Ophthalmic Formulation Containing Sulfoalkyl Ether Cyclodextrin and Corticosteroid

BY:

James D. Pipkin and Rupert O. Zimmerer

FIELD OF THE INVENTION

The present invention relates to methods of and systems for administering ophthalmic formulations of sulfoalkyl ether cyclodextrin and corticosteroid, such as budesonide. The invention also relates to methods of treating diseases or disorders of the eye and tissues surrounding the eye.

BACKGROUND OF THE INVENTION

Corticosteroids have been used to treat diseases, disorders or symptoms of the eye. For example, corticosteroids have been used to treat inflammatory disorders or inflammation of the eye or of tissues surrounding the eye. Corticosteroid-containing solution or -suspension formulations, containing corticosteroid as a sole therapeutic agent or in combination with another therapeutic agent, have been disclosed for use in the treatment of eye diseases or disorders such as conjunctivitis, inflammation of tissue(s) in the eye, dry eye, filamentary keratitis, delayed tear clearance, pain, keratoconjunctival dryness, keratoconjunctivitis sicca, lesions/tumors of the eye, infectious processes of the eye, bacterial infections, viral infections, glaucoma, uveitis, diabetic retinopathy, eye trauma, blepharitis, blepharoconjunctivitis, and other diseases or disorders.

Corticosteroid-containing solutions for ophthalmic use generally have been prepared by the addition of a cosolvent, surfactant, or buffer. However, cosolvents, such as ethanol, polyethylene glycol and propylene glycol are only tolerated in low amounts when administered to the eye due to irritation. There are limits to acceptable levels of these cosolvents in ophthalmic products. The limits are set by the propensity of these solvents either to cause local irritation or destruction of eye tissue.

Pflugfelder et al. (U.S. Patent No. 6,153,607) disclose a non-preservd topical corticosteroid formulation for the treatment of dry eye, filamentary keratitis, and delayed tear clearance (turnover).

Sackeyfio et al. (U.S. Patent No. 6,955,815) disclose the treatment of inflammatory disorders by the coadministration of a corticosteroid and amoxapine. The formulation can be administered ophthalmically.

Guo et al. (U.S. Patents No. 6,548,078 and No. 6,217,895) disclose a method of treating and/or preventing retinal diseases by administering a corticosteroid to a posterior segment of the eye.

Sher (U.S. Patent No. 6,117,907) discloses a method of treating ocular pain after corneal surgery by the topical administration of a corticosteroid.

Clark et al. disclose a method of preventing intraocular pressure increase caused by corticosteroids by coadministration of tetrahydrocortisol (U.S. Patent No. 5,358,943) or tetrahydrocortexolone (U.S. Patent No. 4,945,089) with the corticosteroid.

Schwartz discloses a method of treating intraocular pressure increase by administration of a corticosteroid and an alpha- adrenergic compound (U.S. Patent No. 5,212,168) or a beta-adrenergic compound (U.S. Patent No. 4,904,649). Saidi et al. (U.S. Patent No. 6,241,969) disclose the preparation of corticosteroid- containing solutions. The dissolved corticosteroids are present in a concentrated, essentially non-aqueous form for storage or in a diluted, aqueous-based form for for nasal and pulmonary administration.

Budesonide ((R ₅ S)-I lβ, 16α, 17, 21-tetrahydroxypregna-l, 4-diene-3, 20-dione cyclic 16, 17-acetal with butyraldehyde; C25H34O6; Mw: 430.5) is well known. It is provided commercially as a mixture of two isomers (22R and 22S). Budesonide is an antiinflammatory corticosteroid that exhibits potent glucocorticoid activity. Administration of budesonide is indicated for maintenance treatment of asthma and as prophylactic therapy in children. Commercial formulations of budesonide are sold by AstraZeneca LP (Wilmington,

DE) under the trademarks ENTOCORT™ EC, PULMICORT RESPULES®, Rhinocort Aqua®, Rhinocort® Nasal Inhaler and Pulmicort Turbuhaler®, and under its generic name. PULMICORT RESPULES® suspension is a sterile aqueous suspension of micronized budesonide. The general formulation for a unit dose of the PULMICORT RESPULES is set forth in U.S. Patent No. 6,598,603, and it is an aqueous suspension in which budesonide is suspended in an aqueous medium comprising about 0.05 to 1.0 mg of budesonide, 0.05 to 0.15 mg of NaEDTA, 8.0 to 9.0 mg of NaCl, 0.15 to 0.25 mg of polysorbate, 0.25 to 0.30 mg of anhydrous citric acid, and 0.45 to 0.55 mg of sodium

citrate per one ml of water. RHINOCORT ^® NASAL INHALER™ is a metered-dose pressurized aerosol unit containing a suspension of micronized budesonide in a mixture of propellants. RHINOCORT ^® AQUA™ is an unscented metered-dose manual-pump spray formulation containing a suspension of micronized budesonide in an aqueous medium. Commercial ophthalmic formulations containing corticosteroids are available under the trademarks MAXIDEX™ 0.1% (dexamethasone), CORTISPORIN™ 1% (hydrocortisone + neomycin + polymyxin B), INFLAMASE™ (1.25 or lOmg/mL prednisolone sodium phosphate) HMS, (medrysone), AK-Neo-Dex (dexamethasone sodium phosphate + neomycin sulfate), Actinac (chloramphenicol + hydrocortisone acetate), Vasocidin (prednisolone sodium phosphate + sulfacetamide sodium), Tobradex, (Dexamethasone + Tobramycin). Other exemplary corticosteroids suitable for ophthalmic use include mometasone, beclomethasone, dexamethasone, fluticasone, hydrocortisone, prednisolone, fluorometholone,.

Cheruvu et al. (Invest. Ophthalmol. Vis. Sci. (2006), 47(10), 4513-22) disclose the results of a study on the influence of drug lipophilicity and Choroid-Bruch's layer on the transscleral transport of various drugs, including budesonide.

Kompella et al. (Invest. Ophthalmol. Vis. Sci. (2003), 44(3), 1192-201) disclose the results of a study on the subconjunctival sustained delivery of budesonide using nano- and microparticles. Keller et al. (in Respiratory Drug Delivery IX (2004) 221-231) disclose solution formulations containing budesonide and surfactants.

Lintz et al. (AAPS Annual Meeting and Exposition, Baltimore, Nov. 8, 2004; Poster Ml 128) disclose liquid formulations containing budesonide, water, citrate salt, sodium chloride and alcohol, propylene glycol and/or surfactant, such as Tween, Pluronic, or phospholipids with HLB-values between 10 and 20.

Schueepp et al. (ATS 99 ^th International Conference, Seattle, May 16^-2I ⁵ ', 2003; poster 1607) disclose an experimental budesonide solution (100 μg in 0.5 ml).

Waldrep et al. (J. Aerosol Med. (1994), 7(2), 135-145) reportedly succeeded in preparing a liposome formulation of budesonide and phosphatidylcholine derivatives. Solubilization of drugs by cyclodextrins and their derivatives is well known.

Cyclodextrins are cyclic carbohydrates derived from starch. The unmodified cyclodextrins differ by the number of glucopyranose units joined together in the cylindrical structure. The parent cyclodextrins contain 6, 7, or 8 glucopyranose units and

- A - are referred to as CC-, β-, and γ-cyclodextrin respectively. Each cyclodextrin subunit has secondary hydroxyl groups at the 2 and 3 positions and a primary hydroxyl group at the 6-position. The cyclodextrins may be pictured as hollow truncated cones with hydrophilic exterior surfaces and hydrophobic interior cavities. In aqueous solutions, these hydrophobic cavities provide a haven for hydrophobic organic compounds that can fit all or part of their structure into these cavities. This process, known as inclusion complexation, may result in increased apparent aqueous solubility and stability for the complexed drug. The complex is stabilized by hydrophobic interactions and does not involve the formation of any covalent bonds. This dynamic and reversible equilibrium process can be described by Equations 1 and 2, where the amount in the complexed form is a function of the concentrations of the drug and cyclodextrin, and the equilibrium or binding constant, K _b . When cyclodextrin formulations are administered by injection into the blood stream, the complex rapidly dissociates due to the effects of dilution and non-specific binding of the drug to blood and tissue components.

Drug + Cyclodextrin <— ^ — > Complex Equation 1

[Complex]

K _h = T π r Equation 2 ^b LϋrugJ lCyclodextrinJ

Binding constants of cyclodextrin and an active agent can be determined by the equilibrium solubility technique (T. Higuchi et al. in "Advances in Analytical Chemistry and Instrumentation Vol. 4"; CN. Reilly ed.; John Wiley & Sons, Inc, 1965, pp. 117-212). Generally, the higher the concentration of cyclodextrin, the more the equilibrium process of Equations 1 and 2 is shifted to the formation of more complex, meaning that the concentration of free drug is generally decreased by increasing the concentration of cyclodextrin in solution.

Chemical modification of the parent cyclodextrins (usually at the hydroxyls) has resulted in derivatives with improved safety while retaining or improving the complexation ability. Of the numerous derivatized cyclodextrins prepared to date, only two appear to be commercially viable: the 2-hydroxypropyl derivatives (HP-CD; neutral

or ( -(CH ₂ VSO ₃ Na) _n where n=6.0-7.1

Sulfobutyl Ether-β-Cyclodextrin (Captisol ^® ) cyclodextrins being commercially developed by Janssen and others), and the sulfoalkyl ether derivatives, such as sulfobutyl ether, (SBE-CD; anionic cyclodextrins being developed by CyDex, Inc.) However, the HP-β-CD still possesses toxicity that the SBE-CD does not.

U.S. Patents No. 5,376,645 and No. 5,134,127 to Stella et al, U.S. Patent No. 3,426,011 to Parmerter et al., Lammers et al. (Reel. Trav. CHm. Pays-Bas (1972), 91(6), 733-742); Staerke (1971), 23(5), 167-171) and Qu et al. (J. Inclusion Phenom. Macro. Chem., (2002), 43, 213-221) disclose sulfoalkyl ether derivatized cyclodextrins. The references suggest that SAE-CD should be suitable for solubilizing a range of different compounds. However, Stella discloses that the molar ratio of sulfoalkyl ether derivatized cyclodextrin to active ingredient suitable for solubilization of the active ingredient, even a corticosteroid, in water ranges from 10:1 to 1:10.

A sulfobutyl ether derivative of beta cyclodextrin (SBE-β-CD), in particular the derivative with an average of about 7 substituents per cyclodextrin molecule (SBE7-β- CD), has been commercialized by CyDex, Inc. as CAPTISOL ^® . The anionic sulfobutyl ether substituent dramatically improves the aqueous solubility of the parent cyclodextrin. In addition, the presence of the charges decreases the ability of the molecule to complex

with cholesterol as compared to the hydroxypropyl derivative. Reversible, non-covalent, complexation of drugs with CAPTISOL ^® cyclodextrin generally allows for increased solubility and stability of drugs in aqueous solutions. While CAPTISOL ^® is a relatively new but known cyclodextrin, its use in the preparation of corticosteroid-containing solutions for ophthalmic administration has not previously been evaluated.

U.S. Patent No. 5,914,122 to Otterbeck et al. discloses the preparation of stable budesonide-containing solutions for rectal administration as a foam. Cyclodextrin is also suggested as a solubilizer for increasing the concentration of budesonide in solution.

U.S. Pregrant Patent Publication No. 20020055496 to McCoy et al. discloses essentially non-aqueous intra-oral formulations containing HP-β-CD. The formulations may be administered with an aerosol, spray pump or propellant.

Russian Patent No. 2180217 to Chuchalin discloses a stable budesonide-containing solution. The solution comprises budesonide, propylene glycol, poly(ethylene oxide), succinic acid, Trilon B, nipazole, thiourea, water, and optionally HP-β-CD. Muller et al. {Proceed. Int'l. Symp. Control. ReI. Bioact. Mater. (1997), 24, 69-70) discloses the results of a study on the preparation of budesonide microparticles by an ASES (Aerosol Solvent Extraction System) supercritical carbon dioxide process for use in a dry powder inhaler. HP-β-CD is suggested as a carrier for a powder.

Worth et al. (24 ^th International Symposium on Controlled Release of Bioactive Materials (1997)) disclose the results of a study evaluating the utility of steroid/ cyclodextrin complexes for pulmonary delivery.

Kinnarinen et al. (11 ^th International Cyclodextrin Symposium CD, (2002)) disclose the results of a study of the in vitro pulmonary deposition of a budesonide/γ-CD inclusion complex for dry powder inhalation. Vozone et al. (11 ^th International Cyclodextrin Symposium CD, (2002)) disclose the results of a study on the complexation of budesonide with γ-cyclodextrin for use in dry powder inhalation.

Rajewski et al. (J. Pharm. ScL (1996), 85(11), 1142-1169) provide a review of the pharmaceutical applications of cyclodextrins. In that review, they cite studies evaluating the use of cyclodextrin complexes in nasal administration. Kaur et al. (Curr. Drug Deliv. (2004), 1(4), 351-360) provide a general review on the use of cyclodextrins in ophthalmic formulations. Shimpi et al. (Acta Pharm. (2005), 55(2), 139-56) provide a general review on the use of cyclodextrins in a variety of different formulations including ophthalmic formulations.

U. S. Pat. No. 5,472,954 discloses the use of hydroxypropylmethylcellulose and hydroxypropyl cyclodextrins to solubilize hydrocortisone. U.S. Publication No. 2002/0198174 discloses a composition comprising "cyclodextrin", "prednisolone acetate", and "PHMB (1 ppm)" among other components. European Publication No. EP 0435682 A2 discloses the use of cyclodextrins in ophthalmic compositions with prostaglandins to treat ocular hypertension.

Lyons et al. (abstract in AAPS Annual Meeting and Exposition, Denver, CO USA, October 1-25, 2001) disclose an ophthalmic formulation comprising hydroxypropyl ether cyclodextrin derivative and prednisolone acetate. Singh et al. (U.S. Patents No. 7,128,928 and No. 6,696,426) disclose an ophthalmic formulation containing two polymers, a cyclodextrin (which can be SBE-CD), and an active agent (which can be oxazolidinone, or any of a long list of drugs including betamethasone, dexamethasone, fluorocinolone, fluorometholone, fluticasone, hydrocortisone, methylprednisolone, or prednisolone). Loftsson (U.S. Patents No. 7,115,586, No. 5,472,954, and No. 5,324,718) discloses a cyclodextrin-containing formulation comprising a polymer, a drug (which can be a corticosteroid such as hydrocortisone, dexamethasone, prednisolone, or triamcinolone) and a cyclodextrin derivative (which can be sulfobutyl ether cyclodextrin among others).

Chang et al. (U.S. Patent No. 6,969,706) disclose and claim a preserved pharmaceutical composition containing a cyclodextrin (which can be SBE-CD), a guanidine -based cationic preservative, an ophthalmic liquid, and an active agent (which can be a corticosteroid such as cortisone, hydrocortisone, prednisone, prednisolone, methylprednisone, triamcinolone, fluoromethalone, dexamethasone, medrysone, betamethasone, loteprednol, fluocinolone, fluomethasone, or mometasone). Beck et al. (U.S. Patents No. 6,723,353 and No. 6,358,935) disclose preserved liquid compositions containing cyclodextrin (which can be SBE-CD), a preservative, and a drug (which can be a corticosteroid such as beclomethasone, betamethasone, cortisone, dexamethasone, hydrocortisone, prednisolone, prednisone, or triamcinolone). The formulation can be administered to the eye. Buchanan et al. (U.S. Patent No. 6,610,671) disclose liquid formulations containing a cyclodextrin sulfonate and a drug (which can be a corticosteroid). The formulations can be for ophthalmic use.

Pitha (U.S. Patents No. 6,576,261 and No. 5,935,941) disclose liquid formulations containing two different types of cyclodextrin derivatives and a drug (which can be hydrocortisone). The formulation can be for ophthalmic use.

Buchanan et al. (U.S. Patent No. 6,610,671) disclose liquid formulations containing a cyclodextrin hydroxybutenyl derivative and a drug (which can be a corticosteroid). The formulations can be for ophthalmic use.

Kis (U.S. Patent No. 6,468,548) discloses and claims an autoclavable ophthalmic liquid composition containing a drug (which can be dexamethasone) and a cyclodextrin derivative. Muller et al. (U.S. Patent No. 6,407,079) disclose liquid formulations containing a drug (which can be a dexamethasone or hydrocortisone) and a mixture of two different types of cyclodextrin ether derivatives.

Viegas et al. (U.S. Patents No. 6,136,334, No. 5,587,175, and No. 5,958,443) disclose liquid formulations containing at least one ionic polysaccharide, at least one film forming agent (which can be a cyclodextrin), and a drug. The formulation can be administered to the eye.

Pate et al. (U.S. Patent No. 5,977,180) disclose ophthalmic compositions containing a cyclodextrin and a drug for the treatment of intraocular hypertension.

Amselem et al. (U.S. Patent No. 5,747,061) disclose a suspension formulation containing a corticosteroid, a nonionic polymer (which can be a cyclodextrin), a nonionic tonicity agent, and a nonionic surfactant.

Wiebe et al. (U.S. Patent No. 5,739,121) disclose a compostion containing a fluorocyclodextrin derivative and a drug (which can be a corticosteroid). The composition can be administered to the eye. Guy (U.S. Patent No. 5,576,311) discloses an ophthalmic suspension containing a corticosteroid, an aqueous medium and a cyclodextrin derivative wherein the drug does not form a soluble inclusion complex with the cyclodextrin.

Babcock et al. (U.S. Patent No. 5,538,721) disclose an ophthalmic liquid formulation containing a cyclodextrin derivative and an amino-substituted steroid. Folkman et al. (U.S. Patent No. 5,227,372) disclose an ophthalmic formulation containing a cyclodextrin sulfate derivative and a drug (which can be hydrocortisone).

Lipari (U.S. Patent No. 4,383,992) discloses and claims an ophthalmic formulation containing beta-cyclodextrin and a steroid, such as dexamethasone or hydrocortisone.

PCT International Publication No. WO 2004/087043 to Sun Pharmaceutical Industries Ltd. discloses an ophthalmic formulation containing a cyclodextrin derivative, an anti-infective agent, and a corticosteroid.

U.S. Patents No. 5,134,127 to 5,376,645 to Stella et al. disclose liquid formulations containing SAE-CD and steroids, such as corticosteroids. They disclose that SAE-CD formulations can be administered intraocularly.

Saari et al. (Graefes Arch. Clin. Exp. Ophthalmol. (2006), 244(5), 620-6) disclose the results of a study comparing the topical administration of a solution containing 0.7% wt dexamethasone-cyclodextrin with 0.1% wt. dexamethasone sodium phosphate for the treatment of postcataract inflammation.

