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Novel Long-Acting Crystal Formulation of Human Growth Hormone

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Purpose

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.

Methods

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.

Results

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.

Conclusions

The approach described here offers an exciting possibility of being broadly applicable to other therapeutic proteins.

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Notes

  1. Poly(arginine) with a weight-average molecular weight of ∼7,500 corresponds to ca. +50 charges/molecule if all guanidinium groups were protonated. Calculations based on average hGH crystal size of 6 × 0.4 × 0.4 μm determined from light and scanning electron microscopies and laser diffraction particle sizing. Traditional BET surface area measurements were not performed due to expected mechanical destruction of the hGH crystals during the repeated in vacuo freeze/thaw cycles at liquid nitrogen temperatures. Even if possible, a BET surface area would not be relevant to these studies as this technique uses very small probes of the surface (e.g., N2 molecule) and would not yield the area accessible to a linear macromolecule. Coulomb unit ≡ C.

Abbreviations

μE:

electrophoretic mobility

ζ:

Zeta potential

σ:

surface charge density

C:

Coulomb

SC:

subcutaneous

PK:

pharmacokinetic

PD:

pharmacodynamic

IGF-1:

insulin-like growth factor 1

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Acknowledgments

The authors would like to thank R. Patel for technical assistance and D. Miller and R. Forrest for their assistance in writing this paper.

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Correspondence to Alexey L. Margolin.

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Govardhan, C., Khalaf, N., Jung, C.W. et al. Novel Long-Acting Crystal Formulation of Human Growth Hormone. Pharm Res 22, 1461–1470 (2005). https://doi.org/10.1007/s11095-005-6021-x

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  • DOI: https://doi.org/10.1007/s11095-005-6021-x

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