WO2009112231A2

WO2009112231A2 - New drospirenone/17beta-estradil regimen, pharmaceutical combination product and kit for performing this regimen

Info

Publication number: WO2009112231A2
Application number: PCT/EP2009/001687
Authority: WO
Inventors: Rolf Schürmann; Vladimir Hanes; Bernd Düsterberg; Joachim Marr; Hartmut Blode
Original assignee: Individual
Current assignee: Individual
Priority date: 2008-03-10
Filing date: 2009-03-10
Publication date: 2009-09-17
Anticipated expiration: 2010-09-10
Also published as: WO2009112231A3; CL2009000609A1; TW200942242A

Abstract

The present invention relates to a triphasic pharmaceutical combination product comprising 24 consecutive daily dosage units in its three phases comprising in each phase of the triphasic product 6 to 10 daily dosage units wherein the amount of drospirenone in each daily dosage in each phase is the same and is from 1.5 to 3.0 mg and the amount of 17β-estradiol increases from 1.0 mg in each dosage unit in the first phase to an amount of 2.0 mg of 17β-estradiol in the third phase and wherein the amount of 17β-estradiol in each daily dosage unit of the second phase is more than 1.0 mg and less than 2.0 mg and 4 active ingredient-free placebo pills or other indications to show that the daily administration of the 24 dosage units is to be followed by 4 pillfree or placebo pill days.

Description

New Drospirenone/17β-Estradiol Regimen, Pharmaceutical Combination Product and Kit for performing this Regimen

The present invention relates to a new regimen for administration of a pharmaceutical composition containing drospirenone (DRSP) and 17β-Estradiol (E2) to human females for Contraception as well as for Contraception and Hormone Therapy in

Perimenopausal Women. drospirenone containing OCs (Oral Contraceptives) already available are the products

Yasmin, Yasminelle and Yaz. For Hormone Therapy the product Angeliq containing drospirenone and 17β-Estradiol has been developed.

Standard contraceptive pills are administered in 28-day cycles, utilizing usually 21 days of active pills containing progestin plus estrogen, followed by a 7 days of hormone free or inactive pills period (21 + 7 regimen). The administration of active pills has recently been extended to 24 days with only 4 hormone free days (24 + 4 regimen). Also, extended regimens have been developed with continuous administration of active pills for up to three months (84 +7 regimen). The extended regimens are an option for women who wish to reduce the frequency of withdrawal bleeding for convenience or due to symptoms and complaints associated with menstruation and hormone withdrawal.

The synthetic progestin drospirenone has pharmacodynamic properties very similar to those of progesterone and it differs from the classic progestins in its derivation from spirolactone. The major effect of drospirenone besides its progestational activity is its anti-aldosterone activity. Based on these properties of drospirenone, a decrease of salt and water retention and lowering blood pressure effects were observed in hypertensive subjects. The affinity of drospirenone for the mineralocorticoid receptor is about five times that of aldosterone, the naturally occurring mineralocorticoid. Drospirenone has been developed for contraception in combination with ethinyl estradiol (EE) in fertile women (daily administration of 3 mg DRSP combined with 20 or 30 μg EE, 21 -day and 24-day regimens). Also, several continuous combination of drospirenone with 17-β estradiol have been developed for the hormone therapy of postmenopausal women.

Perimenopause marks the interval in which a woman's body begins its transition into menopause. The perimenopause encompasses the years leading up to menopause - anywhere from two to eight years - plus the first year after the final period. During this time, function of the ovaries declines and the body's estrogen levels drop. For most women, this takes place between ages 35 and 50. Most perimenopausal women experience changes in their menstrual cycle. When estrogen levels begin to drop, the follicular phase of the cycle may be shortened, and this can shorten the total cycle from 28-30 days to 24-26 days, resulting in more frequent periods. On the other hand, some women begin having longer cycles because they are not ovulating as frequently. These changes can be quite different on an individual basis. Additionally, this declining/fluctuating estrogen level can produce a host of disturbing symptoms: hot flashes, increasing vaginal dryness, sleep problems, mood swings, PMS-like symptoms, decreased sex drive, breast tenderness and many other signs and symptoms.

