Compositions containing opioid antagonists

Abstract

Compositions containing opioid antagonists, particularly alvimopan and its active metabolite, with improved solubility and bioavailability for oral or parenteral administration, injectable dosage formulations, kits, and methods of making and using same are disclosed. In preferred embodiments, invention provides injectable formulations containing opioid antagonists, particularly alvimopan and its active metabolite, having low solubility that may be readily prepared, are stable during storage, and provide maximum levels of opioid antagonists when administered parenterally, particularly via injection. The results are achieved by a combination of processing techniques and component selection.

1 - 102 . (canceled) 
     
     
         103 . A composition comprising:
 a. a pharmaceutically-acceptable metal salt of the compound of Formula II:   
       
         
           
           
               
               
           
         
       
       and
 b. at least one bulking agent that crystallizes;
 wherein the composition has a density of less than about 1.0 g/cm 3 ; 
 wherein, upon administration to a patient, the composition has improved solubility and bioavailability for oral or parenteral administration. 
 
 
     
     
         104 . A composition according to  claim 103 ,
 wherein the composition has a density of less than about 0.5 g/cm 3 .   
     
     
         105 . A composition comprising:
 a. a pharmaceutically-acceptable metal salt of the compound of Formula II:   
       
         
           
           
               
               
           
         
       
       and
 b. at least one bulking agent that crystallizes; 
 c. less than about 1% by weight, based on the total weight of the composition, of a solubilizing surfactant; 
 d. less than about 10% by weight, based on the total weight of the composition, of a non-aqueous solvent; and 
 e. less than about 500% by weight, based on the total weight of the composition, of cyclodextrin;
 wherein, upon administration to a patient, the composition has improved solubility and bioavailability for oral or parenteral administration. 
 
 
     
     
         106 . A composition according to  claim 103  or  105 ,
 wherein said pharmaceutically-acceptable metal salt of the compound of Formula II is present at a level of at least about 0.1 mg/mL. 
 
     
     
         107 . A composition according to  claim 103  or  105 ,
 wherein said pharmaceutically-acceptable metal salt of the compound of Formula II is present at a level of at least about 1 mg/mL. 
 
     
     
         108 . A composition according to  claim 103  or  105 ,
 wherein said pharmaceutically-acceptable metal salt of the compound of Formula II is present at a level of at least about 2 mg/mL. 
 
     
     
         109 . A composition according to  claim 103  or  105 ,
 wherein the composition has a shelf life of at least about 18 months. 
 
     
     
         110 . A composition according to  claim 103  or  105 , further comprising at least one opioid. 
     
     
         111 . A composition according to  claim 110 ,
 wherein said opioid is selected from the group consisting of alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil, and tramadol.   
     
     
         112 . A composition according to  claim 103  or  105 , further comprising at least one pharmaceutically acceptable solvent. 
     
     
         113 . A composition according to  claim 112 ,
 wherein said pharmaceutically acceptable solvent is aqueous.   
     
     
         114 . A composition according to  claim 113 ,
 wherein said pharmaceutically acceptable solvent is water, isotonic sodium chloride solution, Ringer's solution, dextrose solution, or lactated Ringer's solution.   
     
     
         115 . A composition according to  claim 103  or  105 ,
 wherein said pharmaceutically-acceptable metal is sodium, calcium, magnesium, or combinations thereof. 
 
     
     
         116 . A composition according to  claim 103  or  105 ,
 wherein said pharmaceutically-acceptable metal is sodium. 
 
     
     
         117 . A composition according to  claim 103  or  105 ,
 wherein said bulking agent is a polyol. 
 
     
     
         118 . A composition according to  claim 117 ,
 wherein said polyol is a carbohydrate or sugar alcohol.   
     
     
         119 . A composition according to  claim 118 ,
 wherein said polyol is a carbohydrate.   
     
     
         120 . A composition according to  claim 119 ,
 wherein said carbohydrate is sucrose, trehalose, lactose, maltose, or mixtures thereof.   
     
     
         121 . A composition according to  claim 118 ,
 wherein said polyol is a sugar alcohol.   
     
     
         122 . A composition according to  claim 121  wherein said sugar alcohol is mannitol, xylitol, erythritol, lactitol, isomalt, polyalditol, or maltitol. 
     
     
         123 . A composition according to  claim 122 ,
 wherein said sugar alcohol is mannitol.   
     
     
         124 . An injectable dosage formulation, comprising the composition of  claim 103  or  105 . 
     
     
         125 . A kit, comprising:
 a. a container comprising an injectable dosage formulation of  claim 124 ; and   b. instructions for preparing an injectable solution.   
     
     
         126 . A kit according to  claim 125 , further comprising a syringe. 
     
     
         127 . A product prepared by a process comprising:
 a. providing a pharmaceutical composition, comprising:
 (i) a pharmaceutically-acceptable metal salt of the compound of Formula II: 
   
       
         
           
           
               
               
           
         
         
           (ii) at least one bulking agent that crystallizes; 
           (iii) at least one weak base; and 
           (iv) water; 
           wherein said composition has an initial pH of at least about 10.5; and 
         
         b. adjusting said pH of said composition to a final pH in the range of about 9 to about 11;
 wherein, upon administration to a patient, said composition has improved solubility and bioavailability for oral or parenteral administration. 
 
       
     
     
         128 . A product according to  claim 127 , wherein the method further comprises drying said composition to remove at least a portion of said water to form a partially or fully dried product. 
     
     
         129 . A product according to  claim 128 , further comprising reconstituting said dried product by combining therewith a pharmaceutically acceptable solvent to form a solution of said dried product. 
     
     
         130 . A product according to  claim 127 ,
 wherein said pharmaceutically-acceptable metal salt of said compound of Formula II is formed in situ.   
     
