Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Glycoprotein – e.g. – mucins – proteoglycans – etc.
Patent
1989-02-07
1992-07-07
Moskowitz, Margaret
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Glycoprotein, e.g., mucins, proteoglycans, etc.
530397, 530350, 530413, 530412, 530415, C07K 318, C07K 320, C07K 328
Patent
active
051284537
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to urinary follicle stimulating hormone, to pharmaceutical compositions containing it and to a method for its purification.
BACKGROUND OF THE INVENTION
Follicle stimulating hormone (FSH) is known to be useful in the treatment of infertility. Preparations containing this hormone have been employed to assist in effecting pregnancy using both in-vivo and in-vitro techniques. Human FSH has been isolated from human pituitary glands and from post-menopausal urine. More recently, it has been produced using recombinant DNA techniques.
The first commercially available product comprising human FSH contained HMG (e.g., Pergonal.RTM. Serono), i.e., human menopausal gonadotropin extracted from post-menopausal urine which is a mixture of FSH, Luteinizing Hormone (LH) and other urinary proteins. Meanwhile, several attempts were made to obtain pure FSH preparations, both for scientific and therapeutic purposes. The product Metrodin.RTM. (Serono), currently available in commerce, is a preparation of urinary FSH containing other urinary proteins, but minimum quantities of LH and is used for the treatment of infertility. Use of this product is particularly advantageous when administration of exogenous LH together with FSH is undesirable, e.g., in the polycystic ovary syndrome (PCOS).
So far, administration of FSH for therapeutic purposes has been carried out, successfully, exclusively by intramuscular injection. Since intramuscular injections are generally performed by the physician or by the medical professional staff, the patient is expected to visit a surgery or a hospital regularly in order to receive the treatment. This creates a considerable discomfort. Moreover, the time taken up by this type of application often leads to unsatisfactory compliance by the patient as the treatment normally extends over several weeks or months.
Administration by subcutaneous injection would render possible the self-administration by the patient and consequently improve patient's cooperation and compliance.
The subcutaneous administration of Human Menopausal Gonadotropin (HMG) has already been described (Nakamura Y. et al., Fertility and Sterility, 46(1):46-54, 1986) in connection with the treatment of female infertility by pulsatile administration of HMG via the subcutaneous peristaltic pump. The subcutaneous administration may suffer the drawback of the appearance of local allergies due to the presence of impurities in the product used and, consequently, result in the suspension of the treatment.
P. Roos ("Human Follicle Stimulating Hormone", Acta Endocrinologica Supplementum 131, 1968) described and characterized highly purified preparations of pituitary and urinary FSH obtained from frozen pituitaries and from post-menopausal urinary concentrate, respectively. Biological potencies as high as about 14,000 I.U. of FSH activity per mg for pituitary FSH and 780 I.U. of FSH activity per mg for urinary FSH were obtained. The content of LH contamination in the most active pituitary and urinary preparations was estimated to correspond to approximately 0.1 percent by weight. The purification procedures involved one or more of such techniques as chromatography on DEAE-Cellulose, gel-filtration on Sephadex G-100, hydroxylapatite chromatography, polyacrylamide gel electrophoresis, and the like.
One of the best purified urinary FSH preparations was described by Donini et al. ("Purification and partial Chemico-physical characterization of FSH from Menopausal Urine", Gonadotrophins and Ovarian Development (Proceedings of two workshop meetings), E and S Livingstone, Edinburgh and London, 1970) and had a biological potency of 1255.6 I.U. FSH per mg with an LH contamination as low as 3.2 I.U. LH per mg.. In this case, the starting material was a Human Menopausal Gonadotropin (HMG) preparation (Pergonal.RTM.) which, as stated above, is a mixture of FSH and LH hormones and other urinary proteins. This result was achieved by batchwise purification of the starting HMG on DEAE-Cellulose followed by chromatog
REFERENCES:
(Abstract, DBA Accession/vo. 87-09420 of Dialog File 357) of Jack et al. 1987, J. Chem. Technol. Biotech 39(1):45-58.
(Abstract, accession No. 88140703 of Dialog File 155) of Miller et al. 1987, J. Endocrinol. 115(2):382-388.
Chappel et al., Endocrine Reviews 4:179 (1983).
Hallin et al., J. Liq. Chromat. 9:2855 (1986).
Donini et al. (I), Acta Endocrinologica 52:186 (1966).
Donini et al. (II), Gonadotropins and Ovarian Development (EPS Livingstone) pp. 39-56 (1970).
Donini, The Endocrine Function of the Human Testis (Academic Press) pp. 195-221 (1973).
Arpaia Guiseppe
Serani Serenella
Sirna Antonino
Villa Stefano
Furman Keith C.
Istituto DiRicerca Cesare Serono SpA
Moskowitz Margaret
Williams Stephan P.
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