Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-03-25
2003-07-15
Low, Christopher S. F. (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S970000, C530S324000, C530S350000, C530S399000
Reexamination Certificate
active
06593296
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a national phase application of PCT International Application No. PCT/AU97/00075, filed Feb. 12, 1997, which is entitled to priority to Australian patent application PN 8012, filed Feb. 12, 1996.
FIELD OF THE INVENTION
This invention relates to stabilised growth hormone (GH) formulations and in particular to liquid formulations of human growth hormone (hGH) which are stabilized by the incorporation of stabilizing excipients. These liquid formulations of hGH have improved chemical and physical stability. The present invention relates particularly to a method for the preparation of these stabilized GH formulations.
BACKGROUND OF THE INVENTION
The growth hormones of humans and animals are proteins containing approximately 191 amino acids which are found in the anterior pituitary. A major biological action of GH is to promote somatogenesis in young humans and animals and to maintain tissues in older creatures. Organs affected by GH include the skeleton, muscles, connective tissue and the viscera. Growth hormone acts by interacting with specific receptors on the target cell membranes.
Human growth hormone (hGH) is a key hormone involved in the regulation of normal human somatic growth and also affects a variety of physiological and metabolic functions, including linear bone growth, lactation and cellular energy use, among others. Deficiency of hGH in young children leads to short stature, and this condition has been treated by exogenous administration of hGH.
In the past, attention has been focused on determining the molecular functions of the growth hormones of various species. Commercial interest has been strong from both medical and veterinary circles, and the hGH gene has been cloned. Both hGH and a derivative thereof, methionyl-hGH (met-hGH), are now being biosynthetically produced in mammalian and bacterial cell culture systems.
In order for hGH to be available commercially as a therapeutic pharmaceutical preparation, stable formulations must be prepared. Such formulations must be capable of maintaining activity for appropriate storage times, they must be readily formulated and be acceptable for administration by patients.
Human GH has been formulated in a variety of ways. By way of example, U.S. Pat. No. 5,096,885 discloses a stable pharmaceutically acceptable formulation of hGH comprising, in addition to the hGH, glycine, mannitol, a buffer and optionally a non-ionic surfactant, the molar ratio of hGH:glycine being 1:50-200. International Patent Publication No. WO 93/19776 discloses injectable formulations of GH comprising citrate as buffer substance and optionally growth factors such as insulin-like growth factors or epidermal growth factor, amino acids such as glycine or alanine, mannitol or other sugar alcohols, glycerol and/or a preservative such as benzyl alcohol. International Patent Publication No. WO 94101398 discloses a GH formulation containing hGH, a buffer, a non-ionic surfactant and, optionally, mannitol, a neutral salt and/or a preservative.
In European Patent Publication No. 0131864 (and corresponding Australian Patent No. 579016) there is disclosed an aqueous solution of proteins with molecular weight above 8500 daltons, which have been protected from adsorption at interfaces, against denaturing and against precipitation of the protein by addition of a linear polyoxyalkylene chain-containing surface-active substance as a stabilizing agent.
European Patent Publication No. 0211601 discloses a growth promoting formulation comprising an aqueous mixture of growth promoting hormone and a block copolymer containing polyoxyethylene-polyoxypropylene units and having an average molecular weight of about 1,100 to about 40,000 which maintains the fluidity of the growth promoting hormone and its biological activity upon administration. Subsequent European Patent Publication No. 0303746 discloses various other stabilizers for growth promoting hormone in aqueous environments including certain polyols, amino acids, polymers of amino acids having a charged side group at physiological pH and choline salts.
Pharmaceutical preparations of hGH tend to be unstable, particularly in solution. Chemically degraded species such as deamidated or sulfoxylated forms of hGH occur, and dimeric or higher molecular weight aggregated species may result from physical instability (Becker et al (1988) Biotechnol Applied Biochem 10, 326; Pearlman and Nguyen (1989), In D. Marshak and D. Liu (eds),
Therapeutic Peptides and Proteins, Formulations, Delivery and Targeting, Current Communications in Molecular Biology
, Cold-Spring Harbour Laboratory, Cold Spring Harbour, N.Y., pp 23-30; Becker et al (1987)
Biotechnol Applied Biochem
9, 478).
As a consequence of the instability of hGH in solution, pharmaceutical formulations of hGH tend to be presented in lyophilised form, which must then be reconstituted prior to use. Lyophilisation is often used to maintain bioactivity and biochemical integrity of polypeptides under a range of storage conditions where stability in solution is not adequate, however it would be advantageous to avoid lyophilisation as this is a costly and time-consuming production step. Lyophilised formulations of hGH are reconstituted before use, usually by the addition of a pharmaceutically acceptable diluent such as sterile water for injection, sterile physiological saline or an appropriate sterile physiologically acceptable diluent. Reconstituted solutions of hGH are preferably stored at 4° C. to minimize chemical and physical degradation reactions, however some degradation will occur during such storage which can be for a period of up to 14 days.
A pharmaceutical formulation of hGH provided in a liquid form, particularly one that maintained stability of hGH over a prolonged period of time, would be particularly advantageous. As described above, current liquid formulations are limited in storage time by the products of chemical and physical degradation reactions that occur during processing and storage. The problems associated with dimer formation have been reported in Becker, et al. (1987), supra., and previous attempts to avoid hGH dimer formation have not succeeded.
It is an object of the present invention to provide stable liquid formulations of hGH that do not result in the formation of undesirable aggregated species or cause chemical changes that reduce biological activity or alter receptor recognition. Another object is to provide a formulation that may be delivered via the needleless injector for subcutaneous injection, or aerosolised for pulmonary use.
SUMMARY OF THE INVENTION
According to the present invention, there is provided a method for the preparation of a stable, liquid formulation of growth hormone comprising growth hormone, a buffer and a stabilizing effective amount of at least one stabilizing agent selected from the group consisting of:
(i)
polyoxyethylene-polyoxypropylene block copolymer non-ionic
surfactants,
(ii)
taurocholic acid or salts or derivatives thereof, and
(iii)
methylcellulose derivatives,
wherein the method comprises admixing the growth hormone with the buffer and the stabilizing agent(s) under conditions such that the growth hormone is not exposed to concentrations of the buffer or stabilizing agent(s) which are greater than 2× the final concentrations of the buffer or stabilizing agent(s) in the formulation.
The present invention also extends to a stable, liquid formulation of growth hormone, prepared by the method as broadly described above.
In yet another aspect, the invention also extends to a stable, liquid formulation of growth hormone, comprising growth hormone, a buffer and a stabilizing effective amount of at least one stabilizing agent selected from taurocholic acid or salts or derivatives thereof, and methyl cellulose derivatives.
Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or group of integers but not the excl
Charman Susan Ann
Charman William Neil
McNamara Michael Kevin
CSL Limited
Low Christopher S. F.
Mohamed Abdel A.
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