WO2006013464A1

WO2006013464A1 - Hormone replacement therapy comprising a combination of 17-beta-oestradiol and chlormadinone acetate

Info

Publication number: WO2006013464A1
Application number: PCT/IB2005/002506
Authority: WO
Inventors: Alain Munoz; Anthony Munoz; Jack Auzerie
Original assignee: AMISTAD PHARMA Sas
Current assignee: AMISTAD PHARMA Sas
Priority date: 2004-07-27
Filing date: 2005-07-26
Publication date: 2006-02-09
Anticipated expiration: 2007-01-27

Abstract

A composition for limiting the effects induced during the menopause and subsequently, without the onset of periods, characterised in that it comprises, in combination, from about 0.5 to about 1 mg of 17β-oestradiol and from about 0.5 to about 1 mg chlormadinone acetate, preferably from about 0.5 to about 0.9 mg of 17β-oestradiol and from about 0.5 to about 0.9 mg chloradinone acetate, is disclosed. Also disclosed is a method of treating menopausal and post-menopausal women by administration of a composition according to the invention. Furthermore the use of the composition according to the invention in the treatment of the effects induced during the menopause and subsequently, without the onset of periods is provided.

Description

HORMONE REPLACEMENT THERAPY COMPRISING A COMBINATION OF 17-BETA-OESTRADIOL AND CHLORMADINONE ACETATE

Technical Field of the Invention

5 The present invention relates to a hormone replacement therapy and in particular relates to a composition for limiting the effects induced during the menopause and subsequently. The invention also relates to the treatment of menopausal women using this composition.

Background to the Invention 10

Following the menopause, the majority of the current treatments are recommended as therapy for symptomatic disorders rather than being recommended as a long-term treatment to improve the quality of the ageing process.

15 Furthermore, the majority of women would prefer a hormone treatment that does not result in the return of their periods. In particular this is critical if the treatment is envisaged as a long-term therapy of greater than 3 years duration.

Prior art treatments suffer from numerous disadvantages, including low efficacy in 20 controlling unwanted bleeding, the irregularity of these bleeding episodes, undesirable side-effects such as weight gain, endometrial hyperplasia and proliferation and inability to take account of variability between patients and variability within the same patient over time. As a result, patient tolerability is not high, making the therapy ineffective, particularly when assessed in a population. 25

The currently available treatments generally have to be taken for from 9 to 12 months before all bleeding and/or metrorrhagia is eliminated. This is often unacceptable to the women taking the treatment and results in the abandonment of the treatment.

30 Moreover the presently available therapies are not straightforward to administer.

J. Endocrinol. Invest (1992) 15: 533 to 538 studies the effect of transdermal 17β-estradiol combined with oral progestogen in postmenopausal women. Treatment included doses of 100 μg transdermal 17β-estradiol from day 1 to day 21 of the cycle and 2 mg daily doses of oral chlormadinone acetate on days 15 to 21.

Other known treatments that are currently administered, consist in a complex regime of taking several combined products, at given times of the day, over sequential periods, the cycles of which are superimposed. Such complex regimes often lead to abandonment of the treatment, especially in more elderly individuals, such that only 10 to 20% of menopausal women are treated. Furthermore the majority of this 10 to 20% of menopausal women treated only remain on the therapy for a maximum of three years. Therefore the percentage of women being treated 3 years post-menopause is even lower.

It has been noted that certain recommended doses, such as 2 mg of oestrogen when administered orally or 50 μg oestrogen when administered transdermally, are not tolerated by all patients for the duration of the therapy. This leads to the therapy being abandoned by the patient.

Furthermore certain progestative agents, by their nature as norsteroids, pose problems of carbohydrate tolerance, virilization and even involvement in carcinogenesis. The induced effects are also problematic in certain cases: weight gain, drowsiness or digestive disorders. Moreover high doses of progestative agents block the uterine mucosal hyperplasia.

WO 96/10991 discloses a pharmaceutical composition for transmucal administration, the composition being an oil-in-water emulsion containing, dissolved in the dispersed oil phase, 17B-estradiol together with a progestin.

EP 968 717 discloses a preparation directed towards limiting the effects induced during the menopause and subsequently, without periods, characterised in that it comprises, in combination, 17B-oestradiol and chlormadinone acetate.

It is thus necessary to be able to provide an oral therapy that provides an effective, reduced dosage that is tolerated by the patient. Summary of the Invention

The present invention provides a composition for limiting the effects induced during the menopause and subsequently, without the onset of periods, characterised in that it comprises, in combination, from about 0.5 to about 1 mg of 17β-oestradiol and from about 0.5 to about 1 mg chlormadinone acetate.

