Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Separation or purification
Patent
1995-05-24
1998-03-31
Ulm, John
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Separation or purification
530399, 530418, 530419, 530422, C07K 1461, C07K 114, C07K 130
Patent
active
057340269
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for manufacturing crystals of growth hormone (GH) or functional derivatives thereof. It also relates to crystals of growth hormone and compositions containing them.
Growth hormone can be both human and animal such as human growth hormone (hGH), bovine growth hormone (bGH), fish and porcine growth hormone (pGH).
hGH is a protein consisting of a single chain of 191 amino acids. The molecule is cross-linked by two disulphide bridges and the monomeric form has a molecular weight of 22 kDa. However, pituitary human growth hormone is not homogeneous. For example, a smaller 20 kDa hGH variant produced from the same gene is also known. The "basic hGH" variant (hGH-V) expressed by the placenta during pregnancy is another analogue which is a product of a separate gene. Like the 22 kDa hGH it consists of 191 amino acids but in various positions throughout the molecule 13 of them are different. See e.g. Bewley T. A. et al; Adv Enzymol; 42; 73-166; 1975 and Frankenne F. et al; J Clin. Endocrin and Metabol; 66; 1171-80; 1988.
Recombinant hGH (22 kDa) has been commercially available for several years. It is preferred over the pituitary derived products because the product prepared from human tissue might contain infectious agents such as that for the Creutzfeldt-Jacob's disease. Two types of therapeutically useful recombinant hGH preparations are present on the market: the authentic one, e.g. Genotropin.RTM., Kabi Pharmacia AB, and an analogue with an additional methionine residue at the N-terminal end, e.g. Somatonorm.RTM..
hGH is used to stimulate linear growth in patients with hypopituitary dwarfism or Turner's syndrome but other indications have also been suggested.
The stability of proteins is generally a problem in the pharmaceutical industry.
It has often been solved by drying the protein in different drying processes, such as freeze-drying. The protein has thereafter been distributed and stored in dried form. The patient necessarily has to reconstitute the dried protein in a solvent before use, which is a disadvantage and of course is an inconvenience for the patient.
The freeze-drying process is a costly and time consuming process step, and it would be of great advantage if this step could be avoided, when preparing a commercial product of a protein.
For a patient, who needs daily injections of a growth hormone e.g. hGH, and especially when the patient is a child, it is of importance that the product is easy to handle, to dose and inject. The reconstitution of freeze-dried hGH demands prudence and carefulness and should preferably be avoided, but is the only method available today.
Different solutions to this problem have been disclosed, but until now no product has appeared on the market.
In WO 89/09614 to Genentech, a stabilized formulation of hGH comprising glycine, mannitol and a buffer is disclosed and in a preferred embodiment a non-ionic surfactant such as polysorbate 80 is added. Sodium-phosphate is suggested as buffer substance. The formulation has an increased stability in a lyophilized formulation and upon reconstitution.
Another possibility of administering growth hormone in a solution is to add a block copolymer containing polyoxyethylene-polyoxypropylene according to EP 211 601 to International Minerals and Chemical Corporation. This solution provides for a prolonged release upon administration to the animal.
A different way to circumvent the stability and production problems of GH is presented in this patent application.
By crystallization a new way of manufacturing growth hormone can be achieved.
Crystals of growth hormone can also be used for various new formulations of the hormone like e.g. injectable suspensions, implants and topical formulations of various types.
Crystallization of growth hormone has not previous been possible to perform in an industrial way.
Clarkson et al reports in J Mol Biol (1989), 208, 719-721 of three distinct crystallization methods, different from the earlier described method.
The following methods were used: tetragonal bipy
REFERENCES:
Crystallization and X-ray Data Collection on Human Growth Hormone, J. Mol. Biol. (1989) vol. 208, pp. 719-721.
Jones et al., Crystallization of Authentic Recombinant Human Growth Hormone, Bio/Technology, vol. 5 (1987), pp. 499-500.
Jones et al., Crystallization of Authentic Recombinant Human Growth Hormone, Chemical Abstracts, vol. 107 (1987), Item 109575.
McPherson "Preparation and Analysis of Protein Crystals" John Wiley and Sons, pp. 102-104, 1982.
Ollis et al "Protein Crystallization" Academic Press pp. 646-659, 1990.
Florin-Robertsson Ebba
Hokby Elvy
Lundin Ronny
Thome Sirkka
Westin-Sjodahl Gertrud
Pharmacia & Upjohn Aktiebolag
Saoud Christine
Ulm John
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