Loftsson et al. (Acta Ophthalmol. Scand. (2002), 80(2), 144-50) disclose that inclusion of cyclodextrins in eye drop formulations enhances delivery to the eye. They also provide a review (Adv. Drug. Deliv. Rev. (1999), 36(1), 59-79) on the general use of cyclodextrins in eye drops. Kristinsson et al. (Invest. Ophthalmol. Vis. Sci. (1996), 37(6), 1199-203) disclose a liquid eye drop formulation containing cyclodextrin (HP-CD) and a high concentration of dexamethasone.

Usayapant et al. (Pharm. Res. (1991), 8(12), 1495-9) disclose an ophthalmic liquid formulation containing HP-CD and dexamethasone or dexamethasone acetate. Bary et al. (Eur. J. Pharm. Biopharm. (2000), 50(2), 237-244) disclose an ophthalmic formulation containing HP-CD and hydrocortisone.

Jarvinen et al. (J. Ocul. Pharmacol. Ther. (1995), 11(2), 95-106; Curr. Eye Res. (1994), 13(12), 897-905) report that coadministration of SBE-CD with pilocarpine improves the tolerability of ophthalmically applied pilocarpine by decreasing irritation; however, increasing SBE-CD concentration resulted in reduced Imax and AUC values.

Considerations when formulating an ophthalmic solution include solubility of the formula ingredients, clarity, tonicity, buffers, pH, sterility, and appropriate selection of preservatives when indicated. Particle size and the selection of a suspending agent are important when compounding an ophthalmic suspension. The particles in the suspensions must be small and uniformly suspended after shaking. The desired properties for an ophthalmic solution suitable for administration include: proper viscosity, therapeutic effecact, little to no irritation and itching upon administration, rapid symptom relief, and minimal content of organic cosolvent. Conversely, undesired properties for an ophthalmic

solution include: little to no efficacy, irritation to the eye upon administration, very low viscosity, very high viscosity, allergic reaction, steroid-induced glaucoma, steroid-induced cataracts, immunosuppression and subsequent infection.

Zannou et al. ("Osmotic properties of sulfobutyl ether and hydroxypropyl cyclodextrins", Pharma. Res. (2001), 18(8), 1226-1231) compared the osmolality of solutions containing SBE-CD and HP-CD. SBE-CD containing solutions have a greater osmolality than HP-CD containing solutions comprising similar concentrations of cyclodextrin derivative.

A need remains in the art for ophthalmic formulations, containing cyclodextrin and corticosteroid, that provide improved performance over other ophthalmic formulations, such as over suspension formulations or surfactant/organic solvent based formulations.

SUMMARY OF THE INVENTION

The present invention seeks to overcome the disadvantages present in known formulations. As such, a derivatized cyclodextrin-based, e.g., sulfoalkyl ether cyclodextrin (SAE-CD)-based, ophthalmic formulation is provided. The present formulation includes a corticosteroid as a principle active agent. The present formulation may provide enhanced solubility and/or enhanced chemical, thermochemical, hydrolytic and/or photochemical stability of the active agent or other ingredients in the formulation. Moreover, the present formulation may possess other advantages, e.g. enhanced drug delivery, increased rate of drug administration, reduced toxicity, ease of manufacture, assurance of sterility, improved stability, enhanced bioabsorption, enhanced pharmacokinetic profile, and/or reduced corticosteroid-related side effects, over other solution or suspension formulations containing a corticosteroid, such as budesonide.

The invention provides an ophthalmic formulation, and method of use thereof for treating a disease or disorder of the eye that is therapeutically responsive to corticosteroid therapy. The liquid formulation of the invention comprises a dose of corticosteroid, an aqueous liquid carrier and sulfoalkyl ether cyclodextrin.

The invention provides a method of treating, preventing or ameliorating in a subject a corticosteroid-responsive disease or disorder of the eye, meaning a disease or disorder in the eye of a subject that can be treated with a therapeutically effective amount of corticosteroid to provide a clinical or therapeutic benefit to the subject.

The method comprises: providing an aqueous ophthalmic formulation comprising a corticosteroid, an aqueous liquid carrier, and sulfoalkyl ether cyclodextrin; and delivering topically or via injection to the eye of a subject in need thereof a dose of about at least 5 μg, 40 μg, at least 45 μg, at least 48 μg, 45-1000 μg, about 1 μg to 20 mg, or 1 μg to 10 mg, 0.01 mg to 10 mg, 0.025 mg to 10 mg, 0.05 mg to 5 mg, 0.1 mg to 5 mg, 0.125 mg to 5 mg, 0.25 mg to 5 mg, 0.5 mg to 5 mg, 0.05 mg to 2 mg, 0.1 mg to 2 mg, 0.125 mg to 2 mg, 0.25 mg to 2 mg, 0.5 mg to 2 mg, 1 μg, 10 μg, 25 μg, 50 μg, 100 μg, 125 μg, 200 μg, 250 μg, 25 to 66 μg, 48 to 81 μg, 73 to 125 μg, 40 μg, 64 μg, 95 μg, 35 to 95 μg, 25 to 125 μg, 60 to 170 μg, 110 μg, 170 μg, 45 to220 μg, 45 to 85 μg, 48 to 82 μg, 85 to 160 μg, 140 to 220 μg, 120 to 325 μg, 205 μg, 320 μg, 325 μg, 90 to 400 μg, 95 to 170 μg, 165 to 275 μg, or 275 to 400 μg of the corticosteroid. In some embodiments, the corticosteroid is budesonide.

In some embodiments, the ophthalmic formulation has a volume of about 10 μl to 100 ml, 50 μl to 50 ml, 50 μl to 10 ml, 0.1 to 10 ml, 0.1 ml to less than 10 ml, 0.1 ml to 7.5 ml, 0.1 ml to 5 ml, 0.1 ml to 3 ml, 0.1 ml to 2 ml, 0.1 ml to 1 ml, 0.05 ml to 7.5 ml, 0.05 ml to 5 ml, 0.05 ml to 3 ml, 0.05 ml to 2 ml, or 0.05 ml to 1 ml.

The ophthalmic formulation can be administered via the use of a dropper, tube, eye spray device, eye wash unit, and others known to those of ordinary skill in the art.

An SAE-CD-containing formulation can be prepared with sufficient active agent solubility and stability for a commercial product. If needed, the SAE-CD-containing formulation can be prepared as a clear aqueous solution that can be sterile filtered through a filter having a pore size of 0.45 μm or less and that is stable and preserved under a variety of storage conditions. The invention thus provides a filtration- sterilized liquid formulation comprising a solution of the invention and a method of sterilizing a solution of the invention by sterile filtration through a filter. Sterile filtration can be done without substantial mass loss of solubilized corticosteroid, meaning less than 5% mass loss.

Any corticosteroid suitable for ophthalmic administration can be used according to the invention. Exemplary suitable corticosteroids are listed herein. Some embodiments of the invention comprise a corticosteroid having a lipophilicity approximating or exceeding that of flunisolide. Some embodiments of the invention exclude a corticosteroid having a lipophilicity less than flunisolide, i.e, embodiments excluding hydrocortisone,

prednisolone, prednisone, dexamethasone, betamethasone, methylprednisolone, triamcinolone, fluocortolone.

One aspect of the invention provides a liquid formulation comprising an effective amount of corticosteroid, such as budesonide, a liquid carrier, and a SAE-CD, wherein the SAE-CD is present in an amount sufficient to dissolve and stabilize the corticosteroid during storage.

Another aspect of the invention provides a method of improving the clinical benefit provided by ophthalmic administration of corticosteroid to a subject in need thereof, the method comprising: providing in a unit dose an aqueous suspension formulation comprising water and corticosteroid suspended therein; combining the suspension with an amount of SAE-CD sufficient to and for a period of time sufficient to solubilize the corticosteroid and form an ophthalmic solution; and administering the solution to the subject, wherein the ophthalmic solution provides an improved clinical benefit over as provided by the same therapeutic dose of corticosteroid in the suspension under similar, or otherwise comparable, conditions.

The invention also provides a method of treating an inflammatory disease, disorder or symptom of the eye comprising: administering to the eye a liquid formulation comprising sulfoalkyl ether cyclodextrin, corticosteroid, and liquid carrier.

In some embodiments, the liquid formulation is a solution, and in others it is a suspension. In some embodiments, the liquid carrier is aqueous, and in others it is non-aqueous. In some embodiments, the corticosteroid is budesonide. As used herein, the term budesonide refers to the racemic, optically pure, or optically enriched forms thereof. The corticosteroid can be present in amorphous or crystalline form or a mixture thereof, or the corticosteroid can be present in dissolved form in solution. In some embodiments, a majority or substantially all of the corticosteroid is dissolved. In other embodiments, a minority of the corticosteroid is dissolved.

In some embodiments, the formulation of the invention and method of the invention employ a combination of two or more corticosteroids. In some embodiments, the formulation comprises a single corticosteroid. In some embodiments, budesonide is the sole corticosteroid in the formulation.

The invention also provides a method of improving the ophthalmic administration of an aqueous corticosteroid-containing suspension unit dose formulation, the method comprising the step of adding SAE-CD to an aqueous corticosteroid-containing suspension unit dose formulation in an amount sufficient to solubilize the corticosteroid to form an ophthalmic aqueous corticosteroid-containing solution unit dose formulation, the improvement comprising providing an anti-inflammatory effect with a faster recovery to normal intraocular pressure. As used herein, the term "normal intraocular pressure" means the intraocular pressure of a subject prior to injury or prior to inflammation of eye tissue. The liquid formulation and composition of the invention provide an enhanced bioavailability/bioabsorption of the corticosteroid as compared to a suspension-based aqueous formulation containing approximately the same amount of corticosteroid and excluding SAE-CD. Thus, the liquid formulation and/or composition provides an improved clinical benefit or therapeutic benefit over the suspension-based formulation. Accordingly, some aspects of the invention provide a method of treating a disease or disorder of the eye in a subject, the method comprising: administering to the eye of the subject a solution formulation comprising a therapeutically effective amount of corticosteroid, sulfoalkyl ether cyclodextrin, and a liquid medium thereby providing an improved clinical benefit over that provided by a suspension formulation comprising substantially the same amount of corticosteroid and liquid medium but excluding the sulfoalkyl ether cyclodextrin. The improved clinical effect can be: a) a more rapid return to normal intraocular pressure; b) a more rapid anti-inflammatory therapeutic effect; c) a more rapid clinical benefit; and/or d) a more rapid reduction in inflammation of eye tissue.

In some embodiments, the invention provides an improved method for the treatment of inflammation of the eye of a subject comprising administering to an inflamed eye or tissue surrounding the eye of a subject, the eye having a less than normal intraocular pressure, an aqueous liquid formulation comprising a therapeutically effective dose of budesonide, sulfoalkyl ether cyclodextrin, and aqueous liquid carrier, the improvement comprising providing a faster rate of resolution of intraocular pressure to normal intraocular pressure as compared to the rate of resolution following treatment with an aqueous suspension formulation comprising substantially the same therapeutically effective dose of budesonide and aqueous liquid carrier but excluding the sulfoalkyl ether cyclodextrin. In some embodiments, the inflammation is caused by injury to the eye or

tissue surrounding the eye. In some embodiments, the comparator suspension formulation excludes a cyclodextrin, surfactant, and/or organic solvent. The diseases, disorders or symptoms can be of the eye and/or of tissue surrounding the eye.

In some embodiments, SAE-CD is present in an amount sufficient to decrease the amount of unsolubilized corticosteroid in the suspension formulation and to improve the ophthalmic administration of the suspension formulation. In some embodiments, SAE-CD is present in an amount sufficient to solubilize enough corticosteroid such that the suspension formulation to which the SAE-CD was added is converted to a solution, substantially clear solution (containing less than 5% precipitate or solid), or a clear solution. It is possible that other components of the suspension formulation will not completely dissolve in, or may separate out from, the solution formulation containing SAE-CD.

Some embodiments of the invention include those wherein the corticosteroid to SAE-CD molar ratio is 0.5 to 0.0001 (1:2 to 1:10,000), 1:1 to 1:100, 1:1 to 1:10,000, or 0.1 (1:10) to 0.03 (1:33.33). The molar ratio of SAE-CD to corticosteroid in the formulation or system is generally greater than 10:1, greater than about 11:1, greater than 13:1, or greater than 14:1. Depending upon the corticosteroid used in the formulation, the molar ratio of corticosteroid to SAE-CD can vary in order to obtain a solution suitable for ophthalmic administration for the treatment of a disease, symptom or disorder of the eye. In some embodiments, the composition comprises at least 4.8±0.5% wt./vol of SAE-CD to provide a self-preserved formulation for a period predetermined period of time. In some embodiments, the composition comprises less than or about 21.5 ± 2% wt./wt. of SAE- CD. In some embodiments, the SAE-CD is present in an amount sufficient to provide a clear solution. For example, the ophthalmic composition can be visibly clear as viewed by the unaided eye.

Some suitable SAE-CD' s include, for example, sulfobutyl ether 4-β-CD or sulfobutyl ether 7-β-CD, sulfobutyl ether 6-γ-CD, sulfobutyl ether 4-γ-CD, sulfobutyl ether 3 to 8-γ-CD, or a sulfobutyl ether 5-γ-CD, or a compound of the formula 1 or a mixture thereof. A composition of the invention can further comprise a conventional preservative, an antioxidant, a buffering agent, an acidifying agent, a solubilizing agent, a complexation enhancing agent, saline, an electrolyte, another therapeutic agent, an alkalizing agent, a tonicity modifier, surface tension modifier, viscosity modifier, surfactant, density

modifier, or a combination thereof. If desired, the composition further comprises a liquid carrier other than water. If a conventional preservative is included in the composition, the corticosteroid, such as budesonide, may have a greater binding with the SAE-CD than does a conventional preservative. A composition can be purged with an inert gas prior to storage to remove substantially all of the oxygen contained in the formulation. In general, the formulation or composition of the invention has a shelf-life of at least 6 months depending upon the intended use.

The formulation can be prepared at a temperature at or above 5°C, at or above 25°C, at or above 35°C, at or above 45°C or at or above 50°C. Specific embodiments of the methods of preparing a liquid formulation include those wherein: 1) the method further comprises the step of sterile filtering the formulation through a filtration medium having a pore size of 0.1 microns or larger; 2) the liquid formulation is sterilized by irradiation or autoclaving; 3) the ophthalmic solution is purged with nitrogen or argon or other inert pharmaceutically acceptable gas prior to storage such that a substantial portion of the oxygen dissolved in, and/or in surface contact with the solution is removed.

The invention provides a method of stabilizing corticosteroid in an aqueous corticosteroid-containing formulation comprising the step of adding SAE-CD to an aqueous corticosteroid-containing suspension or solution formulation in an amount sufficient to reduce the rate of degradation of corticosteroid as compared to a control sample excluding SAE-CD.

The invention also provides an ophthalmic composition comprising a water soluble γ-CD derivative, a corticosteroid (either esterified or unesterified) and an aqueous liquid medium. Another embodiment of the invention also provides an ophthalmic composition comprising a water soluble β-CD derivative, a corticosteroid (unesterified) and an aqueous liquid medium.

The invention can be used to provide a drug composition comprising a therapeutically effective amount of corticosteroid, liquid carrier and SAE-CD present in an amount sufficient to solubilize the corticosteroid when presented to an aqueous environment, wherein the molar ratio of corticosteroid to SAE-CD is in the range of about 0.072 (1:13.89 or about 1:14) to 0.0001 (l:10,000)or 0.063 (1:15.873 or about 1:16) to 0.003 (1:333.33 or about 1:333). The molar ratio of SAE-CD to corticosteroid ranges from > 10:1 to about 1000:1, about from > 10:1 to about 100:1, from > 10:1 to about 50:1, from > 10:1 to about 30:1, from > 10:1 to about 500:1

As a result of using SAE-CD corticosteroid therapy with an ophthalmic solution, one can expect advantages such as enhanced drug delivery, increased rate of drug absorption, enhanced pharmacokinetic profile, reduced treatment time, improved formulation stability and/or improved patient compliance as compared to comparable corticosteroid therapy with an ophthalmic suspension or solution.

The invention can be employed in a kit comprising SAE-CD, an aqueous carrier, and corticosteroid, wherein the kit is adapted for the preparation of an ophthalmic solution. Embodiments of the kit are detailed below. The invention provides the potential to accommodate combination products to overcome incompatibilities with suspension by other solution dosage forms.

In some embodiments, the unit dose comprises at least 45 μg, at least 48 μg, 45- 1000 μg , about 1 μg to 20 mg, about 1 μg to 10 mg, 0.01 mg to 10 mg, 0.025 mg to 10 mg, 0.05 mg to 5 mg, 0.1 mg to 5 mg, 0.125 mg to 5 mg, 0.25 mg to 5 mg, 0.5 mg to 5 mg, 0.05 mg to 2 mg, 0.1 mg to 2 mg, 0.125 mg to 2 mg, 0.25 mg to 2 mg, 0.5 mg to 2 mg, 1 μg, 10 μg, 25 μg, 50 μg, 100 μg, 125 μg, 200 μg, 250 μg, 25 to 66 μg, 48 to 81 μg, 73 to 125 μg, 40 μg, 64 μg, 95 μg, 35 to 95 μg, 25 to 125 μg, 60 to 170 μg, 110 μg, 170 μg, 45 to220 μg, 45 to 85 μg, 48 to 82 μg, 85 to 160 μg, 140 to 220 μg, 120 to 325 μg, 205 μg, 320 μg, 325 μg, 90 to 400 μg, 95 to 170 μg, 165 to 275 μg, or 275 to 400 μg of corticosteroid. The liquid formulation can be administered with any type of device suitable for administration of a liquid formulation to the eye. For example, the formulation can be administered with eye dropper, tube, eye spray device, eye wash unit and other devices known to those of ordinary skill in the art.

In some embodiments, the ophthalmically administered dose of corticosteroid may be absorbed into the bloodstream of a subject.

The invention includes all combinations of the embodiments and aspects disclosed herein. Accordingly, the invention includes the embodiments and aspects specifically disclosed, broadly disclosed, or narrowly disclosed herein, as well as combinations thereof and subcombinations of the individual elements of said embodiments and aspects. These and other aspects of this invention will be apparent upon reference to the following detailed description, examples, claims and attached figures.

BRIEF DESCRIPTION OF THE FIGURES

The following drawings are given by way of illustration only, and thus are not intended to limit the scope of the present invention.

Figure 1 depicts a graph of the osmolality of SBE-CD containing solutions of various degrees of substitution and HP-β-CD containing solutions comprising similar concentrations of cyclodextrin derivative.

Figure 2 depicts a phase solubility graph of the concentration (molar) of cyclodextrin versus the concentration (molar) of budesonide for γ-CD, HP-β-CD and SBE7-β-CD. Figure 3 depicts a semi-log plot of the % of initial concentration of the R- and S- isomers of budesonide in solutions with and without CAPTISOL versus time at 60° C in solution.

