Tetracycline compositions

Abstract

The present invention relates to compositions, pharmaceutical compositions, and methods for preparing the same, comprising a tetracycline with improved stability and solubility. Some embodiments include a tetracycline with an excess of a divalent or trivalent cation.

1 .- 138 . (canceled) 
     
     
         139 . A pharmaceutical composition comprising an aqueous solution of single antibiotic ingredient and a magnesium cation, wherein the single antibiotic ingredient consists of a 7-dimethylamino-tetracycline antibiotic, wherein the molar ratio of magnesium to 7-dimethylamino-tetracycline antibiotic is greater than 3:1, wherein the solution does not comprise a pharmaceutically acceptable oil, has a pH greater than 4 and less than 7, has an osmolality less than about 500 mOsmol/kg, and is suitable for intravenous administration, wherein intravenous administration of the composition results in reduced injection site hemolysis relative to intravenous administration of a composition that does not include magnesium. 
     
     
         140 . The pharmaceutical composition of  claim 139 , wherein the solution has a pH of less than 6. 
     
     
         141 . The pharmaceutical composition of  claim 139 , wherein the solution has a pH of less than 5. 
     
     
         142 . The pharmaceutical composition of  claim 139 , wherein the molar ratio of magnesium cation to 7-dimethylamino-tetracycline antibiotic is greater than 5:1. 
     
     
         143 . The pharmaceutical composition of  claim 139 , wherein the molar ratio of magnesium cation to 7-dimethylamino-tetracylcine antibiotic is from 5:1 to 10:1. 
     
     
         144 . The pharmaceutical composition of  claim 139 , wherein the molar ratio of magnesium cation to 7-dimethylamino-tetracylcine antibiotic is 5:1. 
     
     
         145 . The pharmaceutical composition of  claim 139 , wherein the molar ratio of magnesium cation to 7-dimethylamino-tetracycline antibiotic is greater than 8:1. 
     
     
         146 . The pharmaceutical composition of  claim 139 , wherein the molar ratio of magnesium cation to 7-dimethylamino-tetracycline antibiotic is greater than 10:1. 
     
     
         147 . The pharmaceutical composition of  claim 139 , wherein the osmolality of the solution is less than 400 mOsm/kg. 
     
     
         148 . The pharmaceutical composition of  claim 139 , wherein the osmolality of the solution is less than 350 mOsm/kg. 
     
     
         149 . The pharmaceutical composition of  claim 139 , wherein the solution comprises a magnesium salt selected from the group consisting of magnesium sulfate, magnesium oxide, magnesium acetate, and magnesium chloride. 
     
     
         150 . The pharmaceutical composition of  claim 139 , wherein the solution comprises a buffer. 
     
     
         151 . The pharmaceutical composition of  claim 150 , wherein the buffer comprises acetate. 
     
     
         152 . The pharmaceutical composition of  claim 139 , wherein the solution comprises a base. 
     
     
         153 . The pharmaceutical composition of  claim 152 , wherein the base comprises NaOH. 
     
     
         154 . The pharmaceutical composition of  claim 139 , wherein the 7-dimethylamino-tetracycline antibiotic is selected from the group consisting of minocycline, and PTK796, and a glycylcycline. 
     
     
         155 . The pharmaceutical composition of  claim 139 , wherein the 7-dimethylamino-tetracycline antibiotic is minocycline. 
     
     
         156 . The pharmaceutical composition of  claim 155 , wherein the concentration of minocycline is at least 1 mg/ml. 
     
     
         157 . The pharmaceutical composition of  claim 155 , wherein the concentration of minocycline is at least 5 mg/ml. 
     
     
         158 . The pharmaceutical composition of  claim 155 , wherein the concentration of minocycline is at least 10 mg/ml. 
     
     
         159 . The pharmaceutical composition of  claim 155  comprising 10 mg/ml minocycline, MgSO 4 , and sodium acetate, wherein the magnesium cation to minocycline molar ratio is 5:1, and the pH is greater than 4.5 and less than 5.5, wherein the solution has an osmolality greater than 275 mOsm/kg and less than 375 mOsm/kg. 
     
