride, sodium edetate, chitosan suspension, and the pH was adjusted to 6.8 to form the final formulation. The final formulation was a white, smooth gel with a viscosity of 7921 mPa·s or cps as measured by a Brookfield viscometer.

[0101] Since loteprednol etabonate was present as a solid dispersion in compositions 7 and 8, it was not possible to visually observe whether chitosan and ketorolac tromethamine formed an insoluble precipitate as observed in Example 5 above. To examine this hypothesis, compositions 7 and 8 were prepared as above, except for loteprednol etabonate. In the first experiment, chitosan was added to a clear, colorless solution of mannitol and poloxamer 407. In the second experiment, chitosan was added to a clear, colorless solution of mannitol, poloxamer 407, and ketorolac tromethamine. The addition of chitosan to a clear, colorless solution of mannitol and poloxamer 407 formed a clear, colorless solution with a pH of 3.9. In contrast, the addition of chitosan to a clear, colorless solution of mannitol, poloxamer 407, and ketorolac tromethamine formed a white suspension with pH 4.7 (composition 7, high ketorolac concentration) and pH 4.6 (composition 8, low ketorolac concentration). Compositions 7 and 8 were then adjusted to pH 6.8 to form the final formulations. Both compositions contain white aggregates derived from the chitosan / ketorolac salt complex. Thus, both compositions 7 and 8 are essentially free of the ketorolac compound in dissolved form.

[0102] List of Items Among other things, the following list of numbered items are specific embodiments encompassed by the present invention.

[0103] 1. An aqueous liquid composition for ophthalmic administration comprising a therapeutically effective amount of a ketorolac compound and a corticosteroid, wherein the ketorolac compound is present in essentially dissolved form and the corticosteroid is present in the form of suspended particles, the composition exhibits an acidic pH of about 6.5 or less, and the viscosity of the aqueous liquid composition is in the range of about 1 to about 60 centipoise (cps) or millipascal seconds (mPa·s).

[0104] 2. The composition according to item 1, wherein the corticosteroid is selected from dexamethasone, prednisolone, fluorometholone, betamethasone, difluprednate, triamcinolone, remexolone, loteprednol and clobetasol, or any salt, ester, acetonide or other hydrolyzable prodrug thereof.

[0105] 3. The composition according to item 1, wherein the corticosteroid is selected from dexamethasone, prednisolone, fluorometholone, betamethasone, difluprednate, triamcinolone, remexolone, loteprednol and clobetasol, or any salt, ester, acetonide thereof.

[0106] 4. The composition according to any one of items 1 to 3, which is essentially free of a buffer system, where essentially free refers to a composition which comprises less than a functional amount of a buffer system, typically less than 1 wt%, preferably less than 0.1 wt% or even less than 0.01 wt%, including 0 wt%.

[0107] 5. The composition according to any one of items 1 to 4, which is essentially free of sodium chloride, where essentially free refers to a composition containing less than a functional amount of sodium chloride, typically less than 1 wt.%, preferably less than 0.1 wt.% or even less than 0.01 wt.%, including 0 wt.%.

[0108] 6. The composition according to any one of items 1 to 5, having a pH of about 5 to 6.

[0109] 7. The composition according to any one of the preceding claims, further characterized in that it exhibits a surface tension in the range of about 20-70 dynes per centimeter (dyn / cm) or about 0.020-0.070 Newtons per meter (N / m), and / or a zeta potential in the range of about + / - 10 to + / - 40 millivolts (mV).

[0110] 8. The composition according to any one of items 1 to 7, wherein the ketorolac compound is ketorolac tromethamine.

[0111] 9. The composition according to item 8, wherein the concentration of ketorolac tromethamine in the composition is about 0.2% by weight to about 1.0% by weight, preferably about 0.3% by weight to about 0.6% by weight.

[0112] 10. The composition according to any one of items 1 to 9, wherein the corticosteroid is a loteprednol compound, preferably loteprednol etabonate.