Figure 4 depicts a semi-log plot of the % of initial concentration of budesonide versus Lux hours when the samples are exposed to fluorescent lamps. Figure 5 depicts a phase solubility diagram for fluticasone propionate in the presence of several different cyclodextrins.

Figure 6 depicts a phase solubility diagram for mometasone furoate in the presence of several different cyclodextrins.

Figure 7 depicts a phase solubility diagram for esterified and non-esterified fluticasone in the presence of SAE(5-6)-γ-CD.

Figure 8 depicts a bar chart summarizing the aqueous solubility of beclomethasone dipropionate in the presence of various SAE-CD derivatives.

Figures 9a and 9b depict charts detailing the changes in ocular pressure of rabbits treated according to Example 17.

DETAILED DESCRIPTION OF THE INVENTION

The presently claimed formulation overcomes many of the undesired properties of other known aqueous ophthalmic solution or suspension corticosteroid-containing formulations. By including SAE-CD, in an ophthalmic liquid formulation containing corticosteroid, the corticosteroid is dissolved. Unexpectedly, the clinical benefit provided by the corticosteroid is improved as compared to an otherwise similar formulation

excluding SAE-CD. Moreover, the corticosteroid exhibits greater stability in the presence of SAE-CD than it does in its absence.

The formulation of the invention may provide an improved pharmacokinetic profile over a suspension formulation comprising approximately the same amount of corticosteroid and delivered under substantially the same conditions. The term "enhanced pharmacokinetic profile" is taken to mean a higher AUC (e.g. AUCi _as t or AUQo→∞)) per μg of corticosteroid delivered or administered, a higher Cmax per μg of corticosteroid delivered or administered, increased bioavailability, absorption or distribution of the corticosteroid at the site of delivery, a shorter Tmax or a longer Tmax.

Alternatively, the formulation of the invention provides substantially the same pharmacokinetic profile or an enhanced pharmacokinetic profile over a suspension formulation comprising approximately a higher amount of corticosteroid and delivered under substantially the same conditions. The corticosteroid in the formulation can be present at a dose that is less than 80%, less than 70% less than 60% less than 50%, less than 40%, less than 20%, and less than 10% of that in the suspension.

The corticosteroid can be present in an amount sufficient for single dose or multi- dose administration. SAE-CD can be present in an amount sufficient to solubilize the corticosteroid when the two are placed in the aqueous carrier. The aqueous carrier can be present in an amount sufficient to aid in dissolution of the corticosteroid and form an ophthalmic solution of sufficient volume and desired viscosity to permit single dose or multi-dose administration.

The present invention provides SAE-CD based formulations, wherein the SAE-CD is a compound, or mixture of compounds, of the Formula 1:

wherein: n is 4, 5 or 6;

R ₁ , R ₂ , R ₃ , R ₄ , R5, R _O , R7, Rs and R ₉ are each, independently, -O- or a -0-(C ₂ - C ₆ alkylene)-SO ₃ ^~ group, wherein at least one of R ₁ to R ₉ is independently a -0-(C ₂ - C _O alkylene)-SO ₃ ^~ group, preferably a -O-(CH ₂ ) _m SO ₃ ^~ group, wherein m is 2 to 6, preferably 2 to 4, (e.g.-OCH ₂ CH ₂ CH ₂ SO ₃ ^" Or-OCH ₂ CH ₂ CH ₂ CH ₂ SO ₃ ); and Si, S ₂ , S ₃ , S ₄ , S ₅ , S ₆ , S ₇ , Sg and S ₉ are each, independently, a pharmaceutically acceptable cation which includes, for example, H ⁺ , alkali metals (e.g. Li ⁺ , Na ⁺ , K ⁺ ), alkaline earth metals (e.g., Ca ⁺² , Mg ⁺² ), ammonium ions and amine cations such as the cations of (Ci - C ₆ )- alkylamines, piperidine, pyrazine, (Ci - C _ό )-alkanolamine and (C ₄ - C ₈ )-cycloalkanolamine. Exemplary embodiments of the SAE-CD derivative of the invention include derivatives of the Formula II (SAEx-α-CD), wherein "x" ranges from 1 to 18; of the

Formula III (SAEy-β-CD), wherein"y" ranges from 1 to 21; and of the Formula IV

(SAEz-γ-CD), wherein"z" ranges from 1 to 24 such as:

SAEx-α-CD SAEy- β-CD SAEz-γ-CD Name

SEEx-α-CD SEEy-β-CD SEEz-γ-CD Sulfoethyl ether CD

SPEx-α-CD SPEy-β-CD SPEz-γ-CD Sulfopropyl ether CD

SBEx-α-CD SBEy-β-CD SBEz-γ-CD Sulfobutyl ether CD

SptEx-α-CD SPtEy-β-CD SPtEz-γ-CD Sulfopentyl ether CD

SHEx-α-CD SHEy-β-CD SHEz-γ-CD Sulfohexyl ether CD

"SAE" represents a sulfoalkyl ether substituent bound to a cyclodextrin. The values "x", "y" and "z" represent the average degree of substitution as defined herein in terms of the number of sulfoalkyl ether groups per CD molecule.

The SAE-CD used is described in U.S. Patents No. 5,376,645 and No. 5,134,127 to Stella et al, the entire disclosures of which are hereby incorporated by reference. U.S. Patent No. 3,426,011 to Parmerter et al. discloses anionic cyclodextrin derivatives having sulfoalkyl ether substituents. Lammers et al. (Reel. Trav. Chim. Pays-Bas (1972), 91(6), 733-742); Staerke (1971), 23(5), 167-171) and Qu et al. (J. Inclusion Phenom. Macro. Chem., (2002), 43, 213-221) disclose sulfoalkyl ether derivatized cyclodextrins. U.S. Patent No. 6,153,746 to Shah et al. discloses a process for the preparation of sulfoalkyl ether cyclodextrin derivatives. An SAE-CD can be made according to the disclosures of Stella et al., Parmerter et al., Lammers et al. or Qu et al., and if processed to remove the

major portion (>50%) of the underivatized parent cyclodextrin, used according to the present invention. The SAE-CD can contain from 0% to less than 50% wt. of underivatized parent cyclodextrin.

The terms "alkylene", "alkyl," as used herein (e.g., in the -0-(C ₂ - C ₆ - alkylene)SO ₃ ^~ group or in the alkylamines), ethyl, propyl butyl, pentyl and hexyl include linear, cyclic, and branched, saturated and unsaturated (i.e., containing one double bond) divalent alkylene groups and monovalent alkyl groups, respectively. The term "alkanol" in this text likewise includes both linear, cyclic and branched, saturated and unsaturated alkyl components of the alkanol groups, in which the hydroxyl groups may be situated at any position on the alkyl moiety. The term "cycloalkanol" includes unsubstituted or substituted (e.g., by methyl or ethyl) cyclic alcohols.

An embodiment of the present invention provides compositions containing a mixture of cyclodextrin derivatives, having the structure set out in formula (I), where the composition overall contains on the average at least 1 and up to 3n + 6 alkylsulfonic acid moieties per cyclodextrin molecule. The present invention also provides compositions containing a single type of cyclodextrin derivative, or at least 50% of a single type of cyclodextrin derivative. The invention also includes formulations containing cyclodextrin derivatives having a narrow or wide and high or low degree of substitution. These combinations can be optimized as needed to provide cyclodextrins having particular properties.

Exemplary SAE-CD derivatives include SBE4-β-CD, SBE7-β-CD, SBEl l-β-CD, SBE3.4-γ-CD, SBE4.2-γ-CD, SBE4.9-γ-CD, SBE5.2-γ-CD, SBE6.1-γ-CD, SBE7.5-γ-CD, SBE7.8-γ-CD and SBE5-γ-CD which correspond to SAE-CD derivatives of the formula I wherein n = 5, 5, 5 and 6; m is 4; and there are on average 4, 7, 11 and 5 sulfoalkyl ether substituents present, respectively. These SAE-CD derivatives increase the solubility of poorly water soluble active agents to varying degrees.

Since SAE-CD is a poly-anionic cyclodextrin, it can be provided in different salt forms. Suitable counterions include cationic organic atoms or molecules and cationic inorganic atoms or molecules. The SAE-CD can include a single type of counterion or a mixture of different counterions. The properties of the SAE-CD can be modified by changing the identity of the counterion present. For example, a first salt form of SAE-CD can have a greater corticosteroid stabilizing and/or solubilizing power than a different second salt form of SAE-CD. Likewise, an SAE-CD having a first degree of substitution

can have a greater corticosteroid stabilizing and/or solubilizing power than a second SAE- CD having a different degree of substitution. The enhanced solubilization of a corticosteroid by one SAE-CD versus another is demonstrated by the data in the following tables which depict the molar solubility for fluticasone propionate with different SAE-CDs at about 0.03 to 0.12M concentrations such that the solubilizing power followed about this rank order over this concentration range of SAE-CD: SBE5.2-γ-CD > SPE5.4-γ-CD > SBE6.1-γ-CD > SBE9.7-γ-CD » SBE7-CC-CD > SBE6.7-β-CD > SPE7-β-CD. For mometasone furoate, the solubilizing power followed about this rank order over this concentration range of SAE-CD: SBE9.7-γ-CD > SBE6.1-γ-CD > SBE5.2-γ-CD » SPE5.4-γ-CD > SBE7-CC-CD > SBE6.7-β-CD > SPE7-β-CD. Differences were also observed for the binding of budesonide and triamcinolone with specific embodiments of SAE-CD. According to the invention, a SAE-γ-CD binds a corticosteroid better than a SAE-β-CD does. Also, a SAE-β-CD binds budesonide better than a SAE-α-CD does. The data is summarized in FIGS 5, 6, and 7..

Solubility of selected steroids enhanced by alpha-cyclodextrins

Solubility of selected steroids enhanced by gamma-cyclodextrins

The inventors have also discovered that SAE-γ-CD is particularly suitable for use in complexing esterified and non-esterified corticosteroids as compared to complexation of the same corticosteroids with SAE-β-CD or SAE-α-CD. The table above also summarizes the phase solubility data depicted in FIG. 5 and 7 for fluticasone and fluticasone propionate with various different SAE-γ-CD species having a degree of substitution in the range of 5-10.

The present inventors have discovered that SAE-γ-CD is also much more effective at binding with a particular regioisomer of esterified corticosteroids than is SAE-β-CD or SAE-α-CD. The procedure set forth in Example 18 details the comparative evaluation of the binding of SAE-γ-CD and SAE-β-CD with a series of structurally related corticosteroid derivatives. The table below summarizes the results of a study comparing the binding of SBEx-γ-CD, wherein x represents the average degree of substitution, derivatives and SBE-β-CD derivative with different forms of beclmethasone.

The survey study shows that in the presence of SBE(3.4) γ-CD (0.04M), all of the forms of beclomethasone were at or near their highest solubilities. B17P, the active metabolite of BDP, has the highest solubility of the esterified beclomethasone forms in any of the derivatized CDs. The results indicate that SBE-γ-CD complexes with beclomethasone dipropionate better than Captisol or γ-CD alone. Of the SAE-CD derivatives evaluated, the optimal degree of substitution of the SBE γ-CD that provides the greatest enhancement in solubility of BDP is DS = 3.4, and solubility decreases almost linearly as the degree of substitution increases. This is true for both the 24 hr and 5 day equilibration times. So in terms of BDP solubilization with SAE-CD: SBE(3.4)γ-CD > SBE(5.2)γ-CD > SBE(6.1)γ-CD > SBE(7.5)γ-CD > γ-CD > Captisol (SBE7-β-CD). The data is summarized in FIG 8. Therefore, the present inventors have discovered that SAE- γ-CD cyclodextrin derivatives are unexpectedly better at solubilizing corticosteroids than are SAE-β-CD derivatives. By "complexed" is meant "being part of a clathrate or inclusion complex with", i.e., a complexed therapeutic agent is part of a clathrate or inclusion complex with a cyclodextrin derivative. By "major portion" is meant at least about 50% by weight. Thus, a formulation according to the present invention may contain an active agent of which more than about 50% by weight is complexed with a cyclodextrin. The actual percent of

active agent that is complexed will vary according to the complexation equilibrium constant characterizing the complexation of a specific cyclodextrin to a specific active agent. The invention also includes embodiments wherein the active agent is not complexed with the cyclodextrin or wherein a minor portion of the active agent is complexed with the derivatized cyclodextrin. It should be noted that an SAE-CD, or any other anionic derivatized cyclodextrin, can form one or more ionic bonds with a positively charged compound. This ionic association can occur regardless of whether the positively charged compound is complexed with the cyclodextrin either by inclusion in the cavity or formation of a salt bridge. The binding of a drug to the derivatized cyclodextrin can be improved by including an acid or base along with the drug and cyclodextrin. For example, the binding of a basic drug with the cyclodextrin might be improved by including an acid along with the basic drug and cyclodextrin. Likewise, the binding of an acidic drug with the cyclodextrin might be improved by including a base (alkaline material) along with the acidic drug and cyclodextrin. The binding of a neutral drug might be improved by including a basic, acidic or other neutral compound along with the neutral drug and cyclodextrin. Suitable acidic compounds include inorganic and organic acids. Examples of inorganic acids are mineral acids, such as hydrochloric and hydrobromic acid. Other suitable acids include sulfuric acid, sulfonic acid, sulfenic acid, and phosphoric acid. Examples of organic acids are aliphatic carboxylic acids, such as acetic acid, ascorbic acid, carbonic acid, citric acid, butyric acid, fumaric acid, glutaric acid, glycolic acid, α-ketoglutaric acid, lactic acid, malic acid, mevalonic acid, maleic acid, malonic acid, oxalic acid, pimelic acid, propionic acid, succinic acid, tartaric acid, or tartronic acid. Aliphatic carboxylic acids bearing one or more oxygenated substituents in the aliphatic chain are also useful. A combination of acids can be used.

Suitable basic compounds include inorganic and organic bases. Suitable inorganic bases include ammonia, metal oxide and metal hydroxide. Suitable organic bases include primary amine, secondary amine, tertiary amine, imidazole, triazole, tetrazole, pyrazole, indole, diethanolamine, triethanolamine, diethylamine, methylamine, tromethamine (TRIS), aromatic amine, unsaturated amine, primary thiol, and secondary thiol. A combination of bases can be used.

An anionic derivatized cyclodextrin can complex or otherwise bind with an acid- ionizable agent. As used herein, the term acid-ionizable agent is taken to mean any

compound that becomes or is ionized in the presence of an acid. An acid-ionizable agent comprises at least one acid-ionizable functional group that becomes ionized when exposed to acid or when placed in an acidic medium. Exemplary acid-ionizable functional groups include a primary amine, secondary amine, tertiary amine, quaternary amine, aromatic amine, unsaturated amine, primary thiol, secondary thiol, sulfonium, hydroxyl, enol and others known to those of ordinary skill in the chemical arts.

The degree to which an acid-ionizable agent is bound by non-covalent ionic binding versus inclusion complexation formation can be determined spectrophotometrically using methods such as ¹ HNMR, ¹³ CNMR, or circular dichroism, for example, and by analysis of the phase solubility data for the acid-ionizable agent and anionic derivatized cyclodextrin. The artisan of ordinary skill in the art will be able to use these conventional methods to approximate the amount of each type of binding that is occurring in solution to determine whether or not binding between the species is occurring predominantly by non-covalent ionic binding or inclusion complex formation. An acid- ionizable agent that binds to derivatized cyclodextrin by both means will generally exhibit a bi-phasic phase solubility curve. Under conditions where non-covalent ionic bonding predominates over inclusion complex formation, the amount of inclusion complex formation, measured by NMR or circular dichroism, will be reduced even though the phase solubility data indicates significant binding between the species under those conditions; moreover, the intrinsic solubility of the acid-ionizable agent, as determined from the phase solubility data, will generally be higher than expected under those conditions.

As used herein, the term non-covalent ionic bond refers to a bond formed between an anionic species and a cationic species. The bond is non-covalent such that the two species together form a salt or ion pair. An anionic derivatized cyclodextrin provides the anionic species of the ion pair and the acid-ionizable agent provides the cationic species of the ion pair. Since an anionic derivatized cyclodextrin is multi-valent, an SAE-CD can form an ion pair with one or more acid-ionizable agents.

The parent cyclodextrins have limited water solubility as compared to SAE-CD and HPCD. Underivatized α-CD has a water solubility of about 14.5% w/v at saturation. Underivatized β-CD has a water solubility of about 1.85% w/v at saturation. Underivatized γ-CD has a water solubility of about 23.2% w/v at saturation. Dimethyl- beta-cyclodextrin (DMCD) forms a 43% w/w aqueous solution at saturation. The

SAE-CD can be combined with one or more other cyclodextrins or cyclodextrin derivatives in the ophthalmic solution to solubilize the corticosteroid.

The present invention also provides compositions containing a mixture of cyclodextrin derivatives wherein two or more different types of cyclodextrin derivatives are included in the composition. By different types, is meant cyclodextrins derivatized with different types of functional groups e.g., hydroxyalkyl and sulfoalkyl. Each independent different type can contain one or more functional groups, e.g. SBE-CD where the cyclodextrin ring has only sulfobutyl functional groups, and hydroxypropyl-ethyl-β- CD where the cyclodextrin ring has both hydroxypropyl functional groups and ethyl functional groups. The amount of each type of cyclodextrin derivative present can be varied as desired to provide a mixture having the desired properties.

Other water soluble cyclodextrin derivatives that can be used according to the invention include the hydroxyethyl, hydroxypropyl (including 2- and 3-hydroxypropyl) and dihydroxypropyl ethers, their corresponding mixed ethers and further mixed ethers with methyl or ethyl groups, such as methylhydroxyethyl, ethyl-hydroxyethyl and ethyl- hydroxypropyl ethers of alpha-, beta- and gamma-cyclodextrin; and the maltosyl, glucosyl and maltotriosyl derivatives of alpha, beta- and gamma-cyclodextrin, which may contain one or more sugar residues, e.g. glucosyl or diglucosyl, maltosyl or dimaltosyl, as well as various mixtures thereof, e.g. a mixture of maltosyl and dimaltosyl derivatives. Specific cyclodextrin derivatives for use herein include hydroxypropyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, hydroxyethyl- gamma-cyclodextrin, dihydroxypropyl-beta-cyclodextrin, glucosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin, diglucosyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin, maltosyl -beta-cyclodextrin, maltosyl-gamma-cyclodextrin, maltotriosyl-beta-cyclodextrin, maltotriosyl-gamma-cyclodextrin and dimaltosyl-beta-cyclodextrin, and mixtures thereof such as maltosyl-beta-cyclodextrin/dimaltosyl-beta-cyclodextrin, as well as methyl-beta- cyclodextrin. Procedures for preparing such cyclodextrin derivatives are well-known, for example, from Bodor United States Patent No. 5,024,998 dated June 18, 1991, and references cited therein. Other cyclodextrins suitable for use in the present invention include the carboxyalkyl thioether derivatives such as ORG 26054 and ORG 25969 made by ORGANON (AKZO-NOBEL), hydroxybutenyl ether derivatives made by EASTMAN, sulfoalkyl-hydroxyalkyl ether derivatives, sulfoalkyl-alkyl ether derivatives, and other derivatives as described in US Pregrant Patent Application Publications No.

