Solid pharmaceutical dosage forms comprising bisphosphonates and modified amino acid carriers

Abstract

The present invention provides novel solid pharmaceutical dosage forms for oral administration comprising a bisphosphonate, or a pharmaceutically acceptable salt thereof, which bisphosphonate is present in an amount not therapeutically effective when the bisphosphonate is orally administered alone; and a modified amino acid carrier, or a pharmaceutically acceptable salt thereof, which modified amino acid carrier is present in an amount effective to facilitate absorption of the bisphosphonate in the gastrointestinal tract such that the bisphosphonate is therapeutically effective. The ratio of bisphosphonate to modified amino acid carrier is from about 1:30 to about 1:1, respectively. These novel solid pharmaceutical dosage forms are useful in the treatment or control of bone diseases and particular disorders in calcium metabolism, including, for example, osteoporosis, hypercalcaemia of cancer, and the treatment of metastatic bone pain. The present invention also provides a method for treating these diseases employing the solid pharmaceutical dosage forms and a method for preparing the pharmaceutical dosage forms.

1 . A solid pharmaceutical dosage form for oral administration comprising: 
 (a) a bisphosphonate, or a pharmaceutically acceptable salt thereof, which bisphosphonate is present in an amount not therapeutically effective when the bisphosphonate is orally administered alone; and    (b) a modified amino acid carrier, or a pharmaceutically acceptable salt thereof, which modified amino acid carrier is present in an amount effective to facilitate absorption of the bisphosphonate in the gastrointestinal tract such that the bisphosphonate is therapeutically effective;    wherein the ratio of bisphosphonate to modified amino acid carrier is from about 1:30 to about 1:1, respectively.    
   
   
       2 . The dosage form according to  claim 1 , wherein the bisphosphonate is selected from the group consisting of alendronate, clodronate, etidronate, ibandronate, incadronate, olpadronate, pamidronate, risedronate, titudronate, zoledronate, and pharmaceutically acceptable salts thereof.  
   
   
       3 . The dosage form according to  claim 2 , wherein the bisphosphonate is ibandronate, or a pharmaceutically acceptable salt thereof.  
   
   
       4 . The dosage form according to  claim 3 , wherein the bisphosphonate is ibandronate sodium.  
   
   
       5 . The dosage form according to  claim 1 , wherein the modified amino acid carrier is selected from the group consisting of N-(8-(2-hydroxybenzoyl)amino)caprylate, N-(10-(2-hydroxybenzoyl)amino)capricate, N-(2-methoxybenzoyl)-3-(4-aminophenyl)proprionate, N-(3-dimethylaminobenzoyl)-3-(4-aminophenyl)butyrate, N-(2-methoxybenzoyl)-3-(4-aminophenyl)butyrate, N-(2-aminobenzoyl)-3-(4-aminophenyl)butyrate, N-(4-(3-cyclohexylproprionyl)amino)butyrate, and N-(6-(4-methylcyclohexylcarbonyl)amino)caproate, their free acids, and pharmaceutically acceptable salts thereof.  
   
   
       6 . The dosage form according to  claim 5 , wherein the modified amino acid carrier is N-(8-(2-hydroxybenzoyl)amino)caprylate, or a pharmaceutically acceptable salt thereof.  
   
   
       7 . The dosage form according to  claim 6 , wherein the modified amino acid carrier is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate.  
   
   
       8 . The dosage form according to  claim 1 , wherein the ratio of bisphosphonate to modified amino acid carrier is such that absorption of the bisphosphonate in the gastrointestinal tract is at least 2 times greater than that of the bisphosphonate when administered alone.  
   
   
       9 . The dosage form according to  claim 3 , wherein the amount of ibandronate present is from about 0.25 mg to about 175 mg.  
   
   
       10 . The dosage form according to  claim 4 , wherein the amount of ibandronate sodium present is such as to be equivalent to from about 0.25 mg to about 175 mg of ibandronic acid.  
   
   
       11 . The dosage form according to  claim 1 , wherein the ratio of bisphosphonate to modified amino acid carrier is about 1:20, respectively.  
   
   
       12 . The dosage form according to  claim 1 , wherein the ratio of bisphosphonate to modified amino acid carrier is about 1:10, respectively.  
   
   
       13 . The dosage form according to  claim 1 , wherein the ratio of bisphosphonate to modified amino acid carrier is about 1:5, respectively.  
   
   
       14 . The dosage form according to  claim 1 , further comprising povidone present in an amount from about 2% to about 30% by weight of the total composition.  
   
   
       15 . The dosage form according to  claim 14  wherein the povidone is present in an amount from about 10% to about 20%.  
   
