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

Abstract

Since the availability of recombinant human growth hormone (rhGH) enabled the application of human growth hormone both in clinical and research use in the 1980s, millions of patients were prescribed a daily injection of rhGH, but noncompliance rates were high. To address the problem of noncompliance, numerous studies have been carried out, involving: sustained-release preparations, prolonged half-life derivatives, new injectors that cause less pain, and other noninvasive delivery methods such as intranasal, pulmonary and transdermal deliveries. Some accomplishments have been made and launched already, such as the Nutropin Depot microsphere and injectors (Zomajet, Serojet, and NordiFlex). Here, we provide a review of the different technologies and illustrate the key points of these studies to achieve an improved rhGH product.

Keywords: hydrogel; intranasal; microneedle; microsphere; pulmonary; transdermal.

Figure 1

Three-dimensional structure of human growth hormone. Notes: Reproduced from Chantalat L, Jones ND, Korber F, Navaza J, Pavlovsky AG. The crystal-structure of wild-type growth-hormone at 2.5 angstrom resolution. Protein Pept Lett. 1995;2:333–340.

Figure 2

Preparation of rhGH microspheres by an atomizer. Notes: Reprinted from Pharmaceutical Research, 14(6), 1997, pages 730–735, The stabilization and encapsulation of human growth hormone into biodegradable microspheres, Johnson OL, Jaworowicz W, Cleland JL, et al, Figure 1. With kind permission from Springer Science and Business Media. Copyright © 1997, Plenum Publishing Corporation. The rhGH:Zn complex was suspended in dichloromethane containing PLGA polymer. The suspension was atomized by an ultrasonic nozzle and frozen by liquid nitrogen. After the evaporation of liquid nitrogen, the ethanol melted and extracted dichloromethane from the microspheres, which were then filtered and dried. Abbreviations: PLGA, poly(lactic-co-glycolic acid); rhGH, recombinant human growth hormone.

Figure 3

Schematic illustrations of different release behaviors of rhGH from rhGH alone loaded hydrogel (A) and PLA/rhGH complex-loaded hydrogel (B), which can inhibit the initial burst. Note: Reprinted from Journal of Controlled Release, 147(3), Park MR, Chun C, Ahn SW, Ki MH, Cho CS, Song SC, Sustained delivery of human growth hormone using a polyelectrolyte complex-loaded thermosensitive polyphosphazene hydrogel, pages 359–367. Copyright © 2010, with permission from Elsevier. Abbreviations: PLA, poly(lactic acid); hGH, human growth hormone; rhGH, recombinant human growth hormone.

Figure 4

Dissolving microneedles made of chondroitin sulfate as the base used in the in vivo rat absorption studies. Notes: (A) An overview of the microneedle patch. (B) rhGH chondroitin sulfate dissolving microneedles. (C) DDAVP chondroitin dissolving microneedles. The inserted schema shows the following length: (a) whole length, (b) diameter of the basement, and (c) length of the drug loaded space. Adapted from Springer and Pharmaceutical Research, 28(1), 2011, pages 7–21, Two-layered dissolving microneedles for percutaneous delivery of peptide/protein drugs in rats, Fukushima K, Ise A, Morita H, et al, Figure 1, copyright © 2010 Springer, with kind permission from Springer Science and Business Media. Abbreviations: DDAVP, desmopressin acetate; rhGH, recombinant human growth hormone.