Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-06-25
2002-09-10
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S021800
Reexamination Certificate
active
06448225
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to pharmaceutical formulations containing human growth hormone (hGH) and to methods for making and using such formulations. More particularly, this invention relates to such pharmaceutical formulations having increased stability in aqueous formulation.
BACKGROUND OF THE INVENTION
Human growth hormone formulations known in the art are all lyophilized preparations requiring reconstitution. Per vial, Protropin® hGH consists of 5 mg hGH, 40 mg mannitol, 0.1 mg monobasic sodium phosphate, 1.6 mg dibasic sodium phosphate, reconstituted to pH 7.8 (
Physician's Desk Reference,
Medical Economics Co., Orawell, N.J., p. 1049, 1992). Per vial, Humatrope® hGH consists of 5 mg hGH, 25 mg mannitol, 5 mg glycine, 1.13 mg dibasic sodium phosphate, reconstituted to pH 7.5 (
Physician's Desk Reference,
p. 1266, 1992).
For a general review for growth hormone formulations, see Pearlman et al.,
Current Communications in Molecular Biology,
eds. D. Marshak and D. Liu, pp. 23-30, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989. Other publications of interest regarding stabilization of proteins are as follows.
U.S. Pat. No. 4,297,344 discloses stabilization of coagulation factors II and VIII, antithrombin III, and plasminogen against heat by adding selected amino acids such as glycine, alanine, hydroxyproline, glutamine, and aminobutyric acid, and a carbohydrate such as a monosaccharide, an oligosaccharide, or a sugar alcohol.
U.S. Pat. No. 4,783,441 discloses a method for the prevention of denaturation of proteins such as insulin in aqueous solution at interfaces by the addition of up to 500 ppm surface-active substances comprising a chain of alternating, weakly hydrophilic and weakly hydrophobic zones at pH 6.8-8.0.
U.S. Pat. No. 4,812,557 discloses a method of stabilization of interleukin-2 using human serum albumin.
European Patent Application Publication No. 0 303 746 discloses stabilization of growth promoting hormones with polyols consisting of non-reducing sugars, sugar alcohols, sugar acids, pentaerythritol, lactose, water-soluble dextrans, and Ficoll, amino acids, polymers of amino acids having a charged side group at physiological pH, and choline salts.
European Patent Application Publication No. 0 211 601 discloses the stabilization of growth promoting hormones in a gel matrix formed by a block copolymer containing polyoxyethylene-polyoxypropylene units and having an average molecular weight of about 1,100 to about 40,000.
European Patent Application Publication No. 0 193 917 discloses a biologically active composition for slow release characterized by a water solution of a complex between a protein and a carbohydrate.
Australian Patent Application No. AU-A-30771/89 discloses stabilization of growth hormone using glycine and mannitol.
U.S. Pat. No. 5,096,885 (which is not prior art) discloses a formulation of hGH for lyophilization containing glycine, mannitol, a non-ionic surfactant, and a buffer. The instant invention provides an unexpectedly stabilized aqueous formulation in the absence of glycine.
hGH undergoes several degradative pathways, especially deamidation, aggregation, clipping of the peptide backbone, and oxidation of methionine residues. Many of these reactions can be slowed significantly by removal of water from the protein. However, the development of an aqueous formulation for hGH has the advantages of eliminating reconstitution errors, thereby increasing dosing accuracy, as well as simplifying the use of the product clinically, thereby increasing patient compliance. Thus, it is an objective of this invention to provide an aqueous hGH formulation which provides acceptable control of degradation products, is stable to vigorous agitation (which induces aggregation), and is resistant to microbial contamination (which allows multiple use packaging).
SUMMARY OF THE INVENTION
One aspect of the invention is a stable, pharmaceutically acceptable, aqueous formulation of human growth hormone comprising human growth hormone, a buffer, a non-ionic surfactant, and optionally, a neutral salt, mannitol, and a preservative.
A further aspect of the invention is a method of preventing denaturation of human growth hormone aqueous formulations comprising mixing human growth hormone and a non-ionic surfactant in the range of 0.1-5% (w/v) (weight/volume). In yet another aspect of the invention, this stabilized formulation is stored for 6-18 months at 2-8° C.
DESCRIPTION OF THE FIGURES
FIG. 1
is a size exclusion chromatogram of aqueous growth hormone formulation stored for 28 days at 40° C. (i.e., thermally stressed) and for one year at 5° C. (i.e., recommended conditions for storage).
FIG. 2
is a plot of Arrhenius rate analysis of growth hormone aggregation in aqueous formulation.
FIG. 3
is an anion exchange chromatogram comparing a thermally stressed (40° C.) aqueous formulation hGH sample with an aqueous formulation hGH sample stored under recommended conditions (2-8° C.) for one year.
FIG. 4
is a plot of Arrhenius rate analysis of hGH deamidation in aqueous formulation.
FIG. 5
is a graph of the percentage monomer present in the various formulations where mannitol has been substituted with a neutral salt.
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O'Connor Barbara H.
Oeswein James Q.
Genentech Inc.
Low Christopher S. F.
Marschang Diane L.
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