Drug Delivery Systems Comprising Solid Solutions of Weakly Basic Drugs

Abstract

The present invention is directed to pharmaceutical compositions and dosage forms comprising TPR beads, wherein said TPR beads comprise a solid dispersion of at least one active pharmaceutical ingredient in at least one solubility-enhancing polymer, and a TPR coating comprising a water insoluble polymer and an enteric polymer, wherein the active pharmaceutical ingredient comprises a weakly basic active pharmaceutical ingredient having a solubility of not more than 100 μg/mL at pH 6.8.

1 . A pharmaceutical composition comprising TPR beads, wherein said TPR beads comprise: 
 a solid dispersion of at least one active pharmaceutical ingredient in at least one solubility-enhancing polymer; and    a TPR coating comprising a water insoluble polymer and an enteric polymer;    wherein the active pharmaceutical ingredient comprises a weakly basic active pharmaceutical ingredient having a solubility of not more than 100 μg/mL at pH 6.8.    
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the composition provides a therapeutically effective plasma concentration of the active pharmaceutical ingredient over a period of at least about 18 hours.  
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the ratio of water-insoluble polymer to enteric polymer in the TPR coating ranges from about 9:1 to about 1:9.  
     
     
         4 . The pharmaceutical dosage form of  claim 3 , wherein the TPR coating further comprises about 3% to about 30% by weight of a plasticizer (compared to the total weight of the TPR coating).  
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the solid dispersion of the active pharmaceutical ingredient and solubility-enhancing polymer is deposited on an inert core.  
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the solubility-enhancing polymer is selected from the group consisting of polyvinylpyrrolidone, vinyl acetate/vinyl pyrrolidone copolymers, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene oxide, polyethylene glycol, and cyclodextrins.  
     
     
         7 . The pharmaceutical composition of  claim 5 , wherein the solid dispersion further comprises a pharmaceutically acceptable organic acid.  
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the ratio of organic acid to active pharmaceutical ingredient ranges from about 4/1 to about 1/9 by weight.  
     
     
         9 . The pharmaceutical composition of  claim 5 , wherein the water-insoluble polymer is selected from the group consisting of polymers or copolymers of methacrylic acid esters having quaternary ammonium groups, polyvinyl acetate polymers or copolymers, cellulose acetate, cellulose acetate butyrate, ethylcellulose, and mixtures thereof  
     
     
         10 . The pharmaceutical composition of  claim 5 , wherein the TPR beads comprise IR beads coated with the TPR coating; and 
 the IR beads comprise inert cores coated with the solid dispersion.    
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the ratio of active pharmaceutical ingredient to solubility-enhancing polymer ranges of from about 6:1 to about 1:9.  
     
     
         12 . The pharmaceutical composition of  claim 10 , wherein the TPR beads further comprise an enteric coating applied over the solid dispersion; 
 the enteric coating is up to about 40% of the total weight of the TPR beads; and    the TPR beads provide a lag time of about 1-4 hours.    
     
     
         13 . The pharmaceutical composition of  claim 10 , wherein the TPR beads further comprise an enteric coating applied over the TPR coating; 
 the enteric coating is up to about 40% of the total weight of the TPR beads; and    the TPR beads provide a lag time of up to about 4 hours.    
     
     
         14 . The pharmaceutical composition of  claim 10 , wherein the TPR beads further comprise a first enteric coating applied over the solid dispersion; 
 a second enteric coating applied over the TPR coating;    the first and second enteric coatings are each up to about 40% of the total weight of the TPR beads; and    the TPR beads provide a lag time of up to about 4 hours.    
     
     
         15 . The pharmaceutical composition of  claim 11 , comprising a combination of IR and TPR beads, wherein the ratio of IR to TPR beads is 1:9 to 5:5.  
     
     
         16 . The pharmaceutical composition of  claim 1 , wherein said composition is an orally disintegrating tablet comprising TPR beads and rapidly-dissolving microgranules; 
 wherein the average particle size of the TPR beads and rapidly-dissolving microgranules is not more than 400 μm;    the rapidly-dissolving microgranules comprise particles of at least one disintegrant, and a sugar alcohol and/or saccharide, said particles having an average particle size of not more than 30 μm.    
     