The present invention also provides a method of treating menopausal women and post- menopausal women, without the onset of periods, with a composition comprising, in combination, from about 0.5 to about 1 mg of 17β-oestradiol and from about 0.5 to about 1 mg chlormadinone acetate.

The present invention also provides a use of a composition comprising, in combination, from about 0.5 to about 1 mg of 17B-oestradiol and from about 0.5 to about 1 mg chlormadinone acetate for the manufacture of a medicament for treating menopausal women and post-menopausal women, without the onset of periods.

The present invention also provides a kit adapted for use during one month for limiting the effects induced during the menopause and subsequently, without the onset of periods, characterised in that it consists of from 21 to 31 sequential daily doses, wherein each daily dose comprises, in combination, from about 0.5 to about 1 mg of 17B-oestradiol and from about 0.5 to about 1 mg chlormadinone acetate.

Description of the Invention

Preferably the composition comprises, in combination, from about 0.5 to about 0.9 mg of 17β-oestradiol and from about 0.5 to about 0.9 mg chlormadinone acetate. Suitable preferred compositions comprise about 0.5 mg 17β-oestradiol and about 0.5 mg chlormadinone acetate, or comprise about 1 mg 17B-oestradiol and about 1 mg chlormadinone acetate, or comprise about 0.5 mg 17β-oestradiol and from about 0.5 mg to about 1 mg chlormadinone acetate, most preferably about 0.5 mg 17β-oestradiol and about 0.9 mg chlormadinone acetate.

In one preferred embodiment, the dosage comprises equal parts of the two products and more particularly 0.5 mg 17β-oestradiol and 0.5 mg chlormadinone acetate, or 1 mg 17β- oestradiol and 1 mg chlormadinone acetate, or 0.9 mg 17β-oestradiol and 0.9 mg chlormadinone acetate.

In another preferred embodiment, the dosage comprises less 17β-oestradiol compared to chlormadinone acetate.

The 17β-oestradiol is preferably in micronized form.

Preferably the composition is provided in the form of a tablet. The tablet may optionally be splittable to allow a half dosage. Thus, should the patient find that the prescribed dose becomes intolerable, the patient is able to simply reduce the dose prescribed, rather than perhaps stopping the treatment. AU that is needed is to split the tablet in two and take only half. It is an advantage that it is possible to check immediately whether the dose taken is a whole or half dose.

The present invention also provides a method of treating menopausal women and post¬ menopausal women, without the onset of periods, with a composition comprising, in combination, from about 0.5 to about 1 mg of 17β-oestradiol and from about 0.5 to about 1 mg chlormadinone acetate.

The present invention also provides a use of a composition comprising, in combination, from about 0.5 to about 1 mg of 17β-oestradiol and from about 0.5 to about 1 mg chlormadinone acetate for the manufacture of a medicament for treating menopausal women and post-menopausal women, without the onset of periods. Preferably the treatment comprises use of a composition comprising, in combination, from about 0.5 to about 0.9 mg of 17β-oestradiol and from about 0.5 to about 0.9 mg chlormadinone acetate.

Preferably the treatment of menopausal and post-menopausal women consists in administering to a patient half to one tablet per day for from 21 to 31 days of a month, preferably from 23 to 27 days of the month, most preferably 25 days, followed by a break of from 3 to 7 days, preferably from 5 to 7 days.

The product is preferably packaged in a presentation box that contains from 21 to 31 tablets, preferably 25 tablets, providing treatment for 1 month. This very simple presentation is easy to use, even for the elderly.

The product provided is suitable for long-term treatment. In particular the doses are lower compared to existing therapies.

A single daily dose is required. This has many advantages including the fact that the need to manage a pill box is avoided.

The claimed invention possesses significant advantages over these prior art compositions. Principal among these are as follows.

1) Functional signs related to menopause are effectively controlled;

2) At the dosage used, the positive metabolic effect of estrogen on cholesterol is maintained and the anti-estrogenic action objectives are more than satisfied — the endometrium is not hyperplasia Furthermore the percentage of proliferation is very low and even equal to zero using a 0.5 mg dose of 17B-oestradiol and chlormadinone acetate.

3) Efficacy is optimised and secure clinical, biological and endometrial tolerance are attained;

4) Significant adverse side-effects are minimised;

5) The patient's metabolic profile is good; specifically no change in glucose blood levels occurred during a one year clinical trial. 6) There is no change in body weight;

7) Bleeding profiles are very satisfying — there is a low abundance of bleeding episodes and any bleeding that does occur is cyclic and thus predictable;

8) Low drop-out rate among patients.

hi addition, the splittable aspect of one preferred embodiment of the invention allows modulation of the estradiol intake and in rum the estrogenic effect, which can not only vary from patient to patient, but can vary with time in the same patient. This flexibility contributes to the product's acceptability.

