Stabilized azithromycin compositions

Abstract

Compositions and methods of stabilizing azithromycin compositions are described. Stabilized azithromycin compositions comprise an intimate admixture of azithromycin and a stabilizing-effective amount of an antioxidant to improve the resistance of the azithromycin to degradation. Coprecipitation or co-milling of azithromycin and an antioxidant are particularly preferred means of achieving an intimate admixture. Pharmaceutical formulations comprising a stabilized azithromycin composition and methods of making such formulations are also described.

1 - 150 . (canceled)  
     
     
         151 . A dry blend, used for forming azithromycin tablets by direct compression, comprising: (a) azithromycin; and (b) at least one pharmaceutically acceptable excipient, wherein said azithromycin is not azithromycin dihydrate.  
     
     
         152 . A dry blend, used for forming azithromycin tablets, comprising: (a) azithromycin; and (b) at least one pharmaceutically acceptable excipient, wherein said azithromycin is not azithromycin dihydrate.  
     
     
         153 . The dry blend of  claim 151  or  152  wherein said azithromycin comprises azithromycin ethanolate monohydrate.  
     
     
         154 . The dry blend of  claim 151  or  152  wherein the azithromycin is non-granulated.  
     
     
         155 . The dryblend of  claim 151  or  152  comprising from about 58% to about 64%, by weight, of the azithromycin.  
     
     
         156 . The dry blend of  claim 151  or  152  comprising from about 11% to about 31%, by weight, of a diluent.  
     
     
         157 . The dry blend of  claim 151  or  152  comprising (a) from about 58% to about 64%, by weight, of the azithromycin; and (b) from about 11% to about 31%, by weight, of the diluent.  
     
     
         158 . The dry blend of  claim 157  wherein the diluent is dibasic calcium phosphate dihydrate.  
     
     
         159 . The dry blend of  claim 151  or  152  wherein the diluent is selected from the group consisting of spray dried lactose, anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose, microcrystalline cellulose, dibasic calcium phosphate anhydrous, dibasic calcium phosphate dihydrate, calcium carbonate and calcium sulfate.  
     
     
         160 . The dry blend of  claim 151  or  152  comprising from about 4.1% to about 5.6%, by weight, of a disintegrant.  
     
     
         161 . The dry blend of  claim 151  or  152  comprising: (a) from about 4.1% to about 5.6%, by weight, of the disintegrant; and (b) from about 1.7% to about 2.4%, by weight, of a lubricant.  
     
     
         162 . The dry blend of  claim 151  or  152  comprising from about 1.7% to about 2.4%, by weight, of a lubricant.  
     
     
         163 . The dry blend of  claim 151  or  152  comprising about 0.5% to 7.0%, by weight, of a lubricant.  
     
     
         164 . The dry blend of  claim 151  or  152  wherein the lubricant is selected from the group consisting of magnesium stearate, talc, stearic acid, glyceryl behenate, polyethylene glycol, ethylene oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine and colloidal silica.  
     
     
         165 . The dry blend of  claim 151  or  152  further comprising a glidant.  
     
     
         166 . The dry blend of  claim 151  or  152  wherein the glidant is selected from the group consisting of colloidal silicon dioxide and talc.  
     
     
         167 . The dry blend of  claim 151  or  152  comprising: (a) from about 58% to about 64%, by weight, azithromycin; (b) from about 4.1% to about 6.7%, by weight, binder; (c) from about 11% to about 31%, by weight, diluent; (d) from about 4.1% to about 5.6%, by weight, disintegrant; and (e) from about 1.7% to about 2.4%, by weight, lubricant.  
     
     
         168 . The dry blend of  claim 167  wherein the azithromycin is non-granulated.  
     
     
         169 . An azithromycin tablet comprising azithromycin and at least one pharmaceutically acceptable excipient, wherein said azithromycin is not azithromycin dihydrate.  
     
     
         170 . The azithromycin tablet of  claim 169  wherein the azithromycin comprises azithromycin ethanolate monohydrate.  
     
     
         171 . An azithromycin tablet of  claim 169  wherein said tablet is produced by: (a) forming a dry blend of azithromycin and at least one pharmaceutically acceptable excipient; and (b) direct compressing said dry blend to form the azithromycin tablet.  
     
     
         172 . An azithromycin tablet of  claim 171  wherein the azithromycin, in the dry blend, is non-granulated.  
     
     
         173 . An azithromycin tablet of  claim 171  wherein the dosage of azithromycin in said tablet is 500 mg.  
     
     
         174 . The azithromycin tablet of  claim 173  wherein the azithromycin, in the dry blend, is non-granulated.  
     
     
         175 . A method of forming an azithromycin tablet, comprising: (a) mixing particles of azithromycin and at least one pharmaceutically acceptable excipient to form a dry blend; and (b) direct compressing said dry blend to form the azithromycin tablet, wherein the azithromycin is not azithromycin dihydrate.  
     
     
         176 . The method of  claim 175  wherein the azithromycin comprises azithromycin ethanolate monohydrate.  
     
     
         177 . The method of  claim 175  wherein the azithromycin is non-granulated.  
     
