DE4313926A1 - Multiphase pharmaceutical product for hormonal contraception - Google Patents

Abstract

The invention relates to a multiphase pharmaceutical product for oral hormonal contraception. The low-dose sequential or combination or phasic products are being increasingly used. All low-dose phasic products reliably inhibit the preovulatory LH peak. By contrast, follicle ripening is not completely blocked in every case. The object of the present invention is to administer hormones in analogy to the woman's normal physiological cycle throughout the cycle by creating an at least 4-phase combination product. The at least 4-phase pharmaceutical product for contraception consists according to the invention of a fixed or sequential at least 3-phase combination of ethinyloestradiol or mestranol or another synthetic oestrogen plus a progestogen and an oestrogen product which is to be administered at least in the 4th phase of the cycle and contains ethinyloestradiol or mestranol and/or another synthetic and/or endogenous oestrogen.

Description

The invention relates to a pharmaceutical multiphase preparation for oral hormonal contraception.

On the one hand, ovulation inhibitors have been used since the 1960s Combination preparations and stage preparations as well as on the other hand as combination preparations and step preparations as well on the other hand known as sequence preparations.

Single-phase preparations (usually as combination preparations are characterized by a constant Concentration of the respective estrogen and progestogen in every daily dose.

Through the simultaneous administration of the progestogen component with the Combined preparations develop estrogen content from the first day of application high contraceptive security.

In all forms of combination products, the ovulatory LH summit reliably suppressed, so that both Ovulation as well as corpus luteum formation can be suppressed (ELSTEIN, M. et al: Studies on low dose oral contraceptives: cervical mucus and plasma hormone changes in relation to circulating d-norgestrel and 17-ethinyl estradiol concentrations. Fertil Sterile 27: 892 (1976)).

On the other hand, early secretory transformation can the appearance of the little developed endometrium of bleeding especially during the first few cycles have as a consequence.

Sequence preparations contain 7 to a maximum of 11 in the first Days of use a pure estrogen component and only in the following 10 to a maximum of 14 days a progestogen fraction. In doing so, they cause endometrial changes, the very physiological cycle dependent  come close and thus lead to good cycle control.

Sequence preparations lower the basal gonadotropin levels in similar to combination products, the FSH levels are obviously more suppressed than LH levels (AKTORIES, K. et al: Influencing the Ovarian Cycle through different types of hormonal contraceptives. Obstetrics Gynecology 36: 318 (1976)).

On the other hand, the anti-conceptual protection of the sequence preparation is achieved not the strength of the combination drug.

After a tablet-free interval of 7 days, the sole administration of ethinylestradiol on the 7th day of the cycle in the Usually on a pre-matured follicle. The only one The estrogen may be given for the next 6 days do not suppress the maturation of the dominant follicle that preovulatory FH and FSH increases and ovulation with Risk of pregnancy not always successfully avoided can be.

There are modified combination or stage preparations So far two-phase (2-stage preparations) and three-phase (3- Stage preparations).

2-stage preparations are those that are already in contain a low dose of progestogen in the first intake phase, but in the 2nd half of the cycle - with the same Estrogen dose - is increased. The phase of the low gestagen dose lasts 11 for a total of 21-22 days Days.

3-stage preparations included in the first few days of taking low-dose estrogens, low-dose gestagens, which in 2 steps to the highest progestogen dosage in the last 7 to 10 days increase while the estrogen percentage  either remains the same or over the medium term at short notice the duration of 5 to 6 days in analogy to the normal physiological Cycle is increased.

3-stage preparations offer the possibility of the total share to keep lower on applied progestin than on others oral contraceptives (CARLBORG, L .: Comparison of contraceptive acceptability of levonorgestrel and ethinyl oestradiol administered in one three-phasic (Trionetta) and one monophasic (Neoletta) version. Contraception, 27: 5 (1983)).

The mechanism of action corresponds to that of the conventional one Combination preparations.

A major advantage when using 3-stage contraceptives consists in reducing the occurrence of side effects and complications compared to other oral ones Anticonceptives (HALE, R.W .: Phasic approach to oral contraceptives. At the. J. Obstet. Gynecol. 157: 4 (1984)).

Change in serum lipids and lipoproteins that are responsible for oral contraceptives known artherogenic effects with the Risk of cardiovascular disease when using 3-stage preparations in much less Dimensions compared to other contraceptives (MARCH, W .: A randomized crossover comparison of two low-dose contraceptives: Effects on serum lipids and lipoproteins. At the. J. Obstet. Gynecol. 153: 3 (1985)).