[0113] 11. The composition according to item 10, wherein the concentration of loteprednol etabonate in the composition is about 0.1% by weight to about 1.2% by weight, preferably about 0.5% by weight or about 1.0% by weight.

[0114] 12.(a) Polymeric thickeners; (b) a non-ionic surfactant; and / or (c) Low molecular weight polyol Further comprising: Low molecular weight polyol refers to an organic compound that contains more than one hydroxyl (-OH) group and has a molecular weight of about 45 g / mol to about 450 g / mol. The composition according to any one of items 1 to 11.

[0115] 13. The composition according to item 12, wherein the polymeric thickener is a non-ionic water-soluble polymer, preferably selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP).

[0116] 14. The composition according to item 12 or 13, wherein the polymeric thickener is polyvinylpyrrolidone.

[0117] 15. The composition according to item 13 or 14, wherein the weight ratio of ketorolac tromethamine to polyvinylpyrrolidone is about 1:10 to about 5:1, preferably about 1:3 to about 2:1.

[0118] 16. The composition according to item 12, wherein the nonionic surfactant is tyloxapol and the concentration of tyloxapol in the composition is from about 0.1% to about 1.2% by weight, preferably from more than about 0.2% to less than about 1.0% by weight.

[0119] 17. The composition according to item 12, wherein the low molecular weight polyol is glycerol and the concentration of glycerol in the composition is from about 0.5% to about 2.5% by weight.

[0120] 18. The composition according to any one of items 12 to 17, comprising a further polymeric thickener, the further polymeric thickener being selected from anionic carbohydrates, including any salts thereof, preferably hyaluronic acid, gellan gum, or carboxymethylcellulose.

[0121] 19. The composition according to item 18, wherein the anionic carbohydrate is at least partially neutralized carboxymethylcellulose.

[0122] 20. The composition according to item 18 or 19, wherein the carboxymethylcellulose is sodium carboxymethylcellulose, and the weight ratio of sodium carboxymethylcellulose to polyvinylpyrrolidone is about 1:10 to about 5:1, preferably about 1:2 to about 2:1.

[0123] 21. The composition according to any one of items 1 to 20, which is essentially free of poloxamer, where essentially free refers to a composition which contains less than a functional amount of poloxamer, typically less than 1 wt%, preferably less than 0.1 wt% or even less than 0.01 wt%, including 0 wt%.

[0124] 22. The composition according to any one of items 8 to 21, further comprising a cyclodextrin, preferably 2-hydroxypropyl-β-cyclodextrin or sulfobutylether-β-cyclodextrin, wherein the molar ratio of cyclodextrin to ketorolac tromethamine is from about 1:85 to about 6:1, preferably from about 1:25 to about 1:2.

[0125] 23. The composition according to any one of items 1 to 22, further comprising ethylenediaminetetraacetic acid (EDTA), preferably at a concentration of about 0.1% by weight or less.

[0126] 24. The composition according to any one of items 1 to 23, further comprising a preservative.

[0127] twenty five. The carboxymethylcellulose is sodium carboxymethylcellulose, and the composition comprises: (a) ketorolac tromethamine, preferably from about 0.3% to about 0.6% by weight; (b) corticosteroids; (c) preferably about 0.2% to about 1% by weight of tyloxapol; (d) preferably about 0.4% to about 0.8% by weight of polyvinylpyrrolidone; (e) preferably about 0.4% to about 0.8% by weight of sodium carboxymethylcellulose; (f) glycerol, preferably from about 0.5% to about 2.5% by weight; (g) EDTA, preferably from about 0.01% to about 0.1% by weight; (h) benzalkonium chloride, preferably from about 0.005% to about 0.02% by weight; (i) water; and, optionally, (k) preferably about 0.1% to about 0.8% by weight of 2-hydroxypropyl-β-cyclodextrin; and / or an acid or base to adjust the pH of the composition to about 5-6. 25. The composition according to item 23 or 24, consisting essentially of

