Cyclodextrin nanotechnology for ophthalmic drug delivery

Abstract

The invention provides an ophthalmic composition which is an aqueous suspension comprising drug, cyclodextrin and water, the composition having an aqueous phase of from about 0.1% (w/v) to about 90% (w/v) of the drug in solution, as dissolved free drug and as dissolved drug/cyclodextrin complex(es), and a solid phase of from about 10% (w/v) to about 99.9% (w/v) of the drug as solid drug/cyclodextrin particles, suspended in the aqueous phase; the size of the solid particles being from about 10 nm to about 1 mm, the drug/cyclodextrin particles being capable of dissolving in aqueous tear fluid within 24 hours of application to the eye surface. The aqueous eye suspension can be in the form of eye drops, eye gel or eye mist. Further, the invention provides a method for treating a condition of the posterior segment and/or anterior segment of the eye comprising applying to the eye surface, in an amount which delivers to said segment or segments a therapeutically effective amount of a drug suitable for treating said condition, an ophthalmic composition which is as defined above. Nasal compositions and methods and ophthalmic and nasal compositions in powder form are also provided.

1 . An ophthalmic composition which is an aqueous suspension comprising drug, cyclodextrin and water, the composition having an aqueous phase of from about 0.1% (w/v) to about 90% (w/v) of the drug in solution, as dissolved free drug and as dissolved drug/cyclodextrin complex(es), and a solid phase of from about 10% (w/v) to about 99.9% (w/v) of the drug as solid drug/cyclodextrin particles, the size of the particles in the solid phase being from about 10 nm to about 1 mm, the drug/cyclodextrin particles being capable of dissolving in tear fluid, the cyclodextrin comprising at least one natural cyclodextrin selected from the group consisting of α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. 
     
     
         2 . The composition according to  claim 1 , in the form of eye drops, an eye mist or an eye gel. 
     
     
         3 . The composition according to  claim 1 , comprising from about 0.25% to about 40% of cyclodextrin, and further comprising up to about 5% (w/v) of water-soluble polymer, up to about 5% (w/v) of metal salts and up to about 5% (w/v) of organic salts, and optionally further comprising at least one buffer salt and/or at least one preservative. 
     
     
         4 . The composition according to  claim 1 , comprising from about 2% (w/v) to about 20% (w/v) of cyclodextrin, and further comprising from about 0.1% (w/v) to about 1% (w/v) of water-soluble polymer, up to about 2% (w/v) of metal salts and up to about 3% (w/v) or organic salts, and optionally further comprising at least one buffer salt and/or at least one preservative. 
     
     
         5 . The composition according to  claim 3 , wherein said metal salt has a divalent or trivalent cation and/or wherein said organic salt is a salt of or an ionized form of acetic acid, glutaric acid, a hydroxy acid or an amino acid. 
     
     
         6 . The composition according to  claim 3 , wherein said metal salt is a magnesium salt and/or wherein said organic salt is a salt of or the ionized form of citric acid, lactic acid, ascorbic acid, tartaric acid or lysine. 
     
     
         7 . The composition according to  claim 5 , wherein said magnesium salt is magnesium chloride. 
     
     
         8 . The composition according to  claim 1 , wherein the aqueous phase comprises from about 5% (w/v) to about 50% (w/v) of the drug in solution, as free drug and dissolved drug/cyclodextrin complex(es), and from about 50% (w/v) to about 95% (w/v) of the drug as solid drug/cyclodextrin particles; and/or wherein the size of the particles in the solid phase is from about 0.1 μm to about 500 μm; and/or wherein the drug/cyclodextrin particles dissolve within from about 10 to about 24 hours after administration to the eye surface. 
     
     
         9 . The composition according to  claim 1 , wherein the cyclodextrin further comprises at least one pharmaceutically acceptable cyclodextrin derivative selected from the group consisting of hydroxyalkyl-β-cyclodextrins, hydroxyalkyl-γ-cyclodextrins, randomly methylated β-cyclodextrin, β-cyclodextrin sulfobutyl ether, γ-cyclodextrin sulfobutyl ether, branched β-cyclodextrins and branched γ-cyclodextrins. 
     
     
         10 . The composition according to  claim 9 , wherein the at least one pharmaceutically acceptable cyclodextrin derivative is hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated β-cyclodextrin, β-cyclodextrin sulfobutyl ether, γ-cyclodextrin sulfobutyl ether or glucosyl-β-cyclodextrin. 
     
     
         11 . The composition according to  claim 1 , wherein the cyclodextrin comprises at least γ-cyclodextrin and/or wherein the cyclodextrin further comprises at least hydroxypropyl-γ-cyclodextrin. 
     
     
         12 . The composition according to  claim 3 , wherein said polymer is methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, carboxymethylcellulose, polyvinyl alcohol, poly(methyl methacrylate), polycarbophil, gelatin, alginate, poly(acrylic acid), polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide or chitosan, or a derivative of one of the foregoing. 
     
