WO2011055156A2 - Pharmaceutical compositions with enhanced stability - Google Patents

Pharmaceutical compositions with enhanced stability Download PDF

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Publication number
WO2011055156A2
WO2011055156A2 PCT/HU2010/000119 HU2010000119W WO2011055156A2 WO 2011055156 A2 WO2011055156 A2 WO 2011055156A2 HU 2010000119 W HU2010000119 W HU 2010000119W WO 2011055156 A2 WO2011055156 A2 WO 2011055156A2
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Prior art keywords
gestagen
type
eudragit
estrogen
pharmaceutical compositions
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PCT/HU2010/000119
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French (fr)
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WO2011055156A3 (en
Inventor
Jonathan Mihály NAGY KASZA
László BODAI
Attila Bódis
Ramóna RAJSZKINÉ LABOS
Original Assignee
Richter Gedeon Nyrt.
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Priority to HU0900698A priority Critical patent/HU0900698A2/en
Priority to HUP0900698 priority
Application filed by Richter Gedeon Nyrt. filed Critical Richter Gedeon Nyrt.
Publication of WO2011055156A2 publication Critical patent/WO2011055156A2/en
Publication of WO2011055156A3 publication Critical patent/WO2011055156A3/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/565Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/565Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane, progesterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/58Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/286Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Abstract

The present invention relates to ovulation inhibiting pharmaceutical compositions with enhanced stability containing an estrogen and a gestagen type component, and the manufacturing process thereof.

Description

Pharmaceutical compositions with enhanced stability

The present invention relates to ovulation inhibiting pharmaceutical compositions with enhanced stability containing an estrogen and a gestagen type component, and the manufacturing process thereof.

Background of the invention

Oral contraceptives including the combination of gestagen and estrogen components are used for decades, for example Yasmin, Yasminelle (ethinylestradiol-drospirenon; Bayer-Schering), Dienille (dienogest- ethinylestradiol; Ladee Pharma), Loette, Tri-Regol (levonorgestrel- ethinylestradiol; Wyeth, Gedeon Richter), Mercilon (desogestrel-ethinylestradiol; Organon), etc.

Numbers of problems occur in connection with these preparations. On the one hand, these pharmaceutical compositions contain natural or synthetic sex hormones in low dose, as the daily dose of these active ingredients is extremely low. This means amounts between 0.1 μg - 500 μg, which lead to serious technical challenges, such as to achieve technological reproducibility and the homogenous distribution of the active ingredients. On the other hand, the stability of the active ingredients causes problems, which influences the shelf life of the composition, and this may be related to the low dose of the active ingredient and to the interaction with the different excipients. This is a crucial parameter in the case of estrogen, particularly the ethinylestradiol containing oral contraceptives. There are numbers of attempts to improve the stability of estrogen, especially ethinylestradiol containing pharmaceutical compositions.

The first step of the experiments to increase the stability of the compositions was to provide a stability enhancing coating for the active ingredient containing composition or to increase the thickness of the coating. Although, the change of coating type had not brought adequate result, the thickness of the coating enhanced the stability in some cases, such as in the case of sugar coatings. However this procedure caused a significant increase of the time of the manufacturing process, the analytical sample preparation, and it complicated the extraction of the active ingredient. The significance of the development of oral contraceptives with sugar coating is decreased owing to the long process time and the accessorial exacting processes (for example cleaning of devices) as well as the upcoming analytical problems.

The efforts to make the active ingredient more stabile in the pharmaceutical composition proved to be more effective. Significant progress was for example that the active ingredient was not dissolved during the process, but it was applied in its micronized form. In the patent EP 0503521B1 the micronized estrogen (eihinylestradiol) and the gestagen component (desogestrel) are homogenized with excipients, which enable direct compression avoiding that the active ingredients meet with moisture. Nevertheless the decomposition of eihinylestradiol could not be decreased adequately; moreover, this technology is limited in terms of gestagen component. The dry blending technology is also risky, since the distribution of the active ingredient in the end-product is not always homogenous.