   
       16 . The dosage form according to  claim 15  wherein the povidone is present in an amount from about 12% to about 15%.  
   
   
       17 . A method for treating osteoporosis comprising administering to a subject in need thereof a solid pharmaceutical dosage form for oral administration comprising: 
 (a) a bisphosphonate, or a pharmaceutically acceptable salt thereof, which bisphosphonate is present in an amount not therapeutically effective when the bisphosphonate is orally administered alone; and    (b) a modified amino acid carrier, or a pharmaceutically acceptable salt thereof, which modified amino acid carrier is present in an amount effective to facilitate absorption of the bisphosphonate in the gastrointestinal tract such that the bisphosphonate is therapeutically effective;    wherein the ratio of bisphosphonate to modified amino acid carrier is from about 1:30 to about 1:1, respectively.    
   
   
       18 . The method according to  claim 17 , wherein the bisphosphonate is selected from the group consisting of alendronate, clodronate, etidronate, ibandronate, incadronate, olpadronate, pamidronate, risedronate, titudronate, zoledronate, and pharmaceutically acceptable salts thereof.  
   
   
       19 . The method according to  claim 18 , wherein the bisphosphonate is ibandronate, or a pharmaceutically acceptable salt thereof.  
   
   
       20 . The method according to  claim 19 , wherein the bisphosphonate is ibandronate sodium.  
   
   
       21 . The method according to  claim 17 , wherein the modified amino acid carrier is selected from the group consisting of N-(8-(2-hydroxybenzoyl)amino)caprylate, N-(10-(2-hydroxybenzoyl)amino)capricate, N-( 2-methoxybenzoyl)-3-(4-aminophenyl)proprionate, N-(3-dimethylaminobenzoyl) -3-(4-aminophenyl)butyrate, N-(2-methoxybenzoyl)-3-(4-aminophenyl)butyrate, N-( 2-aminobenzoyl)-3-(4-aminophenyl)butyrate, N-(4-(3-cyclohexylproprionyl)amino)butyrate, N-(6-(4-methylcyclohexylcarbonyl)amino)caproate, their free acids, and pharmaceutically acceptable salts thereof.  
   
   
       22 . The method according to  claim 21 , wherein the modified amino acid carrier is N-(8-(2-hydroxybenzoyl)amino)caprylate, or a pharmaceutically acceptable salt thereof.  
   
   
       23 . The method according to  claim 22 , wherein the modified amino acid carrier is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate.  
   
   
       24 . The method according to  claim 17 , wherein the ratio of bisphosphonate to modified amino acid carrier is such that absorption of the bisphosphonate in the gastrointestinal tract is at least 2 times greater than that of the bisphosphonate when administered alone.  
   
   
       25 . The method according to  claim 19 , wherein the amount of ibandronate administered is from about 0.25 mg to about 75 mg.  
   
   
       26 . The method according to  claim 20 , wherein the amount of ibandronate sodium administered is such as to be equivalent to from about 0.25 mg to about 75 mg of ibandronic acid.  
   
   
       27 . The method according to  claim 26 , wherein the amount of ibandronate sodium administed daily is such as to be equivalent to from about 0.25 mg to about 1.25 mg of ibandronic acid.  
   
   
       28 . The method according to  claim 26 , wherein the amount of ibandronate sodium administed monthly is such as to be equivalent to from about 15 mg to about 75 mg of ibandronic acid.  
   
   
       29 . The method according to  claim 17 , wherein the ratio of bisphosphonate to modified amino acid carrier is about 1:20, respectively.  
   
   
       30 . The method according to  claim 17 , wherein the ratio of bisphosphonate to modified amino acid carrier is about 1:10, respectively.  
   
   
       31 . The method according to  claim 17 , wherein the ratio of bisphosphonate to modified amino acid carrier is about 1:5, respectively.  
   
   
       32 . The method according to  claim 17 , wherein the pharmaceutical dosage form further comprises povidone present in an amount from about 2% to about 30% by weight of the total composition.  
   
   
       33 . A method for treating hypercalcemia of cancer comprising administering to a subject in need thereof a solid pharmaceutical dosage form for oral administration comprising: 
 (a) a bisphosphonate, or a pharmaceutically acceptable salt thereof, which bisphosphonate is present in an amount not therapeutically effective when the bisphosphonate is orally administered alone; and    (b) a modified amino acid carrier, or a pharmaceutically acceptable salt thereof, which modified amino acid carrier is present in an amount effective to facilitate absorption of the bisphosphonate in the gastrointestinal tract such that the bisphosphonate is therapeutically effective;    wherein the ratio of bisphosphonate to modified amino acid carrier is from about 1:30 to about 1:1, respectively.    
   
