Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1999-03-01
2002-09-17
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C514S021800, C530S399000
Reexamination Certificate
active
06451347
ABSTRACT:
BACKGROUND OF THE INVENTION
Human growth hormone (hGH) is a protein secreted by the pituitary gland which consists of 191 amino acids and has a molecular weight of about 21,500. hGH can also be produced by recombinant genetic engineering. Two species of note which are obtained recombinantly are the 191 amino acid native species (somatropin), and the 192 amino acid N-terminal methionine (met) species (somatrem). hGH will cause growth in all bodily tissues which are capable of growth.
hGH is typically used to treat patients suffering from hypopituitary dwarfism. hGH can be administered, for example, as a subcutaneous bolus three times a week, or once daily, to patients to maintain suitable serum levels of hGH. For patients chronically receiving hGH, this method of frequent injections often results in poor patient compliance. An alternative to the use of repetitive injections, can be found in the use of sustained release devices comprising a polymeric matrix of a biocompatible polymer and particles of biologically active, metal cation-stabilized hGH dispersed within in the polymer, as described in U.S. Pat. No. 5,667,808 to Johnson et al. the entire content of which is hereby incorporated by reference.
SUMMARY OF THE INVENTION
It has been found that the formation of a metal cation complexed hGH is inhibited by the presence of degradation products, in particular, deamidated and oxidized forms of hGH. Consequently, the complexation of native hGH is more complete than the complexation of the deamidated and oxidized forms resulting from degradation of the protein. In view of the above, this invention relates to a method of purifying human growth hormone (hGH) from deamidated hGH, oxidized hGH or both. The method comprises the steps of forming a metal cation-complexed hGH composition enriched in native hGH under conditions wherein none or less than all of the deamidated hGH, oxidized hGH or both complex with a metal cation and, isolating the metal cation-complexed hGH composition from the deamidated hGH, oxidized hGH or a combination thereof. The method can further comprise releasing hGH from the complex. Alternatively, the metal cation-complexed hGH can be encapsulated into a biocompatible polymer for sustained release of hGH. The method can be performed one or more times with the hGH released from the metal cation-complexed hGH composition. The method can be repeated until the desired level of purity for the hGH is reached.
In a specific embodiment, native human growth hormone is purified from deamidated hGH, oxidized hGH or both by making an aqueous solution of an hGH composition comprising native hGH, and one or both deamidated hGH and oxidized hGH and adding a metal cation component to said aqueous solution under conditions wherein none or less than all of the deamidated hGH, oxidized hGH or both complex with the metal cation component thereby forming a metal cation-complexed hGH composition enriched in native hGH as compared to said aqueous composition of hGH. The metal cation-complexed hGH composition is then precipitated and the precipitate can be isolated. The method can further comprise the step of releasing the hGH from the metal cation-complexed hGH composition. The method can be repeated one or more times with the hGH released from the metal cation-complexed hGH composition, depending on the level of purity desired.
In another embodiment, the metal cation-complexed hGH composition prepared according to the method of the invention can be encapsulated into a biocompatible polymer for sustained release of human growth hormone, for example, as described in U.S. Pat. No. 5,667,808 to Johnson et al. the entire content of which is hereby incorporated by reference.
The method of the invention provides a simple and cost efficient method of purifying hGH, in particular, for removing deamidated and oxidized impurities.
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Yu-Chang John Wang, et al., “Parenteral Formulations of Proteins and Peptides: Stability and Stabilizers,”Journal of Parenteral Science and Technology,42(2S): S3-S26 (1988).
Cunningham, B.C., et al., “Dimerization of Human Growth Hormone by Zinc,”Science,253: 545-548 (Aug. 2, 1991).
Alkermes Controlled Therapeutics Inc.
Hamilon, Brook, Smith & Reynolds, P.C.
Russel Jeffrey E.
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