     
         13 . The composition according to  claim 1 , wherein said drug is a carbonic anhydrase inhibitor, a steroid, a GABAergic drug, a non-steroidal anti-inflammatory drug, an antibiotic, an antiviral agent or a prostaglandin. 
     
     
         14 . The composition according to  claim 13 , wherein said GABAergic drug is a benzodiazepine. 
     
     
         15 . The composition according to  claim 13 , wherein said carbonic anhydrase inhibitor is dorzolamide, acetazolamide, methazolamide, ethoxyzolamide or brinzolamide; or wherein said steroid is dexamethasone, hydrocortisone, triamcinolone, triamcinolone acetonide, prednisolone, fluorometholone, medrysone, rimexolone, pregnanolone, loteprednol etabonate or etiprednol dicloacetate; or wherein said GABAergic drug is baclofen, tiagabine, valproic acid, progabide, muscimol, etomidate, propofol, diazepam, alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam, temezepam or lorazolam; or wherein the non-steroidal anti-inflammatory drug is naproxen or ketoprofen; or wherein the prostaglandin is latanoprost. 
     
     
         16 . The composition according to  claim 1 , wherein said drug is cyclosporin A. 
     
     
         17 . A nasal composition which is an aqueous suspension comprising drug, cyclodextrin and water, the composition having an aqueous phase of from about 1% (w/v) to about 95% (w/v) of the drug in solution, as dissolved free drug and as dissolved drug/cyclodextrin complex(es), and a solid phase of from about 5% (w/v) to about 99% (w/v) of the drug as solid drug/cyclodextrin particles, the size of the particles in the solid phase being from about 10 nm to about 1 mm, the drug/cyclodextrin particles being capable of dissolving in nasal mucus fluid within about 24 hours after application to the nasal mucosa, the cyclodextrin comprising at least one natural cyclodextrin selected from the group consisting of α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. 
     
     
         18 . An ophthalmic composition which is a powder obtained by lyophilizing or spray-drying an aqueous suspension as claimed in  claim 1 . 
     
     
         19 . The composition according to  claim 1 , wherein said cyclodextrin is a mixture of a natural α-, β- or γ-cyclodextrin and the corresponding water-soluble α-, β- or γ-cyclodextrin derivative. 
     
     
         20 . The composition according to  claim 19 , wherein said water-soluble derivative is selected from the group consisting of hydroxyalkyl-β-cyclodextrins, hydroxyalkyl-γ-cyclodextrins, randomly methylated β-cyclodextrin, the sulfobutyl ether of β-cyclodextrin, the sulfobutyl ether of γ-cyclodextrin, branched β-cyclodextrins and branched γ-cyclodextrins. 
     
     
         21 . The composition according to  claim 20 , wherein said water-soluble derivative is selected from the group consisting of hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated β-cyclodextrin, the sulfobutyl ether of β-cyclodextrin, the sulfobutyl ether of γ-cyclodextrin, glucosyl β-cyclodextrin and glucosyl γ-cyclodextrin. 
     
     
         22 . The composition according to  claim 19 , wherein said cyclodextrin is a mixture of γ-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin, or a mixture of γ-cyclodextrin and the sulfobutyl ether of γ-cyclodextrin, or a mixture of β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin, or a mixture of β-cyclodextrin and the sulfobutyl ether of β-cyclodextrin, or a mixture of β-cyclodextrin and randomly methylated β-cyclodextrin. 
     
     
         23 . The composition according to  claim 1 , wherein the drug is AG013958, triamcinolone acetonide, ranibizumab, macugen or sham, said composition being in the form of eye drops. 
     
     
         24 . The solid ophthalmic formulation according to  claim 18 , wherein said drug is AG013958, triamcinolone acetonide, ranibizumab, macugen or sham. 
     
     
         25 . A method for the treatment of a condition of the posterior segment and/or the anterior segment of the eye comprising applying topically to the eye surface of a subject in need of such treatment, in an amount which delivers to said segment or segments a therapeutically effective amount of a drug suitable for treating said condition, an ophthalmic composition according to  claim 1 . 
     
     
         26 . A method according to  claim 25 , wherein the drug is a corticosteroid and the condition is a disease of the retina and/or optic nerve which is responsive to treatment with a corticosteroid; or wherein the drug is a carbonic anhydrase inhibitor and the condition is a disease of the retina and/or optic nerve which is responsive to treatment with a carbonic anhydrase inhibitor; or wherein the drug is a GABA agonist and the condition is a disease of the retina which is responsive to treatment with a GABA agonist; or wherein the condition is age-related macular degeneration and the drug is AG013958, triamcinolone acetonide, ranibizumab, macugen or sham. 
     
     
         27 . A method according to  claim 25 , wherein the drug is an antibiotic and the condition is a bacterial eye infection; or wherein the drug is an antiviral agent and the condition is a viral eye infection.