AU3662300A - Use of sex hormones to obtain a nasal pharmaceutical composition that is useful in the treatment of undesirable uterine bleeding - Google Patents

Description

USE OF SEX HORMONES TO OBTAIN A NASAL PHARMACEUTICAL COMPOSITION THAT IS USEFUL IN THE TREATMENT OF UNDESIRABLE UTERINE BLEEDING The present invention relates to the use of sex hormones to obtain a pharmaceutical composition suitable for administration by the nasal route that is useful in the treatment of undesirable uterine bleeding phenomena in women. In therapies requiring the administration of sex hormones, uterine bleeding is very frequently observed outside the anticipated normal periods. Sex hormones may be administered in the treatment of disorders caused by oestrogen deficiency, and by oestrogen-deficiency symptoms associated especially with artificial or natural menopause. Such oestrogen deficiencies are likewise implicated in the occurrence of post-menopausal osteoporosis and in cerebral ageing phenomena and cardiovascular disorders. On the other hand, sex hormones are likewise administered in various doses for contraceptive purposes or in the treatment of amenorrhoea that is not associated with the menopause. The sex hormone-containing pharmaceutical compositions currently available to the medical profession are compositions that are suitable for oral administration (tablets), transcutaneous administration (gels, transdermal systems), parenteral administration (intramuscular injections, implants) or vaginal administration (creams, gels...). In a certain number of cases, those various types of treatment cause uterine bleeding, episodic or systematic, outside the anticipated periods of menstruation. The problem caused by such bleeding phenomena is such that it gives rise to worry among patients, who cannot themselves make a distinction between a side effect associated with the treatment and the occurrence of a uterine disorder. Such phenomena result in the attending physician requesting several kinds of supplementary investigations in order to determine the cause of the bleeding. When the bleeding is simply associated with -2 the treatment, the patients then want to turn to other types of treatment or prefer to discontinue the treatment. Bleeding thus appears to be one of the main causes of abandoning treatment. At present, all of the available types of treatment result in compliance difficulties, which hitherto have been only partially improved by the pharmaceutical forms currently available. The Applicant has now discovered that the use of sex hormones to obtain a pharmaceutical composition that is suitable for administration by the nasal route has surprisingly enabled treatment of the uterine bleeding observed outside menstrual periods. That surprising effect, achieved by nasal administration, has not been observed with the other formulations currently available to the medical profession. The improvement is all the more significant and of interest since it demonstrates long term effectiveness, it being possible, indeed, for treatment to be extended for several years. Among the sex hormones that can be used in the pharmaceutical compositions according to the invention there may be mentioned, without implying any limitation, natural steroid oestrogens, such as 17p-oestradiol (estradiol), oestrone and their derivatives, synthetic steroid oestrogens, such as ethynyl oestradiol, progestogens, such as progesterone, pregnanes derived from progesterone or from 17a-OH progesterone, such as dydrogesterone, chlormadinone acetate, medrogesterone, medroxyprogesterone acetate, norpregnanes, such as demegestone, promegestone, nomegestrol acetate or 19-nortestosterone compounds, such as norethisterone, ethynodiol diacetate, norgestrel, levonorgestrel, desogestrel, gestodene or norgestimate, or androgens, such as testosterone or dihydrotestosterone. The sex hormones preferred according to the invention are oestradiol and oestradiol/ progestogen mixtures.

-3 The pharmaceutical compositions suitable for the nasal administration of sex hormones are more specifically those which contain one or more sex hormones at doses that vary as a function of the requirements of the patient, and a cyclodextrin. Preferably, the pharmaceutical compositions according to the invention are characterised in that the cyclodextrin is a partially methylated cyclodextrin. A preferred composition according to the invention is one that contains oestradiol or an oestradiol/progestogen mixture and a cyclodextrin methylated partially and in random manner. When the composition contains a progestogen, the preferred progestogen is norethisterone. The preferred use according to the invention of the pharmaceutical compositions is in the treatment of undesirable uterine bleeding during menopause. By way of non-limiting example, a pharmaceutical composition suitable for the nasal administration of oestradiol was prepared and tested clinically in order to observe the treatment of uterine bleeding phenomena in menopausal women. The composition is a solution containing 0.21 g of oestradiol hemihydrate, 2.10 g of randomly and partially methylated cyclodextrin, 0.9 g of sodium chloride and purified water (ad 100 ml) after adjustment of the pH of the solution to 6. The solution was packaged in a bottle fitted with a dispensing pump enabling nasal sprays of 0.07 ml to be dispensed. Each spray thus delivers a dose of 150 pg of oestradiol hemihydrate. Clinical studies : Clinical studies were carried out on a population of patients who had been post menopausal for less than 10 years.

-4 The patients were divided into groups that, during a 28-day cycle, were given either: - a nasal oestradiol composition of the kind described hereinabove (oestradiol spray) and an oral placebo composition, or - an oral oestradiol formulation and a nasal placebo composition (placebo spray). In each group, the patients were administered with a progestogen for at least 10 to 14 days per cycle at the doses recommended for each product. The treatments were given in accordance with a randomisation code and lasted 3, 6 or 12 months. The daily dose administered for the nasal spray form is 300 jig of oestradiol (2 sprays per day), corresponding to a dose of 2 mg when administration is carried out by the oral route. Results In the course of the clinical studies, it was observed that uterine bleeding in patients from the group treated with the oestradiol nasal spray was approximately 30 % less frequent than in the patients treated with an oral form of oestradiol.