HK1112200A - Contraceptive pharmaceutical preparation - Google Patents

Description

Contraceptive pharmaceutical preparation

Technical Field

The present invention relates to a pharmaceutical composition comprising dienogest in an amount corresponding to a daily dosage unit of 1.5mg or 2.0mg when said composition is administered and ethinylestradiol in an amount corresponding to a daily dosage unit of 0.015mg or 0.020mg when said composition is administered and one or more pharmaceutically acceptable carriers for at least 21 daily dosage units.

The invention also relates to a pharmaceutical product for oral contraception, comprising 1.5mg of 17 α -cyanomethyl-17- β -hydroxyestra-4, 9-dien-3-one (dienogest) and 0.015 or 0.020mg of 17 α -ethinylestradiol (ethinylestradiol) or 2.0mg of dienogest and 0.015mg of ethinylestradiol in combination with one or more pharmaceutically acceptable carriers in at least 21 daily dosage units of a 28-day menstrual cycle.

Prior Art

Oral contraceptive compositions consisting of a progestogenic component and an estrogenic component are first marketed in the early sixties of the twentieth century. Three basic properties characterize a "contraceptive pill": contraceptive reliability, very good cycle control and minimal side effects. Contraceptive reliability comes primarily from the progestogenic component. Its action is to inhibit gonadotropin release in the pituitary and to inhibit ovulation. In addition, the peripheral effect of progestagens on the endometrium results in a reduced likelihood of implantation of a fertilized egg; the peripheral action on the cervix results in the secretion of viscous secretions, which reduce sperm in the uterus. Attention should also be paid to the peripheral effects on the fallopian tubes.

The estrogenic component enhances the ovulation-inhibiting action of the progestogen and is responsible for satisfactory cycle control. Since the introduction of hormonal contraceptives, research has been directed to the development of products that reduce undesirable side effects such as arterial and venous thrombosis and effects on carbohydrate and lipid metabolism while maintaining good contraceptive reliability and cycle control. In particular, first generation oral contraceptives containing higher progestogen and estrogen levels than required for contraception are known to have these side effects.

WO 98/004269 discloses in particular the oral administration of a combination of 250 μ g to 4mg of dienogest and 10 μ g to 20 μ g of ethinyl estradiol for contraception. To achieve a substantial reduction in total contraceptive steroid administered per cycle while maintaining good cycle control, a low dose progestogen/estrogen combination is administered on days 23 to 25 of a 28 day menstrual cycle. However, this patent does not disclose results and information that prove that the idea of the invention is also successful.

WO01/015701 claims a pharmaceutical composition comprising drospirenone and ethinylestradiol, in particular also in low doses, in micronized form, also for oral administration on day 21 of a 28-day menstrual cycle. Of particular note here is the immediate release of the steroid.

It is known from the expert and patent literature that steroid active ingredients are metabolized by the cytochrome P450 enzyme system, which is also responsible for the breakdown of many drugs. Certain drugs such as barbiturates, antiepileptic drugs and selected virostatic drugs induce the enzyme system and reduce the concentration of the steroid active ingredient in the blood. To compensate for this, it would be necessary to actually increase the progestogen content or at least maintain, rather than decrease, the progestogen content, which, however, would lead to the side effects described above.

Detailed Description

The present invention is based on the object of indicating a pharmaceutical composition based on dienogest and ethinylestradiol, in which the total steroid dose is reduced while the balance between dienogest and ethinylestradiol is maintained, good contraceptive efficacy and cycle control is achieved, and side effects, such as additional reduction in the blood level of the active ingredient while further medication is taken, are compensated.

This object is achieved according to the invention by a pharmaceutical composition comprising dienogest in an amount corresponding to a daily dosage unit of 1.5mg or 2.0mg when said composition is administered and ethinylestradiol in an amount corresponding to a daily dosage unit of 0.015mg or 0.020mg when said composition is administered and one or more pharmaceutically acceptable carriers for at least 21 daily dosage units.

This object is also achieved according to the invention by a pharmaceutical product for oral contraception comprising 1.5mg of 17 α -cyanomethyl-17- β -hydroxyestra-4, 9-dien-3-one (dienogest) and 0.015 or 0.020mg of 17 α -ethinylestradiol (ethinylestradiol) or 2.0mg of dienogest and 0.015mg of ethinylestradiol and one or more pharmaceutically acceptable carriers constituting at least 21 daily dosage units of a 28-day menstrual cycle.

