AU2006215822B2

AU2006215822B2 - Solid peroral contraceptive drug

Info

Publication number: AU2006215822B2
Application number: AU2006215822A
Authority: AU
Inventors: Alexander Buske; Sabine Fricke; Hagen Gerecke; Ralf Ladwig; Harald Rathe
Original assignee: Bayer Schering Pharma AG
Current assignee: Bayer Pharma AG
Priority date: 2005-02-15
Filing date: 2006-02-15
Publication date: 2008-09-04
Anticipated expiration: 2026-02-15
Also published as: PL1848406T3; BRPI0606297A2; CY1108265T1; WO2006087177A8; DK1848406T3; HRP20080394T3; KR20070087141A; DE502006000771D1; EP1848406B1; CA2594939A1; PT1848406E; RS50597B; WO2006087177B1; WO2006087177A2; SI1848406T1; IL184257A0; WO2006087177A3; EA200701389A1; EP1848406A2; AU2006215822A1

Abstract

Disclosed is a solid peroral contraceptive drug containing 17a-cyanomethyI-17-ß-hydroxyestra-4,9-dien-3on (dienogest) at a daily dose that is equal to or smaller than 2.0 mg as one active component and 17a-ethinyl estradiol (ethinyl estradiol) at a daily dose of less than 0.03 mg as another active component along with one or several pharmaceutically acceptable carriers. The dienogest is proportionately released in at least two phases while the ethinyl estradiol is released at the same time as the first phase of the dienogest.

Description

WO 2006/087177 PCT/EP2006/001358 1 Solid peroral contraceptive drug Description Field of the invention The invention relates to a solid oral pharmaceutical form for contraception which comprises 17a-cyanomethyl- 17-P-hydroxyestra-4,9-dien-3-one (dienogest) equal to or less than 2.0 mg and 17a-ethinylestradiol (ethinylestradiol) less than 0.030 mg, and where the dienogest is released proportionately in two phases and one of the phases is released with a time delay relative to the other phase. The pharmaceutical form additionally comprises a total ethinylestradiol content intended for non-slow (rapid) release.

General prior art Oral contraceptive compositions consisting of a progestogen component and of an estrogen component were marketed for the first time in the early 1960s. Three essential properties characterize the profile of the "contraceptive pill": contraceptive reliability, a very good cycle control and a minimum of side effects.

Since the introduction of hormonal contraceptives, research has been directed at the possibility of producing pharmaceutical forms which, while the contraceptive reliability and cycle control remain good, reduces unwanted side effects such as, for example, arterial and venous thromboses and influencing of carbohydrate and lipid metabolism caused by a higher content of progestogen and estrogen than needed for contraception. WO 98/004269 disclose inter alia the oral administration of a combination of 250 ug 4 mg of dienogest and 10 ug 20 pg of ethinylestradiol for contraception. In order to achieve the essential reduction in the total contraceptive steroid administered per cycle, while maintaining good cycle P \WPXOCS\CRN\JXJ\Spec\223627 specdoc-8/11/2008 00

O

O 2 control, the low-dose progestogen/estrogen combination is administered for 23 to 25 days of a 28-day menstrual cycle.

However, the patent does not disclose results and C- information proving that the inventive idea is also 00 0 5 successful, and what is the desired mode of release of the steroids.

NO WO 01/015701 claims a pharmaceutical composition also for 0 oral administration of 21 days of a 28-day menstrual cycle, which comprises drospirenone and ethinylestradiol, inter alia also in low doses, the drospirenone being present in micronized form. Particular attention is directed in this case at rapid release of the steroids.

EP 0 803 250 discloses a pharmaceutical tablet which has a pharmacologically active ingredient-free tablet core and whose outer sugar coating may comprise inter alia dienogest and ethinylestradiol and where the desired rapid release thereof is influenced by microcrystalline cellulose.

It is also known that it is absolutely necessary with lowdose oral contraceptives to pay attention to intake being in the same period each day. If this period is not complied with, the effective active ingredient concentration is below that necessary for oral contraception, and oral contraception is no longer ensured. This means that the user is required to keep track of her intake cycle very deliberately and with great care.

Detailed disclosure of the invention The invention is based on creating a possibility for reducing the conventional dienogest/ ethinylestradiol active ingredient combination for oral contraceptives and at the same time ensuring contraceptive efficacy analogous to conventional oral contraceptives.