2002/0128468, No. 2004/0106575, No. 2004/0109888, and No. 2004/0063663, or U.S. Patents No. 6,610,671, No. 6,479,467, No. 6,660,804, or No. 6,509,323.

The HP-β-CD can be obtained from Research Diagnostics Inc. (Flanders, NJ).

HP-β-CD is available with different degrees of substitution. Exemplary products include ENCAPSIN™ (degree of substitution~4; HP4-β-CD) and MOLECUSOL™ (degree of substitution- 8; HP8-β-CD); however, embodiments including other degrees of substitution are also available. Since HPCD is non-ionic, it is not available in salt form.

Dimethyl cyclodextrin is available from FLUKA Chemie (Buchs, CH) or Wacker (Iowa). Other derivatized cyclodextrins suitable in the invention include water soluble derivatized cyclodextrins. Exemplary water-soluble derivatized cyclodextrins include carboxylated derivatives; sulfated derivatives; alkylated derivatives; hydroxyalkylated derivatives; methylated derivatives; and carboxy-β-cyclodextrins, e.g. succinyl-β- cyclodextrin (SCD), and 6 ^A -amino-6 ^A -deoxy-N-(3-carboxypropyl)-β-cyclodextrin. All of these materials can be made according to methods known in the prior art. Suitable derivatized cyclodextrins are disclosed in Modified Cvclodextrins: Scaffolds and Templates for Supramolecular Chemistry (Eds. Christopher J. Easton, Stephen F. Lincoln, Imperial College Press, London, UK, 1999) and New Trends in Cyclodextrins and Derivatives (Ed. Dominique Duchene, Editions de Sante, Paris, France, 1991).

Sulfobutyl ether β-cyclodextrin (CAPTISOL, CyDex Inc., degree of substitution = 6.6), 2-hydroxypropyl β-cyclodextrin (HP-β-CD, CERESTAR, degree of substitution = 5.5), succinylated-β-cyclodextrin (S-CD, Cyclolab), and 2,6,di-o-methyl-β-cyclodextrin (DM-CD, Fluka) %w/w solutions were prepared at their native pH or buffered as needed. Sulfoalkyl ether γ-CD and sulfoalkyl ether α-CD derivatives were obtained from CyDex, Inc. (Lenexa, KS) and The University of Kansas (Lawrence, KS). The amount of derivatized cyclodextrin required to provide the desired effect will vary according to the materials comprising the formulation.

Different cyclodextrins are able to solubilize a corticosteroid to different extents. FIG. 2 depicts a molar phase solubility curve for budesonide with HP-β-CD, SBE7-β-CD, and γ-CD as compared to water. The inventors have found that SAE-CD is superior to other cyclodextrins and cyclodextrin derivatives at solubilizing budesonide. On a molar basis, SBE-β-CD is a better solubilizer of budesonide than HP-β-CD. In addition, the solubilizing power among the SAE-CD derivatives followed about this rank order for

budesonide over a SAE-CD concentration range of 0.04 to 0.1 M: SBE5.2-γ-CD ~ SPE5.4-γ-CD > SBE6.1-γ-CD > SBE7-CC-CD > SBE9.7-γ-CD ~ SBE6.7-β-CD > SPE7-β- CD. For example, a 0.1 M concentration of SBE7-β-CD was able to solubilize a greater amount of budesonide than either γ-CD or HP-β-CD. The formulation of the present invention can be made with other suspension-based aqueous formulations. Exemplary suspension-based aqueous formulations include the UDB formulation (Sheffield Pharmaceuticals, Inc.), VANCENASE™ AQ (beclomethasone dipropionate aqueous suspension; Schering Corporation, Kenilworth, NJ), ATOMASE™ (beclomethasone dipropionate aqueous suspension; Douglas Pharmaceuticals Ltd., Aukland, Australia), BECONASE™ (beclomethasone dipropionate aqueous suspension; Glaxo Wellcome, NASACORT AQ™ (triamcinolone acetonide nasal spray, Aventis Pharmaceuticals), TRI- NASAL™ (triamcinolone acetonide aqueous suspension; Muro Pharmacaceuticals Inc.) and AEROBID-M™, (flunisolide inhalation aerosol, Forest Pharmaceuticals), NASALIDE™ and NASAREL™ (flunisolide nasal spray, Ivax Corporation), FLONASE™ (fluticasone propionate, GlaxoSmithKline), and NASONEX™ (mometasone furoate, Schering-Plough Corporation).

The suspension formulation can comprise corticosteroid present in particulate, microparticulate, nanoparticulate or nanocrystalline form. Accordingly, an SAE-CD can be used to improve the administration of a corticosteroid suspension-based unit dose formulation. Moreover, the SAE-CD outperforms other cyclodextrin derivatives.

According to one embodiment, SAE-CD (in solid or liquid form) and a suspension- based unit dose formulation comprising corticosteroid are mixed. The SAE-CD is present in an amount sufficient to increase the amount of solubilized corticosteroid, i.e. decrease the amount of unsolubilized corticosteroid, therein. Prior to administration, the liquid may be optionally aseptically filtered or terminally sterilized. The liquid is then administered to the eye of a subject. As a result, the amount of drug that the subject receives is higher than the subject would have received had the unaltered suspension formulation been administered.

According to another embodiment, SAE-CD (in liquid form, as ready-to-use liquid or as a concentrate) and a solid unit dose formulation comprising corticosteroid are mixed to form a liquid formulation. The SAE-CD is present in an amount sufficient to solubilize a substantial portion of the corticosteroid. The liquid is then administered ophthalmically.

According to another embodiment, SAE-CD (in solid form) and a solid unit dose formulation comprising corticosteroid are mixed to form a solid mixture to which is added an aqueous liquid carrier in an amount sufficient to form an ophthalmic formulation. Mixing and/or heating are optionally employed upon addition of the liquid carrier to form the formulation. The SAE-CD is present in an amount sufficient to solubilize a substantial portion of the corticosteroid. The formulation is then administered ophthalmically.

The size of the reservoir, in a device containing a formulation of the invention, varies from one type of device to another. The volume of the liquid formulation may be adjusted as needed to provide the required volume for loading into the reservoir of a particular type or brand of device. The volume can be adjusted by adding additional liquid carrier or additional solution containing SAE-CD. In general, the reservoir volume is about 10 μl to 100 ml.

Unless otherwise specified, the term "dose", which is understood to include an effective dose, is taken to mean a nominal dose, administered, nominal available dose, dose to subject, dose to eye of subject, or other such term of art. The term "nominal dose" refers to an amount of corticosteroid placed in the reservoir of a device, wherein the volume of liquid in the reservoir is determined according the size of the reservoir. The term "nominal available dose" refers to the amount of corticosteroid that is determined could be or should have been available to a subject when administered a formulation of the invention but the formulation is/was not administered in its entirety. The term "administered dose" refers to the amount of corticosteroid emitted from a device containing the formulatin. The term "dose to subject" refers to the amount of corticosteroid delivered to and retained by a subject following administration of a formulation of the invention. The term "dose to eye" refers to the amount of corticosteroid delivered to and retained by the eye of a subject following administration of a formulation of the invention.

In general, a single-use suspension-based unit dose formulation of corticosteroid contains about 0.125, 0.25, 0.5, 1, 2, or about 0.125 to about 2 mg of corticosteroid suspended in about 50 μl to 10 ml or about 0.2 to 5 ml or higher of liquid carrier. Alternatively, the corticosteroid is present at a concentration of about 20 meg to about 30 mg of corticosteroid per ml of suspension. As a result, about 10 to 500 mg of SAE-CD, or 10 to 250 mg of SAE-CD, or 10 to 300 mg of SAE-CD, be it in solid form or dissolved in a liquid carrier, is added to each ml the suspension in order to dissolve a substantial

portion of the corticosteroid and form a unit dose liquid formulation that is then administered to a subject.

The formulation, method or system can employ a dose of about 1 μg to 20 mg, 1 μg to 10 mg, 0.01 mg to 10 mg, 0.025 mg to 10 mg, 0.05 mg to 5 mg, 0.1 mg to 5 mg, 0.125 mg to 5 mg, 0.25 mg to 5 mg, 0.5 mg to 5 mg, 0.05 mg to 2 mg, 0.1 mg to 2 mg, 0.125 mg to 2 mg, 0.25 mg to 2 mg, 0.5 mg to 2 mg of corticosteroid. These dose amounts are suitable for the corticosteroids of the invention, in particular corticosteroids that are as lipophilic as or more lipophilic than flunisolide, which corticosteroids include beclomethasone, beclomethasone dipropionate, beclomethasone monopropionate, budesonide, ciclesonide, desisobutyryl-ciclesonide, flunisolide, fluticasone, fluticasone propionate, mometasone, mometasone furoate.

The formulation of the invention comprises a dose of corticosteroid in an approximate solution volume of 10 μl to 100 ml, 50 μl to 50 ml, 50 μl to 10 ml, 0.1 to 10 ml, 0.1 ml to less than 10 ml, 0.1 ml to 7.5 ml, 0.1 ml to 5 ml, 0.1 ml to 3 ml, 0.1 ml to 2 ml, 0.1 ml to 1 ml, 0.05 ml to 7.5 ml, 0.05 ml to 5 ml, 0.05 ml to 3 ml, 0.05 ml to 2 ml, or 0.05 ml to 1 ml.

Due to the wide range of reservoir volumes available and of varying dose requirements among the corticosteroids, a formulation of the invention can comprise 1 μg to 20 mg of corticosteroid in 0.01 ml to 100 ml of solution volume. In general, a multi-use suspension-based unit dose formulation of corticosteroid contains approximately 0.125 to 2 mg of corticosteroid suspended in 1 to 100 ml of liquid carrier. A multi-use formulation actually contains two or more unit doses of corticosteroid. Single unit dose aliquots are taken from a multi-use unit dose formulation, and the single unit dose are typically administered one-at-a-time to a subject. As a result, about 10 to 500 mg of SAE-CD, be it in solid form or dissolved in a liquid carrier, is added to each ml the suspension in order to dissolve a substantial portion of the corticosteroid and form a multi-use unit dose liquid formulation that is then administered to a subject in single unit dose aliquots.

One aspect of the invention is that a suspension-based unit dose formulation is converted to a liquid unit dose formulation prior to to a subject. The conversion can take place in the same container in which the suspension is provided or in a different container. In order to form a liquid formulation, a substantial portion of the corticosteroid must be dissolved. As used in reference to the amount of dissolved corticosteroid, a "substantial

portion" is at least 20% wt, at least 30% wt, at least 40% wt, or at least 20% wt and less than 50% wt. of the corticosteroid. As used in reference to the amount of dissolved corticosteroid, a "major portion" is at least 50% wt. of the corticosteroid.

It is well known that pharmacists working in compounding pharmacies can and do prepare a suspension-based unit dose formulation comprising corticosteroid. Such pharmacists will now be able to prepare a single use or multi-use liquid unit dose formulation by employing a method described herein. Alternatively, a subject (patient) undergoing corticosteroid treatment may convert the suspension-based formulation to a liquid formulation of the invention by employing a method described herein. Instead of preparing the liquid formulation from the suspension at the pharmacy, a kit containing the suspension formulation and SAE-CD can be prepared.

The concentration of SAE-CD in solution can be expressed on a weight to weight or weight to volume basis; however, these two units are interconvertible. When a known weight of cyclodextrin is dissolved in a known weight of water, the %w/w cyclodextrin concentration is determined by dividing the cyclodextrin weight in grams by the total weight (cyclodextrin + water weight) in like units and multiplying by 100. When a known weight of cyclodextrin is dissolved to a known total volume, the %w/v cyclodextrin concentration is determined by dividing the cyclodextrin weight in grams by the total volume in milliliters and multiplying by 100. The correlation between the two cyclodextrin concentration percentages was experimentally determined by preparing various %w/w cyclodextrin solutions and measuring the density of each with a pycnometer at 25°C. The density (g/mL) of each %w/w CAPTISOL solution is presented in the table below.

The resulting linear relationship readily enables the conversion of CAPTISOL concentrations expressed in %w/w to that of %w/v by the following equation:

%w/v = ((%w/w * slope) + y-intercept) * %w/w where the slope and intercept values are determined from a linear regression of the density data in the table. For example, by using the above equation, a 40%w/w CAPTISOL solution would be equivalent to a -48.3% w/v CAPTISOL solution.

The performance of a solution of the invention may depend upon the viscosity of the solution. The viscosity of an aqueous solution of SBE7-β-CD changes with respect to concentration approximately as indicated in the table above. Viscosity of the solution can have an impact on percentage of composition emitted from a device.

An in vivo study according to Example 17 was conducted in rabbits to compare the ability of budesonide to provide an anti-inflammatory therapeutic effect or other clinical benefit. A solution formulation of the invention was compared to a suspension-based formulation of budesonide. As part of an ocular wound healing study, rabbits were subject to right-eye injury using a laser to irritate the corneal surface. The anti-inflammatory effect of four samples (A- 4% CAPTISOL in saline; B- PULMICORT RESPULES suspension of budesonide (250 mcg/ml); C- 1% Prednisolone acetate ophthalmic solution (PRED FORTE); D- CAPTISOL ENABLED budesonide solution containing 250 meg of budesonide/ml). Animals were divided into four corresponding groups. An aliquot (40 μl) of sample solution was applied (four times per day) to each eye of each rabbit within a group for a period of three days. The right eye of each rabbit was then injured with a laser and followed with QID administration of sample solution to each eye. The eyes were

examined for injury and recovery for seven days following injury. The results are summarized below.

1. Average score of 4 animals. Day 0: the day injury was induced. 2 Group 2 and 3 each had one animal scored as 1+, all others were 0.

Slit lamp examinations revealed aqueous flare, conjunctivitis, iritis, and/or superficial keratitis of the right eye following the laser injury in all animals. Aqueous flare had resolved by Day 3 in all animals but one in the Pulmicort Respules group.

Decreased eye pressure in the right eye was observed in all animals following laser injury on Day 0. Eye pressure returned to normal values in the CAPTIS OL-ENAB LED budesonide solution group by Day 1, and in CAPTISOL vehicle controls, Pulmicort Respules, and PRED FORTE by Day 3, 7, and 3, respectively. The results are summarized in the table below and in FIGS. 9a and 9b. Eye Pressure (Mean±SD)

The results showed that CE-Budesonide solution effectively reduced inflammatory reactions following laser injury to the iris of rabbits. The resolution of laser-induced eye injury by Captisol-enabled Budesonide occurs more rapidly than by either PULMICORT RESPULES, or PRED FORTE. Intraocular pressure returned to normal values more quickly in the CE-Budesonide solution treatment group than in all other treatment groups and the vehicle control.

Accordingly, the invention provides an improved method for the treatment of inflammation caused by injury to the eye of a subject comprising administering to an inflamed and injured eye of a subject, the eye having a less than normal intraocular pressure, an aqueous liquid formulation comprising a therapeutically effective dose of corticosteroid, sulfoalkyl ether cyclodextrin, and aqueous liquid carrier, the improvement comprising providing a faster resolution of intraocular pressure to normal intraocular pressure as compared to treatment with an aqueous suspension formulation comprising substantially the same therapeutically effective dose of corticosteroid and aqueous liquid carrier but excluding the sulfoalkyl ether cyclodextrin. In some embodiments, the suspension formulation excludes a cyclodextrin, surfactant, and/or organic solvent.

By virtue of the use of sulfoalkyl ether cyclodextrin to dissolve a corticosteroid according to the invention, the composition or formulation of the invention will provide an improved therapeutic benefit or improved clinical benefit over an equivalent dose of corticosteroid administered as an aqueous suspension.

In some aspects, the method and dosage form of the invention thus provides an improved method of administering a corticosteroid suspension-based unit dose, the method comprising the step of adding a sufficient amount of SAE-CD to convert the

suspension to a clear solution and then administering the clear solution to a subject. As a result, the method of the invention provides increased total delivery of the corticosteroid as well as increased rate of administration as compared to the initial unit dose suspension formulation. The corticosteroids that are useful in the present invention generally include any steroid produced by the adrenocortex, including glucocorticoids and mineralocorticoids, and synthetic analogs and derivatives of naturally occurring corticosteroids having antiinflammatory activity. Suitable synthetic analogs include prodrugs, ester derivatives Examples of corticosteroids that can be used in the compositions of the invention include aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide (Altana Pharma AG), cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, rofleponide, RPR 106541, tixocortol, triamcinolone, and their respective pharmaceutically acceptable derivatives, such as beclomethasone dipropionate (anhydrous or monohydrate), beclomethasone monopropionate, dexamethasone 21-isonicotinate, fluticasone propionate, icomethasone enbutate, tixocortol 21-pivalate, and triamcinolone acetonide. Particularly preferred are compounds such as beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, mometasone furoate, and triamcinolone acetonide. Other corticosteroids not yet commercialized, but that are commercialized subsequent to the filing of this application, are considered useful in the present invention unless it is otherwise established experimentally that they are not suitable. Corticosteroids can be grouped according to their relative lipophilicity as described by Barnes et al. (Am. J. Respir. Care Med. (1998), 157, p. S1-S53), Miller-Lars son et al. (Am J. Respir. Crit. Care Med. (2003), 167, A773), D.E. Mager et al. (J. Pharm. ScL (Nov. 2002), 91(11), 2441-2451) or S. Edsbacker (Uptake, retention, and biotransformation of corticosteroids in the lung and airways. In: Schleimer RP, O'Byrne PMO, Szefler SJ, Brattsand R, editor(s). Inhaled steroids in asthma: optimizing effects in the airways. New York: Marcel Dekker, 2002: 213-246). Generally, the less lipophilic a corticosteroid is, the lower the amount of SAE-CD required to dissolve it in an aqueous medium and vice versa. Corticosteroids that are less lipophilic than flunisolide generally

require a SAE-CD to corticosteroid molar ratio of less than 10:1 to dissolve the corticosteroid in an aqueous medium. Exemplary corticosteroids of this group include hydrocortisone, prednisolone, prednisone, dexamethasone, betamethasone, methylprednisolone, triamcinolone, and fluocortolone. Some embodiments of the invention exclude corticosteroids that are less lipophilic than flunisolide.