     
         160 . The pharmaceutical composition of  claim 155  comprising 10 mg/ml minocycline, MgSO 4 , and NaOH, wherein the magnesium cation to minocycline molar ratio is 5:1, and the pH is greater than 4.5 and less than 5.5, wherein the solution has an osmolality greater than 150 mOsm/kg and less than 250 mOsm/kg. 
     
     
         161 . The pharmaceutical composition of  claim 155  comprising 10 mg/ml minocycline, MgCl 2 , and NaOH, wherein the magnesium cation to minocycline molar ratio is 5:1, and the pH is greater than 4.5 and less than 5.5. 
     
     
         162 . The pharmaceutical composition of  claim 155  comprising 10 mg/ml minocycline and magnesium acetate, wherein the magnesium cation to minocycline molar ratio is 5:1, and the pH is greater than 4.5 and less than 5.5. 
     
     
         163 . The pharmaceutical composition of  claim 154 , wherein the glycylcycline is tigecycline. 
     
     
         164 . The pharmaceutical composition of  claim 163  comprising 5 mg/ml tigecycline, NaOH, and MgSO 4 , wherein the magnesium cation to tigecycline molar ratio is 5:1, and the pH is greater than 5.5 and less than 6.5. 
     
     
         165 . The pharmaceutical composition of  claim 163  comprising 5 mg/ml tigecycline, NaOH, and MgSO 4 , wherein the magnesium cation to tigecycline molar ratio is 12:1, and the pH is greater than 5.5 and less than 6.5. 
     
     
         166 . The pharmaceutical composition of  claim 163  comprising 5 mg/ml tigecycline, NaOH, and MgCl 2 , wherein the magnesium cation to tigecycline molar ratio is 5:1, and the pH is greater than 5.5 and less than 6.5. 
     
     
         167 . The pharmaceutical composition of  claim 163  comprising 5 mg/ml tigecycline, NaOH, and MgCl 2 , wherein the magnesium cation to tigecycline molar ratio is 12:1, and the pH is greater than 5.5 and less than 6.5. 
     
     
         168 . The pharmaceutical composition of  claim 163  comprising 5 mg/ml tigecycline, NaOH, MgSO 4 , wherein the magnesium cation to tigecycline molar ratio is 5:1, and the pH is greater than 6.0 and less than 7.0, and is suitable for topical administration. 
     
     
         169 . The pharmaceutical composition of  claim 163  comprising 5 mg/ml tigecycline, NaOH, MgSO 4 , wherein the magnesium cation to tigecycline molar ratio is 12:1, and the pH is greater than 6.0 and less than 7.0, and is suitable for topical administration. 
     
     
         170 . The pharmaceutical composition of  claim 139 , wherein the solution does not comprise a component selected from the group consisting of polyoxyethylene hydrogenated castor oil, an antioxidant, a pyridine-containing compound, nicotinamide, an alcohol, glycerol, polyethylene glycol, gluconate, a pyrrolidone compound, a water-miscible local anaesthetic, procaine, urea, lactose, and a dehydrating agent selected from the group consisting of ethyl acetate, acetic anhydride, absolute ethanol, and mixtures thereof. 
     
     
         171 . The pharmaceutical composition of  claim 139 , wherein the composition consists of an aqueous solution consisting of minocycline or a salt thereof, a salt that comprises a magnesium cation, and a base, wherein the molar ratio of magnesium cation to minocycline is greater than about 4:1, and wherein the composition has a pH that is no less than 4 and no greater than 6. 
     