This is achieved according to the invention by a solid oral pharmaceutical form for contraception which P:\WPDOCS\C1N\JXJ\Spec\202S3627 specdoc-8/11/2008 00 (1 2A comprises as active ingredient combination dienogest equal to or less than 2.0 mg and ethinylestradiol less than 0.030 mg, where the pharmaceutical form dienogest is C( released proportionately in at least two phases and of these 00 l- 5 at least one of the phases is released with a time delay relative to the other phase(s).

IN A first aspect of the invention provides a solid oral O pharmaceutical form for contraception, comprising 17acyanomethyl-17-P-hydroxyestra-4,9-dien-3-one (dienogest) equal to or less than 2.0 mg and 17-ethinylestradiol (ethinylestradiol) less than 0.030 mg, wherein the pharmaceutical form represents a tablet having a tablet core with a proportion, intended for slow release, of the total dienogest content and a coating with a proportion, intended for non-slow (rapid) release, of the total dienogest content and a total ethinylestradiol content intended for non-slow (rapid) release.

P \WPDDCS\CRN\JXJ\Spec\20233627 spec doc-8/11/2008 00 3 In the pharmaceutical form of the invention, preferably the dienogest has a rapid (non-slow) in vitro release within the first phase and a delayed (slow) in vitro release within the C( second phase and the ethinylestradiol has a conventional 00 S 5 rapid in vitro release. The pharmaceutical form advantageously represents a tablet having a tablet core with NO a proportion, intended for slow release, of the total 0 dienogest content and a coating with a proportion, intended for non-slow (rapid) release, of the total dienogest content and a total ethinylestradiol content intended for non-slow (rapid) release.

The tablet may be a film-coated tablet, in which case the .coating is a film coating.

The pharmaceutical form according to the invention preferably comprises the active ingredient combination with mg to 2.0 mg of dienogest and 0.015 mg to 0.020 mg of ethinylestradiol.

It is preferred for at least 10%, preferably 30% of dienogest to be slowly dissolved out of the tablet core after more than 30 minutes, as determined by the dissolution test with use of water at 37 0 C as dissolution medium and with a stirring speed of 50 rpm.

The determination takes place in accordance with Ph. Eur.

using a rotating basket apparatus with use of 1000 ml of water.

The dissolution of the proportion of dienogest and of the total ethinylestradiol content from the film coating is at least 75% in not more than 45 min, preferably 70% in 30 min, as determined by the dissolution test with use of water at 37 0 C as dissolution medium and with a stirring speed of rpm.

It has been found that ethinylestradiol is stabilized 4 by ascorbic acid as soon as it is added to the active ingredient-containing film coating.

The proportion of ascorbic acid in this case is 0.02 to preferably 0.025 to 0.25%.

A preferred pharmaceutical form according to the invention constitutes the number of daily dose units which comprise the combination of dienogest and ethinylestradiol being 21, 22, 23, 24 or 25 and the number of daily dose units which comprise no active ingredient being 7, 6, 5, 4 or 3.

The release of the slow-release proportion of the dienogest active ingredient can be controlled by a large number of release-slowing principles. Examples of these release-slowing principles are inert plastics matrices, hydrocolloids, ion exchangers, slow-release coatings, gastro-resistant coatings, pellet mixtures, mixtures of minitablets and/or granules, microcapsules, osmotically controlled systems, erosion-controlled systems, diffusion-controlled systems and combinations thereof, fat- and wax-containing matrices.

The tablet forms shown in the examples are various embodiments of the pharmaceutical form according to the invention. The tablet forms such as oblong tablets are conceivable, as are tablet forms which in their configuration influence the erosion behaviour of hydrophilic matrices.

It has been found that, surprisingly, the partly delayed release of dienogest from the pharmaceutical form makes low dosage of the dienogest/ethinylestradiol active ingredient combination possible with the same contraceptive efficacy as conventional oral contraceptives comprising dienogest and ethinylestradiol, and ensures intake reliability without it being absolutely necessary to pay attention to intake being in the same period each day.

With suitable embodiments of the pharmaceutical product according to the invention, the number of daily dose units can be 21, 22, 23, 24 or 25 daily dose units, and the number of active ingredient-free daily dose units 5 is then 7, 6, 5, 4 or 3 in the 28-day menstrual cycle.

Further embodiments with a number of daily dose units of 28 or a multiple of 28, for example 2 to 3 times 28, which comprise dienogest equal to or less than 2.0 mg and ethinylestradiol less than 0.030 mg are possible.