The exogenous hormone intake through 3-stage preparations applies through the balanced, different in three cycle phases, Estrogen / progestogen composition as the menstrual cycle the woman's least stressful variant of the oral Anti-conception. 3-stage contraceptives are hormonal in their Composition of the normal physiological cycle modeled. However, this only applies to 21 days of Menstrual cycle, because in the 7-day tablet-free interval,  in which with 3-stage preparations up to now Hormone intake has been omitted, the body will not or not taking hormones every day.

In several U.S. patents (U.S. Patents 4,530,839, 4,544,554, 4,628,051 and 4,921,843 S.A. Pasquale) were different multi-phase oral contraceptives are described, according to which a constant amount of ethinylestradiol over 26 days of the cycle and for example a constant from day 9 or increasing amount of a progestogen to improve the Cycle stability can be administered.

In German patent DE 32 29 612 C2 (R. A. Edgren) a four-phase contraceptive described, according to the previously a 7-day interval without a preparation Lactose, corn starch, polyvenyl pyrrolidone and talc, so a hormone-free preparation.

A means of oral contraception, which consists of two in a packaging unit that is made up separately, intended for sequential oral administration Hormone components exist, describes the German Patent P 41 04 385 (M. Ehrlich; H. Kuhl).

It was also used for combination and sequence preparations already proposed (P 42 29 832.6, M. Oettel) that from 22nd to 28th day the body's own estrogen, namely 1 mg / d Estradiol, 2 mg / d estradiol valerate (EV) or 1.5 mg / d Estrone sulfate (ES) is administered.

The continuous reduction of the drug dose also in Multi-stage preparations as well as constant further development of the active substances, especially the progestin, led in the course of years to improve oral tolerance  Contraceptives with high contraception.

There have been increasing the low-dose sequence or Combination or step preparations prevailed, too the risk of undesirable hormonal effects and side effects could be reduced depending on the dose.

All low-dose stage preparations reliably inhibit the preovulatory LH summit. However, follicular maturation is not completely blocked in every case; one can suspect this from the gonadotropin levels that less are strongly suppressed than with higher-dose preparations (DERICKS-TAN, J.S.E. et al: The mechanism of action of a new low-dose combined oral contraceptive. Arch. Gynec. 229: 107 (1980)).

The object of the present invention is to create a at least 4-stage combination product over the entire cycle in analogy to normal physiological Cycle of woman administering hormones. So that will described a preparation that compared to all previous, the hormonal changes of normal physiological Most likely to feel the cycle.

According to the invention, there is the at least four-phase pharmaceutical Contraceptive product from a fixed or sequential at least three-phase combination of ethinylestradiol or mestranol or another synthetic Estrogen plus a progestogen and at least one to be administered in the fourth phase of the cycle estrogen preparation, the ethinyl estradiol or mestranol and / or a other synthetic and / or an endogenous estrogen contains.

The cycle phases are divided as follows, with deviations  in the individual periods by one day after Tolerated above or below:

first cycle phase: 1st to 7th cycle day
second cycle phase: 8th to 14th cycle day
third cycle phase: 15th to 21st cycle day
fourth cycle phase: 22nd to 28th cycle day

In the additional according to this invention (for example fourth) stage, only a pure estrogen can be applied, to guarantee the gestagen withdrawal bleeding.

In addition, this form of application already the early follicular maturation is influenced in the sense of an inhibition and good endometrial proliferation in the early proliferative phase causes.

The additional (for example fourth) according to the invention Stage has increased contraceptive safety of the low-dose Multi-stage combination products result.

Another advantage of using this new ovulation inhibitor principle becomes cardiovascular in the decreased occurrence related side effects. Through estrogen waste conditional vascular contraction effects, especially Headache and migraine reactions during postovulatory and premenstrual estrogen waste, should be considered Follow continuous estradiol administration throughout Cycle duration occur in frequency and strength less.

The following examples illustrate the invention.  

Example 1 (Four-stage preparation: hard gelatin capsules according to table) Manufacturing

Lactose and starch are mixed with aqueous gelatin solution in the Fluidized bed spray granulator granulated. On the granules an ethanolic solution of the specified drugs sprayed. Subsequently until dried to a residual moisture of approx. 3%.

50 mg each of the dry granules are placed in hard gelatin capsules filled in size 1.

dosage

1 capsule 7 days a day, 1 capsule 7 days a day according to level 2, 7 capsules daily according to level 2 and then 7 days 1 capsule according to level 4 etc.  

