Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-12-19
1999-07-20
Moezie, F. T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 3, 514 8, 514 12, 514 13, 514 14, 514 15, 424422, 424423, 424425, 424426, A61D 1900, A61D 700
Patent
active
059256192
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to pharmaceutical and veterinary formulations for the sustained release of deslorelin which is an agonist of the peptide gonadotropin releasing hormone (GnRH). Uses of the formulations include prevention of reproductive function, particularly in dogs and cats, and treatment, particularly in humans, of prostate and breast cancer and other diseases or conditions where suppression of testosterone or estradiol levels is beneficial.
BACKGROUND OF THE INVENTION
Uncontrolled reproduction in domestic pets is a world wide problem. In less developed countries, reproduction of domestic cats and dogs is relatively uncontrolled. Sporadic programs of work exist aimed at controlling reproduction in these animals by surgical castration. In the more developed countries, reproduction is controlled more by ovarectomy in females and in some cases, by orchidectomy in males, or by physically locking away animals to prevent mating.
Surgical techniques, no matter how minor, carry some risk. Many pet owners are also loathe to have their animal surgically modified and will tolerate the problems of uncontrolled reproduction and associated behaviour. To remove the ability to reproduce from domestic pets without the use of surgery and without resorting to lengthy kennelling procedures has been an objective of the small animal research industry for some years. Drugs which are currently available for this process, are steroid-based drugs. They produce unpleasant side effects, particularly after lengthy use, and they are not widely used.
The peptide gonadotrophin releasing hormone (GnRH) has been the subject of intensive research for many years. It is a hypothalamic decapeptide which is synthesised and stored in neurosecretory cells of the medial basal hypothalamus. The releasing hormone is released in a pulsatile manner into the hypophysial portal circulation and is transported to the anterior pituitary. Here, it regulates the secretion of the gonadotrophins, leuteinising hormone (LH) and follicle stimulating hormone (FSH), into the systemic circulation. Thus, GnRH is a humoral link between the neural and endocrine components of reproductive function (for review see Conn P. M. (ed) 1996 Gonadotropin-releasing hormone Endocrine Review 7:1). GnRH binds to a single class of receptors on gonadotrope cells. Prolonged exposure of these cells to the GnRH results in loss of responsiveness to the hormone, through receptor alteration (reviewed in Hazum E. and Conn P. M. (1988) Endocrine Review 9:379-856). The outcome of down-regulation of responsiveness to GnRH is suppression of circulating levels of gonadotropins and sex hormones. This has the consequence of suppressing reproductive function and other processes affected by sex hormone levels.
For many years, researchers have tried to develop a commercial vaccine, based on forming antibodies to GnRH, to cut this hormone axis and hence act as a contraceptive. The present applicants have commercialised such a vaccine; however, the developed technology is not suitable for contraception in pets. This lack of suitability is due to the biological variation of response in individual pets to a vaccine and the lack of predictability of the length of effect of the vaccine.
It is generally accepted in the marketplace that for a pet contraceptive to be successful, it would be preferably efficacious in all treated animals and its length of response time would be predictable. This response should preferably either be for six or twelve months. Reversibility of the effect would be an additional desirable benefit.
In 1987, Brian Vickery from Louisiana (Vickery, B. H. and Nestor, J. J. (1987) In LHRH and its Analogues, Part 2, p 517-543), demonstrated that overdosing dogs/bitches with the superagonist of GnRH, nafarelin, shut down reproductive function for a variable period of three to eighteen months. The difficulties facing product development in this area have been: price; and at a controlled rate over six to twelve months, at a rate and dose that will shut down animals predicta
REFERENCES:
patent: 3917825 (1975-11-01), Matsuzawa et al.
patent: 5538739 (1996-07-01), Bodmer et al.
Journal of Clinical Endocrinolgy and Metabolism, 1991 by The Endocrine Society; Effects of Pitsuitary-Testicular Axis Suppression in Utero and During the Early Neonatal Period With Long-Acting Luteinizing Hormone-Releasing Hormone Analog on Gential Development, Somatic Growth, and Bone Density in Male Cynomolgus Monkeys in the First 6 Months of Life, By Linda Liu et al, pp. 1038-1043.
British Poultry Science, vol. 33, No. 3 1992, (Edinburgh, Scotland), A.J. Tilbrook et al, "Short-term reduction in Egg Production in Laying Hens Treated With an Agonist of GnRH". pp. 621-638.
Journal of Animal Science, vol. 74, No. 1, 1996 (Champaign, Illinois, U.S.A.), D'Occhio, M.J. et al "Controlled Reversible Suppression of Beef Heifers and Cows using Agonists of Gonadotrophin-Releasing Hormone", pp. 218-225, see especially p. 233.
Biology of Reproduction, vol. 42, No. 1, 1996(champaign, Illinoise, U.S.A.), D'Occhio, M.J. et al "Characteristics Hormones (LH) and Testosterone Secretion, Pituitary Responses to LH-Releasing Hormone (LHRH), and Reproductive Function in Young Bulls Receiving the LHRH Agonist Deslorelin: Effect of castration on LH responses to LRRH" pp. 45-52, See especially p. 46.
Stedman's Medical Dictionary, 25.sup.th Ed., Williams & Wilkins, Baltimore, USA p. 1472.
Trigg Timothy E.
Walsh John D.
Moezie F. T.
Peptech Limited
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