There were also efforts to put some stability enhancing excipients into the composition. According to the patent EP 0707848B1 the steroids were applied in dissolved, emulsified or suspended form in different oily excipients, receiving a system more hydrophobic, which could protect the active ingredient from moisture and the oxygen-content of air. The patent US 4378356 describes that the compositions of desogestrel and eihinylestradiol contained a-tocopherol as antioxidant in order to stabilize the system decreasing the decomposition of the active ingredients.

The wet granulation plays a very important role in the industry. In the pharmaceutical industry usually two different processes are applied: the fluidization and the high shear granulation, which can be combined with vacuum microwave drying. In both types of granulation liquid binder is applied, therefore the system is getting wet during the process, so this can have negative effect on the stability of the product. The most common binders in the pharmaceutical industry are the different types of polyvinylpyrrolidone, the different cellulose derivatives (such as HPMC, HPC, etc.). Nowadays even new binders are coming up, such as Kollicoat IR, the copolymer of polyethylene glycol and polyvinyl alcohol. The application of these binders can be advantageous in the case of those active ingredients, which tend to decompose via oxidation, as their peroxide content is low.

The "single pot technique" could not be applied in the case of older high shear granulation methods, since the wet mass had to be moved to a drying device. However the modern high shear single pot techniques have their own disadvantages too. On the one hand, the process time of drying is long, in contrast to fluidization drying. On the other hand, the distribution of heat may be inhomogeneous, which results "hot spot", where the local overheating of the material can occur. Both effects may worsen the quality of the product consisting of thermo- sensitive drugs.

Further possibility to prepare the product is the fluidization and drying in the same device. In this case the active ingredient is sprayed onto the powder blend as a solution or suspension. The spraying influences the dispersity rate of particles as a function of atomizing pressure under controlled conditions, nevertheless the chance that before these small drops meet with the powder blend, they are getting dried, and a part of them leave the system with the fluidizing air or stuck on the wall of the colonna in wet phase. These effects could cause loss of active ingredient and inhomogeneity in the product. Therefore it can be stated that atomizing can produce loss of active ingredient. The less the drug content of the system, the more this phenomenon is observed. Consequently this problem exists to a greater extent in the case of hormone-containing products. If the active ingredient is sprayed as suspension and not as solution the problem of inhomogeneity can occur.

According to the patent US 6156341 the low-dose steroid products can be stabilized with propyl gallate. In this case propyl gallate is dissolved in the binder liquid and sprayed onto the powder blend by fluidization.

Further solution to enhance the stability of estrogens, especially that of ethinylestradiol, is the complexation with another material. Different types of cyclodextrins were used as complexation materials. These methods are described in the patents US 4727064 and EP 0579435.

Despite the achieved results there is a need for such products of estrogen-gestagen combinations, which possess enhanced stability, homogenous distribution, and are easy to manufacture. Therefore the aim of our invention was to produce a stable and homogeneous pharmaceutical composition of estrogen-gestagen combination.

Summary of the invention

Surprisingly it was found that applying a type of an Eudragit E as excipient, the stability of product shows significant increase. Thus the invention provides a pharmaceutical composition with enhanced stability comprising the combination of an estrogen and a gestagen type component, a type of Eudragit E and one ore more excipients, wherein the estrogen component can be ethinylestradiol or estradiol-valerate, and the gestagen type component is selected from the group gestoden, drospirenon, levonorgestrel, desogestrel, norethisteron, norgestimate, dienogest.

Further object of the invention is the manufacturing process of the above mentioned pharmaceutical compositions, wherein the solution of a type of an Eudragit E is sprayed onto the mixture of granulated excipients usually employed in the pharmaceutical technology and the added gestagen type active ingredients, then the system is granulated, afterward the estrogen type component is added, followed by the homogenization and compression, and finally by coating.

Further object of the invention is the application of the above mentioned pharmaceutical compositions for inhibition of ovulation in mammals, especially in humans.

An additional object of the invention is a method to inhibit ovulation in mammals, especially in humans, wherein the ethinylestradiol and the gestagen type active ingredient is administered to the mentioned mammal in a pharmaceutically effective dose.

