Injectable hyaluronic acid microhydrogels for controlled release formulation of erythropoietin.
An injectable hyaluronic acid (HA) microhydrogel was successfully developed as a novel drug carrier for controlled release formulation of protein drugs. HA hydrogels were prepared by the disulfide bond formation of thiolated HA (HA-SH). EPO was loaded in situ during HA-SH hydrogel preparation using an accelerating agent of sodium tetrathionate. The gelation time was drastically reduced from a day to 30 min when sodium tetrathionate was added for HA-SH hydrogel preparation. In vitro release of EPO in PBS at 37 degrees C showed that EPO was rapidly released for 3 days with an initial burst and then slowly up to 9 days from HA-SH hydrogels. HA-SH microhydrogels were prepared by the reactive spray drying of diluted HA-SH precursor solution. The mean particle size was approximately 2.3 mum and the water content after spray drying was approximately 14%. Ellman's test showed that sodium tetrathionate contributed not only for rapid crosslinking reaction but also for the reduction of residual free thiol content in HA-SH microhydrogels after spray drying. EPO recovery from HA-SH microhydrogels after degradation with hyaluronidase SD was higher than 95%. The released EPO appeared to be intact from the analysis with RP-HPLC. According to in vivo release test of EPO from HA-SH microhydrogels in Sprague Dawley (SD) rats, elevated plasma concentration of EPO higher than 0.1 ng/mL, which is a critical minimal concentration for EPO efficacy, was maintained up to 7 days. There was no adverse effect during and after the in vivo tests.
Hahn
Sei Kwang
SK
Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), San 31, Hyoja-dong, Nam-gu, Pohang, 790-784, Korea. skhanb@postech.ac.kr
Kim
Ji Seok
JS
Shimobouji
Tsuyoshi
T
D000818:Animals; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000494:pharmacology; D004921:Erythropoietin / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D006820:Hyaluronic Acid / Q000138:chemical synthesis / Q000737:chemistry; D020100:Hydrogels / Q000138:chemical synthesis / Q000737:chemistry; D008422:Materials Testing; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins
D003692:Delayed-Action Preparations; D020100:Hydrogels; D011994:Recombinant Proteins; D004921:Erythropoietin; D006820:Hyaluronic Acid