     
         178 . The method of  claim 175  further comprising the step of mixing a lubricant with the dry blend prior to direct compressing.  
     
     
         179 . The method of  claim 177  further comprising the step of precompressing the dry blend.  
     
     
         180 . The method of  claim 177  further comprising the step of force feeding the dry blend into a tabletting means.  
     
     
         181 . The method of  claim 177  wherein the dry blend comprises: (a) from about 58% to about 64%, by weight, azithromycin; (b) from about 4.1% to about 6.7%, by weight, binder; (c) from about 11% to about 31%, by weight, diluent; (d) from about 4.1% to about 5.6%, by weight, disintegrant; and (e) from about 1.7% to about 2.4%, by weight, lubricant.  
     
     
         182 . A method of treating a bacterial infection in a human or non-human animal comprising administering to said human or non-human animal an azithromycin tablet of any of claims  169 ,  170 ,  171 ,  172 ,  173  or  174 .  
     
     
         183 . A method of forming azithromycin granules, comprising: a) mixing (i) a granulating amount of a granulating liquid, (ii) optionally, one or more pharmaceutically acceptable excipients, and (iii) azithromycin particles to form wet granules, wherein the wet granules comprise azithromycin and the granulating liquid; and b) drying the wet granules to remove the granulating liquid and thereby form azithromycin granules, wherein the azithromycin is not azithromycin dihydrate.  
     
     
         184 . The method of  claim 183  wherein the azithromycin comprises azithromycin ethanolate monohydrate.  
     
     
         185 . The method of  claim 183  wherein the azithromycin particles comprise azithromycin powder.  
     
     
         186 . The method of  claim 183  wherein the azithromycin is crystalline.  
     
     
         187 . The method of  claim 183  wherein the granulating liquid is a non-aqueous liquid  
     
     
         188 . The method of  claim 187  wherein the non-aqueous liquid is denatured alcohol.  
     
     
         189 . The method of  claim 183  further comprising the step of dissolving a binder in the granulating liquid prior to mixing the granulating liquid with the azithromycin.  
     
     
         190 . The method of  claim 189  wherein the binder is polyvinylpyrrolidone  
     
     
         191 . The method of  claim 189  wherein the binder is selected from the group consisting of acacia, cellulose derivatives, gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, starch paste, sucrose, sorbitol, pregelatinized starch, gum tragacanth, alginic acids and salts thereof such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, bentonites.  
     
     
         192 . The method of  claim 183  further comprising the step of preblending the azithromycin with at least one pharmaceutically acceptable excipient prior to mixing with the granulating liquid.  
     
     
         193 . A granule comprising azithromycin and, optionally, one or more excipients wherein said granule is formed by a wet granulation process and the azithromycin is not azithromycin dihydrate.  
     
     
         194 . The granule of  claim 193  wherein said azithromycin comprises azithromycin ethanolate monohydrate.  
     
     
         195 . The granule of  claim 193  comprising about 82%, by weight, azithromycin, about 5.7% binder, about 9.0% filler, and about 2.8% disintegrant.  
     
     
         196 . A granule comprising 98-100%, by weight, azithromycin and 0-2%, by weight, of one or more pharmaceutically acceptable excipients.  
     
     
         197 . A pharmaceutical composition comprising granules of azithromycin, wherein said granules are formed by a wet granulation process, and at least one pharmaceutically acceptable excipient, wherein said azithromycin is not azithromycin dihydrate.  
     
     
         198 . The pharmaceutical composition of  claim 197  wherein the azithromycin comprises azithromycin ethanolate monohydrate.  
     
     
         199 . A pharmaceutical formulation, comprising: a tablet, capsule, sachet or powder for suspension which comprises a) granules of azithromycin; and b) at least one pharmaceutically acceptable excipient, wherein said azithromycin is not azithromycin dihydrate.  
     
     
         200 . The pharmaceutical formulation of  claim 199  wherein said azithromycin comprises azithromycin ethanolate monohydrate.  
     
     
         201 . The pharmaceutical formulation of  claim 199  wherein the dosage of azithromycin is 500 mg.  
     
     
         202 . A pharmaceutical formulation, comprising: a) a capsule; b) granules of azithromycin; and c) at least one pharmaceutically acceptable excipient, wherein said azithromycin is not azithromycin dihydrate.  
     
     
         203 . The pharmaceutical formulation of  claim 202  wherein said azithromycin comprises azithromycin ethanolate monohydrate.  
     
     
         204 . A pharmaceutical formulation, comprising a) granules of azithromycin, wherein said granules consist essentially of 98-100%, by weight, azithromycin and 0-2%, by weight, of one or more pharmaceutically acceptable excipients; and b) at least one pharmaceutically acceptable excipient, wherein said azithromycin is not azithromycin dihydrate.  
     
     
         205 . The pharmaceutical formulation of  claim 204  wherein said azithromycin comprises azithromycin ethanolate monohydrate.  
     
     
         206 . A method of treating a bacterial or protozoal infection in a mammal, comprising administering to said mammal an effective amount of a pharmaceutical formulation of any of claims  199 ,  202  or  204 .  
     