Corticosteroids that are at least as lipophilic as or more lipophilic than flunisolide generally require a SAE-CD to corticosteroid molar ratio of more than 10:1 to dissolve the corticosteroid in an aqueous medium. In some embodiments, the corticosteroid used in the invention is at least as lipophilic as or more lipophilic than flunisolide. Exemplary corticosteroids of this group include beclomethasone, beclomethasone dipropionate, beclomethasone monopropionate, budesonide, ciclesonide, desisobutyryl-ciclesonide, flunisolide, fluticasone, fluticasone propionate, mometasone, mometasone furoate, triamcinolone acetonide.

The suitability of a corticosteroid for use in the liquid composition/formulation can be determined by performing a phase solubility binding study as detailed in Example 22. Phase solubility binding data is used to determine the saturated solubility of a corticosteroid in the presence of varying amounts of SAE-CD in an aqueous liquid carrier. The phase solubility binding curve depicted in FIG. 2 demonstrates the saturated solubility of budesonide in an aqueous liquid carrier comprising γ-CD, HP-β-CD or SBE7-β-CD. A phase solubility curve in the graph defines the boundary for the saturated solubility the corticosteroid in solutions containing various different concentrations of cyclodextrin. A molar phase solubility curve can be used to determine the molar ratio of SAE-CD to corticosteroid or of corticosteroid to SAE-CD at various concentrations of corticosteroid. The area below the phase solubility curve, e.g. of FIG. 2, denotes the region where the corticosteroid is solubilized in an aqueous liquid medium to provide a substantially clear aqueous solution. In this region, the SAE-CD is present in molar excess of the corticosteroid and in an amount sufficient to solubilize the corticosteroid present in the liquid carrier. The boundary defined by the phase solubility curve will vary according to the corticosteroid and SAE-CD within a composition or formulation of the invention. The table below provides a summary of the minimum molar ratio of SAE-CD to corticosteroid required to achieve the saturated solubility of the corticosteroid in the composition or formulation of the invention under the conditions studied.

*This value was determined in the presence of SAE-CD under the conditions detailed in Examples 18, 23 accompanying the solubility values presented in the preceding and following text.

The saturated solubility of a corticosteroid in the presence of a fixed amount of SAE-CD will vary according to the identity of the corticosteroid and the SAE-CD. The table below summarizes some solubility data for the listed corticosteroids in the absence (intrinsic solubility of corticosteroid in the aqueous test medium) and in the presence of two different SAE-CD' s as determined herein.

The above data can be used in combination with the phase solubility data to prepare formulations according to the invention having a target concentration of corticosteroid and SAE-CD. Accordingly, some embodiments of the invention comprise a corticosteroid having an intrinsic solubility in water that approximates or is less than the intrinsic solubility of flunisolide (less than about HxIO ^"5 M or less than about 11.3 xlO ^"5 M) in water as determined herein.

Even though a composition or formulation of the invention can comprise the corticosteroid present in an aqueous medium at a concentration up to its saturated solubility in the presence of a particular concentration of SAE-CD, some embodiments of the invention include those wherein the corticosteroid is present at a concentration that is less than its saturated solubility in the presence of that concentration of SAE-CD. The corticosteroid can be present at a concentration that is 95% or less, 90% or less, 85% or less, 80% or less, or 50% or less of its saturated solubility as determined in the presence of SAE-CD. It is generally easier to prepare solutions that comprise the corticosteroid at a concentration that is less than its saturated solubility in the presence of SAE-CD.

Therefore, the molar ratio of SAE-CD to corticosteroid in a formulation or composition of the invention can exceed the molar ratio obtained at the saturated solubility of the corticosteroid in the presence of SAE-CD, such as defined by the phase solubility binding curve for the corticosteroid. In such a case, the molar ratio of SAE-CD to

corticosteroid in the composition or formulation will be at least 1%, at least 2%, at least 5%, at least 7.5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 50%, at least 75%, at least 100% , or at least 200% greater than the molar ratio at the saturated solubility of the corticosteroid in the presence of SAE-CD. For example, if the molar ratio at the saturated solubility is about 14:1, then the molar ratio in the composition or formulation can be at least 14.1:1 (for at least 1% higher), at least 14.3:1 (for at least 2% higher), at least 14.7:1 (for at least 5% higher), at least 15.4:1 (for at least 10% higher), at least 16.1:1 (for at least 15% higher), at least 16.8:1 (for at least 20% higher), at least 17.5:1 (for at least 25% higher), at least 21:1 (for at least 50% higher), at least 24.5:1 (for at least 75% higher), at least 28:1 (for at least 100% higher), or at least 42:1 (for at least 100% higher).

Changes in the molar ratio of SAE-CD to corticosteroid can also have an impact upon the dissolution rate of corticosteroid in an aqueous medium. A study was conducted on a roller mixer having containers with solutions containing varying amounts of SAE- CD, e.g. CAPTISOL, and a fixed amount of fluticasone propionate or mometasone furoate. The samples were prepared by mixing the corticosteroid with a solution containing the SAE-CD in a vortexer for about 30 seconds and then placing the containers on the roller mixer. Aliquots were taken periodically from each container and the amount of dissolved corticosteroid was determined. The SAE-CD to corticosteroid molar ratios used were 10:1, 14:1, and 20:1. The data indicate that increasing the molar ratio resulted in an increase in the rate of dissolution of the corticosteroid.

The corticosteroid compound is present in the final, diluted corticosteroid composition adapted for ophthalmic administration in an amount from about 1 μg/ml to about 10 mg/ml, about 10 μg/ml to about 1 mg/ml, or about 20 μg/ml to about 500 μg/ml. For example, the drug concentration can be between about 30 and 1000 μg/ml for triamcinolone acetonide, and between about 50 and 2000 μg/ml for budesonide, depending on the volume to be administered. By following the preferred methods of the present invention, relatively high concentrations of the corticosteroid can be achieved in an aqueous-based composition. Similarly, the corticosteroid compound is present in the final, diluted corticosteroid composition designed for nasal administration in an amount from about 10 μg/ml to 6 mg/ml, 50 μg/ml to about 10 mg/ml, about 100 μg/ml to about 2 mg/ml, or about 300

μg/ml to about 1 mg/ml. For example, the drug concentration can be between about 250 μg/ml and 1 mg/ml or 250 μg/ml and 6 mg/ml for triamcinolone acetonide, and between about 400 μg/ml and 1.6 mg/ml or 250 μg/ml and 6 mg/ml for budesonide, depending on the volume to be administered. For the treatment of disorders and diseases of the eye, the diluted corticosteroid composition is prepared as described herein. The corticosteroid for such treatment is preferably, beclomethasone dipropionate, beclomethasone monopropionate, betamethasone, budesonide, ciclesonide, desisobutyryl-ciclesonide, dexamethasone, flunisolide, fluorometholone, fluticasone, fluticasone propionate, fluticasone furoate, hydrocortisone, medrisone, mometasone, mometasone furoate, predinisolone, or triamcinolone acetonide, and is formulated in the concentrations set forth herein. The daily dose of the corticosteroid is generally about 0.0025 to 10 mg, 0.005 to 1 mg, 0.01 to 0.5 mg, depending on the drug and the disease, in accordance with the Physician's Desk Reference (PDR). However, in view of the improved bioavailability of a corticosteroid when administered as a solution of the invention, the dose required to achieve a desired clinical endpoint, clinical benefit or therapeutic benefit may be lower than the corresponding dose indicated in the PDR.

A unit dose of budesonide may also be administered once daily, once every two days, once every week, once every month, or even less frequently, wherein a dose comprises 0.05 to 2.0 mg or 0.25 to 1.0 mg of budesonide. Administration can be during the daytime and/or nighttime. A dose of budesonide, or corticosteroid, can be administered twice, thrice or more times per day or on an as-needed basis.

In some embodiments, a dose comprises 1 μg to 20 mg, 0.01 mg to 10 mg, 0.025 mg to 10 mg, 0.05 mg to 5 mg, 0.1 mg to 5 mg, 0.125 mg to 5 mg, 0.25 mg to 5 mg, 0.5 mg to 5 mg, 0.05 mg to 2 mg, 0.1 mg to 2 mg, 0.125 mg to 2 mg, 0.25 mg to 2 mg, 0.5 mg to 2 mg, 1 μg, 10 μg, 25 μg, 50 μg, 100 μg, 125 μg, 200 μg, 250 μg, 25 to 66 μg, 48 to 81 μg, 73 to 125 μg, 40 μg, 64 μg, 95 μg, 35 to 95 μg, 25 to 125 μg, 60 to 170 μg, 110 μg, 170 μg, 45 to220 μg, 45 to 85 μg, 48 to 82 μg, 85 to 160 μg, 140 to 220 μg, 120 to 325 μg, 205 μg, 320 μg, 325 μg, 90 to 400 μg, 95 to 170 μg, 165 to 275 μg, or 275 to 400 μg of budesonide, said dose being a nominal dose, nominal available dose, emitted dose, delivered dose, dose to subject, or dose to eye.

The corticosteroid can be present in its neutral, ionic, salt, basic, acidic, natural, synthetic, diastereomeric, isomeric, isomeric, enantiomerically pure, racemic, solvate, anhydrous, hydrate, chelate, derivative, analog, esterified, non-esterfied, or other common form. Whenever an active agent is named herein, all such forms available are included. For example, all known forms of budesonide are considered within the scope of the invention.

The formulation of the invention can be used to deliver two or more different active agents (active ingredients, therapeutic agents, etc.). Particular combinations of active agents can be provided by the present formulation. Some combinations of active agents include: 1) a first drug from a first therapeutic class and a different second drug from the same therapeutic class; 2) a first drug from a first therapeutic class and a different second drug from a different therapeutic class; 3) a first drug having a first type of biological activity and a different second drug having about the same biological activity; 4) a first drug having a first type of biological activity and a different second drug having a different second type of biological activity. Exemplary combinations of active agents are described herein.

A corticosteroid, such as budesonide, can be administered in combination with one or more other drugs (active ingredients, therapeutic agents, active agents, etc., the terms being used interchangeably herein unless otherwise specified). Such other drugs include: adrenoreceptor agonist agent; adrenoreceptor antagonist agent, topical anesthetic, anticholinergic agent, antihistamine agent; antibiotic agent; antifungal agent; antiinfective agent; antiviral agent; antitumor agent; non-steroidal anti-inflammatory agent; growth factor agent; cholinergic agonist agent; adrenergic agonist agent, adrenergic antagonist agent; chemotherapeutic agent; anticancer agent; antitumor agent, mydriatic agent, cycloplegic agent, prostaglandin, parasymptomimetic agent, carbonic anhydrase inhibitor, calcium channel blocker, cytokine, diagnostic agent.

B ₂ - Adrenoreceptor agonists for use in combination with the compositions provided herein include, but are not limited to, Albuterol (alpha ¹ -(((l,l dimethylethyl)amino)methyl)-4-hydroxy- 1 ,3-benzenedimethanol) ; Bambuterol (dimethylcarbamic acid 5-(2-((l,l-dimethylethyl)amino)-l-hydroxyethyl)-l,3-phenylen e ester); Bitolterol (4-methylbenzoic acid 4-(2-((l,l-dimethylethyl)amino)-l-hydroxyethyl)- 1,2-phenyleneester); Broxaterol (3-bromo-alpha-(((l,l-dimethylethyl)amino)methyl)-5- isoxazolemethanol); Isoproterenol (4-(l-hydroxy-2-((l-methylethyl- )amino)ethyl)-l,2-

benzene-diol); Trimetoquinol (l,2,3,4-tetrahydro-l-((3,4- , 5 -trimethoxyphenyl) -methyl) - 6,7-isoquinolinediol); Clenbuterol (4-amino-3,5-dichloro-alpha-(((l,l- diemthylethyl) amino)methyl)benzenemethanol) ; Fenoterol (5 - ( 1 -hydroxy-2- ( (2- (4- hydroxyphenyl)- 1 -methylethyl)amino)ethyl)- 1 ,3-benzenediol) ; Formoterol (2-hydroxy-5- ((lRS)-l-hydroxy-2-(((lRS)-2-(p-methoxyphenyl)-l-methylethyl )amino)ethyl) formanilide); (R,R)-Formoterol; Desforaioterol ((R,R) or (S,S)-3-amino-4-hydroxy-alpha- (((2-(4-methoxyphenyl)-l-methyl-ethyl)amino)methyl)benzeneme thanol); Hexoprenaline (4,4'-(l,6-hexane-diyl)-bis(imino(l -hydroxy-2, l-ethanediyl)))bis-l,2-benzenediol); Isoetharine (4-( 1 -hydroxy-2-(( 1 -methylethyl)amino)butyl)- 1 ,2-benzenediol) ; Isoprenaline (4-(l-hydroxy-2-((l-methylethyl)amino)ethyl)-l,2-benzenediol ); Meta-proterenol (5-(l- hydroxy-2-((l-methylethyl)amino)ethyl)-l,3-benzened- iol); Picumeterol (4-amino-3,5- dichloro-alpha-(((6-(2-(2-pyridinyl)ethoxy)hexyl)-amino)meth yl) benzenemethanol);

Pirbuterol (.alpha. ⁶ -(((l,l-dimethylethyl)-amino)methyl)-3-hydroxy-2,6- pyridinemethanol); Procaterol (((R*,S*)-(.+-.)-8-hydroxy-5-(l-hydroxy-2-((l- methylethyl)amino)butyl)-2(lH)-quinolin-one); Reproterol ((7-(3-((2-(3,5- dihydroxyphenyl)-2-hydroxyethyl)amino)-propyl)-3,7-dihydro- 1 ,3-dimethyl- lH-purine- 2,6-dione); Rimiterol (4-(hydroxy-2-piperidinylmethyl)-l,2-benzenediol); Salbutamol ((.+-. )-alpha ¹ -((( 1 , l-dimethylethyl)amino)methyl)-4-hydroxy- 1 ,3-b- enzenedimethanol); (R)-S albutamol ; S almeterol ((.+-.) -4-hydroxy- . alpha ^l - ( ((6 - (4-phenylbutoxy)hexyl) - amino)methyl)-l,3-benzenedimethanol); (R)-Salmeterol; Terbutaline (5-(2-((l,l- dimethylethyl)amino)-l-hydroxyethyl)-l,3-benzenediol); Tulobuterol (2-chloro-. alpha. - (((1,1 -dimethylethyl)amino)methyl)benzenemethanol); and TA-2005 (8-hydroxy-5-((lR)- l-hydroxy-2-(N-((lR)-2-(4-methoxyphenyl)-l-methylethyl)amino )ethyl)carbostyril hydrochloride). Anticholinergic agents for use herein include, but are not limited to, ipratropium bromide, oxitropium bromide, atropine methyl nitrate, atropine sulfate, ipratropium, belladonna extract, scopolamine, scopolamine methobromide, homatropine methobromide, hyoscyamine, isopriopramide, orphenadrine, benzalkonium chloride, tiotropium bromide and glycopyrronium bromide. In certain embodiments, the compositions contain an anticholinergic agent, such as ipratropium bromide or tiotropium bromide, at a concentration of about 5 μg/mL to about 5 mg/mL, or about 50 μg/mL to about 200 μg/mL. In other embodiments, the compositions for use in the methods herein

contain an anticholinergic agent, including ipratropium bromide and tiotropium bromide, at a concentration of about 83 μg/mL or about 167 μg/mL.

Other active ingredients for use herein in combination therapy, include, but are not limited to, IL-5 inhibitors such as those disclosed in U.S. Patents No. 5,668,110, No. 5,683,983, No. 5,677,280, No. 6,071,910 and No. 5,654,276, the relevant disclosures of which are hereby incorporated by reference; antisense modulators of IL-5 such as those disclosed in U.S. Pat. No. 6,136,603, the relevant disclosure of which is hereby incorporated by reference; milrinone (l,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5- carbonitrile); milrinone lactate; tryptase inhibitors such as those disclosed in U.S. Pat. No. 5,525,623, the relevant disclosure of which is hereby incorporated by reference; tachykinin receptor antagonists such as those disclosed in U.S. Patents No. 5,691,336, No. 5,877,191, No. 5,929,094, No. 5,750,549 and No. 5,780,467, the relevant disclosures of which are hereby incorporated by reference; leukotriene receptor antagonists such as montelukast sodium (Singular™., R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethenyl- ]phenyl]-3-[2-(l-hydroxy-l-methylethyl)phenyl]-propyl]thio]m ethyl] cyclopro- paneacetic acid, monosodium salt), 5-lypoxygenase inhibitors such as zileuton (Zyflo™, Abbott Laboratories, Abbott Park, 111.), and anti-IgE antibodies such as Xolair™ (recombinant humanized anti-IgE monoclonal antibody (CGP 51901; IGE 025 A; rhuMAb-E25), Genentech, Inc., South San Francisco, Calif.), and topical anesthetics such as lidocaine, N- arylamide, aminoalkylbenzoate, prilocaine, etidocaine (U.S. Patents No. 5,510,339, No. 5,631,267, and No. 5,837,713, the relevant disclosures of which are hereby incorporated by reference).

Exemplary combination formulations of the invention can comprise the following components.

A formulation comprising a corticosteroid and another active ingredient can be prepared according to the examples below. In one embodiment, the SAE-CD is present in an amount sufficient to solubilize the corticosteroid and the other active ingredient. In another embodiment, the SAE-CD is present in an amount sufficient to solubilize the corticosteroid or the other active ingredient.

Depending upon the other active ingredient used, it may or may not bind competitively against the corticosteroid with the SAE-CD. In some embodiments, the SAE-CD has a higher equilibrium binding constant for the other active ingredient than it has for the corticosteroid. In some embodiments, the SAE-CD has a higher equilibrium binding constant for the corticosteroid than it has for the other active ingredient. In some embodiments, the SAE-CD has approximately the same equilibrium binding constant for the other active ingredient as it has for the corticosteroid. Alternatively, the other active ingredient does not bind with the SAE-CD even though the corticosteroid does. Accordingly, the invention provides embodiments wherein, the SAE-CD solubilizes the corticosteroid, the other active ingredient, or a combination thereof. The invention also provides embodiments wherein, the SAE-CD solubilizes at least a major portion of the corticosteroid, the other active ingredient, or of each. The invention also provides embodiments wherein, the SAE-CD does not solubilize the other active ingredient. The molar ratio of SAE-CD to corticosteroid and SAE-CD to other active ingredient can vary as needed to provide a combination formulation as described herein. The SAE-CD is generally present in molar excess over the corticosteroid, the other active ingredient, or both.

