title: Injectable hyaluronic acid microhydrogels for controlled release formulation of erythropoietin.
abstract: 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.
authors.affiliation: 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
authors.forename: Sei Kwang
authors.initials: SK
authors.lastname: Hahn
authors.forename: Ji Seok
authors.initials: JS
authors.lastname: Kim
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shimobouji
mesh_terms: 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
chemical_list: D003692:Delayed-Action Preparations; D020100:Hydrogels; D011994:Recombinant Proteins; D004921:Erythropoietin; D006820:Hyaluronic Acid