Transmucosal delivery system for idebenone

Abstract

The invention relates to a transmucosal delivery system for idebenone, comprising an external phase, which contains at least one hydrophilic polymer, and an inner hydrophobic phase, which contains idebenone and at least one hydrophobic substance, wherein the inner hydrophobic phase is emulsified in the form of droplets in the external phase. The invention is characterized in that the inner hydrophobic phase is stabilized by at least one emulsifier in the external phase. The invention also relates to a method for producing the same and its use as a medicament.

Claims

1. A transmucosal delivery system for idebenone, comprising an outer, hydrophilic, phase that makes up 20 to 70 wt. % of the total weight of the transmucosal delivery system for idebenone and which contains at least one hydrophilic polymer, and an inner, hydrophobic, phase which contains idebenone and at least one hydrophobic substance, wherein the at least one hydrophobic substance in the inner, hydrophobic, phase comprises methyl salicylate, tributyl citrate, triethyl citrate, eucalyptol, methyl salicylate, linoleic acid, oleic acid and/or mixtures thereof, wherein the inner, hydrophobic, phase is emulsified in the form of droplets in the outer phase, characterised in that the inner, hydrophobic, phase is stabilised by at least one emulsifier in the outer phase, wherein the at least one emulsifier comprises polysorbate, sorbitan esters, polyoxyethylene fatty acid ethers and/or mixtures thereof, and wherein the transmucosal delivery system for idebenone further comprises a vitamin E free-radical scavenger.

2. The transmucosal delivery system for idebenone according to claim 1, characterised in that idebenone is present substantially in the inner, hydrophobic, phase.

3. The transmucosal delivery system for idebenone according to claim 1, characterised in that idebenone is present dissolved in non-crystalline form.

4. The transmucosal delivery system for idebenone according to claim 1, characterised in that idebenone is present in a pharmaceutically effective concentration below its saturation concentration.

5. The transmucosal delivery system for idebenone according to claim 1, characterised in that the at least one hydrophilic polymer comprises polyvinyl alcohol, polyvinylpyrrolidone, a cellulose derivative and/or copolymers thereof.

6. The transmucosal delivery system for idebenone according to claim 1, characterised in that the at least one hydrophobic substance in the inner, hydrophobic, phase has a logP value of greater than about 1.

7. The transmucosal delivery system for idebenone according to claim 1, characterised in that the at least one emulsifier has an HLB value of 3 to 15.

8. The transmucosal delivery system for idebenone according to claim 1, characterised in that the inner phase makes up 30 to 60 wt. %, relative to the total weight of the transmucosal delivery system for idebenone.

9. The transmucosal delivery system for idebenone according to claim 1, characterised in that the emulsifier makes up 2 to 7 wt. %, relative to the total weight of the transmucosal delivery system for idebenone.

10. The transmucosal delivery system for idebenone according to claim 3, characterised in that idebenone is substantially in the inner, hydrophobic, phase.

11. The transmucosal delivery system for idebenone according to claim 4, characterised by a idebenone concentration which corresponds to 90% of the saturation concentration of idebenone in the at least one hydrophobic substance.

12. The transmucosal delivery system for idebenone according to claim 1, wherein the at least one hydrophobic substance comprises at least one of methyl salicylate and eucalyptol.