As is clear from the expression of claim 2, the user of the pill takes the pill for at least 21 days with an intervening 7-day pill-free period. The significance and extent of the expression "21 days of a 28-day menstrual cycle" in the field of hormonal contraception will be equivalent to the expression "21 days of hormonal pills +7 days without pills" in this field.

The dienogest/ethinylestradiol active ingredient combination in the medicament is admixed with one or more pharmaceutically acceptable carriers or pharmaceutical carriers. An embodiment is a pharmaceutical product in the form of a tablet formulation. The medicament is in this case a film-coated tablet, which consists of a core with a dienogest content and of a film coating containing the active ingredient with a dienogest content and a total ethinylestradiol content.

In a particular embodiment of the pharmaceutical product of the invention, at least 30%, preferably 50% of the dienogest fraction is time-delayed to dissolve from the core after more than 30min, and at least 75% of the dienogest fraction and the total ethinylestradiol content is dissolved from the film coating in a maximum of 45min, preferably 70% in 30min, as determined by a dissolution test using water at 37 ℃ as dissolution medium and a stirring speed of 50 rpm.

It is also possible that the ethinylestradiol moiety with the total ethinylestradiol content is preferably released from the tablet core with a delayed time together with the dienogest moiety.

The number of daily dosage units in suitable embodiments of the pharmaceutical product of the invention may be 22, 23, 24 or 25 daily dosage units, while the number of daily dosage units in a 28-day menstrual cycle without active ingredient is 6, 5, 4 or 3.

It has been found that, surprisingly, according to the present invention, a partial delayed dissolution (release) of dienogest from the tablet formulation allows a low range of dosage of the dienogest/ethinylestradiol active ingredient combination.

Figure 1 shows the corresponding release profile of a film-coated tablet with a total dose of dienogest 1.5mg and ethinyl estradiol 0.015 mg. The release of the dienogest fraction in two phases is very pronounced, namely a slow (delayed) release and a non-slow (immediate) release, see in this connection the dashed marks at 30min and 45 min. In addition, as already explained, a fraction of dienogest which undergoes a slow (delayed) release after 30min and 45min of more than 30%, preferably 50%, is also evident. The release behavior of at least 75% of the active ingredient dose within 45min, preferably 70% within 30min, is called immediate release.

It has also been shown that the active ingredient combination in the medicament of the invention has anti-male properties in addition to contraception and can therefore be used for the prophylaxis and treatment of androgen-induced disorders, in particular acne.

1.5mg to 2.0mg of dienogest and 0.015mg to 0.020mg of ethinylestradiol may be used for producing the pharmaceutical product for inhibiting ovulation or for preparing the pharmaceutical composition for inhibiting ovulation of the present invention.

Contraceptive efficacy of formulations containing dienogest and ethinylestradiol

In a randomized open clinical study, 40 women aged between 18 and 35 years were treated with two different formulations containing dienogest and ethinylestradiol, who had given their written informed consent to participate in the study. The first formulation (A) corresponded to 2mg of dienogest (non-delayed release) and 0.02mg of ethinyl estradiol. The second formulation (B) consisted of 1.5mg of dienogest (50% extended release-0.75 mg) and 0.02mg of ethinyl estradiol.

The trial included a pretreatment cycle (elution phase), 3 treatment cycles, and a post-treatment cycle (follow-up phase).

Various biochemical and functional-testing studies were performed at fixed times (before the start of the first treatment cycle, at the end of the third treatment cycle).

To test for ovulation inhibition, FSH, LH, estradiol, progesterone, "spinobarkeit" and ferning (ferning) were tested. Follicular maturation was detected by ultrasonography. In addition, SHBG, CBG, total testosterone, triglycerides, cholesterol, HDL, LDL, glucose in serum were measured and blood pressure, heart rate, body weight and bleeding behaviour were recorded.