It is an object of the invention to provide a new DRSP/E2 pill regimen and pharmaceutical combination product which may be used as an OC. Such product will combine the natural estrogen E2 and the synthetic progestin DRSP, which is closely related to the natural progestin progesterone in its pharmacological profile but which is effectively bioavailable via the oral route in contrast to progesterone.

It is also an object of the present invention to provide a regimen which allows at the same time making use of the drospirenone related benefits throughout the woman's complete menstrual cycle.

It is a further object of this invention to provide a regimen which has a low total estradiol burden per administration cycle.

EP 0 253 607 already discloses the use of a composition comprising an estrogen selected from

0.075 - 1.50 mg of 17β-estradiol, 0.012 - 0.025 mg of ethinyl estradiol, and

0.025 - 0.050 mg of mestranol;

and a progestogen selected from

0.035 - 0.085 mg of levonorgestrel, 0.015 - 0.060 mg of gestodene, 0.035 - 0.085 mg of desogestrel,

0.035 - 0.085 mg of 3-ketodesogestrel, and 0.10 - 0.30 mg of norethindrone for the manufacture of a dosage form for providing hormonal replacement therapy and contraception for a pre-menopausal woman by administration of the dosage form for 23 to 26 days, beginning at day one of the menstrual cycle, followed by 2 to 5 pill-free or blank pill days, for a total of 28 days in the administration cycle. This composition is not intended to be used as a contraceptive in younger women. Also drospirenone is not mentioned as a possible progestogenic component.

A graduated estrogen contraceptive which provides for the reduction or elimination of estrogen in the initial phase of a multiphasic estrogenic/progestogenic contraceptive regimen without compromising contraceptive efficacy or cycle control is subject of EP 1 689 411 B1.

The daily dose of the estrogen, namely ethinyl estradiol, is either nil or very low, namely 5μg, of ethinyl estradiol in the first phase of the exemplified, preferred compositions whereas the daily amount of ethinyl estradiol in the second and third phase is rather high, namely 30μg and 35μg of ethinyl estradiol, respectively. The total amount of ethinyl estradiol per cycle (24 days of administration) is 520μg whereas the modern monophasic oral contraceptive YAZ has a total amount of 480μg ethinyl estradiol per administration cycle (also 24 days of administration of the active ingredients per administration cycle). According to the exemplified, preferred compositions the daily amount of the progestin therein, namely norethindrone acetate, is the same each day.

A monophasic 24 + 4 regimen which can be used as an oral contraceptive in younger women is described i.a. in PCT/EP94/04274 and US RE37.564 E. Claim 1 of this patent reads on

a combination product for oral contraception, comprising (a) 23 or 24 dosage units, each containing an estrogen selected from > 2.0 to

6.0 mg of 17β-estradiol and 0.02 mg of ethinylestradiol; and a gestagen selected from 1.5 to 3.0 mg of drospirenone and 1 to 2 mg of cyproterone acetate, and (b) 5 or 4, respectively, active ingredient-free placebo pills or other indications to show that the daily administration of the 23 or 24 dosage units respectively, is to be followed by 5 or 4, respectively pill-free or placebo pill days.

The objects of the present invention are achieved by a triphasic pharmaceutical combination product comprising 24 consecutive daily dosage units in its three phases comprising in each phase of the triphasic product 6 to 10 daily dosage units wherein the amount of drospirenone in each daily dosage in each phase is the same and is from 1.5 -A- to 3.0 mg and the amount of 17β-estradiol increases from 1.0 mg in each dosage unit in the first phase to an amount of 2.0 mg of 17β-estradiol in the third phase and wherein the amount of 17β-estradiol in each daily dosage unit of the second phase is more than 1.0 mg and less than 2.0 mg and 4 active ingredient-free placebo pills or other indications to show that the daily administration of the 24 dosage units is to be followed by 4 pill-free or placebo pill days.

In one embodiment of the invention the dosage units in the each phase contain 3.0 mg of drospirenone.

In another embodiment the dosage units in the second phase contain 1.5 mg of 17β- estradiol.

According to a preferred embodiment of the invention each of the three phases has 8 daily dosage units.

The present invention also relates to a kit containing the above described combination product.

