Preclinical and Clinical In Vitro In Vivo Correlation of an hGH Dextran Microsphere Formulation

Abstract

Purpose. To investigate the in vitro in vivo correlation of a sustained release formulation for human growth hormone (hGH) based on hydroxyethyl methacrylated dextran (dex-HEMA) microspheres in Pit-1 deficient Snell dwarf mice and in healthy human volunteers. Materials and Methods. A hGH-loaded microsphere formulation was developed and tested in Snell dwarf mice (pharmacodynamic study) and in healthy human volunteers (pharmacokinetic study).Results. Single subcutaneous administration of the microspheres in mice resulted in a good correlation between hGH released in vitro and in vivo effects for the hGH-loaded microsphere formulation similar to daily injected hGH indicating a retained bioactivity. Testing the microspheres in healthy volunteers showed an increase (over 7-8 days) in hGH serum concentrations (peak concentrations: 1-2.5 ng/ml). A good in vitro in vivo correlation was obtained between the measured and calculated (from in vitro release data) hGH serum concentrations. Moreover, an increased serum concentration of biomarkers (insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3) was found again indicating that bioactive hGH was released from the microspheres. Conclusions. Good in vitro in vivo correlations were obtained for hGH-loaded dex-HEMA microspheres, which is an important advantage in predicting the effect of the controlled drug delivery product in a clinical situations.KEY WORDS: dex-HEMA microspheres; hGH; dextran; in vitro in vivo correlation.

Growth hormone receptor modulators

“…Therefore other sustained release GH formulations have been developed based on hydroxyethyl methacrylated dextran [32] or sodium hyaluronate microparticles [33,34]. However whether these are superior to Nutropin Depot® or hGH-Biosphere® is not yet known.…”

Developments in human growth hormone preparations: sustained-release, prolonged half-life, novel injection devices, and alternative delivery routes

“…Vlugt-Wensink et al developed hydroxyethyl methacrylated dextran microspheres of rhGH to avoid the drawbacks of PLGA: 18 the acidification of PLGA can cause aggregation of protein, and hydrophobic PLGA is unfriendly to sensitive protein. However, the synthesis was complicated, and larger-scale preparation induced more variants which made the microsphere characteristics uncontrollable.…”

Novas opções e preparações na terapia com hormônio de crescimento

“…As microesferas constituem o modo mais antigo de liberação prolongada de GH, sendo também o método mais conhecido (66). O primeiro trabalho com esta forma de administração data de 1979 (67), porém foi pelos trabalhos de Johnson e cols., em 1996, que essas formulações ganharam mais estabilidade e conseguiram induzir elevação de IGF-1 (68).…”

“…O hrGH dextran ainda está em fase de estudo pré-clínico, mas esta formulação hidrofílica tem apresentado bons resultados em estudos com voluntários saudáveis (66), mas ainda não teve seus aspectos farmacocinéticos e farmacodinâmicos avaliados. No entanto, o hrGH Biosphere® e o Nutropin Depot® já tiveram estes aspectos estudados.…”