Example 2 (Four-stage preparation: coated tablets according to the table) Manufacturing

Lactose and starch are mixed with aqueous gelatin solution in the Fluidized bed spray granulator granulated. On the granules an ethanolic solution of the specified drugs sprayed. Subsequently until dried to a residual moisture of approx. 3%.

The dry granules are in the fluidized bed spray granulator Talc and magnesium stearate added. From each 50 mg of this mixture is on a rotary tablet press a tablet core (diameter 5 mm) is pressed.

The drageeker is in the kettle with the specified mixture of additives coated onto 100 mg of final mass.

dosage

7 days a day 1 dragee according to level 1, 7 days a day 1 dragee according to level 2, 7 days a day 1 dragee according to level 2 and then 7 days 1 dragee according to level 4 etc.

Example 3 (Four-stage preparation: film-coated tablets accordingly Table) Manufacturing

Lactose and starch are mixed with aqueous gelatin solution in the Fluidized bed spray granulator granulated. On the granules an ethanolic solution of the specified drugs sprayed. Subsequently until dried to a residual moisture of approx. 3%.

The dry granules are in the fluidized bed spray granulator Talc and magnesium stearate added. From each 47.5 mg of this mixture is placed on a rotary tablet press a tablet (diameter 5 mm) pressed.

The tablet is covered with a film in the driacoater specified excipient mixture coated so that a film-coated tablet  with a mass of 50 mg results.

dosage

7 days a day 1 film-coated tablet according to level 1, 7 days a day 1 Film-coated tablet according to level 2, 7 days a day 1 film-coated tablet according to Level 2 and then 7 days 1 tablet according to Level 4 etc.

Example 4 (Four-stage preparation: thin-film coated tablets accordingly Table) Manufacturing

Lactose and starch are mixed with aqueous gelatin solution in the Fluidized bed spray granulator granulated. On the granules an ethanolic solution of the specified drugs sprayed. Subsequently until dried to a residual moisture of approx. 3%.

The dry granules are in the fluidized bed spray granulator Talc and magnesium stearate added. From each 50 mg of this mixture is on a rotary tablet press a tablet core (diameter 5 mm) is pressed.

The drageeker is in the kettle with the specified mixture of additives coated on 75 mg final mass.

dosage

7 days a day 1 thin-layer coated tablet according to level 1, 7 days a day 1 thin-film coated tablet according to level 2, 7 days a day 1 thin-film coated tablet according to level 2 and then 7 days 1 thin-film dragee according to level 4 etc.

Claims (18)

1. Pharmaceutical multiphase preparation, characterized in that it consists of a fixed or sequential at least three-phase combination of ethinyl estradiol or mestranol or another synthetic estrogen and / or an endogenous estrogen and a progestogen and an at least in the fourth phase to be administered estrogen preparation consisting of ethinyl estradiol or Mestranol and / or an endogenous estrogen. 2. Pharmaceutical multiphase preparation according to claim 1, characterized in that it consists of a combination of

• a) 0.005 to 0.020 mg / day of ethinyl estradiol or
  0.010 to 0.030 mg / day mestranol and
• b) 0.010 to 0.050 mg / day levonorgestrel or
  0.050 to 1,000 mg / day dienogest or
  there is an adequate amount of another progestogen,
  those in the first cycle phase,

a second combination of

• c) 0.075 to 0.030 mg / day of ethinyl estradiol or
  0.015 to 0.030 mg / day mestranol and
• d) 0.050 to 0.075 mg / day levonorgestrel or
  1,000 to 2,000 mg / day dienogest or
  there is an adequate amount of another progestogen,
  those in the second cycle phase,

a third combination of

• e) 0.005 to 0.020 mg / day of ethinyl estradiol or
  0.010 to 0.30 mg / day mestranol and
• f) 0.075 to 0.125 mg / day levonorgestrel or
  1,500 to 2,000 mg / day dienogest or
  there is an adequate amount of another progestogen,
  the third cycle phase,

and a fourth preparation of

• g) 0.005 to 0.020 mg / day of ethinyl estradiol and / or
  1,000 to 2,000 mg / day of estradiol valerate or
  1,000 to 2,000 mg / day of estrone sulfate or
  There is 1,000 to 2,000 mg / day of estradiol,
  which is applied in the fourth cycle phase.

