Thermosensitive and biodegradable microgel and a method for the preparation thereof

Abstract

The present invention provides a thermosensitive and biodegradable microgel and a method of synthesizing such microgels. The thermosensitive and biodegradable microgel is synthesized from a macromer comprising a thermosensitive block polymer co-polymerized with a biodegradable moiety encapped with a cross-linkable or polymerizable moiety at either end. The microgels of the present invention are synthesized by inverse suspension polymerization of the macromers. The microgels are biodegradable into components that are non-toxic and easily removed from the body. The microgel of the present invention is temperature sensitive and is “intelligent” as well as biodegradable. The microgels are preferably used for the controlled release of a drug or in tissue engineering. Most preferably, the microgels are suitable for the control release of biologically active substances such as proteins.

1 . A thermosensitive and biodegradable microgel_wherein 
 a) the microgel has a chemically cross-linked network comprising at least one negative temperature-sensitive macromolecule and one biodegradable group represented by structural formula.    wherein   represents chemical cross-linked bonds;       F(DC) 2  represents a polymeric chain between the cross-linked bonds; F is a temperature-sensitive block copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO); D is a biodegradable moiety; and C is a cross-linked moiety resulting from C*, a cross-linkable moiety; and    b) the microgel is in the form of microparticles prepared by the following steps:    i) co-polymerizing a biocompatible polymer or oligomer F with an internal ester D by ring opening polymerization of D in the presence of F using a catalyst; wherein F is a temperature-sensitive polymer or oligomer; D is a biodegradable moiety;    ii) end capping the copolymer with a crosslinkable moiety C* to provide a macromer with crosslinkable ends;    iii) cross linking the crosslinkable end(s) of the macromer to form the microparticles of the microgel by inverse suspension polymerization, wherein the continuous phase is a water-insoluble organic solvent and the dispersion phase consists of a hydrophilic medium in which the macromer is present;    c. the microgel being useful for encapsulating a drug post polymerization; and    d. the drug encapsulated microgel being injectable into the body.    
   
   
       2 . The thermosensitive and biodegradable microgel of  claim 1 , wherein the temperature-sensitive polymer or oligomer F is a tri-block copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), having the formula  
     
       
         
         
             
             
         
       
       wherein X is from 1 to 300, Y from 1 to 300.  
     
   
   
       3 . The thermosensitive and biodegradable microgel of  claim 1 , wherein D is a biodegradable oligoester or polyester, or is a biodegradable random or block co-oligoester or co-polyester selected from the group consisting of (R 1 ) m , (R 2 ) n , and (R 3 ) l , wherein R 1 , R 2 , and R 3  respectively are represented by:  
     
       
         
         
             
             
         
       
       wherein m=0˜100, n=0˜100, l=0˜100, and not all of m, n and l can be zero.  
     
   
   
       4 . The thermosensitive and biodegradable microgel of  claim 1 , wherein the cross-linked moiety C is  
     
       
         
         
             
             
         
       
     
     wherein R can be —H, —CH 3  or alkyl.  
   
   
       5 . The thermosensitive and biodegradable microgel of  claim 1 , wherein the temperature-sensitive polymer or oligomer F is used as the principal constituent in an amount based on the microgel in the range of 51 wt %˜99.9 wt %.  
   
   
       6 . The thermosensitive and biodegradable microgel of  claim 1 , wherein the chemically cross-linked network is obtained by crosslinking a mixture of different block copolymers, F and D and comprising a crosslinked moiety C.  
   
   
       7 . The thermosensitive and biodegradable microgel of  claim 1 , wherein 0 wt %˜49 wt % of the chemically cross-linked network comprises a dangling unpolymerized end.  
   
   
       8 . The thermosensitive and biodegradable microgel of  claim 1 , wherein the size of the microgel particles is in the range of 5 nm to 5 mm.  
   
   
       9 . The thermosensitive and biodegradable microgel of  claim 1 , wherein the microgel is in a bulk state or admixed with a solvent.  
   
   
       10 . A method of loading a substance into the network of the thermosensitive and biodegradable microgel of  claim 1  by absorbing the substance into the network of the microgel by allowing the microgel to swell in a solution containing the substance at a low temperature below the phase transition temperature of the microgel.  
   
   
       11 . The method of  claim 10 , wherein the substance absorbed in the gel was entrapped by increasing the temperature, or by drying the hydrogel, or by increasing the temperature and then drying the hydrogel.  
   
   
       12 . The method of  claim 10 , wherein the absorbed or entrapped substance from the microgels was released into a solution at a temperature above the phase transition temperature of the microgel.  
   
   
       13 . The method of  claim 10 , wherein the phase transition temperature is below the temperature of a human or a warm-blood animal.  
   
   
       14 . The method of  claim 10 , wherein the swollen microgel is loaded with a substance and entrapped therein at a temperature above the phase transition temperature of the microgel for a time sufficient to cause further gelation of the network to prevent leakage of the entrapped substance.  
   
   
       15 . The method of  claim 10 , wherein the loaded substance is a pure substance of a mixture which does not chemically react with the microgel.  
   
   
       16 . The method of  claim 10 , wherein the loaded substance is biologically active.  
   
   
       17 . The method of  claim 16 , wherein the solvent for the biologically active substance is water, an aqueous solution or PBS.  
   
   
       18 . The method of  claim 16 , wherein the biologically active substance is a biomacromolecule or a derivative thereof.  
   
   
       19 . The method of  claim 18 , wherein the biologically active substance is a protein.