     
         17 . The pharmaceutical composition of  claim 10 , comprising TPR beads, rapidly-dissolving microgranules, and IR beads, wherein the ratio of IR beads to TPR beads ranges from about 10:90 to about 50:50.  
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the IR beads further comprise a taste-masking layer coated over the solid dispersion; and 
 wherein the taste-masking layer comprises a water-insoluble polymer or a water-insoluble polymer in combination with a water-soluble or gastrosoluble pore former.    
     
     
         19 . The pharmaceutical composition of  claim 1 , wherein the one or more active pharmaceutical ingredients are selected from the group consisting of analgesics, anti-convulsants, anti-diabetic agents, anti-infective agents, anti-neoplastic agents, anti-Parkinsonian agents, anti-rheumatic agents, cardiovascular agents, CNS (central nervous system) stimulants, dopamine receptor agonists, anti-emetics, gastrointestinal agents, psychotherapeutic agents, opioid agonists, opioid antagonists, anti-epileptic drugs, histamine H 2  antagonists, anti-asthmatic agents, and skeletal muscle relaxants.  
     
     
         20 . The pharmaceutical composition of  claim 23 , wherein the active pharmaceutical ingredient is lercanidipine, or pharmaceutically acceptable salts, solvates, and/or esters thereof.  
     
     
         21 . The pharmaceutical composition of  claim 17 , wherein: 
 the IR beads further comprise a seal coating comprising hypromellose applied over the solid dispersion;    the solubility-enhancing polymer comprises a vinylpyrrolidone-vinyl acetate copolymer or polyvinyl pyrrolidone;    the TPR coating comprises a pharmaceutically acceptable methacrylate ester/methylmethacrylate ester copolymer and a pH-sensitive methacrylic acid-methylmethacrylate copolymer at a ratio of 9:1 to 1:9;    the weight of the TPR coating is up to about 50% of the weight of the TPR beads; and    the active pharmaceutical ingredient is selected from the group consisting of nifedipine, nicorandil, lercanidipine, iloperidone, clonazepam, and pharmaceutically acceptable salts, solvates and/or esters thereof.    
     
     
         22 . A method of preparing the pharmaceutical composition of  claim 1 , comprising: 
 dissolving the active pharmaceutical ingredient and sufficient solubility-enhancing polymer in a pharmaceutically acceptable solvent;    removing the pharmaceutically acceptable solvent from the solution of active pharmaceutical ingredient and solubility-enhancing polymer, whereby particles of a solid dispersion comprising molecularly dispersed active pharmaceutical ingredient and solubility-enhancing polymer are formed;    dissolving a water insoluble polymer and an enteric polymer in a pharmaceutically acceptable coating solvent, thereby forming a TPR coating solution;    coating the particles of solid dispersion with the TPR coating solution;    removing the coating solvent, thereby forming TPR beads comprising a TPR coating formed on the particles of solid dispersion.    
     
     
         23 . The method of  claim 22 , wherein the solution of active pharmaceutical ingredient and solubility-enhancing polymer is coated onto inert cores prior to forming the solid dispersion particles by removing the pharmaceutically acceptable solvent, whereby IR beads are formed; 
 coating the IR beads with the TPR coating solution, whereby TPR beads are formed.    
     
     
         24 . The method of  claim 23 , further comprising: 
 granulating at least one disintegrant with at least one sugar alcohol and/or at least one saccharide, thereby forming rapidly-dissolving microgranules;    mixing the TPR beads with the rapidly-dissolving microgranules;    compressing the mixture, whereby an orally disintegrating tablet is formed.    
     
     
         25 . The method of  claim 23 , further comprising: 
 granulating at least one disintegrant with at least one sugar alcohol and/or at least one saccharide, thereby forming rapidly-dissolving microgranules;    mixing the TPR beads, IR beads, and the rapidly-dissolving microgranules;    compressing the mixture, whereby an orally disintegrating tablet is formed.