[0128] 26. Suspended particles less than about 20 μm D 90 26. The composition according to any one of items 1 to 25, comprising:

[0129] 27. Suspended particles less than about 3 μm D 90 27. The composition according to any one of items 1 to 26, comprising:

[0130] 28. Suspended particles less than about 1 μm D 50 28. The composition according to any one of items 1 to 27, comprising:

[0131] 29. The composition according to any one of items 1 to 28, which is essentially free of crosslinked carboxy-containing polymer, where essentially free refers to a composition which comprises less than a functional amount of crosslinked carboxy-containing polymer, typically less than 1 wt%, preferably less than 0.1 wt% or even less than 0.01 wt%, including 0 wt%.

[0132] 30. The composition according to any one of items 1 to 29, which is essentially free of chitosan, where essentially free refers to a composition containing less than a functional amount of chitosan, typically less than 1 wt%, preferably less than 0.1 wt% or even less than 0.01 wt%, including 0 wt%.

[0133] 31. The composition according to any one of items 1 to 30, for use in the prevention or treatment of ocular inflammation.

[0134] 32. The composition for use according to item 31, wherein the ocular inflammation is associated with or occurs after cataract surgery.

[0135] 33. The composition for use according to item 31, wherein the ocular inflammation is associated with seasonal allergic conjunctivitis.

[0136] 34. The composition for use according to any one of items 31 to 33, wherein the use comprises ophthalmic administration of the composition once a day, twice a day, or three times a day.

[0137] 35. A method for preventing or treating ocular inflammation in a subject, comprising topically administering to the eye of said subject a composition according to any one of items 1 to 34.

[0138] 36. The method according to item 35, wherein the subject has had cataract surgery.

[0139] 37. The method according to item 35, wherein the ocular inflammation is associated with seasonal allergic conjunctivitis.

[0140] 38. The method according to item 35, wherein administration is once a day, twice a day, or three times a day.

[0141] 39. Use of a composition according to any one of items 1 to 30 for the manufacture of a medicament for preventing or treating ocular inflammation.

[0142] 40. The use according to item 39, wherein the ocular inflammation is associated with or occurs after cataract surgery.

[0143] 41. The use according to item 39, wherein the ocular inflammation is associated with seasonal allergic conjunctivitis.

[0144] 42. The use according to any one of items 39 to 41, wherein the use comprises ophthalmic administration of the composition once a day, twice a day, or three times a day.

Claims

1. 1. An aqueous liquid composition for ophthalmic administration comprising a therapeutically effective amount of a ketorolac compound and a corticosteroid, wherein the ketorolac compound is present in essentially dissolved form and the corticosteroid is present in the form of suspended particles, the composition exhibits an acidic pH of 6.5 or less, and the viscosity of the aqueous liquid composition is in the range of 1 to 60 mPa·s as measured by a Brookfield viscometer.

2. 2. The composition of claim 1, wherein the corticosteroid is selected from dexamethasone, prednisolone, fluorometholone, betamethasone, difluprednate, triamcinolone, remexolone, loteprednol and clobetasol, or any salt, ester, acetonide or other hydrolyzable prodrug thereof.

3. 3. The composition of claim 1 or 2, wherein essentially free of a buffer system, essentially free refers to the composition comprising less than a functional amount of the buffer system, typically less than 1% by weight, including 0% by weight; essentially free of sodium chloride, essentially free refers to the composition comprising less than a functional amount of the sodium chloride, typically less than 1% by weight, including 0% by weight; essentially free of poloxamer, essentially free refers to the composition comprising less than a functional amount of the poloxamer, typically less than 1% by weight, including 0% by weight; and essentially free of chitosan, essentially free refers to the composition comprising less than a functional amount of the chitosan, typically less than 1% by weight, including 0% by weight.

