Release of human growth hormone from an in-situ implant modulated by poly(ethylene glycol) dimethyl ether and tris(hydro
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ORIGINAL RESEARCH
Release of human growth hormone from an in‑situ implant modulated by poly(ethylene glycol) dimethyl ether and tris(hydroxymethyl) aminomethane Siyavash Mirzaei1 · Hamid Mobedi2 · Hamid Gourabi1 · Mohammad Hossein Sanati3 · Sakine Khezli2 · Hamid Omidian4 · Sima Sadrai5 Received: 2 November 2019 / Accepted: 14 August 2020 © Iran Polymer and Petrochemical Institute 2020
Abstract A patient-friendly delivery system to release human growth hormone (hGH) is very desirable. In situ forming implant systems (ISIs) can provide a long acting and effective protein delivery. In these systems, solvents and additives play major roles in drug release. In this study, four groups of PLGA-based ISIs containing hGH were prepared in N-methyl-2-pyrrolidone (NMP) and poly(ethylene glycol) dimethyl ether (PEG-DME) as solvents with and without tris(hydroxymethyl) aminomethane (Tris) as stabilizer. Several analyses were used to investigate the implants, which include release profile, viscosity, contact angle, gel permeation chromatography (GPC), scanning electron microscopy (SEM), hGH and IGF-1 serum measurements and histopathology. In in vitro release experiments, the hGH cumulative release from PEG-DME system was twice that from NMP system during 14 days, and hGH release was tripled in the presence of Tris. With the addition of Tris to the ISIs containing PEG-DME, the water penetration, interconnectivity of pores and inner channels, surface pores and hydrophilicity were increased. Moreover, the effect of Tris on the hGH stabilization synergized its positive effects and increased the hGH final cumulative release. Results of the ISIs containing PEG-DME and Tris injection in rabbits demonstrated a reduced tissue inflammation. Moreover, the 14-days serum levels of the hGH and IGF-1 of this system in recipient rabbits were comparable to those of the commercial daily injection samples. Keywords hGH · In situ forming systems (ISIs) · Proteins stability · Protein delivery · Tris(hydroxymethyl) aminomethane
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13726-020-00857-x) contains supplementary material, which is available to authorized users. * Hamid Mobedi [email protected] 1
Department of Genetics, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
2
Department of Novel Drug Delivery Systems, Iran Polymer and Petrochemical Institute, P.O. Box: 14965/115, Tehran, Iran
3
Medical Genetics Department, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
4
College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA
5
Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Science (TUMS), Tehran, Iran
Human growth hormone (hGH) is a complex polypeptide comprising of 191 amino acids with a molecular weight of 22 kDa. It is supplied as an injectable dosage form and administers daily to treat diseases such as growth hormone deficiency, Prader–Willi syndrome and Tur
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