   
       34 . The method according to  claim 33 , wherein the bisphosphonate is selected from the group consisting of alendronate, clodronate, etidronate, ibandronate, incadronate, olpadronate, pamidronate, risedronate, titudronate, zoledronate, and pharmaceutically acceptable salts thereof.  
   
   
       35 . The method according to  claim 34 , wherein the bisphosphonate is ibandronate, or a pharmaceutically acceptable salt thereof.  
   
   
       36 . The method according to  claim 35 , wherein the bisphosphonate is ibandronate sodium.  
   
   
       37 . The method according to  claim 33 , wherein the modified amino acid carrier is selected from the group consisting of N-(8-(2-hydroxybenzoyl)amino)caprylate, N-(10-(2-hydroxybenzoyl)amino)capricate, N-( 2-methoxybenzoyl)-3-(4-aminophenyl)proprionate, N-(3-dimethylaminobenzoyl) -3-(4-aminophenyl)butyrate, N-(2-methoxybenzoyl)-3-(4-aminophenyl)butyrate, N-( 2-aminobenzoyl)-3-(4-aminophenyl)butyrate, N-(4-(3-cyclohexylproprionyl)amino)butyrate, N-(6-(4-methylcyclohexylcarbonyl)amino)caproate, their free acids, and pharmaceutically acceptable salts thereof.  
   
   
       38 . The method according to  claim 37 , wherein the modified amino acid carrier is N-(8-(2-hydroxybenzoyl)amino)caprylate, or a pharmaceutically acceptable salt thereof.  
   
   
       39 . The method according to  claim 38 , wherein the modified amino acid carrier is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate.  
   
   
       40 . The method according to  claim 33 , wherein the ratio of bisphosphonate to modified amino acid carrier is such that absorption of the bisphosphonate in the gastrointestinal tract is at least 2 times greater than that of the bisphosphonate when administered alone.  
   
   
       41 . The method according to  claim 35 , wherein the amount of ibandronate administered is from about 5 mg to about 175 mg.  
   
   
       42 . The method according to  claim 36 , wherein the amount of ibandronate sodium administered is such as to be equivalent to from about 5 mg to about 175 mg of ibandronic acid.  
   
   
       43 . The method according to  claim 42 , wherein the amount of ibandronate sodium administered daily is such as to be equivalent to from about 5 mg to about 25 mg of ibandronic acid.  
   
   
       44 . The method according to  claim 36 , wherein the amount of ibandronate sodium administered weekly is such as to be equivalent to from about 35 mg to about 175 mg of ibandronic acid.  
   
   
       45 . The method according to  claim 33 , wherein the ratio of bisphosphonate to modified amino acid carrier is about 1:20, respectively.  
   
   
       46 . The method according to  claim 33 , wherein the ratio of bisphosphonate to modified amino acid carrier is about 1:10, respectively.  
   
   
       47 . The method according to  claim 33 , wherein the ratio of bisphosphonate to modified amino acid carrier is about 1:5, respectively.  
   
   
       48 . The method according to  claim 33 , wherein the pharmaceutical dosage form further comprises povidone present in an amount from about 2% to about 30% by weight of the total composition.  
   
   
       49 . A method for treating metastatic bone pain comprising administering to a subject in need thereof a solid pharmaceutical dosage form for oral administration comprising: 
 (a) a bisphosphonate, or a pharmaceutically acceptable salt thereof, which bisphosphonate is present in an amount not therapeutically effective when the bisphosphonate is orally administered alone; and    (b) a modified amino acid carrier, or a pharmaceutically acceptable salt thereof, which modified amino acid carrier is present in an amount effective to facilitate absorption of the bisphosphonate in the gastrointestinal tract such that the bisphosphonate is therapeutically effective;    wherein the ratio of bisphosphonate to modified amino acid carrier is from about 1:30 to about 1:1, respectively.    
   
   
       50 . The method according to  claim 49 , wherein the bisphosphonate is selected from the group consisting of alendronate, clodronate, etidronate, ibandronate, incadronate, olpadronate, pamidronate, risedronate, titudronate, zoledronate, and pharmaceutically acceptable salts thereof.  
   
   
       51 . The method according to  claim 50 , wherein the bisphosphonate is ibandronate, or a pharmaceutically acceptable salt thereof.  
   
   
       52 . The method according to  claim 51 , wherein the bisphosphonate is ibandronate sodium.  
   