     
         207 . A pharmaceutical formulation, comprising: a tablet, capsule, sachet or powder for suspension which comprises a) dry granulated particles of azithromycin; and b) optionally, one or more pharmaceutically acceptable excipients, wherein said azithromycin is not azithromycin dihydrate.  
     
     
         208 . The pharmaceutical formulation of  claim 207  wherein said azithromycin comprises azithromycin ethanolate monohydrate.  
     
     
         209 . The pharmaceutical formulation of  claim 207  wherein the dosage of azithromycin is 500 mg.  
     
     
         210 . The pharmaceutical formulation of  claim 207  comprising a tablet containing about 64%, by weight, azithromycin.  
     
     
         211 . An azithromycin tablet comprising (a) from about 58 to about 64 wt % azithromycin; (b) from about 4.1 to about 6.7 wt % binder; (c) from about 11 to 31 wt % filler; (d) from about 4.1 to about 5.6 wt % disintegrant; and (e) from about 1.7 to about 2.4 wt % lubricant, wherein said azithromycin is not azithromycin dihydrate.  
     
     
         212 . The azithromycin tablet of  claim 211  wherein said azithromycin comprises azithromycin ethanolate monohydrate.  
     
     
         213 . A pharmaceutical formulation in a tablet dosage form, wherein said tablet is produced by: (a) forming a blend of dry granulated particles of azithromycin and at least one pharmaceutically acceptable excipient; and (b) compressing said blend to form the azithromycin tablet, wherein said azithromycin is not azithromycin dihydrate.  
     
     
         214 . The pharmaceutical formulation of  claim 213  wherein the azithromycin comprises azithromycin ethanolate monohydrate.  
     
     
         215 . The pharmaceutical formulation of  claim 213  wherein the dosage of azithromycin is 500 mg.  
     
     
         216 . The pharmaceutical formulation of  claim 213  further comprising the step of precompressing said blend prior to compressing said blend to form the tablet.  
     
     
         217 . The pharmaceutical formulation of  claim 216  comprising a tablet containing about 64%, by weight, azithromycin ethanolate monohydrate.  
     
     
         218 . The pharmaceutical formulation of  claim 216  wherein the dosage of azithromycin is 500 mg.  
     
     
         219 . A pharmaceutical composition comprising dry granulated particles of azithromycin and at least one pharmaceutically acceptable excipient, wherein said azithromycin is not azithromycin dihydrate.  
     
     
         220 . The pharmaceutical composition of  claim 219  wherein said azithromycin comprises azithromycin ethanolate monohydrate.  
     
     
         221 . The pharmaceutical composition of  claim 219  further comprising a capsule.  
     
     
         222 . The pharmaceutical composition of  claim 221  wherein said pharmaceutically acceptable excipients comprise a diluent, a disintegrant and a lubricant.  
     
     
         223 . A dry granulated azithromycin particle, comprising: (a) azithromycin; and (b) at least one pharmaceutically acceptable excipient, wherein said azithromycin is not azithromycin dihydrate.  
     
     
         224 . The dry granulated azithromycin particle of  claim 223  wherein said azithromycin comprises azithromycin ethanolate monohydrate.  
     
     
         225 . The dry granulated azithromycin particle of  claim 223  wherein said pharmaceutically acceptable excipients comprise a diluent, a disintegrant and a lubricant.  
     
     
         226 . The dry granulated azithromycin particle of  claim 225  wherein the diluent is dibasic calcium phosphate dihydrate.  
     
     
         227 . The dry granulated azithromycin particle of  claim 225  wherein the diluent is selected from the group consisting of spray dried lactose, anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose, microcrystalline cellulose, dibasic calcium phosphate anhydrous, dibasic calcium phosphate dihydrate, calcium carbonate and calcium sulfate.  
     
     
         228 . A method of preparing an azithromycin pharmaceutical formulation, in a tablet, capsule, sachet or powder for suspension dosage form, comprising: a) forming a blend of azithromycin and at least one pharmaceutically acceptable excipient; b) compressing the blend to produce a compressed material; c) milling the compressed material to produce granules; d) processing the granules into a tablet, capsule, sachet or a powder for suspension, wherein said azithromycin is not azithromycin dihydrate.  
     
     
         229 . The method of  claim 228  wherein said azithromycin comprises azithromycin ethanolate monohydrate.  
     
     
         230 . The method of  claim 228  further comprising the step of blending at least one pharmaceutically acceptable excipient with the granules to form a blend prior to forming the dosage form.  
     
     
         231 . A method of preparing an azithromycin pharmaceutical formulation, in capsule dosage form, comprising: a) forming a blend of azithromycin and at least one pharmaceutically acceptable excipient; b) compressing the blend to produce a compressed material; c) milling the compressed material to produce granules; d) processing the granules into a capsule, wherein said azithromycin is not azithromycin dihydrate.  
     
     
         232 . The method of  claim 231  wherein said azithromycin comprises azithromycin ethanolate monohydrate.  
     
     
         233 . The method of  claim 231  further comprising the step of blending at least one pharmaceutically acceptable excipient with the granules to form a blend prior to forming the dosage form.