Description

EXAMPLE 1

(1) TABLE-US-00001 Inner, hydrophobic, phase PVA 4-88 Emulsifier HLB value of MS [%] DMI [%] TBC [%] EUC [%] Sample [%] [%] the emulsifier LogP = 2.24 LogP = −0.6 LogP = 4.7 LogP = 2.8 Other [%] Evaluation 38 39.90 — — 25.00 25.00 — 0.10 vitamin E No emulsion 45 38.80 4.74 PS80 15.0 47.46 — — — 0.11 vitamin E Good 46 39.77 —  5.05 25.08 — — 0.11 vitamin E Physical change 47 38.32 4.19 PS80 15.0 23.86 — — 23.93 0.14 vitamin E Good 48 37.92 5.31 PS80 15.0 23.86 — 23.58 — 0.12 vitamin E Good 49 39.95 — — 49.93 — — 0.13 vitamin E Non-homogeneous 50 39.59 — — 24.73 — 24.65 0.12 vitamin E Physical change 51 39.89 — — 27.97 25.02 — 0.11 vitamin E Physical change 52 39.55 1.97 PS80 15.0 — — — 48.56 0.15 vitamin E Slightly non- homogeneous 53 39.42 5.45 PS80 15.0 — — 22.92 22.94 0.10 vitamin E Good 54 37.34 6.79 PS80 15.0 — — 46.43 — 0.11 vitamin E Non-homogeneous 55 37.50 5.00 PS80 15.0 47.40 — — — 0.10 vitamin E Good 56 36.40 8.00 PS80 15.0 — — 45.50 — 0.10 vitamin E Physical change 57 39.50 1.00 PS80 15.0 — 49.40 — — 0.10 vitamin E Non-homogeneous 58 36.90 5.00 PS80 15.0 24.00 — — 24.00 0.10 vitamin E Good 59 35.90 6.00 PS80 15.0 24.00 — 24.00 — 0.10 vitamin E Good 60 39.60 6.00 PS80 15.0 14.00 — 19.00 14.00 0.10 vitamin E Good 61 35.90 6.00 PS80 15.0 14.00  5.00 15.00 14.00 0.10 vitamin E Good 64 32.10 6.00 Atmos 2.5 13.00 — 10.00 13.00 0.10 vitamin E Non-homogeneous 300 15.0 0.10 vit. E. TPGS 6.00 PS80 4.50 sucralose 0.20 patent blue 75 36.90 6.00 PS80 15.0 10.00 — 19.00 18.00 0.10 vitamin E Good 76 36.90 6.00 Brij S2 4.90 10.00 — 19.00 18.00 0.10 vitamin E Good 77 36.90 4.00 PS80 15.0 10.00 — 19.00 18.00 0.10 vitamin E Good 2.00 Brij S2 4.9 78 37.40 3.50 PS80 15.0  9.00 — 17.00 16.00 0.10 vitamin E Good 1.50 Brij S2 4.90 1.00 lemon lime 1.00 peppermint 1.50 sucralose 79 37.00 3.50 PS80 15.0  9.00 — 15.00 14.40 0.10 vitamin E Good 1.50 Brij S2 4.90 5.00 spearmint 3.00 mask flavour 1.50 sucralose
PVA 4-88: polyvinyl alcohol (outer, hydrophilic, phase)
PS80: Polysorbate 80
MS: methyl salicylate
TBC: tributyl citrate
EUC: eucalyptol
DMI: dimethyl isosorbide
Atmos 300: mono- and diglycerides

(2) The examples according to the invention 45, 47, 48, 53, 58 to 61 and 75 to 78 all form a physically and chemically stable emulsion. Comparison example 38, which does not contain any emulsifier or any hydrophobic substance, does not form an emulsion. Comparison examples 49 to 51, which do not contain any emulsifier, are either non-homogeneous or exhibit physical changes. Comparison example 52 exhibits slight inhomogeneity, since it does not contain enough emulsifier. Comparison examples 54, 56 and 57 are non-homogeneous, since they do not contain any hydrophobic substance. Comparison example 64 contains the emulsifier ATMOS 300 which is not according to the invention, the use of which leads to a non-homogeneous emulsion.

EXAMPLE 2

(3) The saturation concentration of idebenone for an exemplified composition according to the invention was determined as follows.

(4) Idebenone is added in excess to the inner, hydrophobic, phase, so that even after relatively long stirring solid dregs of active ingredient are still present. Then the dregs are removed by centrifuging. The resulting supernatant contains idebenone in its saturation concentration. This is determined by analysis for example by means of HPLC.

(5) TABLE-US-00002 Amount [wt. %] Ingredient 0.17 vitamin E 6.74 Polysorbate 80 19.29 methyl salicylate 34.46 eucalyptol 36.44 tributyl citrate 2.89 Brij S2

(6) In the above composition, idebenone has a saturation concentration of 145 g/l at room temperature and of 103 g/l at 4° C.