According to the present invention it has been found that such new dosage regimen ensures reliable induction of the withdrawal bleeding before daily administration of the DRSP/E2-administration commences again.

The new regimens provide an acceptable bleeding profile with respect to parameters as total number of bleeding days, intensity of bleeding, lengths of withdrawal bleeding, etc..

The advantages of the regimen according to the invention can be summarized as follows:

The stepwise increasing E2 dosage stabilizes the endometrium thereby effecting a good cycle control (low incidence of intracyclic bleeding and spottings).

The high E2 dosage of 2.0 mg at the end of the treatment cycle results in a rapid hormone withdrawal which in turn is leading to a safe and reliable, immediate withdrawal bleeding. This is important because further treatment is continued only 4 days thereafter. The estrogenic dominance at the end of the treatment cycle ensures reliable endometrial proliferation, induces both estrogen and progestin receptors and thus sensitizes the endometrium for the progestin action.

The administered E2 dosages are sufficient to maintain normal physiological bone mineral density.

Advantages of the regimen would include maintenance of contraceptive efficacy even in case of missed pill intake due to the constantly high dose of DRSP. Replacement of ethinylestradiol by E2 is expected to provide significant benefits. One thereof is less impact on metabolic parameters, such as liver protein biosynthesis.

In even a further embodiment of the invention a tetrahydrofolate is contained in each daily dosage unit in addition to the estrogen and drospirenone as well as in the remaining daily units without any hormone. Pharmaceutical compositions containing an estrogen and/or a progestin as well as 5-methyl-(6S)-tetrahydrofolate are described in WO 2006/120035 which is incorporated herein by reference.

WO 2006/120035 discloses oral contraceptives which, although able to prevent diseases caused by folate deficiency, at the same time are unable to mask the symptoms of vitamin Bi₂ deficiency. The respective administration regime ensures that the consumer of the pharmaceutical composition of that invention is reliably protected also for a certain time after discontinuation from disorders or malformations caused by folate deficiency, in particular from neural tube defects. Both these also apply in the case of a homozygous or heterozygous polymorphism of methylenetetrahydrofolate reductase in the user, which adversely affects the utilizability of folic acid by the body and thus its biological activity to prevent neural tube defects. The addition of a 5-methyl-(6S)-tetrahydrofolate to the pharmaceutical combination product of the present invention serves the same purpose as it does in WO 2006/120035.

Reference to 5-methyl-(6S)-tetrahydrofolates in the form according to the present invention means the free acid form and pharmaceutically acceptable salts and modifications of 5-methyl-(6S)-tetrahydrofolic acid (N-[4-[[(2-amino-1 ,4,5,6,7,8- hexahydro-4-oxo-5-methyl-(6S)-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid).

Pharmaceutically acceptable salts are intended to be both pharmacologically and pharmaceutically acceptable. Such pharmacologically and pharmaceutically acceptable salts may be alkali metal or alkaline earth metal salts, preferably sodium, potassium, magnesium or calcium salts. The calcium salt is particularly preferred.

The amount used for example of the calcium salt, which is particularly preferred according to the invention, of 5-methyl-(6S)-tetrahydrofolic acid (metafolin) is between 0.1 and 10 mg, preferably 0.4 to 1 mg, particularly preferred 451 μg (equivalent to 400 μg of folic acid or 416 μg of 5-methyl-(6S)-tetrahydrofolic acid (metafolin)).

Crystalline modifications disclosed in EP 1044975 are preferably employed as modifications of 5-methyl-(6S)-tetrahydrofolates.

The present invention also refers to pharmaceutical combination product to perform the above mentioned regimens.

Placebo tablets may be introduced in the regimens on days with no hormone intake with the aim to increase women's compliance and not to forget to take a pill every day.

According to an embodiment of the invention in case that the pharmaceutical combination also contains a 5-methyl-(6S)-tetrahydrofolate each hormone-free "placebo" contains this 5-methyl-(6S)-tetrahydrofolate, too and preferably in the same amount as the daily dosage units do.

In the new regimen and pharmaceutical combination product wherein monophasic DRSP treatment is combined with increasing E2 doses high ovarian suppression is achieved, comparable to that of YAZ. The increasing E2 doses also counteract the potential down-regulation of estrogen receptors during the treatment cycle.