Detailed description of the invention

The present invention provides a pharmaceutical composition with enhanced stability comprising the combination of an estrogen and a gestagen type component as active ingredients, a type of an Eudragit E and one ore more excipients.

The estrogen type active ingredient of the present invention can be ethinylestradiol or estradiol-valerate. As gestagen type active compound all active ingredients can be used, which possess gestagen effect. According to the present invention gestoden, drospirenon, levonorgestrel, desogestrel, norethisteron, norgestimate, dienogest can be used as gestagen type component, preferably drospirenon, levonorgestrel and dienogest.

Surprisingly the use of an Eudragit E type excipient in pharmaceutical compositions resulted in the significant enhancement of the stability thereof, while all the other important properties of the compositions meet the relevant requirements - i.e. disintegration time, dissolution and hardness.

The members of product family of Eudragit E - Eudragit E PO, Eudragit E 100 and Eudragit E 12.5 % - are all derivatives of methacrylic acid. All members of the family are chemically the same, only their appearance is different: Eudragit E 12.5% is an organic dispersion, Eudragit E 100 is a powder suspended in organic solution, Eudragit E PO is a micronized powder. According to the present invention Eudragit E PO and Eudragit E 100 can favorably be used for producing pharmaceutical compositions. Considering the new referring guidelines, which increasingly restrict the use of organic solvents, and make the producing technology even difficult, the micronized form is preferable.

Nevertheless, more problems come up during manufacturing with the application of Eudragit E PO. The use of its micronized form causes problems during tablet compression; therefore the application of the material in solution is more advantageous. However the solubility of Eudragit E PO in water is very low. According to recommendation of the manufacturer sodium lauryl sulphate and stearic acid are needed to add to solve this material in water, then the mixture has to be turraxed for 30-120 minutes, then magnesium stearate or talcum has to be added. During turraxing foaming of the system occurs, which can be inhibited with antifoaming agents, such as silicon, but the application of these materials may influence the quality of the product, therefore it is preferable to avoid it.

Foaming of the system can be avoided with the use of another method of dissolution. In order to prepare the water solution of Eudragit E PO first the sodium lauryl sulphate is dissolved in the required amount of water, then the stearic acid and finally the micronized Eudragit E PO is added to the system. The so obtained mixture is stirred for 8-16 hours, preferably for 10-14 hours. This way the foaming of the system and the application of antifoaming agents can be avoided, a colloid solution is obtained, which is easy to handle, and the protecting layer on the particles is homogenous.

During the manufacturing process of pharmaceutical compositions, first the excipients of the intragranular phase are layered into the fluid granulator. As excipients, lactose monohydrate, maize starch, potato starch, modified maize starch (Starch 1500), calcium phosphate and microcrystalline cellulose can be applied. After the pre-granulation with water solution of PVA-PEG graft copolymer the granulates are dried, then the gestagen type active compound is added dropwise or by spraying into the system. In the case of dropwise addition this should be carried out at 50-80°C inlet air temperature, preferably at 60-75°C.

According to the process of this invention after the addition of the solution of gestagen type active ingredient the solvent is evaporated and the particles are coated with the solution of Eudragit E type excipient. This can be carried out by spraying of the solution of the excipient so that the temperature of the fluid bed is between 18-50°C, preferably between 22-40°C. 00119

6

The further technological manufacturing of the coated particles with Eudragit E type material can be complicated, since the flowability of the obtained granules does not allow the exact dosing, which is very important in the case of hormones. Surprisingly it was found, that after a second granulation step with a binder a system with better properties was obtained, which is easy to treat and compress. The granulation can be made with the water solution of PVA-PEG graft copolymer. The so obtained granules containing gestagen type active ingredient are homogenized with the estrogen compound according to well-known procedures, then magnesium stearate and/or other lubricant is added to the system.

The obtained material is then compressed into tablets; afterward the tablets are film-coated. For film-coating well-known coating materials can be used, such as different types of Opadry, Eudragit or Sepic. The coating is carried out according to methods known from literature. During the process of coating it is important to apply the coloring material to the tablet cores very slowly at the beginning, to ensure the acquired adhesion of coloring material to the tablet cores.