The results of the study demonstrate that both formulations reliably inhibit ovulation as evidenced by a decrease in LH, FSH, progesterone and estradiol during the treatment cycle. Follicular growth in both groups was detectable by concomitant ultrasound examination, however, it resulted in no subject in this study having ruptured follicles and therefore ovulated. In 3 women treated with formulation a in treatment cycles 2 and 3 so-called LUFs (luteinized non-ruptured follicles) were detectable, which represent evidence that follicular maturation occurred but that ovulation did not occur. The increase in SHBG and CB was comparable in both treatment groups. The "spinobarkeit" and ferning parameters, which are mainly influenced by the progestogenic component of the product, showed a tendency to decrease even more in the group treated with formulation B. However, the difference did not reach statistical significance. The increase in HDL-cholesterol and the decrease in LDL-cholesterol in treatment group B was greater than in treatment group A. Shows comparable changes in triglycerides and total cholesterol in both groups. Glucose tolerance in both groups remained essentially unaffected. Total testosterone was reduced in a comparable manner in both treatment groups and was significant. The subjective and objective tolerability of formulation B was evaluated as more favorable. Irregular bleeding occurs less frequently, especially in the first treatment cycle. The intensity of regular progestin withdrawal bleeding (pill breaks) is also low. In addition, women treated with formulation B were reported to have fewer premenstrual symptoms (headache, abdominal pain). No differences were found between the groups and their time course in relation to blood pressure, heart rate and body weight.

Studies performed showed that both products reliably prevented ovulation in all volunteers. Formulation B was found to have a tendency to have an enhanced peripheral anti-contraceptive effect. With formulation B, some adverse side effects (bleeding irregularities, premenstrual symptoms) generally occurred more significantly less. Formulation B was found to have a more favorable lipid profile.

The results show that the prolonged dissolution (release) of dienogest allows the doses of both dienogest and ethinylestradiol to be low (formulation B), i.e. the total ethinylestradiol dose is reduced, while satisfying the requirements for the balance between dienogest and ethinylestradiol. In addition, good contraceptive efficacy and cycle control are achieved, and these side effects, such as additional reductions in blood active ingredient levels with further drug intake, are compensated for.

In case of a reduced progestogen (dienogest) content with the same estrogen (ethinylestradiol) content, different effects will be expected from the beginning, contraceptive efficacy will be impaired, good cycle control will not be achieved and side effects will be enhanced, since a shift of the equilibrium between dienogest and ethinylestradiol will be expected. Contrary to this view, these results show that the prolonged dissolution (release) of dienogest allows a reduction of the dose of both dienogest and ethinylestradiol (formulation B ═ 1.5mg), i.e. the total steroid dose is reduced, while satisfying the requirements for the balance between dienogest and ethinylestradiol. In addition, good contraceptive efficacy and cycle control are achieved, and these side effects are compensated for, for example, by the intake of further drugs with additional reduction in blood levels of active ingredient.

It was also shown that formulation a had a detectable ovulation-inhibiting effect, but was not as extensive as formulation B, which had a lower dose of dienogest and ethinylestradiol, with 2.0mg of dienogest, having the same ethinylestradiol content as in 0.02mg of ethinylestradiol, which contained a lower dose of ethinylestradiol than the conventional product.

Claims (5)

1. A pharmaceutical composition comprising dienogest in an amount equivalent to a daily dosage unit of 1.5mg or 2.0mg and ethinylestradiol in an amount equivalent to a daily dosage unit of 0.015mg or 0.020mg, when said composition is administered, together with one or more pharmaceutically acceptable carriers for at least 21 daily dosage units.

2. A pharmaceutical product for oral contraception comprising 1.5mg of dienogest and 0.015mg or 0.020mg of ethinylestradiol or 2.0mg of dienogest and 0.015mg of ethinylestradiol in combination with one or more pharmaceutically acceptable carriers constituting at least 21 daily dosage units of a 28-day menstrual cycle.

3. The pharmaceutical product according to claim 2, wherein the pharmaceutical product is a film-coated tablet consisting of a core with a dienogest content and a film coating with an active ingredient with a dienogest content and a total ethinylestradiol content.

4. A pharmaceutical product according to any of claims 2 and 3, wherein at least 30%, preferably 50% of the dienogest fraction is time-delayed to dissolve from the core after more than 30min and at least 75% of the dienogest fraction and the total ethinylestradiol content is dissolved from the film coating in a maximum of 45min, preferably 70% in 30min, as determined by a dissolution test using water at 37 ℃ as dissolution medium and a stirring speed of 50 rpm.

5. Pharmaceutical product according to any one of claims 2 to 4, wherein the number of daily dosage units comprising the combination of dienogest and ethinylestradiol is 22, 23, 24 or 25 and the number of daily dosage units without active ingredient is 6, 5, 4 or 3.