Novel Long-acting Crystal Formulation of Human Growth Hormone

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 2005 Sep 1

PMID 16132358

Citations 14

Authors

Chandrika Govardhan

Nazer Khalaf

Chu W Jung

Ben Simeone

Amy Higbie

Susan Qu

Letha Chemmalil

Sergey Pechenov

Sujit K Basu

Alexey L Margolin

Affiliations

Soon will be listed here.

Abstract

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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References

Hatefi A, Amsden B . Biodegradable injectable in situ forming drug delivery systems. J Control Release. 2002; 80(1-3):9-28. DOI: 10.1016/s0168-3659(02)00008-1. View

Pechenov S, Shenoy B, Yang M, Basu S, Margolin A . Injectable controlled release formulations incorporating protein crystals. J Control Release. 2004; 96(1):149-58. DOI: 10.1016/j.jconrel.2004.01.019. View

Johnson O, Cleland J, Lee H, Charnis M, Duenas E, Jaworowicz W . A month-long effect from a single injection of microencapsulated human growth hormone. Nat Med. 1996; 2(7):795-9. DOI: 10.1038/nm0796-795. View

Walsh G . Second-generation biopharmaceuticals. Eur J Pharm Biopharm. 2004; 58(2):185-96. DOI: 10.1016/j.ejpb.2004.03.012. View

Basu S, Govardhan C, Jung C, Margolin A . Protein crystals for the delivery of biopharmaceuticals. Expert Opin Biol Ther. 2004; 4(3):301-17. DOI: 10.1517/14712598.4.3.301. View

Margolin A, Navia M . Protein Crystals as Novel Catalytic Materials. Angew Chem Int Ed Engl. 2001; 40(12):2204-2222. DOI: 10.1002/1521-3773(20010618)40:12<2204::aid-anie2204>3.0.co;2-j. View

Merkle H, Jen A . A crystal clear solution for insulin delivery. Nat Biotechnol. 2002; 20(8):789-90. DOI: 10.1038/nbt0802-789. View

Fu K, Klibanov A, Langer R . Protein stability in controlled-release systems. Nat Biotechnol. 2000; 18(1):24-5. DOI: 10.1038/71875. View

Yang M, Shenoy B, Disttler M, Patel R, McGrath M, Pechenov S . Crystalline monoclonal antibodies for subcutaneous delivery. Proc Natl Acad Sci U S A. 2003; 100(12):6934-9. PMC: 165808. DOI: 10.1073/pnas.1131899100. View

10.

Brodbeck K, Pushpala S, McHugh A . Sustained release of human growth hormone from PLGA solution depots. Pharm Res. 2000; 16(12):1825-9. DOI: 10.1023/a:1018943107688. View

11.

Prabhu S, Jacknowitz A, Stout P . A study of factors controlling dissolution kinetics of zinc complexed protein suspensions in various ionic species. Int J Pharm. 2001; 217(1-2):71-8. DOI: 10.1016/s0378-5173(01)00600-7. View

12.

Jen A, Merkle H . Diamonds in the rough: protein crystals from a formulation perspective. Pharm Res. 2002; 18(11):1483-8. DOI: 10.1023/a:1013057825942. View

13.

Brader M, Sukumar M, Pekar A, McClellan D, Chance R, Flora D . Hybrid insulin cocrystals for controlled release delivery. Nat Biotechnol. 2002; 20(8):800-4. DOI: 10.1038/nbt722. View

14.

Jung C . Surface properties of superparamagnetic iron oxide MR contrast agents: ferumoxides, ferumoxtran, ferumoxsil. Magn Reson Imaging. 1995; 13(5):675-91. DOI: 10.1016/0730-725x(95)00023-a. View

15.

Silverman B, Blethen S, Reiter E, Attie K, Neuwirth R, Ford K . A long-acting human growth hormone (Nutropin Depot): efficacy and safety following two years of treatment in children with growth hormone deficiency. J Pediatr Endocrinol Metab. 2002; 15 Suppl 2:715-22. DOI: 10.1515/jpem.2002.15.s2.715. View

16.

Herbert P, Murphy K, Johnson O, Dong N, Jaworowicz W, Tracy M . A large-scale process to produce microencapsulated proteins. Pharm Res. 1998; 15(2):357-61. DOI: 10.1023/a:1011951626286. View

17.

Okada H, Toguchi H . Biodegradable microspheres in drug delivery. Crit Rev Ther Drug Carrier Syst. 1995; 12(1):1-99. DOI: 10.1615/critrevtherdrugcarriersyst.v12.i1.10. View

18.

Murthy N, Xu M, Schuck S, Kunisawa J, Shastri N, Frechet J . A macromolecular delivery vehicle for protein-based vaccines: acid-degradable protein-loaded microgels. Proc Natl Acad Sci U S A. 2003; 100(9):4995-5000. PMC: 154286. DOI: 10.1073/pnas.0930644100. View