Use of the composition of the present invention by menopausal and post-menopausal women results in cyclic bleeding pattern and low abundance of bleeding episodes before the state of amenorrhea. This makes the preparation extremely desirable to women who would, in the absence of hormone replacement therapy, be experiencing anarchic bleedings. In contrast, existing combined continuous hormone replacement therapy treatments have the problem that bleeding episodes are quite frequent and irregular. The irregularity of bleeding in the treatments of the prior art is particularly unacceptable to women. In contrast, any bleeding that occurs when taking the composition of the present invention prior to the onset of amenorrhea, is cyclical and, therefore, may be easily predicted by the patient, which makes the treatment far more acceptable compared to the treatments of the prior art.

Examples

A Phase III clinical trial was conducted in post-menopausal women for the orally administered Continuelle® product. All participants in the trial signed a confidentiality agreement. All unused tablets were returned. A whole tablet of the product contained 2mg of 17β-oestradiol and 2 mg chlormadinone acetate.

The trial was conducted over the course of 1 year. The therapeutic regimen followed was either 1 or 0.5 tablet per day from day 1 to day 25 followed by a 5 to 6 day therapeutic window during each calendar month for a twelve month period. The tablet being breakable, the patients were allowed to decrease from 1 tablet daily to half a tablet daily according to their climacteric symptoms under the investigators' supervision. Whenever a half tablet dosage was adopted, this had to be maintained until the end of the trial.

The trial started with 360 post-menopausal women.

Methodology

Patients were seen according to the following schedule:

Selection visit, inclusion visit. Then under treatment for follow-up: at the end of month 1, of month 3, of month 6, at the end of month 9 either a phone call or a doctor visit, and at the end of month 12.

During the selection visit and each follow-up visit, a complete clinical examination was performed, and climacteric symptoms assessed according to the Kupperman Index.

A mammography was done at selection if none had been performed or was fully documented in the patient's file within the previous year. Estrogen impregnation was measured at enrolment from vaginal smears. This was repeated under treatment at month 6 and/or month 12.

Transvaginal ultrasound measurement of endrometrial thickness was done at inclusion and at month 6 (optional) and 12. A biopsy was performed on inclusion visit and last visit under treatment (between the 20th and 25th day of the therapeutic month).

Laboratory work was done for blood counts, hepatic functions, fibrinogen, glycemia, creatininemia, and lipidic profiles at selection and at the end of the trial. Patients were instructed to record treatment compliance, bleeding pattern, side effects in a daily logbook. The investigators inspected these logbooks at each visit. Inclusion criteria and diagnostics

The following women were included in the study:

• Women aged between 50 and 75 • Post-menopausal women with intact uterus that met the following criteria: - Either combined sequential HRT for at least 2 cycles

Or, if no current HRT at selection, amenorrhea for at least 6 months with FSH ? 40 IU/I, requiring HRT indicated for treatment of climacteric symptoms or osteoporosis prevention; if FSH is slightly inferior to 40 IU/I an Estradiol value < 20 pg/ml will determine menopause.

• Women having given their informed consent by writing and accepting to submit themselves to all the exams required for the selection checkup.

• Women with normal mammography performed on first visit (or normal mammography performed during the last 12 months prior to first visit): absence of clinically significant micro calcification, fibrocystic disease, cancer and any other suspicious lesion.

• Women with an endrometrial thickness not greater than 8 mm, determined by transvaginal ultrasound measurement (not greater than 6 mm if no previous HRT)

• Normal biopsy on visit 1. (No hyperplasic image)

Evaluation Criteria

Main Criteria Endometrial tolerability measured by the percentage of endometrial hyperplasia after 12 months under treatment. Assessment of biopsies was performed according to European guidelines (CPMP/EWP/021/97). Two independent pathologists conducted a double blind review of the biopsies.

Secondary Criteria: Efficacy on bleeding patterns, climacteric symptoms and level of estrogenic impregnation.

Clinical and biological tolerability Treatment acceptability Compliance to the treatment was assessed at each visit by counting the returned tablets by the patient.

The trial had a very low drop out rate with a total of 336 patients completing the trial. 72.6% of the patients were treated with 1 tablet a day and 27.4% treated with half a tablet a day. The switch to the half tablet a day was motivated by mastodynia and bleeding.