The invention includes methods for the treatment, prevention, or amelioration of one or more symptoms of a corticosteroid-responsive disorder, a disease, symptom or disorder of the eye. Diseases, symptoms, or disorders that are therapeutically responsive to ophthalmic administration of a corticosteroid include, by way of example and without

limitation, inflammation, inflammation caused by injury or trauma to the eye, glaucoma, macular cistoid edema, uveitis, diabetic retinopathy, conjunctivitis, post-surgical trauma, dry eye, filamentary keratitis, delayed tear clearance, pain, keratoconjunctival dryness, keratoconjunctivitis sicca, lesions/tumors of the eye, infectious processes of the eye, bacterial infections, viral infections, glaucoma, blepharitis, blepharoconjunctivitis, and other diseases or disorders.

The method further includes administering a corticosteroid simultaneously with, prior to, or subsequent to administration of one or more of the following second therapeutic agents: adrenoreceptor agonist agent; adrenoreceptor antagonist agent; topical anesthetic; anticholinergic agent; antihistamine agent; antibiotic agent; antifungal agent; antiinfective agent; antiviral agent; antitumor agent; non-steroidal anti-inflammatory agent; growth factor agent; cholinergic agonist agent; adrenergic agonist agent, adrenergic antagonist agent; chemotherapeutic agent; anticancer agent; antitumor agent; mydriatic agent; cycloplegic agent; prostaglandin; parasymptomimetic agent; carbonic anhydrase inhibitor; calcium channel blocker; cytokine; diagnostic agent..

Embodiments of the present invention allow for combinations to be prepared in a variety of ways:

1) Mixing ready to use solutions of a β2-agonist such as levalbuterol or anticholinergic such as ipatropium bromide with a ready to use solution of a corticosteroid in SAE-CD;

2) Mixing ready to use solutions of a second therapeutic agent with a concentrated solution of a corticosteroid dissolved using SAE-CD;

3) Mixing a ready to use solution of a second therapeutic agent with substantially dry SAE-CD and a substantially dry corticosteroid; 4) Mixing a ready to use solution of a second therapeutic agent with a substantially dry mixture of SAE-CD and a corticosteroid or more conveniently a pre-measured amount of the mixture in a unit container such as a capsule (empty a capsule into ready to use solution);

5) Mixing a ready to use solution of a corticosteroid such as budesonide with a substantially dry second therapeutic agent; or

6) Dissolving a substantially dry second therapeutic agent and a substantially dry SAE-CD plus a substantially dry corticosteroid.

The materials used herein can be used in micronized or non-micronized form and crystalline, polymorphic or amorphous form. This is particularly true of the corticosteroids and other active ingredients.

It is well understood by those of ordinary skill in the art that the above solutions or powders may optionally contain other ingredients such as buffers and/or tonicity adjusters and/or antimicrobials and/or additives or other such excipients as set forth herein or as presently used in liquid formulations to improve the clinical benefit provided by an ophthalmic formulation.

Dosing, use and administration of the therapeutic agents disclosed herein is generally intended to follow the guidelines set forth in the Physician's Desk Reference, 61 ^th Edition (Thompson Healthcare, Montvale, NJ, 2005) the relevant disclosure of which is hereby incorporated by reference.

A formulation according to the invention will generally have a storage shelf life of no less than 6 months. In this case, shelf life is determined only as regards the increase in the amount of corticosteroid degradation by-products or a reduction in the amount of corticosteroid remaining in the formulation. For example, for a formulation having a shelf life of at least six months, the formulation will not demonstrate an unacceptable and substantial increase in the amount of degradants during the storage period of at least six months. The criteria for acceptable shelf- life are set as needed according to a given product and its storage stability requirements. In other words, the amount of degradants in a formulation having an acceptable shelf-life will not increase beyond a predetermined value during the intended period of storage. On the other hand, the amount of degradants of a formulation having an unacceptable shelf-life will increase beyond the predetermined value during the intended period of storage. The method of Example 3 was followed to determine the stability of budesonide in solution. The shelf-life was defined as the time to loss of 10% potency. Under the conditions tested, the loss of potency was first order. The shelf life of a Captisol- Enabled® Budesonide Solution (a solution comprising budesonide and SBE7-β-CD) is greater than about 3 years at a pH between 4 and 5, i.e. about 90 months at pH 4.0 and about 108 months at pH 5.0 without the need to add any other stabilizers, such as EDTA, in water in the presence of about 5% wt./vol. SAE-CD. This shelf-life is greater than that reported by Otterbeck (U.S. Patent 5,914,122; up to six weeks at pH 4.0-6.0 in water in the presence of EDTA, HP-β-CD and other additives.)

The inventors have also discovered that SAE-CD is capable of stabilizing the isomers of budesonide to different extents. A study to determine if SBE7-β-CD stabilized budesonide solutions and if it preferentially stabilized one isomer was conducted according to Example 13. Figure 3 is a semi-log plot of the % of initial concentration at each time point for the samples stored at 60 °C. Loss of budesonide was first order at each temperature. The table below shows the pseudo-first order rate constants calculated for each isomer at 60 °C and 80 °C.

Pseudo 1 ^st Order Rate constant (hours ^' )

Temperature 60 ⁰ C

With/without With/without

Rate CAPTISOL Rate CAPTISOL R/S rate

Ph constant ratio for constant ratio for constant R-isomer R-isomers S-isomer S-isomers ratio

4 w/ 0.000597 0.00012 5.06 CAPTISOL 0.547 0.323

4 no 0.00109 0.0037 2.99 CAPTISOL

6 w/ 0.001661 0.000361 4.60 CAPTISOL

0.385 0.193

6 no 0.00432 0.001872 2.31 CAPTISOL

SBE7-β-CD stabilized both R- and S-isomers of budesonide in solutions at both pH 4 and 6. The with/without CAPTISOL ratio of rate constants was much less than 1 at all temperatures. SBE7-β-CD had a greater effect on the stability of both the R and S- isomer at pH 6 than at pH 4. At a given temperature the ratio of rate constants

with/without SBE7-β-CD was less at pH 6 than at pH 4. Although SBE7-β-CD stabilized both isomers, the S-isomer appears to be stabilized to an even greater extent than the R. At all temperatures and pHs tested, the ratio of rate constants with/without SBE7-β-CD was lower for the S isomer. The degree of stabilization affected by SBE7-β-CD at 60 ⁰ C is greater than at 80 ⁰ C. An even greater degree of stabilization would be expected at 40 ⁰ C and/or room temperature (20-30 C).

Samples of the above solutions were also placed in a chamber under a bank of fluorescent lights. Vials were periodically removed and assayed for budesonide. Figure 4 shows the semi-log plot of the % of initial value remaining as a function of light exposure (light intensity * time). As noted in the table below, SBE7-β-CD significantly reduced the photodecomposition of budesonide. The loss of budesonide was first order and independent of pH.

The formulation of the invention can be provided as a kit adapted to form an ophthalmic solution. The kit can comprise a corticosteroid, SAE-CD, an aqueous carrier, and optionally one or more other components. The corticosteroid and SAE-CD can be provided together or separately in solid, suspended or dissolved form. After mixing SAE- CD with corticosteroid in the presence of an aqueous carrier, the solids will dissolve to form a solution rather than suspension. Each component can be provided in an individual container or together with another component. For example, SAE-CD can be provided in an aqueous solution while budesonide is provided in dry solid form or wet suspended form. Alternatively, SAE-CD is provided in dry form and budesonide is provided as an aqueous suspension, e.g., PULMICORT RESPULES™. The kit can instead comprise an admixture of a solid derivatized cyclodextrin and solid corticosteroid and, optionally, at least one solid pharmaceutical excipient, such that a major portion of the active agent is not complexed with the derivatized cyclodextrin prior to reconstitution of the admixture with an aqueous carrier. Alternatively, the composition can comprise a solid mixture

comprising the inclusion complex of a derivatized cyclodextrin and an active agent, wherein a major portion of the active agent is complexed with the derivatized cyclodextrin prior to reconstitution of the solid mixture with an aqueous carrier. Depending upon the storage temperature of the kit, the aqueous carrier may be a liquid or frozen solid. In one embodiment, the kit excludes the aqueous carrier during storage, but the aqueous carrier is added to the SAE-CD and corticosteroid prior to use to form the ophthalmic solution. The corticosteroid and SAE-CD can be complexed and present in aqueous concentrated form prior to addition of the aqueous carrier, which is later added to bring the solution to volume and proper viscosity and concentration. A reconstitutable formulation can be prepared according to any of the following processes. A liquid formulation of the invention is first prepared, then a solid is formed by lyophilization (freeze-drying), spray- drying, spray freeze-drying, antisolvent precipitation, various processes utilizing supercritical or near supercritical fluids, or other methods known to those of ordinary skill in the art to make a solid for reconstitution. Example 24 details a method for the preparation of a lyophilized solid composition comprising corticosteroid and SAE-CD by lyophilization of a liquid composition or formulation of the invention. The lyophilized solid can be dissolved in an aqueous liquid carrier prior to administration. The dried powder would provide a stable form for long-term storage and would also be useful to rapidly prepare ophthalmic compositions on a larger scale, or as an additive to another ophthalmic solution medication to prepare combination products.

While the liquid composition or formulation of the invention can be administered to the eye, it would also be suitable for nasal, oral, pulmonary, otic or topical administration. The liquid composition or formulation may also be administered using a device such as an eye dropper, pump spray, tube, eye spray device, eye wash unit and others known to those of ordinary skill in the art. Accordingly, the invention provides a method of treating a corticosteroid-responsive disease or disorder by administration of the liquid to a subject in need of such treatment.

A liquid vehicle (carrier) included in a formulation of the invention comprises an aqueous liquid carrier, such as water, aqueous alcohol, propylene glycol, or aqueous organic solvent. Example 25 details the preparation of a liquid formulation comprising 20% w/v SAE-CD, corticosteroid, water and ethanol (0-5%). Increasing the concentration of the ethanol in the liquid resulted in a decrease in the maximum saturated solubility of the corticosteroid.

Although not necessary, the formulation of the present invention may include a conventional preservative, antioxidant, antiseptic, buffering agent, acidifying agent, alkalizing agent, , solubility-enhancing agent, complexation-enhancing agent, electrolyte, glucose, stabilizer, tonicity modifier, bulking agent, antifoaming agent, oil, emulsifying agent, cryoprotectant, plasticizer, surface tension modifier, viscosity modifier, density modifier, other excipients known by those of ordinary skill in the art for use in preserved formulations, or a combination thereof.

As used herein, the term "alkalizing agent" is intended to mean a compound used to provide alkaline medium, such as for product stability. Such compounds include, by way of example and without limitation, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, diethanolamine, organic amine base, alkaline amino acids and trolamine and others known to those of ordinary skill in the art. As used herein, the term "acidifying agent" is intended to mean a compound used to provide an acidic medium for product stability. Such compounds include, by way of example and without limitation, acetic acid, acidic amino acids, citric acid, fumaric acid and other alpha hydroxy acids, hydrochloric acid, ascorbic acid, phosphoric acid, sulfuric acid, tartaric acid and nitric acid and others known to those of ordinary skill in the art. An "antiseptic" is a compound used to kill or inhibit the growth of microorganisms on the external surfaces of the body. Such compounds include, by way of example and without limitation, silver chloride, alcohols, quaternary ammonium compounds, boric acid, chlorhexidine gluconate, and octenidine dihydrochloride.

Inclusion of a conventional preservative in the solution formulation is optional, since the formulation is self-preserved by SAE-CD depending upon its concentration in solution. Nonetheless, a conventional preservative can be further included in the formulation if desired. Preservatives can be used to inhibit microbial growth in the compositions. The amount of preservative is generally that which is necessary to prevent microbial growth in the composition for a storage period of at least six months. As used herein, a conventional preservative is a compound used to at least reduce the rate at which bioburden increases, but preferably maintains bioburden steady or reduces bioburden after contamination has occurred. Suitable amounts of conventional preservative can be less than 0.2%, less than 0.1%, less than 0.05%, or less than 0.01 %. Such compounds include,

by way of example and without limitation, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, metacresol, myristylgamma picolinium chloride, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thymol, parahydroxybenzoates, and methyl, ethyl, propyl or butyl parabens and others known to those of ordinary skill in the art.

As used herein, the term "antioxidant" is intended to mean an agent that inhibits oxidation and thus is used to prevent the deterioration of preparations by the oxidative process. Antioxidants are usually used in the range of about 0.01% to 0.2%, or about 0.1 %. Such compounds include, by way of example and without limitation, acetone, potassium metabisulfite, potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid, butylated hydroxyanisole, butylated hydroxytoluene, hypophophorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid, thiourea, EDTA, pentetate, and sodium metabisulfite and others known to those of ordinary skill in the art.

As used herein, the term "buffering agent" is intended to mean a compound used to resist change in pH upon dilution or addition of acid or alkali. Buffers are used in the present compositions to adjust the pH to a range of between about 2 and about 9.5, about 3 to about 9, or about 4 to about 8.5. Such compounds include, by way of example and without limitation, acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, boric acid, sodium borate, citric acid, glycine, maleic acid, monobasic sodium phosphate, dibasic sodium phosphate, HEPES, lactic acid, tartaric acid, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, sodium bicarbonate, tris, sodium tartrate and sodium citrate anhydrous and dihydrate and others known to those of ordinary skill in the art. Other buffers include citric acid/phosphate mixture, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, Mcllvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)imino- tris(hydroxymethyl)methane), ADA (N-(2-acetamido)-2-iminodiacetic acid), ACES (N- (carbamoylmethyl)-2-aminoethanesulfonaic acid), PIPES (piperazine-N,N'-bis(2- ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS- TRIS PROPANE (l,3-bis(tris(hydroxymethyl)methylamino)propane), BES (N,N-bis(2-

hydroxyethyl)-2-aminoethanesulfonaic acid), MOPS (3-(N-morpholino)propanesulfonic acid), TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES (N-(2- hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid), DIPSO (3-(N,N-bis(2- hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS (4-(N-morpholino)- butanesulfonic acid), TAPSO (3-(N-tris(hydroxymethyl)methylamino)-2- hydroxypropanesulfonic acid), TRIZMA™ (tris(hydroxymethylaminomethane), HEPPSO (N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid), POPSO (piperazine- N,N'-bis(2-hydroxypropanesulfonic acid)), TEA (triethanolamine), EPPS (N- (2- hydroxyethyl)piperazine-N'-(3-propanesulfonic acid), TRICINE (N- tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE (N,N-bis(2- hydroxyethyl)glycine), HEPBS (N-(2-hydroxyethyl)piperazine-N'-(4-butanesulfonic acid)), TAPS (N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), AMPD (2- amino-2-methyl-l,3-propanediol), and/or any other buffers known to those of skill in the art. A complexation-enhancing agent can be added to a formulation of the invention.

When such an agent is present, the ratio of cyclodextrin /active agent can be changed. A complexation-enhancing agent is a compound, or compounds, that enhance(s) the complexation of the active agent with the cyclodextrin. Suitable complexation enhancing agents include one or more pharmacologically inert water soluble polymers, hydroxy acids, and other organic compounds typically used in liquid formulations to enhance the complexation of a particular agent with cyclodextrins.

Hydrophilic polymers can be used as complexation-enhancing, solubility- enhancing and/or water activity reducing agents to improve the performance of formulations containing a cyclodextrin. Loftsson has disclosed a number of polymers suitable for combined use with a cyclodextrin (underivatized or derivatized) to enhance the performance and/or properties of the cyclodextrin. Suitable polymers are disclosed in Pharmazie (2001), 56(9), 746-747; International Journal of Pharmaceutics (2001), 212(1), 29-40; Cyclodextrin: From Basic Research to Market, International Cyclodextrin Symposium, 10th, Ann Arbor, MI, United States, May 21-24, 2000 (2000), 10-15 (Wacker Biochem Corp.: Adrian, Mich.); PCT International Publication No. WO 9942111; Pharmazie, 53(11), 733-740 (1998); Pharm. Technol. Eur, 9(5), 26-34 (1997); J. Pharm. ScL 85(10), 1017-1025 (1996); European Patent Application EP0579435; Proceedings of the International Symposium on Cyclodextrins, 9th, Santiago de Comostela, Spain, May

31-June 3, 1998 (1999), 261-264 (Editor(s): Labandeira, J. J. Torres; Vila-Jato, J. L. Kluwer Academic Publishers, Dordrecht, Neth); S.T.P. Pharma Sciences (1999), 9(3), 237-242; ACS Symposium Series (1999), 737(Polysaccharide Applications), 24-45; Pharmaceutical Research (1998), 15(11), 1696-1701; Drug Development and Industrial Pharmacy (1998), 24(4), 365-370; International Journal of Pharmaceutics (1998), 163(1- 2), 115-121; Book of Abstracts, 216th ACS National Meeting, Boston, August 23-27 (1998), CELL-016, American Chemical Society; Journal of Controlled Release, (1997), 44/1 (95-99); Pharm.Res. (1997) 14(11), S203; Investigative Ophthalmology & Visual Science, (1996), 37(6), 1199-1203; Proceedings of the International Symposium on Controlled Release of Bioactive Materials (1996), 23rd, 453-454; Drug Development and Industrial Pharmacy (1996), 22(5), 401-405; Proceedings of the International Symposium on Cyclodextrins, 8th, Budapest, Mar. 31-Apr. 2, (1996), 373-376. (Editor(s): Szejtli, J.; Szente, L. Kluwer: Dordrecht, Neth.); Pharmaceutical Sciences (1996), 2(6), 277-279; European Journal of Pharmaceutical Sciences, (1996) 4(SUPPL.), S144; Third European Congress of Pharmaceutical Sciences Edinburgh, Scotland, UK September 15-17, 1996; Pharmazie, (1996), 51(1), 39-42; Eur. J. Pharm. ScL (1996), 4(SuppL), S143; U.S. Patents No. 5,472,954 and No. 5,324,718; International Journal of Pharmaceutics (Netherlands), (Dec. 29, 1995) 126, 73-78; Abstracts of Papers of the American Chemical Society, (02 APR 1995) 209(1), 33-CELL; European Journal of Pharmaceutical Sciences, (1994) 2, 297-301; Pharmaceutical Research (New York), (1994) 11(10), S225; International Journal of Pharmaceutics (Netherlands), (Apr 11, 1994) 104, 181-184; and International Journal of Pharmaceutics (1994), 110(2), 169-77, the entire disclosures of which are hereby incorporated by reference.