Other embodiments with progestogens such as, for example, levonorgestrel, gestodene and others and/or estradiol valerate, which are suitable also for hormone replacement (also sequentially) besides contraception, are also possible.

The embodiments shown in the examples can also be varied in terms of the dosage. The proportion of dienogest in the second, slow-release phase ought preferably to be greater than 30% of the dienogest dose. This includes embodiments with 35%, 40%, 45%, or 55%, but also for example 70%, 75%, 80% of the total dienogest dose. The time in which the proportion of dienogest in the second, slow-release phase is completely released varies in the examples from 180 min to 360 min. However, shorter or longer release times can also be achieved by variations of the examples.

Owing to the usual range of variation of active ingredient release, the release time is reported in whole hours, for example 1 h, 2 h, 3 h, 4 h as 6 h, 7 h etc.

It has emerged that the active ingredient combination in the pharmaceutical product according to the invention has, besides the contraception, antiandrogenic properties and therefore can be used in the prophylaxis and therapy of androgen-induced disorders, especially acne.

Brief description of the drawings The invention is described in detail with reference to the following drawings, in which Fig. 1 is a plot representing the release profile of Valette® with 2 mg of dienogest and 0.030 mg of 6 ethinylestradiol, produced and measured in accordance with Example 1; Fig. 2 is a plot representing the release profiles of film-coated tablets with 2 mg of dienogest and 0.020 mg of ethinylestradiol, produced and measured in accordance with Examples 2 and 3; Fig. 3 is a plot representing the release profiles of film-coated tablets with 1.5 mg of dienogest and 0.015 mg of ethinylestradiol, produced and measured in accordance with Example 8. The broken-line markings at and 45 min clearly shows the release of proportions of dienogest in 2 phases, i.e. a slow release and a non-slow (rapid) release evident. A release behaviour of at least 75% of the active ingredient dose within not more than 45 min, preferably 70% in 30 min, is called rapid release.

Fig. 4 is a plot representing the release profile of a film-coated tablet with 1.5 mg of dienogest and 0.015 mg of ethinylestradiol in accordance with Example 8, variant 8.5 in analogy to variants 8.1 to 8.4.

Examples Example 1 Description Valette is a conventional sugar-coated tablet for oral contraception, comprising 0.030 mg of ethinylestradiol and 2.0 mg of dienogest in a tablet core which is covered with a sugar-containing sheath.

Test of the release profile Dissolution test of Ph. Eur., 4th edition, main volume 2002, 2.9.3, paddle stirrer apparatus, rpm, dissolution medium 1000 ml of water Measurement of the amount of dienogest and ethinylestradiol released by high pressure liquid chromatography Figure 1 shows the typical release profile of such contraceptive combinations of progestogen and estrogen to be evident. Such behaviour with release of at least 7 of the active ingredient dose within not more than min, preferably of 70% in 30 min, is called fast release.

Example 2 2 mg of dienogest and 0.02 mg of ethinylestradiol, with delayed release of 1 mg of dienogest and fast release of 1 mg of dienogest and 0.02 mg of ethinylestradiol.

Description The example describes a film-coated tablet with matrix core. The core of the film-coated tablet comprises 1 mg of dienogest in a hydrophilic erosion matrix with the basic ingredient Metolose. The active ingredient dienogest is released slowly from this matrix. The core was coated with a quickly dissolving film which comprises 1.0 mg of dienogest and 0.02 mg of ethinylestradiol. For protection from light, the filmcoated tablet was coated with a further quickly dissolving coloured layer comprising iron oxide pigment.

