Patent Application
20080038350
The present invention will now be described in greater detail with reference to the attached drawing in which
Surprisingly, it was found that an increase in the particle size of the dienogest tends to slow down in vitro the fast dissolution of the active compounds from the composition. By fast release is meant a release of at least 70% of the active ingredient within about 30 minutes and preferably of at least 80% in about 20 minutes.
Based on measured human plasma concentrations after oral administration of dienogest (dosage 2 mg, particle size 3 μm), the plasma concentrations were simulated in silico (
As can be seen, the maximum plasma concentration Cmax of micronized dienogest (particle size 3 μm) is reached after two hours independently from the dosage of dienogest that is administered. Moreover, it can also be seen that the greater the particle size at the same dosage of dienogest, the lower is the Cmax without reduction in the bioavailability. The bioavailability of dienogest can be obtained from the area under the curve (AUC) for the plasma concentration. At the same dosage of dienogest but with an increasing particle size, Cmax is nearly halved from 100% (3 μm) to 78% (40 μm) and 54% (65 μm). At the same time, with increasing particle size tmax the time to reach Cmax increases from 2 h at 3 μm to 3.5 h at 40 μm and finally to 6 h at 65 μm. After about 12 h, the absorption process even for dienogest with the maximum particle size of 65 μm is completed. Thereafter, independently of the particle size, dienogest is eliminated from the plasma at the same rate and, hence, the plasma concentrations are similar.
Valette is a conventional sugar-coated tablet for oral contraception containing 0.030 mg of ethinyl estradiol and 2.0 mg of dienogest in a tablet core covered with a sugar-containing coating.
Being a difficultly soluble active ingredient dienogest is usually micronized and used at an average particle size of about 3 μm. With this particle size distribution, the optimum dosage for reliable ovulation inhibition was found to be 2 mg of dienogest.
During the granulation an ethanolic solution of the ethinyl estradiol was sprayed in.
Tablets having the following composition were prepared:
Core:
All substances were granulated and mixed in a suitable manner and then pressed to form tablet cores having a diameter of 5 mm and weighing 50 mg.
Coating:
The substances for the coating were dispersed in water and sprayed onto the tablets by appropriate equipment until the resulting sugar-containing tablet had a final weight of 80 mg.
The tablets were examined for their active ingredient release by the method described in the European Pharmacopeia, 4th edition, original issue 2002, 2.9.3.
The conditions were as follows:
The following in vitro active ingredient releases were measured:
The uniformity of the dienogest content of the tablets was determined according to European Pharmacopeia 2.9.40. The relative standard deviation for the dienogest content of the tablets was 0.7%.
Determination and dissolution and blood level curves for a dienogest/ethinyl estradiol coated tablet (1.5 mg of dienogest=DNG/0.015 mg of ethinyl estradiol=EE) with the dienogest in the core of the coated tablet having an average particle size of 40 μm.
Dienogest with a particle size distribution median of 40 μm was used. This value was measured by laser light diffraction. The ethinyl estradiol in the form of an ethanolic solution was sprayed on during the granulation.
Tablets having the following composition were prepared:
Core:
All substances were granulated and mixed in a suitable manner and then pressed to form tablet cores having a diameter of 5.5 mm and weighing 90 mg.
Coating:
The substances for the coating were dispersed in water and sprayed onto the tablet cores by appropriate equipment until a coated tablet had a final weight of 96 mg.
The tablets were examined for their active ingredient release by the method described in European Pharmacopeia 2.9.3.
The conditions were as follows:
The following in vitro active ingredient releases were measured:
The uniformity of the dienogest content of the tablets was determined according to European Pharmacopeia 2.9.40. The relative standard deviation of the dienogest content of the tablets was 3.3%.
Determination and dissolution and blood level curves for a dienogest/ethinyl estradiol coated tablet (1.5 mg of dienogest=DNG/0.015 mg of ethinyl estradiol=EE) with the dienogest in the core of the coated tablet having an average particle size of 65 μm.
Dienogest with a particle size distribution median of 65 μm was used. This value was measured by laser light diffraction. Ethinyl estradiol in the form of an ethanolic solution was sprayed in during the granulation.
Coated tablets having the following composition were prepared:
Core:
All substances were granulated and mixed in a suitable manner and then pressed to form tablet cores having a diameter of 5.5 mm and weighing 90 mg.
Coating:
The substances were dispersed in water and sprayed onto the tablets by use of appropriate equipment until a coated tablet had a final weight of 96 mg.
The tablets were examined for their active ingredient release by the method described in European Pharmacopeia 2.9.3.
The conditions were as follows:
The following in vitro active ingredient releases were measured:
The uniformity of the dienogest content of the tablets was determined according to European Pharmacopeia 2.9.40. The relative standard deviation of the dienogest content of the tablets was 2.2%.
Preferably the effective ingredients in the peroral medication for preventing conception consist only of crystalline dienogest and ethinyl estradiol.
While the invention has been illustrated and described as embodied in a low-dosage peroral medication for contraception containing crystalline dienogest and ethinyl estradiol, it is not intended to be limited to the details shown, since various modifications and changes may be made without departing in any way from the spirit of the present invention.
Without further analysis, the foregoing will so fully reveal the gist of the present invention that others can, by applying current knowledge, readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this invention.
What is claimed is new and is set forth in the following appended claims.
U.S. Provisional Application No. 60/836,914, filed Aug. 10, 2006, also discloses the invention described and claimed herein and provides a basis for a claim of priority for that invention under 35 U.S.C. 119(e).
| Number | Date | Country | |
|---|---|---|---|
| 60836914 | Aug 2006 | US |
