ULIPRISTAL ACETATE OTF

Abstract

The invention relates to an oral thin film, comprising a polymer matrix and ulipristal acetate as an active agent, wherein ulipristal acetate is dispersed in the polymer matrix and the polymer matrix is a matrix of water-soluble polymer selected from poly(ethylene oxide), poly(vinyl alcohol) or hydroxypropyl methylcellulose. The oral thin film is suitable as emergency contraceptive and can be administered in the oral cavity without water. It quickly disintegrates in the oral cavity wherein the active agent ulipristal acetate is mainly swallowed in undissolved form and absorbed into the gastrointestinal tract.

Claims

1. An oral thin film, comprising a polymer matrix and ulipristal acetate as an active agent, wherein ulipristal acetate is dispersed in the polymer matrix and the polymer matrix is a matrix of water-soluble polymer selected from poly(ethylene oxide), poly(vinyl alcohol) or hydroxypropyl methylcellulose.

2. The oral thin film according to claim 1, wherein ulipristal acetate is micronized ulipristal acetate.

3. The oral thin film according to claim 1, wherein the amount of ulipristal acetate is 10 to 60% by weight based on the total weight of the oral thin film.

4. The oral thin film according to claim 1, wherein in the case where the water-soluble polymer is selected from poly(ethylene oxide) or poly(vinyl alcohol), the amount of ulipristal acetate is 10 to 60% by weight based on the total weight of the oral thin film, and/or in the case where the water-soluble polymer is selected from hydroxypropyl methylcellulose, the amount of ulipristal acetate is 20 to 60% by weight based on the total weight of the oral thin film.

5. The oral thin film according to claim 1, wherein the amount of water-soluble polymer is preferably 20 to 90% by weight based on the total weight of the oral thin film.

6. The oral thin film according to claim 1, wherein in the case where the water-soluble polymer is selected from poly(ethylene oxide) and/or poly(vinyl alcohol), the amount of water-soluble polymer is 25 to 90% by weight based on the total weight of the oral thin film, and/or in the case where the water-soluble polymer is selected from hydroxypropyl methylcellulose, the amount of water-soluble polymer is 30 to 70% by weight based on the total weight of the oral thin film.

7. The oral thin film according to claim 1, wherein the poly(ethylene oxide) (PEO) has a molecular weight in the range of 50,000 to 200,000 Dalton the poly(vinyl alcohol) (PVA) has a molecular weight in the range of 20,000 to 40,000 Dalton and/or a degree of hydrolysis of 84 to 92 mol %, preferably 86 to 90 mol %, and/or the hydroxypropyl methylcellulose (HPMC) has a labelled viscosity in the range of 1 to 100 mPas.

8. The oral thin film according to claim 1, wherein the water-soluble polymer is selected from poly(ethylene oxide) WSR N-10, poly(vinyl alcohol) 4-88, hydroxypropyl methylcellulose 603, hydroxypropyl methylcellulose 60SH50 or a mixture of hydroxypropyl methylcellulose 603 and hydroxypropyl methylcellulose 60SH50.

9. The oral thin film according to claim 1, further comprising one or more plasticizers, preferably glycerol.

10. The oral thin film according to claim 1, wherein the oral thin film is a non-foamed film or a foamed film.

11. The oral thin film according to claim 1, wherein after storing of the oral thin film at a temperature of 40° C. and 75% relative humidity for 6 months the amount of the degradation product N-demethyl ulipristal acetate (DMUA) is less than 1% by weight based on the initial amount of ulipristal acetate in the oral thin film before storage.

12. An oral thin film, comprising a polymer matrix and ulipristal acetate as an active agent, wherein ulipristal acetate is dispersed in the polymer matrix, and wherein after storing of the oral thin film at a temperature of 40° C. and 75% relative humidity for 6 months the amount of the degradation product N-demethyl ulipristal acetate (DMUA) is less than 1% by weight based on the initial amount of ulipristal acetate in the oral thin film before storage.

13. A method for preparing an oral thin film according to claim 1, comprising the following steps: a) mixing water-soluble polymer, solvent comprising or consisting of water or a mixture of water and one or more organic solvents, and solid ulipristal acetate, preferably micronized ulipristal acetate, to obtain a suspension, wherein water-soluble polymer is dissolved in the solvent and ulipristal acetate is suspended in the solvent, b) casting or coating the suspension obtained on a support, coating liner or in a mold to spread the suspension, and c) evaporating the solvent.