The advantage of the above described technological process is, that low dose active ingredients can be homogenously manufactured in solid state or in solution by conventional methods. Although, during manufacturing the agglomeration occurs in the presence of usual moistening materials, the oxidation can be reduced significantly, which usually happen during fluidization granulation. Surprisingly it was found that using a binder in our pharmaceutical composition did not have any negative effect on the stability of estrogen component. However the particles of estrogen type component were not coated with hydrophobic layer or they were not isolated from the surrounding excipients through complexation. The composition formed this way and the manufacturing process is robust enough, easy to carry out technically, as well as the manufacturing is very economical.

In addition, the present invention relates to the application of the above mentioned pharmaceutical composition to inhibit ovulation in mammals, especially in humans.

Furthermore the present invention relates to a method to inhibit ovulation in mammals, preferably in humans, wherein a pharmaceutically effective dose of the pharmaceutical composition of the present invention containing estrogen and gestagen type active ingredients is administered to the above mentioned mammal. In order to determine the pharmaceutically effective dose on one hand the minimally effective dose has to be considered, which has still ovulation inhibiting effect, on the other hand the upper limit is the dose, at which the 10 000119

7

undesired adverse effects still not appear. Consequently there is an interval of dose of active ingredients, which is between 15-35 μg in the case of ethinylestradiol, between 500-4000 μg of estradiol-valerate, 50-100 μg of gestodene, 50-100 μg of drospirenon, 75-150 μg of levonorgestrel, 60-150 μg of desogestrel, 200-300 μg of norgestimat, 350-1000 μg of norethisteron, 500-4000 μg of dienogest. During the process the dose and the correlated rate of all active compounds can be varied in the above mentioned interval.

The stability of the pharmaceutical compositions of the related invention - as the tables show below - increased significantly. To illustrate the increased stability, the following tables show the stability data of the composition of Example 8 with different types of binders. The differences between the compositions and manufacturing occur at accelerated stability tests, therefore this was applied practically. The experiments were carried out at 40°C and 75% relative humidity. Since the critical decomposition products of ethinylestradiol are 6-keto- efhinylestradiol and 9,11 - didehydro- ethinylestradiol, the comparison and the total amount of decomposition products are represented in the tables below.

Explanation of tables:

Table 1 : Change of the amount of decomposition product 6-keto-ethinylestradiol

Table 2: Change of the amount of decomposition product 9,11-didehydro-ethinylestradiol Table 3 : Change of the total amount of decomposition products of ethinylestradiol

Figure imgf000008_0001

QL = 0,1%

Table 1.

Figure imgf000009_0001

Table 2.

Figure imgf000009_0002

QL = 0,1%

Table 3.

A significant increase in stability can be observed in the case of pharmaceutical compositions according to the present invention compared to the compositions produced with previously known methods. The experiments were carried out at 40°C, so the restriction of temperature at storage is not necessary.

In the case of pharmaceutical compositions of the present invention applying a new composition and technology compared to well-known compositions influenced the stability advantageously, while further important parameters such as the dissolution profile remained intact. By oral administration the product gets into the stomach, where the dissolution occurs. The pH interval of the stomach is between 1.3-5, the exact value depends on several factors, such as the fed or empty state of the stomach. The dissolution tests modeling the real conditions showed, that the dissolution profiles of the pharmaceutical compositions of the invention do not change under the pH=5 compared to the other compositions on the market. These are well illustrated by the dissolution profiles, which show the examination of the composition of Example 9 (DR+E) and a product from the market (Y asminelle) containing the same active ingredients in different media. Explanation of figures:

Fig 1 : Drospirenon dissolution profile of Yasminelle and DR+E products in water and 0.001 n HC1, at 37 °C, 50 rpm.

Fig 2: Ethinylestradiol dissolution profile of Yasminelle and DR+E products in water and 0.001 n HC1, at 37 °C, 50 rpm.