Composition Core Granules 1 Dienogest Metolose 90SH-4000 Lactose monohydrate Maize starch Povidone K25 (10% in ethanol Granules 2 Lactose monohydrate Maize starch Maltodextrin in water) Outer phase Carboxymethylstarch sodium Magnesium stearate 1.000 mg 7.500 mg 21.000 mg 14.000 mg 1.500 mg 54.000 mg 27.100 mg 6.900 mg 1.500 mg 1.500 mg Film coating Film 1 active ingredient-contaning Dienogest Ethinylestradiol Methocel 5 Talc Titanium dioxide Film 2 Coloured layer Methocel 5 Talc Titanium dioxide Iron oxide, red 1.000 mg 0.020 mg 2.250 mg 0.450 mg 0.280 mg 3.375 mg 0.675 mg 1.875 mg 0.075 mg 8 Production Granules 1: Dissolve povidone in ethanol and use this solution to granulate the other substances in a fluidized bed granulator Granules 2: Dissolve maltodextrin in water and use this solution to granulate the other substances in a fluidized bed granulator Mix granules 1, granules 2 and outer phase in a container mixer Convert mixture into tablets (136 mg, oblong punch 4.0x10.0 mm, curvature 4.5 mm) Film 1: Coat tablets with suspension of substances in water in a drum coater Film 2: Coat film-coated tablets with suspension of substances in water in a drum coater Testing of the release profile Dissolution test of Ph. Eur., 4th edition, main volume 2002, 2.9.3, rotating basket apparatus, rpm, dissolution medium 1000 ml of water Measurement of the amount of dienogest and ethinylestradiol released by high pressure liquid chromatography Example 3 2 mg of dienogest and 0.02 mg of ethinylestradiol, with delayed release of 1 mg of dienogest and fast release of 1 mg of dienogest and 0.02 mg of ethinylestradiol.

Description The example describes a film-coated tablet with matrix core. The core of the film-coated tablet comprises 1 mg of dienogest in a hydrophilic erosion matrix with the basic ingredient Metolose. The active ingredient dienogest is released slowly from this matrix. To avoid interactions between slow-release core and the active ingredient-containing film, the core was coated with a barrier layer before the active ingredient-containing film was applied. The active ingredient-containing film comprises 1.0 mg of dienogest and 0.02 mg of ethinylestradiol plus iron oxide pigments as protection 9 from light.

Composition Core Granules Dienogest Metolose 90SH-4000 Lactose monohydrate Maize starch Povidone K25 in ethanol Outer phase Tablettose Avicel PH 102 Magnesium stearate 1.000 mg 7.500 mg 31.000 mg 24.000 mg 2.000 mg 21.000 mg 16.200 mg 1.300 mg Film coating Barrier layer Opadry AMB white® consisting of: Polyvinyl alcohol Titanium dioxide Soya lecithin Xanthan Active ingredientcontaining film Dienogest Ethinylestradiol Methocel 5 Talc Titanium dioxide Iron oxide, red 7.000 mg part hydrolysed 1.000 mg 0.020 mg 2.250 mg 0.430 mg 0.280 mg 0.020 mg Production Granules: Dissolve povidone in ethanol and use this solution to granulate the other substances in a fluidized bed granulator Mix granules 1 and outer phase in a container mixer Convert mixture into tablets (104 mg, oblong punch 4.0x10.0 mm, curvature 4.5 mm) Barrier layer: Coat tablets with suspension of substances in water in a drum coater Active ingredient-containing film: Coat filmcoated tablets with suspension of substances in water in a drum coater Testing of the release profile Dissolution test of Ph. Eur., 4th edition, main volume 2002, 2.9.3, rotating basket apparatus, 50 rpm, dissolution medium 1000 ml of water Measurement of the amount of dienogest and 10 ethinylestradiol released by high pressure liquid chromatography The film-coated tablets of Examples 2 and 3 differ in the structure of the film coating. The active ingredient-containing film dissolves rapidly and quickly releases the ethinylestradiol dose and the proportion of the dienogest dose. The coloured layer in Example 2 likewise dissolves rapidly. It ensures that the film-coated tablet is acceptable and protected from light. The barrier layer in Example 3 suppresses interactions between active ingredient-containing film and the core and dissolves more slowly than the active ingredient-containing film. Both film-coated tablets have a matrix core consisting of a hydrophilic erosion matrix. This erosion matrix slowly releases the slowrelease portion of the dienogest dose.

Figure 2 shows the measured release profiles of Examples 2 and 3 shown. The film-coated tablets of both examples release about 80% of the ethinylestradiol dose within 45 min and about 50% of the dienogest dose within 45 min. The remaining proportion of the dienogest dose is released within 360 min in the filmcoated tablet from Example 2 and within 180 min in the case of Example 3.

Example 4 In Example 4, the release of the slow-release proportion of dienogest is controlled with a lipophilic matrix.

Description The example describes a tablet comprising 2 mg of dienogest and 0.020 mg of ethinylestradiol with a lipophilic release-slowing principle. 1 mg of dienogest is incorporated into a lipophilic matrix by spraying.

The fast-release proportion of dienogest and the ethinylestradiol are admixed with this matrix.