   
       53 . The method according to  claim 49 , wherein the modified amino acid carrier is selected from the group consisting of N-(8-(2-hydroxybenzoyl)amino)caprylate, N-(10-(2-hydroxybenzoyl)amino)capricate, N-( 2-methoxybenzoyl)-3-(4-aminophenyl)proprionate, N-(3-dimethylaminobenzoyl)-3-(4-aminophenyl)butyrate, N-(2-methoxybenzoyl)-3-(4-aminophenyl)butyrate, N-(2-aminobenzoyl)-3-(4-aminophenyl)butyrate, N-(4-(3-cyclohexylproprionyl)amino)butyrate, N-(6-(4-methylcyclohexylcarbonyl)amino)caproate, their free acids, and pharmaceutically acceptable salts thereof.  
   
   
       54 . The method according to  claim 53 , wherein the modified amino acid carrier is N-(8-(2-hydroxybenzoyl)amino)caprylate, or a pharmaceutically acceptable salt thereof.  
   
   
       55 . The method according to  claim 54 , wherein the modified amino acid carrier is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate.  
   
   
       56 . The method according to  claim 49 , wherein the ratio of bisphosphonate to modified amino acid carrier is such that absorption of the bisphosphonate in the gastrointestinal tract is at least 2 times greater than that of the bisphosphonate when administered alone.  
   
   
       57 . The method according to  claim 51 , wherein the amount of ibandronate administered is from about 5 mg to about 175 mg.  
   
   
       58 . The method according to  claim 52 , wherein the amount of ibandronate sodium present is such as to be equivalent to from about 5 mg to about 175 mg of ibandronic acid.  
   
   
       59 . The method according to  claim 49 , wherein the ratio of bisphosphonate to modified amino acid carrier is about 1:20, respectively.  
   
   
       60 . The method according to  claim 49 , wherein the ratio of bisphosphonate to modified amino acid carrier is about 1:10, respectively.  
   
   
       61 . The method according to  claim 49 , wherein the ratio of bisphosphonate to modified amino acid carrier is about 1:5, respectively.  
   
   
       62 . The method according to  claim 49 , further comprising povidone present in an amount from about 2% to about 30%, by weight of the total composition.  
   
   
       63 . A method for preparing a solid pharmaceutical dosage form for oral administration comprising admixing: 
 (a) a bisphosphonate, or a pharmaceutically acceptable salt thereof, which bisphosphonate is present in an amount not therapeutically effective when the bisphosphonate is orally administered alone; and    (b) a modified amino acid carrier, or a pharmaceutically acceptable salt thereof, which modified amino acid carrier is present in an amount effective to facilitate absorption of the bisphosphonate in the gastrointestinal tract such that the bisphosphonate is therapeutically effective;    such that the ratio of bisphosphonate to modified amino acid carrier is from about 1:30 to about 1:1, respectively, and wherein the modified amino acid carrier and the bisphosphonate are in intimate contact.    
   
   
       64 . The method according to  claim 63 , wherein the bisphosphonate is ibandronate, or a pharmaceutically acceptable salt thereof.  
   
   
       65 . The method according to  claim 63 , wherein the modified amino acid carrier is selected from the group consisting of N-(8-(2-hydroxybenzoyl)amino)caprylate, N-(10-(2-hydroxybenzoyl)amino)capricate, N-( 2-methoxybenzoyl)-3-(4-aminophenyl)proprionate, N-(3-dimethylaminobenzoyl) -3-(4-aminophenyl)butyrate, N-(2-methoxybenzoyl)-3-(4-aminophenyl)butyrate, N-(2-aminobenzoyl)-3-(4-aminophenyl)butyrate, N-(4-(3-cyclohexylproprionyl)amino)butyrate, and N-(6-(4-methylcyclohexylcarbonyl)amino)caproate, their free acids, and pharmaceutically acceptable salts thereof.  
   
   
       66 . The method according to  claim 65 , wherein the modified amino acid carrier is N-(8-(2-hydroxybenzoyl)amino)caprylate, or a pharmaceutically acceptable salt thereof.  
   
   
       67 . The method according to  claim 65 , wherein the ratio of bisphosphonate to modified amino acid carrier is such that absorption of the bisphosphonate in the gastrointestinal tract is at least 2 times greater than that of the bisphosphonate when administered alone.  
   
   
       68 . The method according to  claim 65 , wherein the amount of ibandronate present is from about 0.25 mg to about 175 mg.  
   
   
       69 . The method according to  claim 65 , wherein the ratio of bisphosphonate to modified amino acid carrier is about 1:20, respectively.  
   
   
       70 . The method according to  claim 65 , wherein the ratio of bisphosphonate to modified amino acid carrier is about 1:10, respectively.  
   
   
       71 . The method according to  claim 65 , wherein the ratio of bisphosphonate to modified amino acid carrier is about 1:5, respectively.  
   
   
       72 . The method according to  claim 65 , wherein the solid pharmaceutical dosage form further comprises povidone present in an amount from about 2% to about 30% by weight of the total composition.