Other suitable polymers are well-known excipients commonly used in the field of pharmaceutical formulations and are included in, for example, Remington's Pharmaceutical Sciences, 18th Edition, Alfonso R. Gennaro (editor), Mack Publishing Company, Easton, PA, 1990, pp. 291-294; Alfred Martin, James Swarbrick and Arthur Commarata, Physical Pharmacy. Physical Chemical Principles in Pharmaceutical Sciences, 3rd edition (Lea & Febinger, Philadelphia, PA, 1983, pp. 592-638); A.T. Florence and D. Altwood, (Physico chemical Principles of Pharmacy, 2nd Edition, MacMillan Press, London, 1988, pp. 281-334. The entire disclosures of the references cited herein are hereby incorporated by references. Still other suitable polymers include water-soluble natural polymers, water-soluble semi- synthetic polymers (such as the water-

soluble derivatives of cellulose) and water-soluble synthetic polymers. The natural polymers include polysaccharides such as inulin, pectin, algin derivatives (e.g. sodium alginate) and agar, and polypeptides such as casein and gelatin. The semi- synthetic polymers include cellulose derivatives such as methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, their mixed ethers such as hydroxypropyl methylcellulose and other mixed ethers such as hydroxyethyl ethylcellulose and hydroxypropyl ethylcellulose, hydroxypropyl methylcellulose phthalate and carboxymethylcellulose and its salts, especially sodium carboxymethylcellulose. The synthetic polymers include polyoxyethylene derivatives (polyethylene glycols) and polyvinyl derivatives (polyvinyl alcohol, polyvinylpyrrolidone and polystyrene sulfonate) and various copolymers of acrylic acid (e.g. carbomer). Other natural, semi- synthetic and synthetic polymers not named here which meet the criteria of water solubility, pharmaceutical acceptability and pharmacological inactivity are likewise considered to be within the ambit of the present invention. An emulsifying agent is intended to mean a compound that aids the formation of an emulsion. An emulsifier can be used to wet the corticorsteroid and make it more amenable to dissolution. Emulsifiers for use herein include, but are not limited to, polyoxyetheylene sorbitan fatty esters or polysorbates, including, but not limited to, polyethylene sorbitan monooleate (Polysorbate 80), polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 65 (polyoxyethylene (20) sorbitan tristearate), polyoxyethylene (20) sorbitan mono-oleate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate; lecithins; alginic acid; sodium alginate; potassium alginate; ammonium alginate; calcium alginate; propane- 1,2-diol alginate; agar; carrageenan; locust bean gum; guar gum; tragacanth; acacia; xanthan gum; karaya gum; pectin; amidated pectin; ammonium phosphatides; microcrystalline cellulose; methylcellulose; hydroxypropylcellulose; hydroxypropylmethylcellulose; ethylmethylcellulose; carboxymethylcellulose; sodium, potassium and calcium salts of fatty acids; mono-and di-glycerides of fatty acids; acetic acid esters of mono- and di- glycerides of fatty acids; lactic acid esters of mono-and di-glycerides of fatty acids; citric acid esters of mono-and di-glycerides of fatty acids; tartaric acid esters of mono-and di- glycerides of fatty acids; mono-and diacetyltartaric acid esters of mono-and di-glycerides of fatty acids; mixed acetic and tartaric acid esters of mono-and di-glycerides of fatty acids; sucrose esters of fatty acids; sucroglycerides; polyglycerol esters of fatty acids;

polyglycerol esters of polycondensed fatty acids of castor oil; propane- 1,2-diol esters of fatty acids; sodium stearoyl-2-lactylate; calcium stearoyl-2-lactylate; stearoyl tartrate; sorbitan monostearate; sorbitan tristearate; sorbitan monolaurate; sorbitan monooleate; sorbitan monopalmitate; extract of quillaia; polyglycerol esters of dimerised fatty acids of soya bean oil; oxidatively polymerised soya bean oil; and pectin extract.

As used herein, the term "stabilizer" is intended to mean a compound used to stabilize the therapeutic agent against physical, chemical, or biochemical process that would reduce the therapeutic activity of the agent. Suitable stabilizers include, by way of example and without limitation, albumin, sialic acid, creatinine, glycine and other amino acids, niacinamide, sodium acetyltryptophonate, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycols, sodium caprylate and sodium saccharin and other known to those of ordinary skill in the art.

As used herein, the term "tonicity modifier" is intended to mean a compound or compounds that can be used to adjust the tonicity of the liquid formulation. Tonicity modifier are used to adjust the tonicity to a range of about 100 to 1000 mθs, about 150 to 600 mOs, about 200 to about 400 mOs or about 250 to 350 mOs. Suitable tonicity modifiers include glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol, trehalose and others known to those of ordinary skill in the art. Other tonicity modifiers include both inorganic and organic tonicity adjusting agents. Tonicity modifiers include, but are not limited to, ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, bismuth sodium tartrate, boric acid, calcium chloride, calcium disodium edetate, calcium gluconate, calcium lactate, citric acid, dextrose, diethanolamine, dimethylsulfoxide, edetate disodium, edetate trisodium monohydrate, fluorescein sodium, fructose, galactose, glycerin, lactic acid, lactose, magnesium chloride, magnesium sulfate, mannitol, polyethylene glycol, potassium acetate, potassium chlorate, potassium chloride, potassium iodide, potassium nitrate, potassium phosphate, potassium sulfate, proplyene glycol, silver nitrate, sodium acetate, sodium bicarbonate, sodium biphosphate, sodium bisulfite, sodium borate, sodium bromide, sodium cacodylate, sodium carbonate, sodium chloride, sodium citrate, sodium iodide, sodium lactate, sodium metabisulfite, sodium nitrate, sodium nitrite, sodium phosphate, sodium propionate, sodium succinate, sodium sulfate, sodium sulfite, sodium tartrate, sodium thiosulfate, sorbitol, sucrose, tartaric acid, triethanolamine,

urea, urethan, uridine and zinc sulfate. In one embodiment, the tonicity of the liquid formulation approximates the tonicity of the tissues in the respiratory tract.

An osmotic agent can be used in the compositions to enhance the overall comfort to the patient upon delivery of the corticosteroid composition. Osmotic agents can be added to adjust the tonicity of SAE-CD containing solutions. Osmolality is related to concentration of SAE-CD in water. At SBE7-β-CD concentrations below about 11-13% w/v, the solutions are hypotonic or hypoosmotic with respect to blood and at SBE7-β-CD concentrations above about 11-13% w/v the SBE7-β-CD containing solutions are hypertonic or hyperosmotic with respect to blood. When red blood cells are exposed to solutions that are hypo- or hypertonic, they can shrink or swell in size, which can lead to hemolysis. Suitable osmotic agents include any low molecular weight water-soluble species pharmaceutically approved for ophthalmic administration such as sodium chloride, lactose and glucose. The formulation of the invention can also include biological salt(s), potassium chloride, or other electrolyte(s). As used herein, the term "antifoaming agent" is intended to mean a compound or compounds that prevents or reduces the amount of foaming that forms on the surface of the liquid formulation. Suitable antifoaming agents include dimethicone, simethicone, octoxynol, ethanol and others known to those of ordinary skill in the art.

As used herein, the term "bulking agent" is intended to mean a compound used to add bulk to the lyophilized product and/or assist in the control of the properties of the formulation during lyophilization. Such compounds include, by way of example and without limitation, dextran, trehalose, sucrose, polyvinylpyrrolidone, lactose, inositol, sorbitol, dimethylsulfoxide, glycerol, albumin, calcium lactobionate, and others known to those of ordinary skill in the art. As used herein, the term "cryoprotectant" is intended to mean a compound used to protect an active therapeutic agent from physical or chemical degradation during lyophilization. Such compounds include, by way of example and without limitation, dimethyl sulfoxide, glycerol, trehalose, propylene glycol, polyethylene glycol, and others known to those of ordinary skill in the art. As used herein, the term "viscosity modifier" is intended to mean a compound or mixture of compounds that alters the viscosity of a formulation or composition of the invention. Viscosity modifiers can be used in the present invention to adjust the viscosity to a range of about 1 to about 10,000 cps, about 1 to about 1,000 cps, about 1 to about 100

cps, or about 1 to about 10 cps. Solution viscosity in the range of 25-50 cps is common. A viscosity modifier is used for a variety of reasons, ranging from improving the form of the formulation for convenient administration to improving the contact with the eye to improve bioavailability. An increase in the viscosity of ophthalmic products will result in a longer residence time in the eye, providing a longer time for drug absorption and effect. A viscosity modifier can increase or decrease viscosity. Exemplary viscosity modifiers that increase viscosity include, without limitation, a polymer containing hydrophilic groups such as monosaccharides, polysaccharides, ethylene oxide groups, hydroxyl groups, carboxylic acids or other charged functional groups. While not intending to limit the scope of the invention, some examples of useful viscosity modifiers are sodium carboxymethylcellulose, hydroxypropyl methylcellulose (in the range of 0.5 to 1%), povidone (1.7%), polyvinyl alcohol (0.5 to 1.5% w/v), polyethylene glycol, a combination of borate, hydroxyethylcellulose (0.8%), methylcellulose (in a concentration of about 0.25% if the 4000 cps grade is used), and poly(vinyl alcohol) polymer, or a combination thereof..

A solubility-enhancing agent or solubility enhancer can be added to the formulation of the invention. A solubility-enhancing agent is a compound, or compounds, that enhance(s) the solubility of the corticosteroid when in an aqueous liquid carrier. When another solubility enhancing agent is present, the ratio of SAE-CD to corticosteroid can be changed, thereby reducing the amount of SAE-CD required to dissolve the corticosteroid. Suitable solubility enhancing agents include one or more cyclodextrins, cyclodextrin derivatives, SAE-CD, organic solvents, detergents, soaps, surfactant and other organic compounds typically used in parenteral formulations to enhance the solubility of a particular agent. Exemplary solubility enhancers are disclosed in U.S. Patent No. 6,451,339; however, other surfactants used in the pharmaceutical industry can be used in the formulation of the invention. Some suitable cyclodextrin include underivatized cyclodextrins and cyclodextrin derivatives, such as SAE-CD, SAE-CD derivatives, hydroxyalkyl ether cyclodextrin and derivatives, alkyl ether cyclodextrin and derivatives, sulfated cyclodextrin and derivatives, hydroxypropyl-β-cyclodextrin, 2-HP-β- CD, methyl-β-cyclodextrin, carboxyalkyl thioether derivatives, succinyl cyclodextrin and derivatives, and other cyclodextrin suitable for pharmaceutical use. SAE-CD cyclodextrins are particularly advantageous.

Suitable organic solvents that can be used in the formulation include, for example, ethanol, glycerin, poly(ethylene glycol), propylene glycol, poloxamer, aqueous forms thereof and others known to those of ordinary skill in the art.

It should be understood that compounds used in the art of pharmaceutical formulations generally serve a variety of functions or purposes. Thus, if a compound named herein is mentioned only once or is used to define more than one term herein, its purpose or function should not be construed as being limited solely to that named purpose(s) or function(s).

An active agent contained within the present formulation can be present as its pharmaceutically acceptable salt. As used herein, "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds wherein the active agent is modified by reacting it with an acid or base as needed to form an ionically bound pair. Examples of pharmaceutically acceptable salts include conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Suitable non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and others known to those of ordinary skill in the art. The salts prepared from organic acids such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and others known to those of ordinary skill in the art. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent active agent which contains a basic or acidic moiety by conventional chemical methods. Lists of other suitable salts are found in Remington's Pharmaceutical Sciences, 17 ^th . ed., Mack Publishing Company, Easton, PA, 1985, the relevant disclosure of which is hereby incorporated by reference.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, the term "patient" or "subject" are taken to mean warm blooded animals such as mammals, for example, cats, dogs, mice, guinea pigs, horses, bovine cows, sheep and humans.

A formulation of the invention will comprise an active agent present in an effective amount, effective dose or therapeutically effective dose. By the term "effective amount" or "effective dose" or "therapeutically effective dose", is meant the amount or quantity of active agent that is sufficient to elicit the required or desired response, or in other words, the amount that is sufficient to elicit an appreciable biological response when administered to a subject. In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many embodiments contemplated by the present invention.

EXAMPLE 1

Exemplary formulations according to the invention were made according to the following general procedures.

Method A

Cyclodextrin is dissolved in water (or buffer) to form a solution containing a known concentration of cyclodextrin. This solution is mixed with an active agent in solid, suspension, gel, liquid, paste, powder or other form while mixing, optionally while heating to form a solution.

Method B

A known amount of substantially dry cyclodextrin is mixed with a known amount of substantially dry active agent. A liquid is added to the mixture to form a suspension, gel, solution, syrup or paste while mixing, optionally while heating and optionally in the presence of one or more other excipients, to form a solution.

Method C

A known amount of substantially dry cyclodextrin is added to a suspension, gel, solution, syrup or paste comprising a known amount of active agent while mixing, optionally while heating and optionally in the presence of one or more other excipients, to form a solution.

The methods of this example may be modified by the inclusion of a wetting agent in the composition in order to facilitate dissolution and subsequent inclusion complexation of the corticosteroid. A surfactant, soap, detergent or emulsifying agent can be used as a wetting agent. Method D

To a solution comprising a known concentration or amount of SAE-CD, aqueous liquid carrier, and optionally one or more other excipients, is added a molar excess of the corticosteroid based upon the molar ratio of SAE-CD to corticosteroid at the point of saturated solubility of the corticosteroid, in the presence of the SAE-CD, as determined herein. For example, corticosteroid would be added at a 5%, 10%, 15%, 20%, 25%, 30% or greater molar excess. The components are mixed until equilibration, the point at which there is only a minor change in the concentration of budesonide over a one -hour period of time. Then, the excess corticosteroid is removed leaving behind the target solution of the invention. The budesonide is added to the SAE-CD-containing solution as either a solid or suspension in an aqueous liquid carrier, which can be water, buffer, aqueous alcohol, aqueous organic solvent or a combination thereof. The alcohol and organic solvent are of a pharmaceutically acceptable grade, such as ethanol, propylene glycol, and others as described herein. Method E

The SAE-CD and corticosteroid are triturated to form a mixture. Then, an aqueous liquid carrier is added to the mixture form the target solution of the invention.

The trituration can be conducted dry or in the presence of moisture, water, buffer, alcohol, surfactant, organic solvent, glycerin, poly(ethylene glycol), poloxamer, or a combination thereof.

Method F

Any of the methods herein are conducted in the presence of heat, e.g. at a temperature of least 40 °C.

Method G

Any of the methods herein are conducted with cooling, e.g. at a temperature of less than 20 °C or less than 10 °C or less than 5 °C.

Method H

Any of the methods herein are conducted in the presence of high shear mixing such as with a sonicator, narrow gauge syringe(s), mixer/homogenizer (POLYTRON from KINEMATICA, Europe; FLUKO, Shanghai, China; ULTIMAGRAL from GEA Niro, Inc., Columbia, MD), rotor-stator mixer, or saw tooth mixer.

Method I

Any of the methods herein are conducted under reduced pressure.

EXAMPLE 2

Preparation of an ophthalmic solution formulation containing budesonide.

EXAMPLE 3

The stability of liquid formulations containing SAE-CD was determined by HPLC chromatography of aliquots periodically drawn from the liquid in storage.

Citrate-phosphate (Mcllvaines) buffer solutions at a pH of 4, 5, 6, 7, or 8 were prepared by mixing various portions of 0.0 IM citric acid with 0.02 M Na ₂ HPO ₄ . These stock solutions contained 5% w/w Captisol. Approximately 250 μg /mL of budesonide was dissolved in each buffer solution. Aliquots of the solutions were stored at 40 °C, 50 °C and 60 °C. Control samples were stored at 5 °C but are not reported here. HPLC analysis of the samples was performed initially and after 1, 2, and 3 months storage.

The HPLC conditions included:

EXAMPLE 4

The viscosity of aqueous solutions containing SAE-CD were measured using a cone and plate viscometer.

A Brookfield Programmable DV-III+ Rheometer, CPE-40 cone and CPE 40Y plate (Brookfield Engineering Laboratories, Middleboro, MA) was used to make measurements on 0.5ml samples at 1, 2, 3, 5 and 10 rpm. Samples were sheered for approximately 5 revolutions prior to each measurement. This allowed accurate rheological characterization of the samples. The temperature of all samples was equilibrated to 25+/- 1 degree centigrade using a double wall viscometer cone supplied with water from an electronically controlled thermostatic circulating water bath (Model, 8001, Fisher Scientific, Pittsburgh, PA). The viscometer was calibrated using 5 and 50 centipoise using silicon oil calibration standards. Viscosity measurements were made at 5 or more rotation speeds to look for sheer thinning behavior (viscosities that decrease as the rate of sheer increases). Higher rotation speeds result in increased rates of sheer.

EXAMPLE 5 An ophthalmic solution comprising a corticosteroid and SAE-CD is prepared as follows.

Method A. fluticasone propionate

A citrate buffer solution at a pH of 4.5 was prepared by mixing various portions of

0.003M citric acid with 0.003M of trisodium citrate. A phosphate buffer solution at a pH of 6.0 was prepared by mixing various portions of 0.003M monobasic sodium phosphate with 0.003M of dibasic sodium phosphate. These stock solutions contained 10% w/v

SBE-Gamma (D.S.= 6.1) and 0.01% Tween. An excess of fluticasone propionate was added to the vials and equilibrated on a rocker for three days. The samples were then filtered using a PVDF 0.22μm syringe filter. Aliquots of the solutions were placed into clear glass 2mL serum vials with aluminum crimp caps and Daikyo Flurotec septums. The concentration of the pH 4.5 solution was 232μg/mL. The concentration of the pH 6.0 solution was 238 μg/mL.

Method B. mometasone furoate

A 50 mL solution of 0.08M Captisol with 80μg/mL of mometasone furoate was prepared by weighing approximately 9.6 grams of Captisol into a 50 mL volumetric flask and qs with a 3 mM citrate buffer pH 4.5. The approximately 4 mg of mometasone furoate was weighed into a media bottle and the Captisol/buffer solution was added to the drug and the bottles were vortexed and sonicated for approximately 5 minutes. The bottles were then placed on a roller mixer (Stuart Scientific SRT2 33 rpm rise/fall 16 mm) protected from light and mixed overnight. After the overnight mixing on the roller mixer the bottles were transferred to a magnetic stirrer, set at 330 RPM, for three days. The solutions were filtered using a PVDF 0.22μm filter and a sample was assayed from each bottle. The results from the assay were about 6% low from target so additional mometasone furoate anhydrous was added to each bottle and were placed back onto the roller mixer for another 3 days. The solutions were aseptically filtered again and 2 mLs were transferred to the 2 mL clear vials with Teflon stoppers.

Method C. mometasone furoate and SBE-γ-CD

A 50 mL solution of 0.08M SBE γ-CD with 400μg/mL of mometasone furoate was prepared by weighing approximately 9.1 grams of SBE γ-CD into a 50 mL volumetric flask and qs with a 3 mM citrate buffer pH 4.5. The approximately 20 mg of mometasone furoate was weighed into a media bottle and the SBE γ-CD /buffer solution was added to the drug and the bottles were vortexed and sonicated for approximately 5 minutes. The bottles were then placed on a roller mixer (Stuart Scientific SRT2 33 rpm rise/fall 16 mm)

protected from light and mixed overnight. After the overnight mixing on the roller mixer the bottles were transferred to a magnetic stirrer, set at 330 RPM, for three days. The solutions were filtered using a PVDF 0.22μm filter and a sample was assayed from each bottle. The results from the assay were about 6% low from target so additional mometasone furoate anhydrous was added to each bottle and were placed back onto the roller mixer for another 3 days. The solutions were aseptically filtered again and 2 mLs were transferred to the 2 mL clear vials with Teflon stoppers.

