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Formulations of Human Growth Hormone Comprising a Non-Naturally Encoded Amino Acid

a human growth hormone and amino acid technology, applied in growth hormones, inorganic non-active ingredients, immunological disorders, etc., can solve the problems of short in vivo half-life of proteins, undesirable side effects, decreased bioavailability and pain at injection sites, etc., to reduce biological activity, reduce formation, and be readily formulated

Inactive Publication Date: 2008-05-15
AMBRX
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The PEGylated hGH formulations offer extended therapeutic half-life, improved stability, and reduced aggregation, allowing for less frequent administration and enhanced patient convenience with maintained biological activity.

Problems solved by technology

A significant challenge to using growth hormone as a therapeutic, however, is that the protein has a short in vivo half-life and, therefore, it must be administered by daily subcutaneous injection for maximum effectiveness (MacGillivray, et al., J. Clin. Endocrinol. Metab.
While the depot permits less frequent administration (once every 2-3 weeks rather than once daily), it is also associated with undesirable side effects, such as decreased bioavailability and pain at the injection site and was withdrawn from the market in 2004.
Although several of the amino acid side chain residues in Pegvisomant™ are derivatized with polyethylene glycol (PEG) polymers, the product is still administered once-daily, indicating that the pharmaceutical properties are not optimal.
In addition to PEGylation and depot formulations, other administration routes, including inhaled and oral dosage forms of hGH, are under early-stage pre-clinical and clinical development and none have yet received approval from the FDA.

Method used

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  • Formulations of Human Growth Hormone Comprising a Non-Naturally Encoded Amino Acid
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  • Formulations of Human Growth Hormone Comprising a Non-Naturally Encoded Amino Acid

Examples

Experimental program
Comparison scheme
Effect test

example 1

Materials and Methods for Formulations for Met-Y35pAF hGH

[0383]This example describes a formulations study that identified and evaluated suitable conditions and excipients that preserve the protein structure and activity of Met-Y35pAF hGH during storage before conjugation with PEG. Liquid formulations of hGH are frozen formulations which contain (1) 2.5 g / L sodium bicarbonate, 20 g / L glycine, 2 g / L mannitol, 2 g / L lactose, at pH 7.3; or 2) sodium citrate, 20 g / L glycine, 5 g / L mannitol, at pH 6.0. An estimated dose of 0.5-4 mg / ml of PEG-hGH is added as an active ingredient. These formulations are currently stored at −20° C. Development of a single-dose lyophilized formulation of PEGylated hGH comprising a non-naturally encoded amino acid or liquid formulation of PEGylated hGH comprising a non-naturally encoded amino acid is desired.

Methods

[0384]Several methods were implemented to characterize the physical and chemical stability of Met-Y35pAF hGH. These methods may be used in the for...

example 2

Results of Formulation Study for Met-Y35pAF hGH

Buffer pH

[0394]The pH of all formulation buffers was analyzed after six weeks at 4° C. It was found that the pH of all buffers chosen was stable over a six week period, with the exception of the sodium bicarbonate buffer (Group E) as shown in FIG. 1. The pH of Group E increased over time.

SDS-PAGE-R and SDS-PAGE-NR

[0395]Analysis of samples with SDS-PAGE reducing and non-reducing gels showed no change either after four weeks (1 month) at 4° C. or during five freeze / thaw cycles. No dimer formation or degradation products were found by this method. Reducing gels for group A (at t=0, t=4 weeks at 4° C.) are shown as FIGS. 2C and 2D, and non-reducing gels for group B (at t=0, t=4 weeks at 4° C.) are shown as FIGS. 2A and 2B.

Differential Scanning Calorimetry (DSC)

[0396]The effects of buffer and excipient on thermal stability of MetY35pAF hGH are shown as FIGS. 3-8. FIG. 3A-F shows overlaid thermoprofiles of formulation groups A-F. FIG. 5 provi...

example 3

[0403]The stability profile of PEG-hGH is examined with key formulation parameters under accelerated stability conditions, major degradation products are identified, and stability indicating assays are confirmed. The main objective of single-dose formulation development is to optimize the formulation for sufficient storage stability minimally at refrigerated temperature and may have sufficient storage stability when stored at ambient temperature. In addition to the lyophilized formulation development, additional studies are investigating the sensitivity to light exposure and agitation, development of the RP-HPLC method distinguishing the PEGylated hGH from the non-PEGylated form, structural analysis, and other studies. Successful lyophilized formulations normally show the following attributes: stability in solution for handling during formulation and fill-finish, good stability during freeze-drying, good storage stability, native structure in the dried state (if relevant), no obviou...

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Abstract

Formulations of modified human growth hormone polypeptides are provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. provisional patent application Ser. No. 60 / 638,616 filed Dec. 22, 2004, U.S. provisional patent application Ser. No. 60 / 680,617, filed May 13, 2005, and U.S. provisional patent application entitled 60 / 728,035, filed Oct. 17, 2005, the specifications of which are incorporated herein in their entirety.FIELD OF THE INVENTION[0002]This invention relates to stabilized human growth hormone (hGH) formulations of hGH polypeptide comprising a non-natural amino acid covalently linked to poly(ethylene glycol) (PEG).BACKGROUND OF THE INVENTION[0003]Human growth hormone participates in much of the regulation of normal human growth and development. This naturally-occurring single-chain pituitary hormone consists of 191 amino acid residues and has a molecular weight of approximately 22 kDa. hGH exhibits a multitude of biological effects, including linear growth (somatogenesis), lactation, activation of macrophage...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/27
CPCA61K47/183C07K14/61A61K47/02A61K9/19A61K47/26A61K9/0019A61K38/27A61P1/00A61P13/12A61P19/00A61P31/18A61P37/02A61P39/06A61P43/00A61P5/06A61P9/02A61P9/04C07H21/04
Inventor HAYS, ANNA-MARIABUECHLER, YINGLITZINGER, DAVID C.
Owner AMBRX
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