Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-02-17
2001-04-03
Moezie, F. T. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S828000, C514S850000, C424S422000, C424S425000, C424S426000
Reexamination Certificate
active
06211152
ABSTRACT:
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.
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 PM (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 PM (1988) Endocrine Review 9: 379-866). 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, p517-543), 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:
(i) to have available a source of GnRH, or an agonist, at a cost effective price; and
(ii) to have a cost-effective delivery system for a peptide which releases at a controlled rate over six to twelve months, at a rate and dose that will shut down animals predictably and reliably for six or twelve months.
The present applicants have developed a formulation comprising deslorelin as the active agent which, when administered to animals, prevents reproductive function over an extended and predictable period of time. The formulation also allows the restoration of reproductive function following termination of administration. Whilst the formulation is particularly described in relation to dogs, it is believed that the formulation will be useful in other animals such as humans.
In addition, the use of GnRH analogues, including deslorelin, for the suppression of hormone levels in humans is well documented. Van Leusden H.A.I.M. (Gynecol Endocrinol 8 (1994) 215-222) has reviewed the use of a variety of GnRH agonist peptides for suppression of estradiol levels in female patients and use for the treatment of endometriosis and leiomyoma. From a survey of a large body of published work, these authors concluded that many GnRH analogues, including deslorelin, were effective in suppressing estradiol levels and hence in treating these sex hormone-accelerated conditions provided that the peptide was delivered so as to maintain a constant minimum blood level. The prerequisite for a peptide to be active was the ability to disturb the pulsatile release of endogenous GnRH. This required a constant minimum plasma level (this level was not defined). They suggested that a mode of delivery was more important than minor differences in potency between different GnRH analogues. These authors also concluded that in a suppressed pituitary, the dose of GnRH analogue needed to maintain suppression gradually decreased with the duration of treatment (also explored in Sandow J and Donnez T (1990) in Brosens I, Jacobs HS and Rennebaum B (eds) LHRH analogues in Gynaecology pp 17-31 Camforth: Parthenon Publishing).
Similarly, the use of GnRH agonists including deslorelin, in the treatment of sex hormone dependent tumours, including breast cancer and prostate cancer, has been described. Redding et al, (1984) Proc Natl Acad Sci USA 81 5845-5848 described the use of a GnRH analogue [D Trp
6
] LH-RH for suppression of prostate cancer in rats and demonstrated that a microencapsulated form of the peptide, delivering a controlled dose over a 30 day period was more effective in suppressing serum testosterone levels and prostate tumour weight than daily subcutaneous administration of equivalent or double doses of the free peptide. The value of this analogue in human prostate cancer patients to suppress testosterone levels and show tumour progression has been demonstrated by Parmar H et al (1985) The Lancet Nov 30, 1201-1205. This one month depot injection of a GnRH agonist has now been registered for use and tested and used widely in the treatment of breast, ovarian and prostate cancer, endometriosis, myoma and in precocious puberty in children, as have other GnRH agonists. (Nelson J R and Corson S L (1993) Fertil Steril 59: 441-3; Paul D, Conte F A, Grumbach, M M and Kaplan S L (1995) J Clin Endocrin Metab 80: 546-551).
A three month depot preparation of a GnRH agonist has also been described (Okada H, Doken Y, Ogawa Y and Toguchi H (1994) Pharm Res (US) 11: 1199-1203.). Linear drug release from the injected microspheres was obtained with persistent suppression of serum LH, FSH (rats) and testosterone (rats and dogs) for over 16 weeks. Doses of GnRH analogues used to suppress sex hormone levels in males and females are the same (e.g. Plosker, G. L. and Brogden, R. V. (1994) Drugs Vol. 48, pages 930-967). Thus, the demonstration of suppression of sex hormone levels in one sex is predictive of similar suppression in the other sex.
Accordingly, the abovementioned deslorelin formulation developed by the present applicants, is also useful for treating a range of hormone dependent diseases and conditions in animals (including humans) such as those mentioned above. Th
Trigg Timothy E.
Walsh John D.
Moezie F. T.
Nixon & Vanderhye
Peptech Limited
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