Sustained GnRH peptide-release formulation

Details Sustained GnRH peptide-release formulation Sustained GnRH peptide-release formulation

1999-02-19

2002-01-08

Moezie, F. T. (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S328000, C424S422000, C424S428000, C514S008100, C514S012200, C514S014800, C514S016700, C514S017400, C514S018700, C514S019300, C514S513000, C514S515000

Reexamination Certificate

active

06337318

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to formulations for the sustained release of peptide agonists and analogues. In a particular application of the invention, the formulation comprises a peptide agonist or analogue of gonadotropin releasing hormone (GnRH) and is used for the treatment of prostate and breast cancer and other diseases and conditions where suppression of testosterone or estradiol levels is beneficial.
BACKGROUND OF THE INVENTION
The peptide gonadotropin 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.
In the present applicant's co-pending International Patent Application No PCT/AU96/00370 (the disclosure of which is incorporated herein by reference) there is described a formulation comprising deslorelin, a GnRH agonist, 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. It is also disclosed that this formulation may be used in the treatment of prostate and breast cancer and other diseases or conditions where suppression of testosterone or estradiol levels is beneficial.
The use of GnRH agonists and analogues for the suppression of hormone levels in humans is well documented. Van Leusden HAIM (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 H S and Rennebaum B (eds) LHRH analogues in Gynaecology pp 17-31 Camforth: Parthenon Publishing).
The use of GnRH agonists or analogues for the treatment of various benign hormone-dependent diseases and conditions has been described. For example, Kappy M, et al. (J. Clin. Endocrinol. Metal. 64 (1987) 1320-1322) and Lee P A, et al. (J. Pediatr. 114 (1989) 321-324) describe the long-term treatment of precocious puberty in children using the GnRH agonist, leuprolide acetate. The use of this GnRH agonist in the treatment of hirsutism (Rittmaster R S & Thompson D L, J. Clin. Endocrinol. Metab. 70 (1990) 1096-1102) and endometriosis (Seltzer V L & Benjamin F, Obstet. Gynecol. 76 (1990) 929) has also been described. In addition, GnRH agonists or analogues may be used for treatments of uterine fibroids (Lumsden M A, et al., Lancet i (1987) 36-37; Healy D L, Gynecol. Endocrinol. 3 (suppl 2) (1989) 33-49), cyclic auditory dysfunction (Andreyko J L & Jaffe R B, Obstet. Gynecol. 74 (1989) 506), porphyria (Bargetzi M J et al., JAMA 261 (1989) 864) and benign prostatic hypertrophy (Gabrilove J L et al., J. Clin. Endocrinol. Metab. 69 (1989) 629).
Similarly, the use of GnRH agonists or analogues in the treatment of sex hormone dependent tumours, including breast cancer and prostate cancer, has been described. For example, de Voogt H J et al. (Scand. J. Urol. Nephrol. Suppl. 138 (1991) 131-136) describes the results obtained in a ten-year study of prostatic cancer patients administered buserelin, and Vogelzang N J et al. (Urology 46 (1995) 220-226) describes the use of monthly subcutaneous injections of goserelin in the treatment of advanced prostatic cancer. The goserelin was found to be well tolerated and as effective as orchiectomy. Redding et al, (1984) Proc Natl Acad Sci USA 81 5845-5848 described the use of a GnRH analogue triptorelin 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 testostrone 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 (see Nelson J R and Corson S L (1993) Fertil Steril 59: 441-3; Paul D et al. (1995) J Clin Endocrin Metab 80: 546-551). A three month depot preparation of a GnRH agonist has also been described (Okada H et al. (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 applicant, is also useful for treating a range of hormone dependent diseases and conditions in animals (including humans) such as those mentioned above. The present applicant has now found that similar formulations including GnRH agonists or analogues other than deslorelin can also be used in treating a range of hormone dependent diseases and conditions in animals, including humans. However, these formulations offer an improved treatment for hormone dependent diseases and conditions, by continuing to deliver the GnRH agonist or analogue over a period of up to 12 months or more, thus reducing the need for frequent subcutaneous injections or implant insertions. Whilst formulations for sustained release of bioactive peptides (including GnRH and its agonists or analogues) for periods of up to 12 months have been previously proposed in U.S. Pat. No. 5,039,660, it is to be noted that the only release results provided in that specification relate to a formulation comprising GHRH placed in a bath of physiological, buffered saline for a period of merely twenty days.
DESCRIPTION OF THE INVENTION
Thus, in a first aspect, the pr

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