     
         131 . A product according to  claim 127 ,
 wherein said pharmaceutically-acceptable metal salt of said compound of Formula II is formed from a pharmaceutically-acceptable metal salt of a weak base.   
     
     
         132 . A product according to  claim 131 ,
 wherein said weak base is added in at least about an equimolar amount to said compound of Formula II.   
     
     
         133 . A product according to  claim 127 ,
 wherein said initial pH is at least about 11.   
     
     
         134 . A product according to  claim 127 ,
 wherein said final pH is in the range of about 9.5 to about 10.5.   
     
     
         135 . A product according to  claim 127 ,
 wherein said composition is prepared by a process comprising first admixing said bulking agent and a pharmaceutically-acceptable metal salt of said weak base in water and then adding said compound of Formula II to said admixture.   
     
     
         136 . A product according to  claim 127 ,
 wherein said composition is prepared by a process comprising substantially simultaneously admixing said compound of Formula II, said bulking agent and a pharmaceutically-acceptable metal salt of said weak base in water.   
     
     
         137 . A product according to  claim 127 ,
 wherein said pharmaceutically-acceptable metal is sodium, calcium or magnesium, or a combination thereof.   
     
     
         138 . A product according to  claim 137 ,
 wherein said pharmaceutically-acceptable metal is sodium.   
     
     
         139 . A product according to  claim 127 ,
 wherein said weak base is bicarbonate or carbonate.   
     
     
         140 . A product according to  claim 139 ,
 wherein said weak base is carbonate.   
     
     
         141 . A product according to  claim 128 ,
 wherein said composition is annealed during said drying step.   
     
     
         142 . A product according to  claim 128 ,
 wherein said drying step comprises a process selected from the group consisting of lyophilization, spray drying and vacuum drying, and a combination thereof.   
     
     
         143 . A product according to  claim 142 ,
 wherein said process is lyophilization.   
     
     
         144 . A product according to  claim 129 ,
 wherein said solution is formed in less than about five minutes under ambient conditions.   
     
     
         145 . A product according to  claim 144 ,
 wherein said solution is formed in less than about one minute under ambient conditions.   
     
     
         146 . A product according to  claim 145 ,
 wherein said solution is formed in less than about 30 seconds under ambient conditions.   
     
     
         147 . A product according to  claim 129 ,
 wherein said pharmaceutically acceptable solvent is aqueous.   
     
     
         148 . A product according to  claim 147 ,
 wherein said pharmaceutically acceptable solvent is water, isotonic sodium chloride solution, Ringer's solution, dextrose solution, or lactated Ringer's solution.   
     
     
         149 . A product according to  claim 147 , further comprising administering said reconstituted solution of said dried product to a patient. 
     
     
         150 . A product according to  claim 149 , wherein said administering occurs prior to surgery. 
     
     
         151 . A product according to  claim 149 ,
 wherein said administering occurs during surgery.   
     
     
         152 . A product according to  claim 149 ,
 wherein said administering occurs in the absence of surgery.   
     
     
         153 . A product according to  claim 149 ,
 wherein said administering is via a non-oral route.   
     
     
         154 . A product according to  claim 153 ,
 wherein said administering is via injection.   
     
     
         155 . A product according to  claim 154 ,
 wherein said injection is subcutaneous, intramuscular, or intravenous.   
     
     
         156 . A product according to  claim 127 ,
 wherein said bulking agent is a polyol.   
     
     
         157 . A product according to  claim 156 ,
 wherein said polyol is a carbohydrate or sugar alcohol.   
     
     
         158 . A product according to  claim 157 ,
 wherein said polyol is a carbohydrate.   
     
     
         159 . A product according to  claim 158 ,
 wherein said carbohydrate is sucrose, trehalose, lactose or maltose, or a mixture thereof.   
     
     
         160 . A product according to  claim 157 ,
 wherein said polyol is a sugar alcohol.   
     
     
         161 . A product according to  claim 160 ,
 wherein said sugar alcohol is mannitol, xylitol, erythritol, lactitol, isomalt, polyalditol or maltitol, or a mixture thereof.   
     
     
         162 . A product according to  claim 161 ,
 wherein said sugar alcohol is mannitol.   
     
     
         163 . A product according to  claim 127 ,
 wherein said composition further comprises at least one opioid.   
     
     
         164 . A product according to  claim 163 ,
 wherein said opioid is selected from the group consisting of alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil, tramadol, and mixtures thereof.   
     
     
         165 . A product according to  claim 128 ,
 wherein the product has a density of less than about 1.0 g/cm 3 .   
     
     
         166 . A method of preventing or treating a side effect associated with an opioid in a patient, comprising the step of:
 administering to said patient an effective amount of the composition of  claim 103  or  105 .   
     
     
         167 . A method according to  claim 166 ,
 wherein said side effect is ileus, pruritis, constipation, urinary retention, biliary spasm, opioid bowel dysfunction, colic, nausea, or vomiting or a combination thereof.   
     
     
         168 . A method according to  claim 167 ,
 wherein said side effect is postoperative ileus, postpartum ileus, pruritis, constipation, urinary retention, biliary spasm, opioid bowel dysfunction, colic, postoperative nausea, or postoperative vomiting of a combination thereof.   
     
     
         169 . A method of treating or preventing pain in a patient, comprising the step of:
 administering to said patient in need thereof an effective amount of the composition of  claim 103  or  105 .   
     
     
         170 . A method according to  claim 169 ,
 wherein said pharmaceutical composition further comprises at least one opioid.   
     
     
         171 . A method according to  claim 170 ,
 wherein said opioid is selected from the group consisting of alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil, tramadol, and mixtures thereof.