Compositions containing inclusion complexes

Abstract

The invention provides a composition containing particulate composite of a polymer and a therapeutic agent. The composition also contains a complexing agent. The polymer interacts with the complexing agent in a host-guest or a guest-host interaction to form an inclusion complex. A therapeutic composition of the invention may be used to deliver the therapeutic agent and to treat various disorders. Both the polymer of the particulate composite and the complexing agent may be used to introduce functionality into the therapeutic composition. The invention also relates to a method of preparing a composition. The method combines a therapeutic agent, a polymer having host or guest functionality, and a complexing agent having guest or host functionality to form the therapeutic composition. The complexing agent forms an inclusion complex with the polymer. The invention also relates to a method of delivering a therapeutic agent. According to the method, a therapeutically effective amount of a therapeutic composition of the invention is administered to a mammal (e.g. person or animal) in recognized need of the therapeutic. Also disclosed are compounds having the formula:

1 . An adamantane derivative of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         J is —NH—, —C(═O)NH—(CH 2 ) d —, —NH—C(═O)—(CH 2 ) d —, —CH 2 SS—, —C(═O)O—(CH 2 ) e —O—P(═O)(O—(CH 2 ) e -Ad)O —, 
       
       
         
           
           
               
               
           
         
       
       a peptide or polypeptide residue, or
   —NH(C═O)—CH(R 1 )—NH—(C═O)—CH(R 1 )—NH—;
 
 Ad is adamantyl; 
 R 1  is —(CH 2 ) a —CO 2 H, an ester or salt thereof; or 
 —(CH 2 ) a —CONH 2 ; 
 PEG is —O(CH 2 CH 2 O) z —, where z varies from 2 to 500; 
 L is H, —NH 2 , —NH—(C═O)—(CH 2 ) e .—(C═O)—CH 2 —, —S(═O) 2 —HC═CH 2 —, —SS—, —C(═O)O— or a carbohydrate residue; 
 a is 0 or 1; 
 b is 0 or 1; 
 d ranges from 0 to 6; 
 e ranges from 1 to 6; 
 y is 0 or 1; and 
 x is 0 or 1. 
 
     
     
         2 . A composition comprising a particulate composite of a polymer and a therapeutic agent and an inclusion complex of said polymer and a complexing agent having a functional group. 
     
     
         3 . The composition of  claim 2 , wherein said polymer has host functionality and said complexing agent has guest functionality. 
     
     
         4 . The composition of  claim 2 , wherein said polymer has guest functionality and said complexing agent has host functionality. 
     
     
         5 . The composition of  claim 2 , wherein said polymer has host and guest functionality and comprising a mixture of complexing agents having guest and host functionality. 
     
     
         6 . The composition of  claim 3  wherein said host functionality is selected from the group of cyclodextrin, a carcerond, a cavitanal, a crown ether, a cryptand, a cucurbituril, a calixerane, a spherand or a mixture thereof. 
     
     
         7 . The composition of  claim 3  wherein said complexing agent further comprises a spacer group. 
     
     
         8 . The composition of  claim 3  wherein said inclusion guest is selected from the group consisting of adamantane, diadamantane, naphthalene, and cholesterol. 
     
     
         9 . The composition of  claim 8 , wherein said host functionality is a cyclodextrin and said inclusion guest is adamantane or diadamantane. 
     
     
         10 . The composition of  claim 2  wherein said functional group of said functional group is a ligand, nuclear localization signal, endosomal release peptide, endosomal release polymer, a second therapeutic agent, a stabilizing polymer/hydrophilic polymer for stabilization or a mixture thereof; and said spacer group is selected from the group consisting of: a direct link, a phophate group, and polyethylene glycol and a short anionic peptide sequence. 
     
     
         11 . The composition of  claim 2  wherein said therapeutic agent is selected from the group consisting of an antibiotic, a steroid, a polynucleotide, small molecule pharmaceutical, a virus, a plasmid, a peptide, a peptide fragment, a chelating agent, a biologically active macromolecule, and mixtures thereof. 
     
     
         12 . The composition of  claim 11 , wherein said therapeutic agent is a polynucleotide. 
     
     
         13 . The method of delivering a therapeutic comprising the step of administering to a person in recognized need of the therapeutic agent a therapeutically effective amount of a composition of  claim 2 . 
     
     
         14 . A method of preparing a composition comprising the step of:
 combining a therapeutic agent, a polymer having host and/or guest functionality, and a complexing agent to form the composition, wherein said polymer and said therapeutic agent form a particulate composite and said polymer and said complexing agent form an inclusion complex.   
     
     
         15 . The method of  claim 14 , wherein said therapeutic agent is first combined with said polymer to form said particulate composite and said particulate composite is then combined with said complexing agent such that said polymer and said complexing agent form an inclusion complex. 
     
     
         16 . The method of  claim 14 , wherein said polymer is first combined with said complexing agent to form and inclusion complex and said inclusion complex is combined with said therapeutic agent such that said polymer and said therapeutic agent form said particulate composite. 
     
     
         17 . A composition comprising a particulate composite of a cyclodextrin containing polymer and a therapeutic agent and an inclusion complex of said cyclodextrin polymer and a complexing agent comprising an inclusion guest selected from adamantane and diadamantane and a functional group. 
     
     
         18 . The composition of  claim 17 , wherein said therapeutic agent is selected from the group consisting of an antibiotic, a steroid, a polynucleotide, small molecule pharmaceutical, a virus, a plasmid, a peptide, a peptide fragment, a chelating agent, a biologically active macromolecule, and mixtures thereof. 
     
     
         19 . The composition of  claim 18 , wherein said therapeutic agent is a polynucleotide. 
     
     
         20 . The composition of  claim 17 , wherein said complexing agent is an adamantane derivative of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         J is —NH—, —C(═O)NH—(CH 2 ) d —, —NH—C(═O)—(CH 2 ) d —, —CH 2 SS—, —C(═O)O—(CH. 2 ) e —O—P(═O)(O—(CH 2 ) e -Ad)O—, 
       
       
         
           
           
               
               
           
         
       
       Or
   —NH(C═O)—CH(R 1 )—NH—(C═O)—CH(R 1 )—NH—;
 
 Ad is adamantyl; 
 R 1  is —(CH 2 ) a —CO 2 H, an ester or salt thereof; or
   —(CH 2 ) a —CONH 2 ;
 
 
 PEG is —O(CH 2 CH 2 O) z —, where z varies from 2 to 300; 
 L is H, —NH 2 , —NH—(C═O)—(CH 2 ) e —(C═O)—CH 2 —, —S(═O) 2 —HC═CH 2 —, —SS—, —C(═O)O— or a carbohydrate residue; 
 a is 0 or 1; 
 b is 0 or 1; 
 d ranges from 0 to 6; 
 e ranges from 1 to 6; 
 n ranges from 0 to 6; 
 y is 0 or 1; and 
 x is 0 or 1. 
 
     
     
         21 . The method of delivering a therapeutic comprising the step of administering to a person in recognized need of the therapeutic agent a therapeutically effective amount of a composition of  claim 17 .