All the benefits known for drospirenone are maintained effectively throughout the complete administration period. These benefits in first instance are the therapeutic activity in treatment of PMDD (Premenstrual Dysphoric Disorders), acne and the ability of Dospirenone to keep the body weight virtually unchanged due to its antimineralcorticoid effect counteracting the water retention by the estrogen. Additional drospirenone benefits include lowering blood pressure in pre-hypertensive and hypertensive.women.

The effect of the regimen with respect of ovulation inhibition and acceptable withdrawal bleeding is tested in clinical studies By these studies the ovulation inhibition effect of the new regimens is evaluated. Also the bleeding pattern, cycle control, and tolerability of the regimen is evaluated.

A multi-center, double-blind, randomized, parallel-group study is conducted to evaluate cycle control and safety of the oral contraceptive containing 17β-estradiol (E2) and drospirenone (DRSP) in healthy female volunteers aged between 18 and 35 years over 7 cycles.

Approximately 100 volunteers are treated according to the below regimen. Route of administration is oral.

Day 1-8: 1 mg E2 + 3 mg DRSP Day 9-16: 1.5 mg E2 + 3 mg DRSP Day 17-24: 2 mg E2 + 3 mg DRSP Day 25: placebo Day 26: placebo Day 27: placebo Day 28: placebo

The volunteers (healthy female volunteers, age 18 - 35 years inclusive) are treated over 7 treatment cycles, each consisting of 28 days (total 196 days), one tablet per day

Efficacy variables

Primary efficacy variable

• Number of intracyclic bleeding episodes (including spotting) in Cycles 2 to 7

Secondary efficacy variables • Number of intracyclic bleeding days (including spotting) in Cycles 2 to 7

• Number of withdrawal bleeding episodes in Cycles 1 to 6

• - Bleeding pattern

- Number of bleeding/spotting days

- Number of bleeding days (excluding spotting) - Number of spotting-only days - Number, mean length, maximum length, and range of length of bleeding/spotting episodes

- Number, mean length, maximum length, and range of length of spotting-only episodes.

• Cycle control

Withdrawal bleeding

- Number of volunteers with/without withdrawal bleeding

- Length of withdrawal bleeding episodes

- Maximum intensity of withdrawal bleeding episodes - Onset of withdrawal bleeding episodes lntracyclic bleeding (including spotting)

- Number of volunteers with/without intracyclic bleeding

- Number and maximum length of intracyclic bleeding episodes

- Number of intracyclic bleeding days -Maximum intensity of intracyclic bleeding episodes

Intracyclic bleeding (excluding spotting)

- Number of volunteers with/without intracyclic bleeding

- Number and maximum length of intracyclic bleeding episodes

- Number of intracyclic bleeding days Women with intracyclic bleeding (including spotting)

- Number of volunteers with at least one intracyclic bleeding episode in Cycles 2 - 6

- Number of volunteers with at least one intracyclic bleeding episode in Cycles 2 - 7 Women with intracyclic bleeding (excluding spotting)

- Number of volunteers with at least one intracyclic bleeding episode in Cycles 2 - 7

• Subjective assessment of treatment

Safety variables:

• Baseline findings and adverse events (AE) • Safety laboratory tests (incl. pregnancy tests)

• Vital signs

• Physical and gynecological examination (incl. breast palpation, transvaginal ultrasonography [TVU] and cytological cervical smear).

The regimen provides an acceptable bleeding profile and good tolerance.

The ovulation inhibition achieved by the regimen according to the present invention is evaluated in a randomized, double-blind clinical study. Approximately 50 volunteers are included within the treatment group. The study encompasses 1 pre-treatment and 3 treatment cycles. The primary clinical endpoint is to determine the number of volunteers with incomplete ovulation inhibition. Incomplete ovulation inhibition is defined by a Hoogland score 6 (ovulation) in treatment cycles 2 or 3. Successful ovulation inhibition is demonstrated if less than 5% of PPS (Per Protocol Set) show incomplete ovulation inhibition.

The regimen inhibits ovulation effectively.

Pharmaceutical combinations of the invention can be formulated according to accepted pharmaceutical practice, with a conventional pharmaceutically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, and/or adjuvant, etc, for any given type of unit dosage form.