Fig 3: Drospirenon dissolution profile of Yasminelle and DR+E products in medium pH=4.5, at 37 °C, 50 rpm.

Fig 4: Ethinylestradiol dissolution profile of Yasminelle and DR+E products in medium pH=4.5, at 37 °C, 50 rpm.

It is remarkable that with the application of Eudragit E the dissolution profiles changed above pH=5 (getting slower), but this did not affect the real conditions modeling dissolution data under pH=5.

The present invention is illustrated by the following not limiting examples.

Examples

Example 1.: Preparation of granulation liquid:

Granulation liquid I.: 12.5 g of PVA-PEG graft copolymer is dissolved in 200.0 g of purified water by mixing for approximately 10 minutes at 300 ± 50 rpm, then the mixing speed is reduced to 150 ± 50 rpm and the liquid is mixed for 1 hour. The so obtained solution is used in pre-granulation.

Granulation liquid II: 12.5 g of PVA-PEG graft copolymer is dissolved in 240.0 g of purified water by mixing for approximately 10 minutes at 300 ± 50 rpm, then the mixing speed is reduced to 150 ± 50 rpm and the liquid is mixed for 1 hour. The so obtained solution is used in the second granulation. Example 2: Solution of active ingredient:

75.0 g of crystalline drospirenon is dissolved in a 2500.0g of 96% ethanol by mixing for approximately 20 - 25 minutes at 250 ± 50 rpm. Example 3.: Colloid solution of Eudragit E PO:

2.5 g of sodium laureth sulphate, then 3.75 g of stearic acid is dissolved in 240 g of purified water, then 25 g of micronized Eudragit E PO is added to the system. The system is mixed for 12 hours with a mixer. Example 4. Process of granulation:

The spraying of ethanol solution of drospirenon, the granulation and the drying is performed in fluid granulation device (Glatt). The intragranular phase is put into the device by layers: firstly the half amount of lactose monohydrate (Flowlac 100), then maize starch, pregelatinized starch, then the second half of lactose monohydrate. After pre-granulation the granules are dried till 36°C product temperature, after this the ethanol solution of active compound is added dropwise onto the blend without spraying. The dropwise addition is carried out on higher inlet air temperature (70 ± 10°C). The evaporation of the solvent is made till 36°C product temperature is reached. Afterwards the water solution of Eudragit E PO is sprayed onto the blend, so that the product temperature stays between 22 - 40°C. Then the whole amount of the granulation liquid II is sprayed onto the blend. The end point of the drying is 2.0 % loss on drying of the product. Regranulation is made in sieve 0.8 mm.

Example 5.: Homogenization with ethinylestradiol and extragranular phase:

The drospirenon granules produced by the method above is homogenized with micronized ethinylestradiol in several steps. At the end, magnesium stearate is added to the system.

Example 6.: Tablet compression on rotary tablet machine

Parameters of tableting: Set values

Main compression force 5 - 6 kN

Velocity of die table 40 rpm

Feeder speed („fill-o-matic") 30 rpm Example 7.: Film-coating

26.0 g of Opadry II 85G18490 white coloring material is dispersed in 148.5 g of purified water at continuous mixing with paddle at 250 ± 50 rpm according to the instructions. At the process of coating it is important to carry up the coloring material to the tablet cores very slowly at the beginning, to ensure the acquired adhesion of coloring material to the tablet cores. The film-coating is sprayed onto the tablet cores in two steps:

Phase I. slow dosing rate, till the mass growth of tablets is 0.5%

Phase II. Faster dosing of film-coating agent till the end of process.

Example 8.: Pharmaceutical composition of the invention 1.

Figure imgf000012_0001

Example 9.: Pharmaceutical composition of the invention 2. ingredients Amount(mg/tablet)

Ethinylestradiol 0.030

Drospirenon, crystalline 3.000

Maize starch 20.400

Modified maize starch 4.500

Mg Stearate 0.800

Lactose monohydrate 48.520

Kollicoat IR 1.500

Eudragit E PO 1.000

Sodium laureth sulfate 0.100

Stearic acid 0.150

Total 80.000 10 000119

12

Example 10.: Pharmaceutical composition of the invention 3.

