Chemoembolisation

Abstract

A composition for chemoembolotherapy of solid tumours comprises particles of a water-insoluble water-swellable synthetic anionic polymer and, absorbed therein an anthracycline. Suitably the polymer is a poly(vinyl alcohol) based polymer and the drug is doxorubicin.

1 . A composition comprising particles having a matrix of water-swellable water-insoluble polymer and, absorbed in the matrix, a water-soluble therapeutic agent, and is characterised in that the polymer has an overall anionic charge at a pH in the range 6 to 8, in that the particles, when swollen to equilibrium in water have particle sizes in the range 40-1500 μM and in that the therapeutic agent is an anthracycline compound having at least one amine group  
     
     
         2 . A composition according to  claim 1  in which the polymer is covalently cross-linked.  
     
     
         3 . A composition according to  claim 1  or  claim 2  in which the polymer comprises cross-linked poly(vinyl alcohol).  
     
     
         4 . A composition according to  claim 3  formed by copolymerising poly (vinyl alcohol) macromer having at least two pendant ethylenically unsaturated groups per molecule with ethylenically unsaturated monomers including anionic monomer.  
     
     
         5 . A composition according to  claim 4  in which the anionic monomer has the general formula I  
       Y 1 BQ  
       in which Y 1  is selected from  
       
         
           
           
               
               
           
         
       
       CH 2 ═C(R)—CH 2 —O—, CH 2 ═C(R)—CH 2 OC(O)—, CH 2 ═C(R)OC(O)—, CH 2 ═C(R)—O—, CH 2 ═C(R)CH 2 OC(O)N(R 1 )—, R 2 OOCCR═CRC(O)—O—, RCH═CHC(O)O—, RCH═C(COOR 2 )CH 2 —C(O)—O—.  
       
         
           
           
               
               
           
         
       
       wherein 
 R is hydrogen or a C 1 -C 4  alkyl group;  
 R 1  is hydrogen or a C 1 -C 4  alkyl group;  
 R 2  is hydrogen or a C 1-4  alkyl group or BQ where B and Q are as defined below;  
 A is —O— or —NR 1 —;  
 K 1  is a group —(CH 2 ) r OC(O)—, —(CH 2 ) r C(O)O—, —(CH 2 ) r OC(O)O—, —(CH 2 ) r NR 3 —, —(CH 2 ) r NR 3 C(O)—, —(CH 2 ) r C(O)NR 3 —, —(CH 2 ) r NR 3 C(O)O—, —(CH 2 ) r OC(O)NR 3 —, —(CH 2 ) r NR 3 C(O)NR 3 — (in which the groups R 3  are the same or different), —(CH 2 ) r O—, —(CH 2 ) r SO 3 —, or, optionally in combination with B 1 , a valence bond and r is from 1 to 12 and R 3  is hydrogen or a C 1 -C 4  alkyl group;  
 B is a straight or branched alkanediyl, oxaalkylene, alkanediyloxaalkanediyl, or alkanediyloligo(oxaalkanecliyl) chain optionally containing one or more fluorine atoms up to and including perfluorinated chains or, if Q or Y 1  contains a terminal carbon atom bonded to B a valence bond; and  
 Q is an anionic group.  
 
     
     
         6 . A composition according to  claim 5  in which Y 1  is CH 2 ═CRCOA in which R is H or methyl, A is NH, and in which B is C 1-12  alkanediyl.  
     
     
         7 . A composition according to  claim 5  in which Q is a carboxylate, carbonate, sulphonate, sulphate, nitrate, phosphonate or phosphate group, preferably a sulphonate group.  
     
     
         8 . A composition according to any of  claims 3  to  7  in which the PVA macromer has average molecular weight in the range 1,000 to 500,000 D preferably in the range 10,000 to 100,000 D.  
     
     
         9 . A composition according to any of  claims 3  to  8  in which the pendant ethylenic groups are linked via cyclic acetal linkages with oxygen atoms from adjacent hydroxyl groups, preferably formed by the reaction of N-(alk)acrylamino-substituted aldehyde, usually in the form of the dialkyl acetal, preferably N-acrylaminoacetaldehyde dimethyl acetal.  
     
     
         10 . A composition according to any preceding claim in which the anthracycline is a compound of the general formula II  
       
         
           
           
               
               
           
         
       
       preferably doxorubicin.  
     
     
         11 . A composition according to any preceding claim in which the particles are microspheres.  
     
     
         12 . A composition according to any preceding claim in which the particles are swollen with and suspended in an aqueous liquid.  
     
     
         13 . A composition according to  claim 12  further comprising an imaging agent, preferably a radiopaque agent.  
     
     
         14 . Use of an anthracycline in the manufacture of a composition according to any preceding claim for use in the treatment by embolotherapy of a solid tumour.  
     
     
         15 . Process for producing a composition according to any of  claims 1  to  13  in which particles of a polymer are contacted with a solution of the anthracycline in the presence of water whereby anthracycline is absorbed into the matrix of the polymer.  
     
     
         16 . Process according to  claim 15  in which the contacting is carried out by suspending the polymer particles in an aqueous solution of the anthracycline  
     
     
         17 . Process according to  claim 16  in which the particles of polymer with anthracycline absorbed in the matrix are recovered from the suspension and dried  
     
     
         18 . Use of an anthracycline compound in the manufacture of a composition for use in the treatment of a solid tumour by embolotherapy, in which treatment the anthracycline is delivered from a polymer matrix formed by the copolymerisation of a poly(vinyl alcohol) macromer having at least 2 pendant ethylenically unsaturated groups per molecule and an ethylenically unsaturated anionic monomer.  
     
     
         19 . Use according to  claim 18  in which the polymer matrix is formed in situ in the vasculature of a patient by introducing a liquid composition comprising macromer and monomer into the circulation and initiating polymerisation.