     
         172 . A water-soluble solid composition, comprising a single antibiotic ingredient and a salt comprising a divalent or trivalent cation, wherein the single antibiotic ingredient consists of 7-dimethylamino-tetracycline antibiotic or a salt thereof, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline is greater than 3:1 and wherein upon dissolution of the solid composition in water to make a solution having a concentration of 7-dimethylamino-tetracycline antibiotic of 1 mg/ml, a solution having a pH greater than 4 and less than 7 is formed, wherein intravenous administration of a solution reconstituted from the solid composition results in reduced injection site hemolysis relative to intravenous administration of a solution that does not include the divalent or trivalent cation. 
     
     
         173 . The water-soluble solid composition of  claim 172 , wherein the salt is selected from magnesium chloride, magnesium bromide, magnesium sulfate, calcium chloride, calcium bromide, calcium sulfate, zinc chloride, gallium chloride, magnesium malate, magnesium citrate, magnesium acetate, calcium citrate, zinc acetate, and zinc citrate. 
     
     
         174 . The water-soluble solid composition of  claim 172 , wherein the salt is magnesium sulfate. 
     
     
         175 . The water-soluble solid composition of  claim 172 , wherein the salt is calcium chloride. 
     
     
         176 . The water-soluble solid composition of  claim 172 , wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline antibiotic is greater than 5:1. 
     
     
         177 . The water-soluble solid composition of  claim 172 , wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracylcine antibiotic is from 5:1 to 10:1. 
     
     
         178 . The water-soluble solid composition of  claim 172 , wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracylcine antibiotic is 5:1. 
     
     
         179 . The water-soluble solid composition of  claim 172 , wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline antibiotic is at greater than 8:1. 
     
     
         180 . The water-soluble solid composition of  claim 172 , wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline antibiotic is greater than 10:1. 
     
     
         181 . The water-soluble solid composition of  claim 172 , wherein upon dissolution of the solid composition in water, a solution having an osmolality of less than 500 mOsm/kg is formed. 
     
     
         182 . The water-soluble solid composition of  claim 172 , wherein upon dissolution of the solid composition in water, a solution having an osmolality of less than 400 mOsm/kg is formed. 
     
     
         183 . The water-soluble solid composition of  claim 172 , wherein upon dissolution of the solid composition in water, a solution having an osmolality of less than 350 mOsm/kg is formed. 
     
     
         184 . The water-soluble solid composition of  claim 172  in the form of a lyophile. 
     
     
         185 . The water-soluble solid composition of  claim 172 , wherein the composition comprises sodium acetate. 
     
     
         186 . The water-soluble solid composition of  claim 172 , wherein the composition comprises NaOH. 
     
     
         187 . The water-soluble solid composition of  claim 172 , wherein the 7-dimethylamino-tetracycline is selected from the group consisting of minocycline, PTK796, and a glycylcycline. 
     
     
         188 . The water-soluble solid composition of  claim 187 , wherein the glycylcycline is tigecycline. 
     
     
         189 . The water-soluble solid composition of  claim 187 , wherein the 7-dimethylamino-tetracycline is minocycline. 
     
     
         190 . The water-soluble solid composition of  claim 187 , wherein the 7-dimethylamino-tetracycline is PTK796. 
     
     
         191 . The water-soluble solid composition of  claim 187 , wherein the composition does not comprise a component selected from the group consisting of an antioxidant, a pyridine-containing compound, nicotinamide, and gluconate. 
     
     
         192 . An article for use in preparing an aqueous intravenous formulation, the article comprising a single-use container comprising a water-soluble solid composition that includes a single antibiotic ingredient and a salt comprising a divalent or trivalent cation, wherein the single antibiotic ingredient consists of a 7-dimethylamino-tetracycline antibiotic or a salt thereof, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline is greater than 3:1, wherein upon dissolution of the water-soluble solid composition in water to make an aqueous solution having a concentration of 7-dimethylamino-tetracycline antibiotic of 1 mg/ml, a solution having a pH greater than 4 and less than 7 is formed, wherein intravenous administration of a solution reconstituted from the solid composition results in reduced injection site hemolysis relative to intravenous administration of a solution that does not include the divalent or trivalent cation. 
     