Figure imgf000013_0002

Example 11.: Pharmaceutical composition of the invention 4.

Figure imgf000013_0001

Claims

Claims
1. Pharmaceutical composition comprising an estrogen and a gestagen type active ingredient, a type of Eudragit E as excipient, PVA-PEG copolymer and one or more excipients.
2. The composition according to claim 1, wherein the gestagen component is selected from a group comprising gestoden, drospirenon, levonorgestrel, desogestrel, norethisteron, norgestimate, dienogest.
3. The composition according to claim 1 to 2 wherein the gestagen component is selected from a group comprising levonorgestrel, drospirenon, dienogest.
4. The composition according to claim 1 to 3 wherein the gestagen component is drospirenon.
5. The composition according to claim 1, wherein the estrogen component is ethinylestradiol or estradiol-valerate.
6. The method of preparation of pharmaceutical compositions according to claim 1 to 5, wherein the solution of type of Eudragit E is sprayed onto the mixture of well known pharmaceutical excipients and the added gestagen type active compound, and granulated with a well known granulation method, the granules are blended with estrogen type compound, and one or more excipients are added.
7. The method according to claim 6, wherein the temperature of the fluid bed at spraying is between 22-40°C.
8. The application of pharmaceutical compositions according to claim 1 to 5 to inhibit ovulation.
9. The method for inhibiting ovulation, wherein the pharmaceutical composition according to claim 1 to 5 is administered in therapeutically effective amount.
PCT/HU2010/000119 2009-11-06 2010-11-05 Pharmaceutical compositions with enhanced stability WO2011055156A2 (en)

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HUP0900698 2009-11-06

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4378356A (en) 1980-03-18 1983-03-29 Akzon N.V. Multi-phase combination-type sequential preparation for oral contraception and method of oral contraception
US4727064A (en) 1984-04-25 1988-02-23 The United States Of America As Represented By The Department Of Health And Human Services Pharmaceutical preparations containing cyclodextrin derivatives
EP0579435A1 (en) 1992-07-14 1994-01-19 CYCLOPS h.f. Cyclodextrin complexation
EP0503521B1 (en) 1991-03-12 1995-07-19 Akzo Nobel N.V. Low dose dry pharmaceutical preparations
US6156341A (en) 1994-07-04 2000-12-05 Schering Aktiensgesellschaft Low-dosed steroid tablets that contain gallic acid ester as an antioxidant, process for production, and use
EP0707848B1 (en) 1994-10-17 2002-01-09 Akzo Nobel N.V. Solid pharmaceutical composition comprising an excipient capable of binding water

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19728516C2 (en) * 1997-07-04 1999-11-11 Sanol Arznei Schwarz Gmbh TTS for the administration of levonorgestrel and estradiol optionally
TW201008569A (en) * 2008-08-08 2010-03-01 Bayer Schering Pharma Ag Progestin-containing drug delivery system
KR20100117603A (en) * 2008-02-13 2010-11-03 바이엘 쉐링 파마 악티엔게젤샤프트 Drug delivery system with stabilising effect

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4378356A (en) 1980-03-18 1983-03-29 Akzon N.V. Multi-phase combination-type sequential preparation for oral contraception and method of oral contraception
US4727064A (en) 1984-04-25 1988-02-23 The United States Of America As Represented By The Department Of Health And Human Services Pharmaceutical preparations containing cyclodextrin derivatives
EP0503521B1 (en) 1991-03-12 1995-07-19 Akzo Nobel N.V. Low dose dry pharmaceutical preparations
EP0579435A1 (en) 1992-07-14 1994-01-19 CYCLOPS h.f. Cyclodextrin complexation
US6156341A (en) 1994-07-04 2000-12-05 Schering Aktiensgesellschaft Low-dosed steroid tablets that contain gallic acid ester as an antioxidant, process for production, and use
EP0707848B1 (en) 1994-10-17 2002-01-09 Akzo Nobel N.V. Solid pharmaceutical composition comprising an excipient capable of binding water

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