14. The method of claim 13, where one or more plasticizers are added in mixing step a).

15. The method of claim 13, wherein the suspension is foamed with a gas before step b).

16. A method for emergency contraception comprising administration of an effective amount of the active agent via the oral thin film of claim 1.

17. The oral thin film according to claim 1, wherein the amount of ulipristal acetate is 20 to 43% by weight based on the total weight of the oral thin film.

18. The oral thin film according to claim 1, wherein in the case where the water-soluble polymer is selected from poly(ethylene oxide) or poly(vinyl alcohol), the amount of ulipristal acetate is 20 to 43% by weight based on the total weight of the oral thin film, and/or in the case where the water-soluble polymer is selected from hydroxypropyl methylcellulose, the amount of ulipristal acetate is 20 to 43% by weight based on the total weight of the oral thin film.

19. The oral thin film according to claim 1, wherein the amount of water-soluble polymer is 40 to 70% by weight based on the total weight of the oral thin film.

20. The oral thin film according to claim 1, wherein in the case where the water-soluble polymer is selected from poly(ethylene oxide) and/or poly(vinyl alcohol), the amount of water-soluble polymer is 35 to 70% by weight, based on the total weight of the oral thin film, and/or in the case where the water-soluble polymer is selected from hydroxypropyl methylcellulose, the amount of water-soluble polymer is 40 to 60% by weight, based on the total weight of the oral thin film, and wherein the poly(ethylene oxide) has a molecular weight in the range of 75,000 to 150,000 Dalton, the poly(vinyl alcohol) has a molecular weight in the range of 25,000 to 35,000 Dalton, and/or a degree of hydrolysis of 86 to 90 mol-%, and/or the hydroxypropyl methylcellulose has a labelled viscosity in the range of 2 to 75 mPas.

Description

EXAMPLES

[0050] In all examples ulipristal acetate having the following particle size distribution as measured by laser diffraction was used:

[0051] d.sub.10=1.48 μm±11.20%; d.sub.50=3.64 μm±8.71%; d.sub.90=6.73 μm±10.40%; d.sub.95=7.86 μm±11.08%; d.sub.99=10.52 μm±16.30%.

[0052] OTF laminates were prepared by standard laboratory methods (stirrers, glass vessels, coating tools, drying oven). The formulations were prepared as suspension formulations by mixing API, matrix polymer and excipients in a process solvent for a suitable time, then coating the prepared mass on a suitable liner, followed by drying in a drying oven. This process yielded laminate pieces that were punched into OTF of a suitable size (about 7 cm.sup.2). PVA 4-88 and Polyox WSR N10 was used as pre-solution (PVA 4-88: 35% in water, Polyox WSR N10: 21% in water). For foam formulations, the suspension obtained in step b) was foamed by a whisk or turbine stirrer with air or nitrogen gas.

Example 1—PEO-Based OTF

[0053] An oral thin film having the following formulation (calculated as dry basis) was prepared as suspension formulation with water as process solvent (solid content 30.4%), alternatively ethanol/water 10/90 is suitable as process solvent (solid content 33%):

TABLE-US-00001 proportion ingredient function [% by weight] Polyox ® WSR N-10 matrix polymer 62.0 ulipristal acetate API 30.0 (micronized) glycerol plasticizer (reduces melting 5.0 temperature and glass transition temperature) saccharin Na sweetening agent 2.0 sucralose sweetening agent 1.0

[0054] It was found that PEO WSR N-10 (Polyox®WSR N10) is a suitable matrix polymer for ulipristal acetate OTF formulations. An ulipristal acetate content of 30% was found to yield a haptically and optically good OTF film.

Example 2—PVA-Based OTF Foam

[0055] An oral thin film having the following formulation (calculated as dry composition) was prepared as suspension formulation with water as process solvent (solid content 40%), air was used for foaming:

TABLE-US-00002 proportion ingredient function [% by weight] PVA 4-88 matrix polymer 63.0 ulipristal acetate API 30.0 (micronized) glycerol plasticizer (reduces melting 4.0 temperature and glass transition temperature) saccharin Na sweetening agent 2.0 sucralose sweetening agent 1.0

[0056] PVA 4-88 was found a suitable polymer for formulating an ulipristal acetate OTF as a foam. An API loading with 30% ulipristal acetate was found suitable. The PVA formulation as OTF foam with 30% ulipristal acetate loading had good optical and haptical properties.

[0057] Tests with higher loading of 40% ulipristal acetate loading leads to tear resistant, but slightly brittle OTF. Formulations using 30% API as above result in better OTFs.

[0058] Furthermore, formulations with 23.7% API loading and nitrogen gas as foaming gas were found suitable and gave tear resistant films:

[0059] Formulation with PVA 4-88 as Matrix polymer and 23.7% API loading with water as process solvent (solid content 40%), nitrogen was used for foaming:

TABLE-US-00003 proportion ingredient function [% by weight] PVA 4-88 matrix polymer 64.2 ulipristal acetate API 23.7 (micronized) glycerol plasticizer (reduces melting 8.8 temperature and glass transition temperature) saccharin Na sweetening agent 2.2 sucralose sweetening agent 1.1

Example 3—PVA-Based OTF (not Foamed)

[0060] An oral thin film having the following formulation (calculated as dry composition) was prepared as suspension formulation with water as process solvent (solid content 40%):

TABLE-US-00004 proportion ingredient function [% by weight] PVA 4-88 matrix polymer 63.0 ulipristal acetate API 30.0 (micronized) glycerol plasticizer (reduces melting 4.0 temperature and glass transition temperature) saccharin Na sweetening agent 2.0 sucralose sweetening agent 1.0

[0061] PVA 4-88 was found a suitable polymer for formulating an ulipristal acetate OTF. An API loading with 30% ulipristal acetate was found suitable. PVA formulations as film with 30% ulipristal acetate loading had good optical and haptical properties.

[0062] Tests with higher loading of 40% ulipristal acetate leads to tear resistant, but slightly brittle OTF. Formulations using 30% API result in better OTFs.

Example 4—HPMC-Based OTF

[0063] An oral thin film having the following formulation (calculated as dry composition) was prepared as suspension formulation with water as process solvent (solid content 31.9%), alternatively ethanol/water 20/80 is suitable as process solvent (solid content 32%):

TABLE-US-00005 Proportion Ingredient Function [% by weight] HPMC 603 matrix polymer 30.55 HPMC 60SH50 matrix polymer 16.45 ulipristal acetate API 40.0 (micronized) glycerol plasticizer (reduces melting 10.0 temperature and glass transition temperature) saccharin sodium sweetening agent 2.0 sucralose sweetening agent 1.0

[0064] HPMC was found a suitable polymer for formulating an ulipristal acetate OTF. It was found that an API loading of 40% gives a stable and haptical good film. The glycerol content was set to 10% in order to improve haptic properties and tear-resistance. A process solvent mixture of 20% ethanol and 80% water (solid content 32%) was found most suitable for manufacturing.

[0065] Tests with loading of 30% and 40% ulipristal acetate leads to acceptable films, but formulations using 26.63% API results in improved OTF:

[0066] An oral thin film having the following formulation (calculated as dry composition) was prepared as suspension formulation with water as process solvent (solid content 32%):

TABLE-US-00006 Proportion Ingredient Function [% by weight] HPMC 603 matrix polymer 37.17 HPMC 60SH50 matrix polymer 20.73 ulipristal acetate API 26.63 (micronized) glycerol plasticizer (reduces melting 12.23 temperature and glass transition temperature) saccharin sodium sweetening agent 2.16 sucralose sweetening agent 1.08

Comparative Example—Kollicoat®IR-Based Formulations

[0067] Kollicoat®IR from BASF, which is a water-soluble polyvinyl alcohol/polyethylene glycol copolymer was tested for preparing an ulipristal acetate OTF. Different ulipristal acetate loadings were investigated, such as 50%, 30% and 20% ulipristal acetate in the formulations. However, these formulations were brittle and without sufficient tear resistance. As a result, Kollicoat®IR was not found a suitable polymer for formulating an ulipristal acetate OTF.

Example 5—Permeation Study

[0068] The permeated amount of the OTFs prepared according Examples 1, 2, 3 and 4 were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) using pig mucosa (mucosa oesophagus). A dermatome was used to prepare mucosa to a thickness of 400 μm, with an intact barrier function for all transmucosal therapeutic systems. Die cuts with an area of 0.524 cm.sup.2 were punched from the OTFs, applied to the mucosa and the mucosa with the OTF was immersed on the top side in artificial saliva (the bottom side being in contact with receptor medium, and the top side being compartmentalized to a mucosa area of 0.985 cm.sup.2). The permeated amount of Ulipristal Acetate in the receptor medium (phosphate buffer solution pH 7.4) at a temperature of 37±1° C. was measured. The results are shown in FIG. 1.

[0069] The in vitro experiments show that the four tested formulations showed a very slow, almost non-detectable, permeation of ulipristal acetate (the high standard deviation of the measurement is due to the low amounts of permeated ulipristal acetate, which were in the range of the detection limit). In the first 5 minutes, no detectable amounts of ulipristal acetate were found for all four formulations. Even after 120 minutes only trace amounts (<0.15 μg/cm.sup.2) were found. As disintegration of the films is fast (example 6) it can be concluded that the ulipristal acetate is swallowed before relevant amounts can permeate and, thus, PEO, PVA and HPMC are suitable matrix polymers for an immediate release product where the ulipristal acetate is swallowed and absorbed through the gastrointestinal tract.

Example 6—Disintegration Study

[0070] Disintegration times of the OTFs prepared according to Examples 1, 2, 3 and 4 were measured, based on USP 701, using a tablet disintegration instrument (Pharma-Test DIST-3 Triple Basket Tablet Disintegration Tester, 30 strokes per min over a distance of 55 mm, in 11 ELGA Water (RWSx002)). Die cuts of the OTFs with a size of 7.04 cm.sup.2 were placed in a basket (“sinker”) and positioned in a glass tube affixed to the instrument. Finally, time was taken until there were only residues of the OTF inside the basket.

[0071] The times indicated in the following table refer to the point when there were only residues of the OTF inside the basket:

TABLE-US-00007 time to complete OTF disintegration Example 1 (PEO-based)  76 s Example 2 (PVA-based foam) 125 s Example 3 (PVA-based film)  53 s Example 4 (HPMC-based)  54 s

[0072] These studies show that the polymers tested are fast dissolving and suitable for releasing the API upon fast disintegration in the mouth.

Example 7—Stability Test

[0073] Stability of the OTFs prepared according to Examples 1, 2 and 4 was measured by storing samples of the OTFs at a temperature of 40° C. and 75% relative humidity. At fixed time intervals of 1, 2, 3 and 6 months, samples of the OTFs were analyzed by HPLC for degradation products. The main degradation product detected was N-demethyl ulipristal acetate (DMUA). Tables 1, 2 and 3 show the amounts of DMUA and the total amounts of degradation product detected (Sum) in % by weight based on the initial amount of ulipristal acetate in the OTFs before storage. The tested formulations were found to be stable, with only minor amounts of degradation products.

TABLE-US-00008 TABLE 1 Summarized values from stability testing protocol for example 2 (PVA formulation) at 40° C. / 75% r.h. Test Parameter inital 1 Month 2 Months 3 Months 6 Months Related substances Sum: Sum: Sum: Sum: Sum: 0.21 0.34 0.64 0.90 1.17 N-Demethyl- 0.16 0.23 0.32 0.37 0.48 Ulipristalacetat Deprotector* 0.02 0.02 0.02 0.01 0.02 *Acetyl group removed (“deprotected”)

TABLE-US-00009 TABLE 2 Summarized values from stability testing protocol for example 1 (PEO formulation) at 40° C. / 75% r.h. Test Parameter inital 1 Month 2 Months 3 Months 6 Months Related substances Sum: Sum: Sum: Sum: Sum: 0.22 0.26 0.36 0.43 0.47 N-Demethyl- 0.16 0.19 0.20 0.22 0.23 Ulipristalacetat Deprotector* 0.02 0.02 0.02 0.02 0.03 *Acetyl group removed (“deprotected”)

TABLE-US-00010 TABLE 3 Summarized values from stability testing protocol for example 4 (HPMC formulation) at 40° C. / 75% r.h. Test Parameter inital 1 Month 2 Months 3 Months 6 Months Related substances Sum: Sum: Sum: Sum: Sum: 0.18 0.23 0.34 0.37 0.40 N-Demethyl- 0.13 0.15 0.17 0.18 0.19 Ulipristalacetat Deprotector* 0.01 0.02 0.03 0.03 0.03 *Acetyl group removed (“deprotected”)