     
         193 . The article of  claim 192 , wherein upon the dissolution of the water-soluble solid composition in water, a solution having a pH greater than 4.5 and less than 5.5 is formed. 
     
     
         194 . The article of  claim 192 , wherein upon the dissolution of the water-soluble solid composition in water, a solution having a pH between 4.5 and 6.0 is formed. 
     
     
         195 . The article of  claim 192 , wherein upon the dissolution of the water-soluble solid composition in water, a solution having a pH greater than 4 and less than 5 is formed. 
     
     
         196 . The article of  claim 192 , wherein upon the dissolution of the water-soluble solid composition in water, a solution having an osmolality less than 500 mOsm/kg is formed. 
     
     
         197 . The article of  claim 192 , wherein upon the dissolution of the water-soluble solid composition in water, a solution having an osmolality less than 400 mOsm/kg is formed. 
     
     
         198 . The article of  claim 192 , wherein upon the dissolution of the water-soluble solid composition in water, a solution having an osmolality less than 350 mOsm/kg is formed. 
     
     
         199 . The article of  claim 192 , wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline antibiotic is greater than or equal to 5:1. 
     
     
         200 . The article of  claim 192 , wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline antibiotic is greater than 8:1. 
     
     
         201 . The article of  claim 192 , wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline antibiotic is greater than or equal to 10:1. 
     
     
         202 . The article of  claim 192 , wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline antibiotic is from 5:1 to 10:1. 
     
     
         203 . The article of  claim 192 , wherein the water-soluble solid composition is in the form of a lyophile. 
     
     
         204 . The article of  claim 192 , wherein the single-use container comprises at least 100 mg of the 7-dimethylamino-tetracycline antibiotic. 
     
     
         205 . The article of  claim 192 , wherein the single-use container comprises about 100 mg of the 7-dimethylamino-tetracycline antibiotic. 
     
     
         206 . The article of  claim 192 , wherein the water-soluble solid composition includes at least 90 mg of the 7-dimethylamino-tetracycline antibiotic. 
     
     
         207 . The article of  claim 192 , wherein the water-soluble solid composition comprises a salt selected from the group consisting of magnesium sulfate, magnesium acetate, and magnesium chloride. 
     
     
         208 . The article of  claim 192 , wherein the water-soluble solid composition comprises acetate. 
     
     
         209 . The article of  claim 192 , wherein the water-soluble solid composition comprises a base. 
     
     
         210 . The article of  claim 209 , wherein the base is NaOH. 
     
     
         211 . The article of  claim 192 , wherein the cation is selected from iron, copper, zinc, manganese, nickel, cobalt, aluminum, calcium, magnesium and gallium. 
     
     
         212 . The article of  claim 211 , wherein the cation is selected from magnesium, calcium, and zinc. 
     
     
         213 . The article of  claim 192 , wherein the cation is magnesium. 
     
     
         214 . The article of  claim 192 , wherein the 7-dimethylamino-tetracycline is selected from minocycline, PTK796, and a glycylcycline. 
     
     
         215 . The article of  claim 214 , wherein the glycylcycline is tigecycline. 
     
     
         216 . The article of  claim 192 , wherein the 7-dimethylamino-tetracycline is minocycline. 
     
     
         217 . The article of  claim 192 , wherein the 7-dimethylamino-tetracycline is PTK796. 
     
     
         218 . The article of  claim 192 , wherein the water-soluble solid composition comprises minocycline, MgCl 2 , and NaOH, wherein the Mg to minocycline molar ratio is 5:1. 
     
     
         219 . The article of  claim 192 , wherein the water-soluble solid composition does not comprise a component selected from the group consisting of an antioxidant, a pyridine-containing compound, gluconate, a pyrrolidone-containing compound, a water-miscible local anaesthetic, urea, lactose, nicotinamide, procaine, and a dehydrating agent selected from the group consisting of ethyl acetate, acetic anhydride, absolute ethanol, and mixtures thereof.