Novel Long-Acting Crystal Formulation of Human Growth Hormone
- 514 Downloads
The aim of the study is to solve a significant challenge of extending the half-life of therapeutic proteins using crystalline biopharmaceuticals and without redesigning the molecules.
Crystals of recombinant human growth hormone were coated with a monomolecular layer of positively charged poly(arginine). The pharmacokinetics and pharmacodynamics of this poly(arginine)-coated human growth hormone crystalline formulation were determined in hypophysectomized rats and monkeys.
Here we have demonstrated for the first time that crystals of human growth hormone coated with positively charged poly(arginine) allowed for in vivo pharmacokinetic release profiles of over several days in animal models. The efficacy of this crystalline formulation injected subcutaneously once a week was found to be equivalent to seven daily soluble injections in the standard weight gain assay using the hypophysectomized rat model and in measurement of serum insulin-like growth factor in monkeys. The nonviscous nature of the suspension facilitated easy administration through a fine, 30-gauge needle and should provide for improved patient convenience and compliance.
The approach described here offers an exciting possibility of being broadly applicable to other therapeutic proteins.
Key Wordscrystalline hGH formulation human growth hormone insulin-like growth factor-1 poly(arginine) adsorption sustained release syringeability
surface charge density
insulin-like growth factor 1
The authors would like to thank R. Patel for technical assistance and D. Miller and R. Forrest for their assistance in writing this paper.
- 2.Okada, H., Toguchi, H. 1995Biodegradable microspheres in drug deliveryCrit. Rev. Ther. Drug Carr. Syst.12199Google Scholar
- 9.Margolin, A. L., Navia, M. A. 2001Protein crystals as novel catalytic materialsAngew. Chem., Int. Ed. Engl.4022042222Google Scholar
- 16.McPherson, A. 1999Crystallization of Biological MacromoleculesCold Spring Harbor Laboratory PressCold Spring Harbor, NYGoogle Scholar
- 18.Tadros, Th. F. 1982Polymer adsorption and dispersion stabilityTadros, Th. F. eds. The Effect of Polymers on Dispersion PropertiesAcademic PressNew York138Google Scholar
- 21.Châtellier, X., Bottero, J.-Y., Pitit, J. 2001Adsorption of a cationic polyelectrolyte on Escherichia coli bacteria: 1. Adsorption of the polymerLangmuir1727822790Google Scholar
- 29.European Pharmacopoeia 2000. European Directorate for the Quality of Medicines. Council of Europe-226 avenue de Colmar BP 907. F-67029 Strasbourg Cedex 1, France.Google Scholar
- 31.Silverman, B. L., Blethen, S. L., Reiter, E. O., Attie, K. M., Neuwirth, R. B., Ford, K. M. 2002A long-acting human growth hormone (Nutropin Depot): efficacy and safety following two years of treatment in children with growth hormone deficiencyJ. Pediatr. Endocrinol. Metab.15715722PubMedGoogle Scholar
- 32.N. Khalaf and C. Govardhan. Complexes of protein crystals and ionic polymers. Patent: WO2004060920 A1, (2004).Google Scholar