Solid-state form of celecoxib having enhanced bioavailability

Abstract

The selective cyclooxygenase-2 inhibitory drug celecoxib is provided in amorphous form. Also provided is a celecoxib drug substance wherein the celecoxib is present, in at least a detectable amount, as amorphous celecoxib. Also provided is a celecoxib-crystallization inhibitor composite comprising particles of amorphous celecoxib or a celecoxib drug substance of the invention in intimate association with one or more crystallization inhibitors, for example polymers. Also provided is a pharmaceutical composition comprising such a celecoxib-crystallization inhibitor composite and one or more excipients. Also provided are processes for preparing amorphous celecoxib, a celecoxib drug substance of the invention, a celecoxib-crystallization inhibitor composite of the invention, and a pharmaceutical composition of the invention. Also provided is a method of treating a medical condition or disorder in a subject where treatment with a cyclooxygenase-2 inhibitor is indicated, comprising administering, for example orally, a composition of the invention in a therapeutically effective amount.

1 . (canceled)  
   
   
       2 . A celecoxib drug substance wherein the celecoxib is present, in at least a detectable amount, as amorphous celecoxib.  
   
   
       3 . The drug substance of  claim 2  wherein the amorphous celecoxib is present in an amount of about 10% to about 100% by weight of the celecoxib.  
   
   
       4 . The drug substance of  claim 2  that comprises substantially phase pure amorphous celecoxib.  
   
   
       5 . A celecoxib-crystallization inhibitor composite comprising particles of amorphous celecoxib in intimate association with one or more crystallization inhibitor(s) in an amount effective to reduce transformation of amorphous celecoxib to crystalline celecoxib.  
   
   
       6 . The composite of  claim 5  wherein the crystallization inhibitor is a polymer.  
   
   
       7 . The composite of  claim 6  wherein the polymer is selected from polyvinylpyrrolidone and hydroxypropylmethylcellulose.  
   
   
       8 . The composite of  claim 6  wherein the polymer is polyvinylpyrrolidone.  
   
   
       9 . The composite of  claim 5  wherein the crystallization inhibitor(s) are present in a total amount of about 10% to about 80% by weight of the composite.  
   
   
       10 . A celecoxib-crystallization inhibitor composite comprising particles of a celecoxib drug substance of  claim 2  in intimate association with one or more crystallization inhibitor(s) in an amount effective to reduce transformation of amorphous celecoxib to crystalline celecoxib.  
   
   
       11 . The composite of  claim 10  wherein the crystallization inhibitor is a polymer.  
   
   
       12 . The composite of  claim 11  wherein the polymer is selected from polyvinylpyrrolidone and hydroxypropylmethylcellulose.  
   
   
       13 . The composite of  claim 11  wherein the polymer is polyvinylpyrrolidone.  
   
   
       14 . The composite of  claim 10  wherein the crystallization inhibitor(s) are present in a total amount of about 10% to about 80% by weight of the composite.  
   
   
       15 . (canceled)  
   
   
       16 . A pharmaceutical composition comprising a celecoxib drug substance of  claim 2  in a total celecoxib dosage amount of about 10 mg to about 1000 mg, and one or more pharmaceutically acceptable excipients.  
   
   
       17 . A pharmaceutical composition comprising a celecoxib-crystallization inhibitor composite of  claim 5 , in a total celecoxib dosage amount of about 10 mg to about 1000 mg, and one or more pharmaceutically acceptable excipients  
   
   
       18 . A pharmaceutical composition comprising a celecoxib-crystallization inhibitor composite of  claim 10 , in a total celecoxib dosage amount of about 10 mg to about 1000 mg, and one or more pharmaceutically acceptable excipients.  
   
   
       19 . (canceled)  
   
   
       20 . A process for preparing a celecoxib-crystallization inhibitor composite, the process comprising 
 (a) dissolving celecoxib and one or more crystallization inhibitors in a solvent liquid to form a solution;    (b) drying the solution to form a celecoxib-crystallization inhibitor composite wherein the celecoxib is present, at least in a detectable amount, in amorphous form; and    optionally    (c) grinding the celecoxib drug substance to form a celecoxib-crystallization inhibitor composite powder.    
   
   
       21 . The process of  claim 20  wherein drying step (b) is performed by spray drying.  
   
   
       22 . The process of  claim 20  wherein the solvent liquid comprises isopropanol.  
   
   
       23 . A process for preparing a pharmaceutical composition, the process comprising 
 (a) blending amorphous celecoxib, or a celecoxib drug substance wherein the celecoxib is present, in at least a detectable amount, as amorphous celecoxib, with one or more excipients to form a blend; and    (b) tableting or encapsulating the blend to form celecoxib tablets or capsules respectively.    
   
   
       24 . The process of  claim 23 , further comprising granulating the blend to form a granulate prior to tableting or encapsulating.  
   
   
       25 . The process of  claim 24  wherein granulating is performed by wet granulation to form a wet granulate, and wherein the wet granulate is dried prior to tableting or encapsulating.  
   
   
       26 . A process for preparing a pharmaceutical composition, the process comprising 
 (a) blending a celecoxib-crystallization inhibitor composite of  claim 5  with one or more excipients to form a blend; and    (b) tableting or encapsulating the blend to form celecoxib tablets or capsules respectively.    
   
   
       27 . The process of  claim 26 , further comprising granulating the blend to form a granulate prior to tableting or encapsulating.  
   
   
       28 . The process of  claim 27  wherein granulating is performed by wet granulation to form a wet granulate, and wherein the wet granulate is dried prior to tableting or encapsulating.  
   
   
       29 . A process for preparing a pharmaceutical composition, the process comprising 
 (a) blending a celecoxib-crystallization inhibitor composite of  claim 10  with one or more excipients to form a blend; and    (b) tableting or encapsulating the blend to form celecoxib tablets or capsules respectively.    
   
   
       30 . The process of  claim 29 , further comprising granulating the blend to form a granulate prior to tableting or encapsulating.  
   
   
       31 . The process of  claim 30  wherein granulating is performed by wet granulation to form a wet granulate, and wherein the wet granulate is dried prior to tableting or encapsulating.  
   
   
       32 . A method of treating a medical condition or disorder in a subject where treatment with a cyclooxygenase-2 inhibitor is indicated, comprising orally administering one or more dose units of a composition of  claim 15  once or twice a day.  
   
   
       33 . A method of treating a medical condition or disorder in a subject where treatment with a cyclooxygenase-2 inhibitor is indicated, comprising orally administering one or more dose units of a composition of  claim 16  once or twice a day.  
   
   
       34 . A method of treating a medical condition or disorder in a subject where treatment with a cyclooxygenase-2 inhibitor is indicated, comprising orally administering one or more dose units of a composition of  claim 17  once or twice a day.  
   
   
       35 . A method of treating a medical condition or disorder in a subject where treatment with a cyclooxygenase-2 inhibitor is indicated, comprising orally administering one or more dose units of a composition of  claim 18  once or twice a day.