11 Composition Dienogest (in ethanolic solution) Cetylstearyl alcohol (in ethanolic solution) Lactose monohydrate Maize starch Dienogest Ethinylestradiol Maltodextrin (20% solution in water) Na carboxymethylstarch Magnesium stearate 1.00 mg 9.00 mg 57.98 mg 10.00 mg 1.00 mg 0.02 mg 9.00 mg 1.00 mg 1.00 mg Production Dissolve slow-release proportion of dienogest and cetylstearyl alcohol in ethanol at 50 0

C

Spray dienogest/cetylstearyl cohol solution onto lactose and maize starch in fluidized bed granules, and dry Admix ethinylestradiol, 2nd half of the dienogest dose dry Dissolve maltodextrin in water Granulate mixture in the fluidized bed with maltodextrin solution Admix Na carboxymethylstarch and magnesium stearate Tablet to give tablets of diameter 5.5 mm and mass mg Example In Example 5, the release of dienogest is controlled by use of different particle sizes.

Description The example describes a tablet in which dienogest is employed with different particle fractions. Targeted adjustment of the particle size takes place by fractional crystallization.

12 Composition Dienogest (average particle size 3 gm) Dienogest (average particle size 180 im) Dienogest (average particle size 270 pm) Ethinylestradiol Lactose monohydrate Maize starch Maltodextrin (20% solution in water) Magnesium stearate 0.667 mg 0.667 mg 0.667 mg 0.02 mg 47.18 mg 24.00 mg 9.00 mg 0.80 mg Production: Granulate the substances with maltodextrin solution Dry the granules Admix magnesium stearate Convert mixture into tablets (diameter 5.5 mm with mass 80 mg) Example 6 A chemical problem arises when the ethinylestradiol dose is reduced. The increase in dilution of the active ingredient in the pharmaceutical form speeds up its chemical decomposition during storage, possibly even during production of the pharmaceutical form.

Surprisingly, ascorbic acid has emerged as effective stabilizer for ethinylestradiol. Example 6 shows the efficacy of ascorbic acid as stabilizer in formulation examples.

Description The example describes the stabilizing effect of ascorbic acid on ethinylestradiol by means of formulation examples in a stress test.

13 Composition Variant 6.1 6.2 6.3 6.4 Ascorbic 0.02 mg 0.20 mg acid, in binder solution Ascorbic 0.02 mg 0.20 mg acid, in mixture Dienogest 2.00 mg 2.00 mg 2.00 mg 2.00 mg 2.00 mg Ethinyl- 0.02 mg 0.02 mg 0.02 mg 0.02 mg 0.02 mg estradiol Lactose 47.18 mg 47.16 mg 46.98 mg 47.16 mg 46.98 mg monohydrate Maize starch 24.00 mg 24.00 mg 24.00 mg 24.00 mg 24.00 mg Maltodextrin 6.00 mg 6.00 mg 6.00 mg 6.00 mg 6.00 mg Magnesium 0.80 mg 0.80 mg 0.80 mg 0.80 mg 0.80 mg stearate Production Mix lactose, maize starch and dienogest in a granulator, spray with a solution of ethinylestradiol in ethanol, and dry Granulate mixture with maltodextrin binder solution in water, dry and mix with magnesium stearate Tablet mixture to give tablets of mass 80 mg and diameter 5.5 mm Test of the content in a stress test The tablets are stored in an open vessel at 60 0 C and 80% relative humidity. After the storage time of 42 days has elapsed, the tablets are removed and investigated. The ethinylestradiol content is measured by HPLC and set in relation to the initial content.

14 Variant 6.1 6.2 6.3 6.4 Ascorbic 0.02 mg 0.20 mg acid, in binder solution Ascorbic 0.02 mg 0.20 mg acid, in mixture Content 79.1% 90.1% 91.9% 91.6% 96.5% after 42 days Example 7 Description In this example, the stabilization of ethinylestradiol in the active ingredient-containing layer of filmcoated tablets is described.