Table 1 shows the histological results on the final visit for all patients treated (336 women). Table 1

Endometrial status 1 Tablet dose 1/2 Tablet dose TOTAL

Insufficient tissue for valid 7 (2.9 %) 4 (4.3 %) 11 (3.3 %) analysis

Atropic Endometrium 173 ( 70.9%) 64 ( 69.6%) 237 ( 70.5%)

Non-secretory Endometrium 18 ( 7.4%) 8 ( 8.7%) 26 ( 7.7%)

Secretory Endometrium 41 ( 16.8%) 16 ( 17.4%) 57 ( 17.0%)

Proliferative Endometrium 5 ( 2.0%) 0 ( 0%) 5 ( 1.5%)

Hyperplasic Endometrium 0 ( 0%) 0 ( 0%) 0 ( 0%)

TOTAL 244 (100.0%) 92 (100.0%) 336 (100.0%)

Administration of 1 mg 17B-oestradiol and 1 mg chlormadinone acetate was surprisingly and very satisfyingly found to be just as effective in controlling the functional signs related to the menopause as the administration of 2 mg 17β-oestradiol and 2 mg chlormadinone acetate. Furthermore, as demonstrated by Table 1, the percentage of proliferation was in fact even more reduced on administration of 1 mg 17β-oestradiol and 1 mg chlormadinone acetate (0%) compared to the administration of 2 mg 17B-oestradiol and 2 mg chlormadinone acetate (2%). For both the administration of 1 mg 17B-oestradiol and 1 mg chlormadinone acetate and the administration of 2 mg 17B-oestradiol and 2 mg chlormadinone acetate there was an absence of significant adverse effects, the women all had a good metabolic profile (lipid and blood glucose) with no change in body weight. Furthermore the women experienced a low abundance of bleeding episodes and any bleeding that did occur was cyclic and thus predicable. The compliance and tolerability was better on administration of 1 mg 17B-oestradiol and 1 mg chlormadinone acetate compared to the administration of 2 mg 17B-oestradiol and 2 mg chlormadinone acetate.

Claims

1. A composition for limiting the effects induced during the menopause and subsequently, without the onset of periods, characterised in that it comprises, in combination, from about 0.5 to about 1 mg of 17β-oestradiol and from about 0.5 to about 1 mg chlormadinone acetate.

2. The composition according to claim 1, wherein it comprises, in combination, from about 0.5 to about 0.9 mg of 17β-oestradiol and from about 0.5 to about 0.9 mg chlormadinone acetate.

3. The composition according to claim 1 or claim 2, wherein it comprises about 0.5 mg of 17β-oestradiol and about 0.5 mg chlormadinone acetate.

4. The composition according to claim 1, wherein it comprises about 1 mg of 17β- oestradiol and about 1 mg chlormadinone acetate.

5. The composition according to claim 1, or claim 2, wherein it comprises about 0.9 mg of 17β-oestradiol and about 0.9 mg chlormadinone acetate.

6. The composition according to claim 1, wherein it comprises about 0.5 mg of 17β- oestradiol and from about 0.5 mg to about 1 mg chlormadinone acetate. .

7. The composition according to claim 1, wherein it comprises about 0.5 mg of 17β- oestradiol and about 1 mg chlormadinone acetate.

8. The composition according to any preceding claim, wherein it is orally deliverable.

9. The composition according to any preceding claim, wherein it is in the form of a tablet.

10. The composition according to any preceding claim, characterised in that the tablet is splittable to allow a half-dose.

11. The composition according to any preceding claim for use in the treatment of the effects induced during the menopause and subsequently, without the onset of periods.

12. A method of treating menopausal women and post-menopausal women, without the onset of periods, by administration of a composition comprising from about 0.5 mg to about 1 mg 17β-oestradiol and from about 0.5 mg to about 1 mg chlormadinone acetate.

13. The method of claim 12, wherein the treatment is by continuous uninterrupted oral administration of from 21 to 31 combined daily doses followed by an interruption for the remainder of the month during which none of the combined daily doses is administered.

14. The method according to claim 13, wherein the interruption is for 5 to 7 days.

15. Use of a composition, wherein the composition comprises, in combination, from about 0.5 to about 1 mg of 17β-oestradiol and from about 0.5 to about 1 mg chlormadinone acetate in the manufacture of a medicament for the treatment of menopausal and post¬ menopausal women, without the onset of periods.

16. A kit adapted for use during one month for limiting the effects induced during the menopause and subsequently, without the onset of periods, characterised in that it consists of from 21 to 31 sequential daily doses, wherein each daily dose comprises, in combination from about 0.5 mg to 1 mg 17β-oestradiol and from about 0.5 mg to about 1 mg chlormadinone acetate.

17. The kit according to any of claim 16, wherein each daily dose is orally deliverable.

18. The kit according to any of claim 16, wherein the daily dose is in the form of a tablet.

19. The kit according to claim 16, wherein the daily dose is splittable to allow a half- dose.