Microspheres useful for therapeutic vascular embolization

Abstract

Provided herein, for example, are microspheres comprising a gelatin or gelatin substitute and a copolymer of a N-tris-hydroxymethyl methylacrylamide monomer unit, a diethylaminoethylacrylamide monomer unit and a N,N-methylene-bis-acrylamide monomer unit. Also provided are methods of producing microspheres comprising a gelatin or gelatin substitute and a copolymer of a N-tris-hydroxymethyl methylacrylamide monomer unit, a diethylaminoethylacrylamide monomer unit and a N,N-methylene-bis-acrylamide monomer unit. Further provided herein, for example, are compositions comprising the microspheres and methods of using the microspheres and compositions thereof.

1 . A microsphere comprising:
 (a) a copolymer comprising a N-tris-hydroxymethyl methylacrylamide monomer unit, a diethylaminoethylacrylamide monomer unit and a N,N-methylene-bis-acrylamide monomer unit, and   (b) crosslinked gelatin;   
       wherein the microsphere exhibits in a  1 H NMR spectrum, a first peak from about 3.5 ppm to about 4 ppm, a second peak from about 3 ppm to about 3.5 ppm, and a third peak from about 1 ppm to about 1.5 ppm; and wherein
 (i) the integration ratio of the second peak to the first peak is from 0.50 to about 0.65, 
 (ii) the integration ratio of the third peak to the first peak is from 0.61 to about 0.75, or 
 (iii) a combination of (i) and (ii). 
 
     
     
         2 . The microsphere of  claim 1 , wherein the first peak is at about 3.77 ppm, the second peak is at about 3.2 ppm, the third peak is at about 1.3 ppm, or a combination thereof. 
     
     
         3 . The microsphere of  claim 2 , wherein the integration ratio of the second peak to the first peak is about 0.574, or wherein the integration ratio of the third peak to the first peak is about 0.625. 
     
     
         4 . The microsphere of  claim 1 , wherein the microsphere is at 25° C. and/or in a deuterated solvent when the  1 H NMR spectrum is recorded. 
     
     
         5 . The microsphere of  claim 4 , wherein the  1 H NMR spectrum is recorded at 400 MHz. 
     
     
         6 . The microsphere of  claim 1 , wherein one, two or three of the N-tris-hydroxymethyl methylacrylamide, diethylaminoethylacrylamide and N,N-methylene-bis-acrylamide monomer units is an ultra-pure monomer unit. 
     
     
         7 . The microsphere of  claim 6 , wherein the N-tris-hydroxymethyl methylacrylamide monomer unit comprises less than 9% of impurities and/or the diethylaminoethylacrylamide monomer unit comprises less than 2% of impurities. 
     
     
         8 . The microsphere of  claim 1 , wherein the microsphere has a diameter from about 1 μm to about 2000 μm, from about 40 μm to about 120 μm, from about 100 μm to about 300 μm, from about 300 μm to about 500 μm, from about 500 μm to about 700 μm, from about 700 μm to about 900 μm, or from about 900 μm to about 1200 μm. 
     
     
         9 . A method of making microspheres comprising:
 (a) preparing an aqueous solution comprising
 (i) a N-tris-hydroxymethyl methylacrylamide monomer, 
 (ii) a diethylaminoethylacrylamide monomer, 
 (iii) a N,N-methylene-bis-acrylamide monomer, and 
 (iv) gelatin, 
 wherein the N-tris-hydroxymethyl methylacrylamide monomer and/or the diethylaminoethylacrylamide monomer is an ultra-pure monomer; 
   (b) adding the aqueous solution to a liquid organic phase that has low miscibility in water, before or while stirring; thereby producing microspheres comprising a copolymer comprising a N-tris-hydroxymethyl methylacrylamide monomer unit, a diethylaminoethylacrylamide monomer unit and a N,N-methylene-bis-acrylamide monomer unit;   (c) optionally subjecting the microspheres to ultrasonication; and   (d) crosslinking the gelatin.   
     
     
         10 . The method of  claim 9 , wherein the aqueous solution is added through a feed ring to the liquid organic phase. 
     
     
         11 . The method of  claim 9 , wherein the N-tris-hydroxymethyl methylacrylamide monomer comprises less than 9% of impurities and/or the diethylaminoethylacrylamide monomer comprises less than 2% of impurities. 
     
     
         12 . The method of  claim 9 , wherein the microspheres are ultra-pure microspheres. 
     
     
         13 . The method of  claim 12 , wherein (i) the ultra-pure microspheres comprise about 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less or 1% or less of impurities, (ii) the ultra-pure microspheres comprise 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more or 99% or more by weight of the N-tris-hydroxymethyl methylacrylamide, the diethylaminoethylacrylamide, the N,N-methylene-bis-acrylamide and the gelatin, or (iii) a combination of (i) and (ii). 
     
     
         14 . The method of  claim 9 , wherein the ultrasonication is done in an ultrasonic bath. 
     
     
         15 . The method of  claim 9 , wherein the method does not comprise sieving the microspheres. 
     
     
         16 . Microspheres prepared by the method of  claim 9 . 
     
     
         17 . The microspheres of  claim 16 , wherein the microspheres exhibit in a  1 H NMR spectrum, a first peak from about 3.5 ppm to about 4 ppm, a second peak from about 3 ppm to about 3.5 ppm, and a third peak from about 1 ppm to about 1.5 ppm; and wherein
 (i.) the integration ratio of the second peak to the first peak is from 0.50 to about 0.65,   (ii.) the integration ratio of the third peak to the first peak is from 0.61 to about 0.75, or   (iii.) a combination thereof.   
     
     
         18 . The microspheres of  claim 16 , wherein the microspheres are uniform in size. 
     
     
         19 . The microspheres of  claim 16 , wherein the microspheres have a diameter from about 1 μm to about 2000 μm, from 40 μm to about 120 μm, from about 100 μm to about 300 μm, from about 300 μm to about 500 μm, from about 500 μm to about 700 μm, from about 700 μm to about 900 μm, or from about 900 μm to about 1200 μm. 
     
     
         20 . The microspheres of  claim 16 , wherein less than 1% of the microspheres are aggregated microspheres. 
     
     
         21 . A method of embolization in a subject, comprising administering to the subject the microsphere of  claim 1 . 
     
     
         22 . A method of embolization in a subject, comprising administering to the subject the microspheres of  claim 16 . 
     
     
         23 . A method of managing or treating an angiogenesis-dependent disease in a subject, comprising administering to the subject the microsphere of  claim 1 . 
     
     
         24 . The method of  claim 23 , wherein the angiogenesis-dependent disease is arteriovenous malformation, uterine fibroid, or benign prostatic hyperplasia. 
     
     
         25 . The method of  claim 24 , wherein the angiogenesis-dependent disease is a cancer or tumor. 
     
     
         26 . The method of  claim 25 , wherein the cancer or tumor is a liver or prostate cancer or tumor.