Composition Core Dienogest Metolose 90SH-4000 Lactose monohydrate Maize starch Povidone K25 (10% in water) Tablettose Avicel PH 102 Magnesium stearate 104 mg 0.750 mg 7.500 mg 45.250 mg 10.000 mg 2.000 mg 30.000 mg 7.200 mg 1.300 mc Barrier layer 6 mg Eudragit RL 30 D (as coating dry matter) 3.500 mg Macrogol 6000 0.700 mg Talc 1.800 mg Active ingredient-containing film 3 mg Dienogest 0.750 mg Ethinylestradiol 0.015 mg Ascorbic acid 0.200 mg Methocel 5 1.6875 mg Talc 0.2375 mg 15 Titanium dioxide 0.210 mg Coloured layer 3 mg Methocel 5 1.500 mg PEG 6000 0.300 mg Talc 0.300 mg Titanium dioxide 0.850 mg Iron oxide, red 0.050 mg Production Dienogest, Metolose 90SH-4000, lactose monohydrate and maize starch are granulated with the aqueous povidone K25 and maltodextrin solution Tablettose, Avicel PH 102 and magnesium stearate are admixed with the dry granules The mixture is tabletted The tablets are coated with the appropriate films in a drum coater Example 8 Description Five variants of film-coated tablets with a total dose of 1.5 mg of dienogest and 0.015 mg of ethinylestradiol are described. The film-coated tablets consist of a slow-release matrix core and a quickly dissolving film coating and of a coloured layer. In two variants, a barrier layer was additionally provided between core and active ingredient-containing film.

In the five variants of the film-coated tablet, the slow-release proportion of the dienogest dose was varied in the range from 33% to 66%. The formulation of the core was adapted to the desired release profiles.

16 Composition Variant 8.1 8.2 8.3 8.4 Core 104 mg 104 mg 104 mg 104 mg Dienogest 0.750 mg 0.500 mg 1.000 mg 0.750 mg Metolose 90SH-4000 7.500 mg 7.500 mg 7.500 mg 9.000 mg Lactose 45.250 mg 39.500 mg 45.000 mg 29.750 mg monohydrate Maize starch 10.000 mg 10.000 mg 10.000 mg 24.000 mg Povidone K25 (10% 2.000 mg 2.000 mg 2.000 mg in water) 8.000 mg Maltodextrin (25% 30.000 mg 30.000 mg 30.000 mg 21.000 mg in water) 7.200 mg 7.200 mg 7.200 mg 16.200 mg Tablettose 1.300 mg 1.300 mg 1.300 mg 1.300 mg Avicel PH 102 Magnesium stearate Barrier layer 6 mg 6 mg-- Eudragit RL 30 D 3.500 mg 3.500 mg (as coating dry matter) 0.700 mg 0.700 mg Macrogol 6000 1.800 mg 1.800 mg Talc Active ingredient- 3 mg 3 mg 3 mg 3 mg containing film Dienogest 0.750 mg 1.000 mg 0.500 mg 0.750 mg Ethinylestradiol 0.015 mg 0.015 mg 0.015 mg 0.015 mg Methocel 5 1.6875 mg 1.4987 mg 1.8848 mg 1.6875 mg Talc 0.3375 mg 0.2998 mg 0.3700 mg 0.3375 mg Titanium dioxide 0.210 mg 0.18650 mg 0.2302 mg 0.210 mg Coloured layer 3 mg 3 mg 3 mg 3 mg Methocel 5 1.500 mg 1.500 mg 1.500 mg 1.500 mg PEG 6000 0.300 mg 0.300 mg 0.300 mg 0.300 mg Talc 0.300 mg 0.300 mg 0.300 mg 0.300 mg Titanium dioxide 0.850 mg 0.850 mg 0.850 mg 0.850 mg Iron oxide, red 0.050 mg 0.050 mg 0.050 mg 0.050 mg 17 Example 8 -variant Composition Variant Core 104 mg Dienogest 0.675 mg Metolose 90SH-4000 9.000 mg Lactose monohydrate 42.925 mg Maize starch 15.000 mg Povidone K25 (10% in water) Maltodextrin (25% in water) 6.000 mg Tablettose 8.500 mg Avicel PH 102 7.000 mg Magnesium stearate 0.900 mg Barrier layer Eudragit RL 30 D (as coating dry matter) Macrogol 6000 Talc Active ingredient-containing film Dienogest 0.825 mg Ethinylestradiol 0.015 mg Methocel 5 4.060 mg Talc 0.836 mg Titanium dioxide 0.264 mg Coloured layer Methocel 5 1.500 mg PEG= Macrogol 6000 0.300 mg Talc 0.300 mg Titanium dioxide 0.850 mg Iron oxide, red 0.050 mg Production Dienogest, Metolose 90SH-4000, lactose monohydrate and maize starch are granulated with the aqueous povidone K25 and maltodextrin solution Tablettose, Avicel PH 102 and magnesium stearate P \WPDDCS\CRN\JXJ\Spec\2O233627 specdoc-8/11/2008 00 O 18 are admixed with the dry granules The mixture is tabletted The tablets are coated with the appropriate films in a