EXAMPLE 6

Preparation of an ophthalmic solution containing budesonide. A buffer solution containing 3mM Citrate Buffer and 82mM NaCl at pH 4.45 is prepared. -12.5 grams of CAPTISOL was placed into a 250 ml volumetric flask. -62.5 mg of budesonide was placed into the same flask. Flask was made to volume with the 3mM citrate buffer/82mM NaCl solution. The flask was well-mixed on a vortexer for 10 minutes and sonicated for 10 minutes. The flask was stirred over weekend with magnetic stirrer. Stirring was stopped after -62 hours and flask was revortexed and resonicated again for 10 minutes each. The solution was filtered through a 0.22 μm Durapore Millex- GV Millipore syringe filter unit. The first few drops were discarded before filter rest of solution into an amber glass jar with a Teflon-lined screw cap. Sample concentration was -237 μg/ml.

EXAMPLE 7

Preparation of an ophthalmic solution containing budesonide. Approximately 5 grams of CAPTISOL was placed into a 100 mL volumetric flask. -26.3 mg of budesonide was placed into the same flask. The flask was made to volume with the 3mM citrate buffer/82mM NaCl solution. The mixture was well-mixed on a vortexer for 10 minutes and sonicated for 10 minutes. The mixture was stirred overnight with a magnetic stirrer. Stirring was stopped after -16 hours and flask was revortexed and resonicated again for 10 minutes each. The solution was filtered through 0.22 μm Durapore Millex-GV Millipore syringe filter unit. The first 5 drops were discarded before filter rest of solution into an amber glass jar with a Teflon-lined screw cap. Sample was analyzed to be 233 μg budesonide/ml.

EXAMPLE 8

Preparation of an ophthalmic solution containing budesonide.

The procedure of Example 7 was followed except that 12.5 g of CAPTISOL, 62.5 mg of budesonide and about 250 ml of buffer were used. Sufficient disodium EDTA was added to prepare a solution having an EDTA concentration of about 0.01 or 0.05 % wt/v EDTA.

EXAMPLE 9

Preparation of a solution containing SAE-CD and budesonide as prepared from a PULMICORT RESPULES suspension. Method A.

To the contents of one or more containers of the Pulmicort Respules (nominally 2 mL of the suspension), about 50 mg (corrected for water content) of CAPTISOL was added per mL of Respule and mixed or shaken well for several minutes. After standing from about 30 minutes to several hours, the solution was used as is for in vitro characterization. In addition to budesonide and water, the PULMICORT RESPULE (suspension) also contains the following inactive ingredients per the label: citric acid, sodium citrate, sodium chloride, disodium EDTA and polysorbate 80.

Method B.

Weigh approximately 200 mg amounts of CAPTISOL (corrected for water content) into 2-dram amber vials. Into each vial containing the weighed amount of

CAPTISOL empty the contents of two Pulmicort Respules containers (0.5 mg/2 mL, Lot #

308016 FebO5) by gently squeezing the deformable plastic container to the last possible drop. The Respules were previously swirled to re-suspend the budesonide particles. The vials are screw capped, mixed vigorously by vortex and then foil wrapped. The material can be kept refrigerated until use.

EXAMPLE 10

Other solutions according to the invention can be prepared as detailed below.

• Dilute Concentrate A at a ratio of 1 to 4 with pH 4.5 salinated citrate buffer (4 mM containing 109 mM sodium chloride) to contain 5% w/v CAPTISOL on an anhydrous basis. Filter the diluted concentrate through a 0.22 μm Millipore Durapore Millex-GV syringe filter unit. Assay the filtered solution by HPLC then add supplemental budesonide as needed to give a solution final concentration of about 250 μg/mL (+ < 5%).

• Dilute Concentrate B at a ratio of 1 to 4 with pH 4.5 salinated citrate buffer (4 mM containing 109 mM sodium chloride) to contain 5% w/v CAPTISOL on an anhydrous basis. Filter the diluted concentrate through a 0.22 μm Millipore Durapore Millex-GV syringe filter unit. Assay the filtered solution by HPLC then dilute further with pH 4.5 salinated citrate buffer (3 mM containing 82 mM sodium chloride containing 5% w/v CAPTISOL) as required to give a final solution concentration of about 250 μg/mL (± < 5%). This technique takes of the excess solid budesonide used to saturate the solution.

EXAMPLE 11

Clarity of solutions was determined by visual inspection or instrumentally. A clear solution is at least clear by visual inspection with the unaided eye. Clarity may also be determined using a HunterLab UltraScan Sphere 8000 Colorimeter, or Hach 2100AN Turbidimeter

EXAMPLE 12

Preparation of ophthalmic budesonide solution and its placebo for in vivo-testing.

Method A.

A buffered, isotonic Captisol solution was prepared. 10OmL water was placed in a suitable vessel. -4.2 grams of Captisol, -32.3 milligrams of citric acid monohydrate, -43.3 milligrams of sodium citrate dihydrate, and -580 milligrams of sodium chloride were added to the vessel. The solution was mixed with a magnetic stir-bar until all solids were dissolved. The measured pH was 4.5 and the tonicity was 30OmOs.

Method B. The same procedure was followed as was in Method A, with the addition of budesonide and polysorbate-80 after the Captisol, citric acid monohydrate, sodium citrate dihydrate, and sodium chloride were dissolved. -26.2 milligrams of budesonide was added to the vessel and allowed to mix for -2.5 hours. -5.0 microliters of polysorbate-80 was added to the vessel and allowed to mix for an additional -2.5 hours. This solution was filtered to remove undissolved excess budesonide, then assayed by HPLC to determine the final budesonide concentration, which was 251 micrograms per milliliter. The measured pH was 4.5 and the tonicity was 30OmOs.

EXAMPLE 13

Solutions of budesonide with and without SBE7-β-CD were prepared at two different pHs (4 and 6) and stored at 2 different temperatures (60 ⁰ C and 80 ⁰ C). Citrate buffers (5OmM) at each pH value were prepared by mixing differing portions of 5OmM citric acid and 5OmM sodium citrate (tribasic, dihydrate) solutions. To achieve a concentration of budesonide in the buffers without SBE7-β-CD sufficient for accurate measurement, the budesonide was dissolved first in 100% ethyl alcohol. An aliquot of the ethanol/budesonide solution was then added drop-wise with stirring to each buffer solution. The theoretical budesonide concentration was 100 μg/mL with a final ethanolic content of 5% in each buffer. All solution preps and procedures involving budesonide were done in a darkened room under red light. After shaking solutions for 24 hours, both buffer solutions were filtered through Millipore Millex-GV 0.22 μm syringe filters to remove any solid that had precipitated (no significant amounts observed) from the solutions. The final budesonide concentration was about 50 μg/mL. Both the pH 4 and 6 solutions were split in two, and solid SBE7-β-CD was added to one of the portions to create solutions with and without 1% w/v SBE7-β-CD at each pH. Each solution was

aliquoted into individual amber vials. They were then placed in ovens at 60 ⁰ C and 80 °C. Sample vials were removed from the ovens and analyzed by HPLC at 0, 96, 164, and 288 hours. The HPLC assay conditions are summarized below.

Chromatographic Conditions

(Adapted from Hou, S., Hindle, M., and Byron, P. R. A. Stability-Indicating HPLC Assay Method for

Budesonide. Journal of Pharmaceutical and Biomedical Analysis, 2001; 24: 371-380.)

EXAMPLE 14

Preparation and use of a combination solution containing SAE-CD, budesonide, and azelastine. A solution may be made according to Example 12, except that 500 mg of azelastine is added to the vessel with the budesonide.

EXAMPLE 15 Preparation and use of a combination solution containing SAE-CD, budesonide, and diclofenac.

A citrate buffer (3 mM pH 4.5) is prepared as follows. Approximately 62.5 mg of citric acid is dissolved in and brought to volume with water in one 100 ml volumetric flask. Approximately 87.7 mg of sodium citrate is dissolved in and brought to volume with water in another 100 mL volumetric flask. In a beaker the sodium citrate solution is added to the citric acid solution until the pH is approximately 4.5.

Approximately 10.4 mg of budesonide, 100 mg of diclofenac and 1247 '.4 mg of

Captisol are ground together with a mortar and pestle and transferred to a 10 mL flask.

Buffer solution is added, and the mixture is vortexed, sonicated and an additional 1.4 mg budesonide added. After shaking overnight, the solution is filtered through a 0.22 μm

Durapore Millex-GV Millipore syringe filter unit. The resulting budesonide concentration will be ~1 mg/ml and the concentration of diclofenac will be ~ 10 mg/ml.

EXAMPLE 16

Preparation and use of a combination ophthalmic solution comprising CAPTISOL, ofloxacin, and mometasone furoate.

A 50 mL solution of 0.08M Captisol with 80μg/mL of mometasone furoate and 3 mg/mL ofloxacin may be prepared by weighing approximately 9.6 grams of Captisol into a 50 mL volumetric flask and qs with a 3 mM citrate buffer pH 4.5. The approximately 4 mg of mometasone furoate and 150 mg ofloxacin are weighed into a media bottle and the

Captisol/buffer solution was added to the drug and the bottles vortexed and sonicated for approximately 5 minutes. The bottles are then placed on a roller mixer (Stuart Scientific SRT2 33 rpm rise/fall 16 mm) protected from light and mixed overnight. After the overnight mixing on the roller mixer the bottles are transferred to a magnetic stirrer, set at

330 RPM, for three days. The solutions are filtered using a PVDF 0.22μm filter and a sample assayed from each bottle.

EXAMPLE 17 In vivo evaluation of a dosage form according to the invention was conducted in rabbits as follows.

A pilot study to test the effectiveness of CE-Budesonide on ocular wound healing was conducted in rabbits. The effectiveness of CE-Budesonide (250 mcg/ml) from Example 12 was compared with commercial products— Pulmicort Respules (a suspension of Budesonide, 250 mcg/ml) and prednisolone acetate (Pred Forte suspension, 1%) and a Captisol placebo.

Treatment protocol:

The animals were administered 40 microliter (10 μg) of test material each to both eyes of animals four times a day (6 hours apart) for 3 days prior to induction of eye injury by laser energy on Day 0 (the day of induction of eye injury). Each animal was placed in the left lateral position and thermal injury was made to the right eye with a semiconductor, diode laser. Laser energy was directed through the peripheral clear cornea to the iris surface using a hand-held fiberoptic laser probe injuring three separate sites measuring 2 mm in diameter. Laser energy treatment of the eyes resulted in inflammatory responses of the iris along with proteinaceous and cellular inflammation in the anterior chamber of the eye on Day 0. The injury was graded for inflammation based on the study Ophthalmologist's routine criteria (0: no inflammation, 1: trace flare or cells (very faint),

2: flare/cell mild but clearly visible in anterior chamber, 3: flare/cell turbity moderate in anterior chamber, 4: flare/cell severe in anterior chamber). Ocular pressure was determined using an applanation tonometer.

EXAMPLE 18 Comparative evaluation of various forms of SAE-CD in the solubilization of corticosteroid derivatives.

The solubility of beclomethasone dipropionate (BDP), beclomethasone 17- monopropionate (B17P), beclomethasone 21-monopropionate (B21P) and beclomethasone (unesterifed) in solutions containing CAPTISOL and various SBE _n γ-CD was evaluated. BDP, B17P and B21P were obtained from Hovione. Beclomethasone was obtained from Spectrum Chemicals. CAPTISOL, SBE(3.4) γ-CD, SBE(5.23) γ-CD and SBE(6.1) γ-CD were provided by CyDex, Inc. (Lenexa, KS). γ-CD was obtained from Wacker Chemical Co. SBE(5.24) γ-CD and SBE(7.5) γ-CD were provided by the University of Kansas.

A 0.04M solution of each selected CD was prepared. Each form of beclomethasone required 2ml of CD solution, therefore the 0.04M solutions were prepared in 20 or 25 mL volumetric flasks in duplicate (N=2). The following table indicates the amount of each CD used after accounting for the content of water in each CD.

Beclomethasone forms were weighed in amounts in excess of the anticipated solubilities directly into 2-dram Teflon-lined screw-capped vials. These amounts typically provided approximately 6 mg/mL of solids. Each vial then received 2 ml of the appropriate CD solution. The vials were vortexed and sonicated for about 10 minutes to aid in wetting the solids with the fluid. The vials were then wrapped in aluminum foil to protect from light and placed on a lab quake for equilibration. The vials were visually inspected periodically to assure that the solids were adequately being wetted and in contact

with the fluid. The time points for sampling were at 24 hrs for all samples and 72 hours for BDP only.

Solutions of SBE(6.1) γ-CD were prepared at 0.04, 0.08, and 0.1M and solutions of SBE (5.23) γ-CD were prepared at only 0.04 and 0.08M. Beclomethasone dipropionate was weighed in amounts in excess of the anticipated solubilities directly into 2-dram teflon-lined screw-capped vials. These amounts typically provided approximately 2 mg/mL of solids. Each vial then received 2 mL of the appropriate CD solution (N = 1). The vials were vortexed and sonicated for about 10 minutes to aid in wetting the solids with the fluid. The vials were then wrapped in aluminum foil to protect from light and placed on a lab quake for a five-day equilibration.

Solutions of γ-CD were prepared at 0.01 and 0.02M. Beclomethasone dipropionate was weighed in amounts in excess of the anticipated solubilities directly into 2-dram teflon-lined screw-capped vials. These amounts typically provided approximately 2 mg/mL of solids. Each vial then received 2 mLs of the γ-CD solution (N = 2). A solution was also prepared to measure the intrinsic solubility of BDP using HPLC grade water in place of the CD. The samples were wrapped in foil and placed on a lab quake for five days.

At the end of the equilibration time for each stage, the vials were centrifuged and 1 ml of the supernatant removed. The removed supernatant was then filtered using the Durapore PVDF 0.22μm syringe filter (discarded first few drops), and diluted with the mobile phase to an appropriate concentration within the standard curve. The samples were then analyzed by HPLC to determine concentration of solubilized corticosteroid.

EXAMPLE 19

Preparation and use of a combination ophthalmic solution containing SAE-CD, budesonide and tobramycin.

An ophthalmic solution of the invention can be made to contain the following ingredients in the approximate amounts indicated per ml of solution.

EXAMPLE 20

Preparation and use of a combination ophthalmic solution containing SAE-CD, budesonide and azithromycin.

EXAMPLE 21

Preparation of ophthalmic solution of SBE γ-CD, Mometasone Furoate, and Timolol

A 50 mL solution of 0.08M SBE γ-CD with 400μg/mL of mometasone furoate and 2.5 mg/mL of timolol may be prepared by weighing approximately 9.1 grams of SBE γ- CD into a 50 mL volumetric flask and qs with a 3 mM citrate buffer pH 4.5. The approximately 20 mg of mometasone furoate and 125 mg of timolol are weighed into a media bottle and the SBE γ-CD /buffer solution is added to the drugs. The bottles are vortexed and sonicated for approximately 5 minutes. The bottles are then placed on a roller mixer (Stuart Scientific SRT2 33 rpm rise/fall 16 mm) protected from light and mixed overnight. After the overnight mixing on the roller mixer the bottles are transferred to a magnetic stirrer, set at 330 RPM, for three days. The solutions are filtered using a PVDF 0.22μm filter.

EXAMPLE 22

Determination of the phase solubility curve for corticosteroid dissolution with SAE-CD.

The solubility of coritco steroid solutions containing SAECD was determined by HPLC chromatography of aliquots from equilibrated filtered or centrifuged corticosteroid solutions as follows.

SAE-CD/steroid solutions were prepared by weighing dry solids of SAE-CD (to provide 0.04 molar) and excess steroid drug (6 mg/mL) together into a screw-capped vial. A volume of water was aliquoted to each vial (separate vial for each steroid). Intrinsic solubility was determined by weighing excess steroid (6 mg/mL) and adding a volume of water in the absence of CD. Vials were capped, initially vortexed and sonicated. Vials were then placed on a roller-mixer (model: SRT2; Manufacturer: Stuart Scientific; Serial number: ROOO 100052) or rocker/mixer (Model: LabQuake; Manufacturer: Barnstead/Thermolyne; Serial number: 1104010438202). Higher excesses of solid steroid (up to 10 mg/mL) were then added to any vial where the liquid contents clarified overnight (e.g. prednisolone, hydrocortisone, and prednisone). Samples were rolled and mixed on the roller or rocker for 72 hours. At various times during the equilibration, samples were additionally vortexed or sonicated briefly (up to 30 minutes). After the designated equilibration time, samples were filtered (0.22 μm, 25 mm, Duropore - PVDF, manufacturer: Millipore) into clean vials except for the intrinsic solubility sample for Beclomethasone Dipropionate which was centrifuged and the supernatant transferred to a clean vial. Samples were analyzed by conventional HPLC methods.

EXAMPLE 24

Preparation and dissolution of a lyophilized formulation comprising SAE-CD and budesonide.

An excess of budesonide, 3.5 mg/mL, was added to 3L of 30% Captisol in 3 mM citrate buffer containing 0.1 mg/mL EDTA. After mixing for 2 days, an additional 1 mg/mL budesonide was added and equilibrated an additional 4 days. The preparation was filtered through a 0.22 μ Durapore filter and placed in three stainless steel trays in a freeze dryer. The solution was frozen at -30 °C for one hour and lyophilized over 30 hours to remove essentially all the water. The lyophile was powdered, screened and the powder

transferred to a plastic bottle. The final composition contained 8.2 mg budesonide per gram of powder.

When approximately 65 mg of powder was added to 2 mL of water, an essentially clear solution containing the same amount of budesonide as in the reference suspension product was rapidly obtained.

EXAMPLE 25

Preparation of an aqueous liquid formulation comprising SAE-CD, ethanol and budesonide.

Captisol/Ethanol solutions were prepared by making a stock captisol solution at 22.2% (-0.1 M) w/v which was diluted with either ethanol or water in varying amounts to create four solutions of 0, 1, 2, 5 % ethanol and about 20% w/v Captisol. Captisol/Ethanol/Budesonide solutions were prepared by adding dry Budesonide (2.5 mg/mL) to a volume of the prepared Captisol/ethanol solutions and then these were equilibrated on a Labquake for 72 hours. These solutions were filtered (Duropore syringe filters) and analyzed by HPLC to determine the concentration (μg/ml) of budesonide dissolved in the formulation.

All documents cited herein are each incorporated by reference herein in its entirety. The above is a detailed description of particular embodiments of the invention. It will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims. All of the embodiments disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure.