Wafer comprising steroid hormones

Abstract

The invention relates to a pharmaceutical composition in the form of a system in film form for transmucosal administration of steroid hormones. An administration system for steroid hormones which dissolves in the mouth and which releases with a high bioavailability is disclosed. The administration system in film form dissolves in the mouth preferably in a period of less than 30 min, and the steroid hormone entering the bloodstream transmucosally from the administration system leads to a rapid rise in the concentration in the blood. It is thus possible to achieve a maximum concentration of this steroid hormone in the blood in a period of less than 60 min after administration.

Claims

1. An administration system in film form for transmucosal administration of a steroid hormone, comprising: 0.01-50% by weight of a steroid hormone which is selected from the group consisting of an estrogen, a progesterone, an androgen, and a mixture thereof; 50-99.99% by weight of a carrier material, selected from the group consisting of cellulose, cellulose derivatives, poly-N-vinylpyrrolidones, vinylpyrrolidone-vinyl acetate copolymers, starch, starch derivatives, gelatin, gelatin derivatives and combinations thereof; wherein the steroid hormone is dissolved in the carrier material; and wherein the administration system: has a weight per unit area of between 50 and 250 g/m.sup.2; has a thickness of between 40 and 130 μm; dissolves in the mouth completely in a period of less than 30 minutes; and releases the steroid hormone contained therein on buccal administration with a bioavailability of at least 50%.

2. The administration system as claimed in claim 1; wherein the carrier material is methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (HPMC) or a combination thereof.

3. The administration system as claimed in claim 1; wherein the carrier material is hydroxypropylmethylcellulose (HPMC).

4. The administration system as claimed in claim 1, further comprising: liquid excipients which are able to dissolve the steroid hormone and to form a second phase in the carrier material.

5. The administration system as claimed claim 4; wherein the steroid hormone is present dissolved in the liquid excipient.

6. The administration system as claimed in claim 1; wherein the steroid hormone is present in an amount of from 2 to 15% by weight.

7. The administration system as claimed in claim 1; wherein the administration system has an area of between 1 and 10 cm.sup.2.

8. The administration system as claimed in claim 1; wherein the administration system has a weight per unit area of between 100 and 150 g/m.sup.2.

9. The administration system as claimed in claim 1; wherein the administration system has a thickness of between 50 and 100 μm.

10. The administration system as claimed in claim 1; wherein the administration system is mucoadhesive.

11. The administration system as claimed in claim 1; wherein the androgen is selected from the group consisting of testosterone, dihydrotestosterone, 7α-methyl-19-nortestosterone (MENT), MENT 17-acetate, 7α-methyl-11β-fluoro-19-nortestosterone (eF-MENT), mesterolone, metenolone, nandrolone, oxandrolone, androstenedione, and mixtures thereof.

12. The administration system as claimed in claim 1; wherein the steroid hormone is 7α-methyl-19-nortestosterone (MENT) or 7α-methyl-11β-fluoro-19-nortestosterone (eF-MENT).

13. The administration system as claimed in claim 1, further comprising: at least one excipient selected from the group consisting of flavorings, colorants, permeation enhancers, sweeteners, fillers, plasticizers, solubilizers, pH stabilizers, and disintegrants.

14. The administration system as claimed in claim 1; wherein the administration system releases the steroid hormone contained therein on buccal application with a bioavailability of between 70 and 75%.

15. A method for the treatment of disorders and/or dysfunctions attributable to a steroid hormone deficiency, comprising: administering a steroid hormone by the application of the administration system of claim 1 to a patient in need thereof.

16. The method as claimed in claim 15, wherein the steroid hormone is administered transmucosally.

17. The method as claimed in claim 15; wherein the disorder and/or dysfunction attributable to a steroid hormone deficiency is an androgen deficiency.

18. The method as claimed in claim 15; wherein the steroid hormone reaches a maximum blood concentration in a period of less than 60 min after administration of the medicament.

19. The method as claimed in claim 18; wherein the steroid hormone reaches a maximum blood concentration in a period of less than 30 min after administration of the medicament.

20. A process for producing an administration system in film form of claim 1 for transmucosal administration of a steroid hormone, comprising: mixing the steroid hormone in the form of a solution in a pharmaceutically acceptable solvent with a water-containing mixture of a carrier material; spreading out the mixture produced by the mixing step as a thin layer, and drying the thin layer by removing the solvent to form a film.

21. The process as claimed in claim 20; wherein the resulting film is divided into individual administration systems by perforation, cutting transversely, and/or cutting longitudinally.

22. A method for the treatment of disorders and/or dysfunctions attributable to a steroid hormone deficiency, comprising: a first step of applying the administration system of claim 1, which comprises at least one steroid hormone, to the mucosa in the mouth; and a second step where the at least one steroid hormone penetrates transmucosally into the bloodstream.

23. The method as claimed in claim 22; wherein the steroid hormone penetrates into the bloodstream in a period of less than 30 min after application of the administration system to the mucosa in the mouth.

24. The administration system as claimed in claim 2; wherein the system comprises: (1) between 3 and 8% by weight of a steroid hormone; (2) has an area of between 5 and 8 cm.sup.2; (3) has a weight per unit area of between 100 to 150 g/m.sup.2; and (4) has a thickness of between 50 and 100 μm.

25. The administration system as claimed in claim 3; wherein the system comprises: (1) between 3 and 8% by weight of a steroid hormone; (2) has an area of between 5 and 8 cm.sup.2; (3) has a weight per unit area of between 100 to 150 g/m.sup.2; and (4) has a thickness of between 50 and 100 μm.

26. The administration system as claimed in claim 24; wherein the steroid hormone is 7α-methyl-19-nortestosterone (MENT) or 7α-methyl-11β-fluoro-19-nortestosterone (eF-MENT).

27. The administration system as claimed in claim 25; wherein the steroid hormone is 7α-methyl-19-nortestosterone (MENT) or 7α-methyl-11β-fluoro-19-nortestosterone (eF-MENT).

28. The administration system as claimed in claim 26; wherein the administration system releases the steroid hormone contained therein on buccal application with a bioavailability of between 70 and 75%.

29. The administration system as claimed in claim 27; wherein the administration system releases the steroid hormone contained therein on buccal application with a bioavailability of between 70 and 75%.

30. The administration system as claimed in claim 1; wherein the estrogen is ethinylestradiol.

31. The administration system as claimed in claim 1; characterized in that wherein the progesterone is selected from the group consisting of drospirenone, dienogest, gestodene, levonorgestrel, cyproterone acetate, and mixtures thereof.

Description

EXAMPLE 1

(1) 5 g of MENT are added to 700 ml of an ethanol/water (50:50) solution and stirred until dissolution is complete. The dissolution is assisted where appropriate by application of ultrasound. 95 g of hydroxypropylmethylcellulose (HPMC) are then added, and the mixture is stirred until dissolution is complete.

(2) The mixture is degassed, spread out with the aid of a spreading box and dried. A thin transparent film which is between 50 and 100 μm thick is produced. Transparent wafers with a content of 1.5 mg of MENT are obtained by cutting out samples of appropriate size.

EXAMPLE 2

(3) 3 g of menthol and 2 g of thymol are added to 26 g of ATMOS 300 (=a mixture of mono- and diglycerides of oleic acid) and 4 g of Tween 80 (=a polyoxyethylene sorbitan oleate ester). The mixture is stirred until the solids have dissolved. Then 5 g of MENT are added to this mixture, which is stirred until the active ingredient has completely dissolved. 60 g of HPMC are added to 600 g of a 50:50 ethanol-water mixture and stirred until dissolution is complete. The organic phase is then added slowly and with high-speed stirring to the aqueous phase, resulting in a thick, creamy composition. Degassing of the mixture and spreading out are followed by drying. A thin translucent film which is between 50 and 100 μm thick is produced. Translucent wafers with a content of 1.5 mg of MENT are obtained by cutting out samples of appropriate size.

EXAMPLE 3

(4) 5 g of MENT are added to a mixture of 20 g of ATMOS 300, 10 g of octanol and 5 g of lecithin. The mixture is stirred until the solids have dissolved. 60 g of HPMC are added to 600 g of water and stirred until dissolved. The organic phase is added with high-speed stirring to the aqueous phase, resulting in a thick creamy composition. Degassing of the mixture and spreading out are followed by drying. A thin translucent film which is between 50 and 100 μm thick is produced. Translucent wafers with a content of 1.5 mg of MENT are obtained by cutting out samples of appropriate size.

(5) TABLE-US-00001 TABLE 1 Compositions of dried MENT wafers ATMOS Tween Example MENT (%) HPMC (%) 300 (%) 80 (%) Octanol (%) Lecithin (%) Menthol (%) Thymol (%) 1 5 95 — — — — — — 2 5 60 26 4 — — 3 2 3 5 60 20 — 10 5 — —

(6) It may be noted that the dried systems of example 1 comprise the steroid hormone dissolved as a mono-molecular dispersion in the carrier material, whereas the steroid hormone in examples 2 and 3 is in the form of a solution in an oil phase which is in turn present in the carrier material as separate phase. The use of liquid, preferably lipophilic excipients which are able to dissolve the steroid hormone and to form a second phase in the (preferably hydrophilic) carrier material thus makes it possible to produce administration systems in film form with steroid hormones as “two-phase system”.

(7) Experimental Data

(8) A clinical pilot study was performed on healthy men to test whether a MENT wafer is suitable in principle for clinical use. Essential aspects of the trial related to the levels of active ingredient which can be achieved in the blood by the wafer and the time course thereof, and the general tolerability. Three different dosages of the wafer were tested. Each subject received all three dosages each as a single administration in a crossover design. There was a washout period of at least 48 hours between the individual administrations.

(9) The three dosages were fixed so that there was a realistic possibility of being able to measure blood levels of MENT with the available methods of measurement, even if the bioavailability was very low, at least at the high dose level and, on the other hand, if the bioavailability is very high the theoretically conceivable peak levels are still within the safety range proven by clinical or preclinical data.

(10) The dose groups were 0.5 mg, 1.5 mg and 3.0 mg. The level of the dosage was determined by the size of the wafer. The wafer used comprised 0.225 mg of MENT/1 cm.sup.2. The single administration took place in a dose of 0.5 mg with a wafer having an area of 2.22 cm.sup.2 (formulation a), for 1.5 mg with a wafer having an area of 6.67 cm.sup.2 (formulation b), and for 3.0 mg with two wafers each of 6.67 cm.sup.2. The wafers were applied to the buccal mucosa by the clinical investigator. The low dose was always introduced on the right-hand side, the middle dose always on the left-hand side, and for the high dose one wafer was used on each side.

(11) In total, 11 men between 23 and 42 years of age received the wafer without relevant side effects being observed. The local tolerability was very good. Visual inspection of the application site revealed no signs of unwanted local reactions. The subjects used a visual analog scale to represent their subjective impression of the local tolerability. There was no evidence of relevant unwanted effects here either.

(12) The wafer had dissolved within 15 minutes for the majority of uses. It took longer in some cases; the maximum time in one case was 33 minutes. The available data support the assumption that the bioavailability is lower when the time taken for the wafer to dissolve is distinctly prolonged.

(13) The MENT wafer showed a surprisingly good bioavailability of about 70-75% (Tab. 2).

(14) TABLE-US-00002 TABLE 2 Bioavailability of the MENT wafer AUC(0-tlast) AUC(0-tlast) AUC(0-tlast) geomean dose- geomean dose- geomean normalized normalized Bioavailability Treatment Formulation Dose (mg) [ng × h/ml] [ng × h/ml] [ng × h/ml] [%} A a 0.50 3.78 3.78 75.9 B b 1.50 11.00 3.67 4.98 73.6 C b 3.00 21.10 3.52 (after i.v. 70.6 admin. of 0.5 mg MENT)

(15) The interindividual variation in the AUC is below 20% which is to be categorized as low.

(16) Both C-max and the AUC show a clear dose-linearity. The highest concentrations are measured within 15 to 30 minutes and then fall rapidly; only insignificant concentrations are measurable after more than 4 hours.

(17) The serum levels of MENT were determined by employing a GC-MS method (coupled gas chromatography-mass spectrometry) (specifically developed and validated for this purpose). The method makes use of the process of negative chemical ionization (NCI) and thus achieves high sensitivity permitting concentrations to be measured down to a lower limit of approximately 60 pg/ml (lower limit of quantification).

(18) A GC-MS method is also available for measurements of lower sensitivity, which employs the process of electron ionization (EI) instead of NCI.

(19) In principle, the MENT concentration can also be determined by other methods which are otherwise suitable for determining steroid hormones. Suitable examples which may be mentioned without a claim to completeness are radioimmunoassays, LC-MS techniques, or HPLC methods (high performance liquid chromatography).

(20) TABLE-US-00003 TABLE 3 Overview of characteristic pharmacokinetic data of the tested dosages of the MENT wafer Cmax Tmax AUC (0-tlast) geomean (CV) median (range) geomean (CV) Treatment Formulation Dose (mg) [ng/ml] [h] [ng × h/ml] A a 0.50 3.29 (67.8%) 0.25 (0.25–2.00) 3.78 (44.5%) B b 1.50 8.98 (39.4%) 0.50 (0.25–0.75) 11.0 (17.8%) C b 3.00 18.2 (31.2%) 0.50 (0.25–0.75) 21.1 (16.2%) CV = coefficient of variation

(21) The available clinical results with MENT indicate that serum concentrations of at least 0.3 ng/ml (about 1 nmol/l) are necessary for effective prevention of hypogonadal symptoms in men. This is about 10-times lower than the minimum concentration of testosterone.

(22) The MENT wafer system achieves these serum levels without difficulty. With the pharmacokinetics found, the MENT wafer approaches an intravenous administration. Because of the short half-life, use of the wafer is worthwhile when a brief but very efficient rise in the androgen level is desirable. “Brief” for this indication is to be regarded as a period of less than 60 min, preferably between 15 and 30 min.

(23) One advantage of the application, which is restricted to the acute case of need, is to be regarded as being that the inhibitory effect on testicular function is only slight and a negligible impairment of the corresponding physiological functions is to be expected. In contrast to androgen products with longer activity, therefore, neither impairment of the available gonadal testosterone synthesis nor inhibition of spermatogenesis is to be expected on use of the inventive administration system with an androgen as active ingredient.

(24) One suitable area of use of the inventive administration system from the area of androgens is therefore administration once a day to restore the circadian androgen rhythmicity in elderly men. The age-associated reduction in the endogenous testosterone concentration in men is characterized in particular by loss of the circadian rhythmicity. The rise in testosterone levels to be observed in the morning substantially disappears. Thus, the largest difference in testosterone levels between young and old men is detectable in blood samples taken in the morning, whereas there are only small differences when taken in the evening. It is possible with the aid of the inventive administration system to treat the age-related relative androgen deficiency in accordance with the androgen rhythmicity, with scarcely any impairment in practice of the available endogenous testosterone production. In these cases, self-treatment of the patient is possible easily and conveniently in an advantageous manner.