(N

(q drum coater 00 I- 5 Testing of the release profile q Dissolution test of Ph. Eur., 4th edition, main volume I 2002, 2.9.3, rotating basket apparatus, 50 rpm, 0 dissolution medium 1000 ml of water Measurement of the amount of dienogest and ethinylestradiol released by high pressure liquid chromatography Example 9 Variants of film-coated tablets with a total dose of 2.0 mg of dienogest and 0.015 mg of ethinylestradiol are described, produced and tested in analogy to the variants in Example 8.

The contraceptive efficacy of formulations comprising dienogest and ethinylestradiol can be demonstrated in investigations, for example in a randomized open clinical study. This entails various biochemical and function-testing investigations being carried out. To detect the ovulationinhibiting effect, FSH, LH, estradiol, progesterone, "spinnbarkeit" and ferning are investigated. Follicle maturation is examined by means of an ultrasound investigation. In addition, SHBG, CBG, total testosterone, triglycerides, cholesterol, HDL, LDL, glucose in serum are determined, and blood pressure, heart rate, body weight and bleeding behaviour are recorded.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or P.\WPDCS\CRN\JXJ\SPCC\20233627 opec.doc-8/11/2008 00 18Agroup of integers or steps but not the exclusion of any other integer or group of integers or steps.

C( The reference in this specification to any prior publication 00 l 5 (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment I or admission or any form of suggestion that prior 0 publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims

1. Solid oral pharmaceutical form for contraception, -q comprising 17 -cyanomethyl-17-0-hydroxyestra-4,9-dien- 00 5 3-one (dienogest) equal to or less than 2.0 mg and 17a- ethinylestradiol (ethinylestradiol) less than 0.030 mg, (N N) wherein the pharmaceutical form represents a tablet 0 having a tablet core with a proportion, intended for (N slow release, of the total dienogest content and a coating with a proportion, intended for non-slow (rapid) release, of the total dienogest content and a total ethinylestradiol content intended for non-slow (rapid) release.

2. Pharmaceutical form according to Claim 1, comprising as an active ingredient a combination of dienogest equal to or less than 2.0 mg and ethinylestradiol less than 0.030 mg, wherein the pharmaceutical form represents a film-coated tablet with a tablet core with a proportion, intended for slow release, of the total dienogest content and a film coating with a proportion, intended for non-slow (rapid) release, of the total dienogest content and a total ethinylestradiol content intended for non-slow (rapid) release.

3. Pharmaceutical form according to Claims 1 or 2, wherein the active ingredient combination comprises 1.5 mg to mg of dienogest and 0.015 mg to 0.020 mg of ethinylestradiol. P:\WPDOCS\GRS\SPECI\20233627 doc-27/11/2007 0 0 20 Z 4. Pharmaceutical form according to any one of Claims 1 to 00 3, wherein at least 10% of the dienogest content is (N slowly dissolved out of the tablet core after more than C, 30 minutes as determined with the dissolution test with 00 5 use of water at 37 0 C as dissolution medium and a In stirring speed of 50 rpm. \O Pharmaceutical form according to Claim 4, wherein at least 30% of the dienogest content is slowly dissolved out of the tablet core after more than 30 minutes as determined with the dissolution test with use of water at 37 0 C as dissolution medium and a stirring speed of rpm.

6. Pharmaceutical form according to any one of Claims 1 to wherein ascorbic acid is added as a stabilizer of the ethinylestradiol to the active ingredient- containing film coating.

7. Pharmaceutical form according to Claim 6, wherein the proportion of ascorbic acid is 0.02 to

8. Pharmaceutical form according to Claim 7, wherein the proportion of ascorbic acid is 0.025 to 0.25%.

9. Pharmaceutical form according to any one of Claims 1 to 8, wherein the number of daily dose units comprising the combination of dienoqest and ethinylestradiol is 21, 22, 23, 24 or 25, and the number of daily dose units comprising no active ingredient is 7, 6, 5, 4 or 3. P \WPDOCS\CRN\jXJ\Spec\20233627 claims doc.I3/O8/2OO8 00 -21 ;Z 10. A solid oral pharmaceutical form for contraception, substantially as hereinbefore described with reference to the Examples. 00