Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-07-28
1997-07-22
Geist, Gary
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 53, 514561, 562575, 127 29, A61K 3118
Patent
active
056503903
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/It92/00165, filed Dec. 17, 1992.
FIELD OF THE INVENTION
The present invention concerns gonadotropin containing pharmaceutical compositions. More precisely, it concerns compositions of sucrose-stabilized gonadotropins. The gonadotropins of the present invention comprise FSH (Follicle Stimulating Hormone), LH (Luteinizing Hormone) and hCG (Human Chorionic Gonadotropin).
BACKGROUND OF THE INVENTION
It is known that highly purified proteins are time-unstable and are stabilized, for instance, in admixture with saccharides, such as lactose and mannitol, or else with proteins and aminoacids, such as albumin and glycine. Other high-molecular-weight compounds, having a biological origin, as, for instance, the marine colloids, dextran and other polysaccharides and the phospholipids often work equally well. Anyway, since the gonadotropins of the present invention are administered parenterally, these excipients are not suited for an injectable composition because of their allergenicity or their insufficient solubility, in some cases because of their potential toxicity or a concourse of these effects.
The composition of lyophilised proteins is described in M. J. Pikal, BioPharm, October 1990, 25-30. There are reported examples of proteins, such as growth hormone and ribonuclease A, formulated by using stabilizing excipients such as mannitol, glycin, arginine and lactose.
In particular, the lyophilisation is described of proteins in the presence of various substances in their amorphous state, as sugars, which increase the collapse temperature and possible to obtain shorter lyophilisation times. However, it is not feasible, according to the author, to foresee a standard formulation for all the proteins, and the choice of the best formulation requires a remarkable selection work.
German patent DE 3520228 describes bioactive proteins such as lymphokines, interferons, TNF (Tumor Necrosis Factor), insulin, growth hormone, in formulations which are stabilized by means of polysaccharides comprising repetitive maltotriose units. The use of sucrose as a stabilizing agent is known, for instance, in a formulation of lyophilized orgotein, as described in U.S. Pat. No. 3,637,640. International patent application WO 89/10407 describes the formulation with sucrose of M-CSF (Macrophage-Colony Stimulating Factor); patent application WO 89/09610 describes, instead, formulations of TNF which have been stabilized with albumin, dextran, polyethylene glycol, 80 polysorbate PVP, lactose, trialose or even sucrose.
The injectable formulations of gonadotropins are obtained by a process which includes their lyophilisation in order to obtain a dry powder. Gonadotropins are highly liable to denaturization during the lyophilisation process and it is desirable to obtain stable formulations able to maintain a longer cycle life when they are stored at room temperature.
European Patent EP 448146 describes lyophilised gonadotropin containing preparations, which are stabilized by means of a dicarboxylic acid salt, as, for instance, citric acid, tartaric acid and aspartic acid. Gonadotropins which are found on the market are stabilized by means of saccharides, for instance hCG is stabilized by means of mannitol (Profasi.RTM., SERONO) and FSH is stabilized by means of lactose (Metrodin.RTM., SERONO).
SUMMARY OF THE INVENTION
We have now found that sucrose confers a better stability to the formulation of gonadotropins and in particular to the form of these glycoproteins which have been prepared by recombinant DNA technique.
The main object of the present invention is to provide a pharmaceutical composition comprising a solid intimate mixture of a gonadotropin, such as FSH, LH or hCG, and a stabilizing amount of sucrose, alone or in combination with other stabilizing agents.
A further object is to provide a process for the preparation of said pharmaceutical composition, the step of lyophilising an aqueous solution of the components. Another object is to provide a dosage form of said pharmaceutical composition comprisi
REFERENCES:
patent: 3637640 (1972-01-01), Huber
patent: 3816617 (1974-06-01), Banik
patent: 5128453 (1992-07-01), Arpaia et al.
Section Ch., Week 9025, Derwent Publications Ltd., London, GB; Class B04, AN 90-188387 & JP, A, 2 121 933 (Kagaku Shiryo Kenky) 9 May 1990 (abstract).
Section Ch., Week 8036, Derwent Publications Ltd., London, GB; Class B04, AN 80-623660 & DD, A 141 996 (Wolf I) 5 Jun. 1980 (abstract).
Natale Patrizia
Samaritani Fabrizio
Applied Research Systems ARS Holding N. V.
Geist Gary
Williams Rosalynd
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