Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
  • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin

Definitions

• the present invention relates to a new regimen for administration of a pharmaceutical composition containing drospirenone (DRSP) and 17 ⁇ -Estradiol (E2) to human females for Contraception as well as for Contraception and Hormone Therapy in
• 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).
• 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 ⁇ g EE, 21 -day and 24-day regimens). Also, several continuous combination of drospirenone with 17- ⁇ estradiol have been developed for the hormone therapy of postmenopausal women.
• EE ethinyl estradiol
• 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.
• 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.
• 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.
• 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.
• EP 0 253 607 already discloses the use of a composition comprising an estrogen selected from
• 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 5 ⁇ g, 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 30 ⁇ g and 35 ⁇ g of ethinyl estradiol, respectively.
• the total amount of ethinyl estradiol per cycle (24 days of administration) is 520 ⁇ g whereas the modern monophasic oral contraceptive YAZ has a total amount of 480 ⁇ g ethinyl estradiol per administration cycle (also 24 days of administration of the active ingredients per administration cycle).
• the daily amount of the progestin therein, namely norethindrone acetate is the same each day.
• a combination product for oral contraception comprising (a) 23 or 24 dosage units, each containing an estrogen selected from > 2.0 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 -A- to 3.0 mg and the amount of 17 ⁇ -estradiol increases from 1.0 mg in each dosage unit in the first phase to an amount of 2.0 mg of 17 ⁇ -estradiol in the third phase and wherein the amount of 17 ⁇ -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.
• the dosage units in the each phase contain 3.0 mg of drospirenone.
• the dosage units in the second phase contain 1.5 mg of 17 ⁇ - estradiol.
• each of the three phases has 8 daily dosage units.
• the present invention also relates to a kit containing the above described combination product.
• 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 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.
• 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 Bi 2 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 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 ⁇ g (equivalent to 400 ⁇ g of folic acid or 416 ⁇ g 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.
• each hormone-free "placebo" contains this 5-methyl-(6S)-tetrahydrofolate, too and preferably in the same amount as the daily dosage units do.
• drospirenone 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.
• a multi-center, double-blind, randomized, parallel-group study is conducted to evaluate cycle control and safety of the oral contraceptive containing 17 ⁇ -estradiol (E2) and drospirenone (DRSP) in healthy female volunteers aged between 18 and 35 years over 7 cycles.
• E2 17 ⁇ -estradiol
• DRSP drospirenone
• 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
• 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.
• PPS Per Protocol Set
• the regimen inhibits ovulation effectively.
• compositions 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.
• 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.
• 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
• sweetening agent or flavoring agent e.g., a sweetening agent or flavoring agent.
• the dosage unitform may contain in addition to materials of the above type a liquid carrier such as a fatty oil.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• the dosage units are arranged in a blister for instance as shown below to support the female patient in following the administration regimen.

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• Health & Medical Sciences (AREA)
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• Pharmacology & Pharmacy (AREA)
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Applications Claiming Priority (6)

Publications (2)

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Citations (4)

• 2009
  • 2009-03-10 WO PCT/EP2009/001687 patent/WO2009112231A2/en active Application Filing
  • 2009-03-10 TW TW098107737A patent/TW200942242A/zh unknown
  • 2009-03-13 CL CL2009000609A patent/CL2009000609A1/es unknown

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