4. The composition according to any one of claims 1 to 3, having a pH of from 5 to 6.

5. 5. The composition according to any one of claims 1 to 4, further characterized in that it exhibits a surface tension in the range of 0.020 to 0.070 N / m and / or a zeta potential in the range of + / - 10 to + / - 40 mV.

6. The composition according to any one of claims 1 to 5, wherein the ketorolac compound is ketorolac tromethamine, and the concentration of ketorolac tromethamine in the composition is 0.2% to 1.0% by weight.

7. 7. The composition of claim 1, wherein the corticosteroid is a loteprednol compound and the concentration of loteprednol etabonate in the composition is 0.1% to 1.2% by weight.

8. (a) a polymeric thickener; (b) a non-ionic surfactant; and / or (c) Low molecular weight polyol Further comprising: The low molecular weight polyol refers to an organic compound containing more than one hydroxyl (—OH) group and having a molecular weight of 45 g / mol to 450 g / mol; The composition according to any one of claims 1 to 7.

9. 9. The composition of claim 8, wherein the polymeric thickener is a non-ionic water soluble polymer selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and polyvinylpyrrolidone (PVP).

10. 10. The composition of claim 9, wherein the polymeric thickener is polyvinylpyrrolidone.

11. The composition of claim 10, wherein the weight ratio of said ketorolac tromethamine to said polyvinylpyrrolidone is from 1:10 to 5:

1.

12. 9. The composition of claim 8, wherein the non-ionic surfactant is tyloxapol and the concentration of tyloxapol in the composition is from 0.1% to 1.2% by weight, and / or the low molecular weight polyol is glycerol and the concentration of glycerol in the composition is from 0.5% to 2.5% by weight.

13. A composition according to any one of claims 8 to 12, comprising a further polymeric thickener, said further polymeric thickener being selected from anionic carbohydrates, including any salts thereof.

14. The composition according to any one of claims 6 to 13, further comprising a cyclodextrin, wherein the molar ratio of said cyclodextrin to said ketorolac tromethamine is from 1:85 to 6:

1.

15. The composition of any one of claims 1 to 14, further comprising ethylenediaminetetraacetic acid (EDTA) at a concentration of up to 0.1% by weight.

16. The composition, (a) 0.3% to 0.6% by weight of ketorolac tromethamine; (b) corticosteroids; (c) 0.2% to 1% by weight of tyloxapol; (d) 0.4% to 0.8% by weight of polyvinylpyrrolidone; (e) 0.4% to 0.8% by weight of sodium carboxymethylcellulose; (f) 0.5% to 2.5% by weight of glycerol; (g) 0.01% to 0.1% by weight of EDTA; (h) 0.005% to 0.02% by weight of benzalkonium chloride; (i) water; and / or an acid or base to adjust the pH of the composition to between 5 and 6. The composition of any one of claims 6 to 15, consisting essentially of 17. The composition comprising: (a) 0.3% to 0.6% by weight of ketorolac tromethamine; (b) corticosteroids; (c) 0.2% to 1% by weight of tyloxapol; (d) 0.4% to 0.8% by weight of polyvinylpyrrolidone; (e) 0.4% to 0.8% by weight of sodium carboxymethylcellulose; (f) 0.5% to 2.5% by weight of glycerol; (g) 0.01% to 0.1% by weight of EDTA; (h) 0.005% to 0.02% by weight of benzalkonium chloride; (i) water; and (j) 0.1% to 0.8% by weight of 2-hydroxypropyl-β-cyclodextrin and / or an acid or base to adjust the pH of the composition to between 5 and 6. The composition of any one of claims 6 to 15, consisting essentially of

18. The suspended particles have a diameter of less than 20 μm, or less than 3 μm D ９０ and / or the suspended particles have a D 50 of less than 1 μm.

19. 19. A composition according to any one of claims 1 to 18 for use in the prevention or treatment of ocular inflammation associated with or occurring after cataract surgery, or wherein the ocular inflammation is associated with seasonal allergic conjunctivitis.