Novel long-acting crystal formulation of human growth hormone.
OBJECTIVE
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.
Govardhan
Chandrika
C
Altus Pharmaceuticals Inc., 625 Putnam Ave., Cambridge, Massachusetts 02139, USA.
Khalaf
Nazer
N
Jung
Chu W
CW
Simeone
Ben
B
Higbie
Amy
A
Qu
Susan
S
Chemmalil
Letha
L
Pechenov
Sergey
S
Basu
Sujit K
SK
Margolin
Alexey L
AL
D000327:Adsorption; D000818:Animals; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D005260:Female; D019382:Human Growth Hormone / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008252:Macaca fascicularis; D008855:Microscopy, Electron, Scanning; D023421:Models, Animal; D010449:Peptide Mapping; D010455:Peptides / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D017550:Spectroscopy, Fourier Transform Infrared; D013816:Thermodynamics
D010455:Peptides; D011994:Recombinant Proteins; D019382:Human Growth Hormone; C015462:polyarginine