3. Pharmaceutical multiphase preparation according to claim 1, characterized in that it consists of a combination of

• a) 0.005 to 0.010 mg / day of ethinyl estradiol or
  0.010 to 0.015 mg / day mestranol
• b) 1,000 mg / day of estradiol valerate or
  1,500 mg / day of estrone sulfate or
  1,000 mg / day estradiol and
• c) 0.010 to 0.050 mg / day levonorgestrel or
  0.050 to 1,000 mg / day dienogest or
  there is an adequate amount of another progestogen,
  those in the first cycle phase,

a second combination of

• d) 0.075 to 0.020 mg / day of ethinyl estradiol or
  0.015 to 0.020 mg / day mestranol,
• e) 1,000 to 1,500 mg / day of estradiol valerate or
  1,000 to 1,500 mg / day of estrone sulfate or
  1,000 to 1,500 mg / day estradiol and
• f) 0.050 to 0.075 mg / day levonorgestrel or
  1,000 to 2,000 mg / day dienogest or
  there is an adequate amount of progestogen,
  those in the second cycle phase,

a third combination of

• g) 0.005 to 0.010 mg / day of ethinyl estradiol or
  0.010 to 0.015 mg / day mestranol and
  1,000 to 2,000 mg / day of estradiol valerate or
  1,000 to 2,000 mg / day of estrone sulfate or
  1,000 to 2,000 mg / day estradiol and
• h) 0.075 to 0.125 mg / day levonorgestrel or
  1,500 to 2,000 mg / day dienogest or
  there is an adequate amount of another progestogen,
  the third cycle phase,

and a fourth preparation of

• i) 0.005 to 0.020 mg / day of ethinyl estradiol and / or
  1,000 to 2,000 mg / day of estradiol valerate or
  1,000 to 2,000 mg / day of estrone sulfate or
  There is 1,000 to 2,000 mg / day of estradiol,
  which is applied in the fourth cycle phase.

4. Pharmaceutical multiphase preparation according to claim 1, characterized in that it consists of a combination of

• a) 1,000 to 3,000 mg / day of estradiol valerate or
  1,000 to 3,000 mg / day of estrone sulfate or
  1,000 to 3,000 mg / day estradiol and
• b) 0.010 to 0.050 mg / day levonorgestrel or
  0.050 to 1,000 mg / day dienogest or
  there is an adequate amount of another progestogen,
  those in the first cycle phase,

a second combination of

• c) 2,000 to 4,000 mg / day of estradiol valerate or
  2,000 to 4,000 mg / day of estrone sulfate or
  2,000 to 4,000 mg / day estradiol and
• d) 0.050 to 0.075 mg / day levonorgestrel or
  1,000 to 2,000 mg / day dienogest or
  there is an adequate amount of another progestogen,
  those in the second cycle phase,

a third combination of

• e) 1,000 to 3,000 mg / day of estradiol valerate or
  1,000 to 3,000 mg / day of estrone sulfate or
  1,000 to 3,000 mg / day estradiol and
• f) 0.075 to 0.125 mg / day levonorgestrel or
  1,500 to 2,000 mg / day dienogest or
  there is an adequate amount of another progestogen,
  the third cycle phase,

and a fourth preparation of

• g) 1,000 to 2,000 mg / day of estradiol valerate or
  1,000 to 2,000 mg / day of estrone sulfate or
  There is 1,000 to 2,000 mg / day of estradiol,
  which is applied in the fourth cycle phase.

The cycle phases are divided as follows, for example:

• - First cycle phase: for example from the 1st to the 7th day of the cycle
• - second cycle phase: for example, from the 8th to the 14th cycle day
• - third cycle phase: for example from the 15th to the 21st cycle day
• - fourth cycle phase: for example from the 22nd to the 28th cycle day

5. Pharmaceutical multiphase preparation according to the claims 1 and 2, characterized in that the combination of Ethinylestradiol or Mestranol or another synthetic Estrogen with progestogen from the 1st to the 21st Cycle day and that the body's own estrogen releasing therapeutic system applied from the 22nd to the 28th day of the cycle becomes. 6. Pharmaceutical multiphase preparation according to the claims 1, 3 and 4, characterized in that the combination from ethinyl estradiol or mestranol or another synthetic estrogen with progestogen from the 1st to the 21st cycle day and that the body's own estrogen releasing therapeutic system from the 1st to the 28th day of the cycle is applied. 7. Pharmaceutical multiphase preparation according to the claims 1, 2, 3, 4, 5 and 6, characterized in that the endogenous estrogen in the form of a transdermal therapeutic System is applied. 8. Pharmaceutical multiphase preparation according to the claims 1, 2, 3, 4, 5 and 6, characterized in that the endogenous estrogen in an intravaginal dosage form (for example in the form of capsules or Ovuli) is applied.