Formulations for oral administration are conventional in the art. For example, tablets generally contain a pharmaceutically acceptable carrier, e.g., a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate or celluose; a disintegrating agent such as corn starch or alginic acid; a lubricant, such as magnesium stearate; and/or a sweetening agent or flavoring agent. When the dosage unitform is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, water, alcohol or the like as the carrier, glycerol assolubilized, sucrose as sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange. When administered orally as a suspension, these compositions may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweetners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, disintegrants, diluents and lubricants known in the art.

Preferrably the drospirenone and estradiol are formulated according to the teaching and Examples of the EP 1 257 280. The drospirenone in the compositions described therein is in micronized form or another form which allows for immediate release of the drospirenone after ingestions and disintegration of the oral dosage form. Also the estradiol is preferrably micronized.

Drospirenone can be obtained from commercial sources (e.g., from Bayer Schering Pharma AG) or can by synthesized by conventional methods, e.g., according to the methods disclosed in USP 6,121 , 465 and Drugs of the Future 2000, 25 (12), 1247- 1256.

While it is clearly preferred according to the invention that the dosage units are adapted for oral administration and the stated daily dosages are given for the oral administration it is also in the ambit of the invention to administer the daily dosages by other routes known to be effective for hormonal contraception, e.g. via the transdermal or transmuccosal route.

If the dosage units are administered by non-oral routes adjustment of the daily doses might be necessary. For instance in case of transdermal administration 0.05 mg of transdermal^ administered E2 roughly translates into 1 mg of orally administered E2, i.e. E2 is about 20 times better available upon transdermal compared to oral administration.

The bioavailabilities of DRSP after oral and transdermal administration are roughly the same i.e. the doses of DRSP to be administered transdermal^ are roughly the same as those given in the present specification relating to oral administration.

A preferred pharmaceutical combination product is provided in a kit containing the below shown compositions per each daily dosage unit:

The dosage units are to be administered by the female patient starting with the first dosage unit of the first phase up to the last dosage unit of the third phase on day 24 of the administration cycle followed by 4 active ingedient-free placebo pills or other indications to show that the daily administration of the 24 dosage units is to be followed by 4 pill-free days. Preferrably the dosage units are arranged in a blister for instance as shown below to support the female patient in following the administration regimen.

C1 = 1mg E2 + 3mg DRSP; C2 = 1 ,5 mg E2 + 3,0mg DRSP; C3 = 2mg E2 + 3mg DRSP; P = Placebo or pill-free

Claims

Claims:

1. Triphasic pharmaceutical combination product comprising 24 consecutive daily dosage units in its three phases comprising in each phase of the triphasic product 6 to 10 daily dosage units wherein the amount of drospirenone in each daily dosage in each phase is the same and is from 1.5 to 3.0 mg and the amount of 17β-estradiol increases from 1.0 mg in each dosage unit in the first phase to an amount of 2.0 mg of 17β-estradiol in the third phase and wherein the amount of 17β-estradiol in each daily dosage unit of the second phase is more than 1.0 mg and less than 2.0 mg and 4 active ingredient-free placebo pills or other indications to show that the daily administration of the 24 dosage units is to be followed by 4 pill-free or placebo pill days.

2. Triphasic pharmaceutical combination product wherein the dosage units in each phase contain 3.0 mg of drospirenone.

3. Triphasic pharmaceutical combination product wherein the dosage units in the second phase contain 1.5 mg of 17β-estradiol.

4. Triphasic pharmaceutical combination product according to claim 1 wherein each of the three phases has 8 daily dosage units.

5. Pharmaceutical combination product according to claim 1 wherein 0.1 to 10 mg of a 5-methyl-(6S)-tetrahydrofolate is contained in each dosage unit.

6. Pharmaceutical combination product according to claim 5 wherein the 5-methyl- (6S)-tetrahydrofolate is Metafolin.

7. Pharmaceutical combination product according to claim 6 wherein 0.4 to 1.0 mg of Metafolin is contained in each dosage unit.

8. A pharmaceutical kit containing a pharmaceutical combination product according to one of the preceding claims 1 to 7.