COMPOSITION COMPRISING EXTRACTS OF EUCOMMIA ULMOIDES, CROCUS SATIVUS AND/OR MAGNOLIA OFFICINALIS AND THE USE THEREOF IN THE TREATMENT OF SLEEP DISORDERS

20220218779

17/610422

June 05, 2020

The present invention relates to a composition comprising a mixture comprising or, alternatively, consisting of (a) an extract of Eucommia ulmoides and at least one among (b.1) saffron comprising safranal and (b.2) an extract of Magnolia officinalis and/or Magnolia champaca comprising honokiol, or the mixture thereof, as active components. Furthermore, the present invention relates to an innovative formulation of said composition for the modulated release of said active components. Lastly, the present invention relates to said composition for use in a method for the treatment of sleep cycle dysfunction, in particular both of disorders in the NON-REM stage of sleep and of disorders in the REM stage of deep sleep.

1. A composition comprising (I) a mixture comprising, or alternatively, consisting of: (a) an extract of Eucommia ulmoides, (b.1) a saffron comprising safranal, and (b.2) an extract of Magnolia officinalis and/or Magnolia champaca comprising honokiol; and, optionally, said composition comprises (II) at least one food grade or pharmaceutical additive and/or excipient.

2. The composition according to claim 1, wherein said (b.1) saffron comprises safranal at a % by weight comprised in a range from 0.01% to 1.5% with respect to the total weight of (b.1), preferably comprised from 0.05% to 1%, more preferably comprised from 0.1% and 0.5%; preferably said saffron is a dry extract of Crocus sativus stigmas.

3. The composition according to claim 1, wherein said (b.2) extract of Magnolia officinalis and/or Magnolia champaca comprises honokiol at a % by weight comprised in a range from 0.1% to 10% with respect to the total weight of (b.2), preferably comprised from 1% to 5%, more preferably comprised from 1.5% to 2.5% preferably said (b.2) is a dry extract of Magnolia officinalis and/or Magnolia champaca bark, leaves and/or flowers, preferably dry extract of bark.

4. The composition according to claim 1, wherein said (I) mixture further comprises (c) magnesium, preferably magnesium oxide.

5. The composition according to claim 1, wherein said (I) mixture comprises or, alternatively, consists of: (a) extract of Eucommia ulmoides, preferably dry extract of bark; (b.1) saffron comprising safranal at % by weight comprised from 0.1% to 0.5% with respect to the total weight of (b.1), preferably saffron such as dry extract of Crocus sativus stigmas; (b.2) extract of Magnolia officinalis and/or Magnolia champaca comprising honokiol at % by weight comprised from 1.5% and 2.5% with respect to the total weight of (b.2), preferably dry extract of bark; and, optionally, (c) magnesium, preferably magnesium oxide.

6. The composition according to claim 1, wherein the composition is in solid form for oral administration and it comprises: (i) a first delayed release formulation comprising said (a) extract of Eucommia ulmoides, wherein said extract (a) is released into the intestinal tract of a subject in a range comprised from 1.5 hours to 8 hours after administration of the composition to said subject, preferably comprised from 2 hours to 7 hours, more preferably comprised from 2.5 hours to 6 hours; (ii.i) a second immediate release formulation comprising: sa id (b.1) saffron, comprising safranal at % by weight comprised from 0.01% to 1.5% with respect to the total weight of (b.1), preferably comprised from 0.05% to 1%, more preferably comprised from 0.1% to 0.5%; wherein said (b.1) is released into the gastric mucosa in a range comprised from 5 minutes to 45 minutes or from 5 minutes to 20 minutes after the administration of the composition to said subject, preferably from 5 minutes to 15 minutes, more preferably from 5 minutes to 10 minutes; (ii.ii) a third intermediate release formulation comprising said (b.2) extract of Magnolia officinalis and/or Magnolia champaca, comprising honokiol at a % by weight comprised from 0.1% to 10% with respect to the total weight of (b.2), preferably comprised from 1% to 5%, more preferably comprised from 1.5% to 2.5%; wherein said extract (b.2) is released in the first intestinal tract within a time comprised in a range from 20 minutes to 120 minutes or from 20 minutes to 90 minutes after the administration of the composition to said subject, preferably comprised from 20 minutes to 60 minutes, more preferably comprised from 20 minutes to 45 minutes.

7. The composition according to claim 6, wherein the composition in solid form for oral administration comprises: (i) said first delayed release formulation comprising said (a) extract of Eucommia ulmoides such as dry extract of Eucommia ulmoides bark; and (ii.i) said second immediate release formulation comprising said (b.1) saffron such as dry extract of Crocus sativus stigmas comprising safranal at % by weight comprised from 0.1% to 0.5% with respect to the total weight of (b.1); and (ii.ii) said third intermediate release formulation comprising said (b.2) dry extract of Magnolia officinalis bark comprising honokiol at a % by weight comprised from 1.5% to 2.5% with respect to the total weight of (b.2).

8. A composition according to claim 6, wherein said (ii.i) second immediate release formulation comprises said (b.1) saffron comprising safranal and (c) magnesium, preferably magnesium oxide, wherein said (b.1) saffron and (c) magnesium are released into the gastric mucosa in a range comprised from 5 minutes to 45 minutes or from 5 minutes to 20 minutes after the administration of the composition to said subject, preferably from 5 minutes to 15 minutes, more preferably from 5 minutes to 10 minutes.

9. A composition according to claim 6, wherein the composition is in multilayer solid form for oral administration comprising: a first layer comprising or, alternatively, consisting of said (ii.i) second immediate release formulation comprising said (b.1) saffron comprising safranal; a second layer, preferably at least partially underlying the first layer, comprising or, alternatively, consisting of said (i) first delayed release formulation comprising said (a) extract of Eucommia ulmoides; and a third layer, preferably at least partially underlying the second layer, comprising or, alternatively, consisting of said (ii.ii) third intermediate release formulation comprising said (b.2) extract of Magnolia officinalis comprising honokiol.

10. A composition according to claim 9, wherein said first layer comprises or, alternatively, consists of said (ii.i) second immediate release formulation comprising said (b.1) saffron comprising safranal and (c) magnesium, preferably magnesium oxide.

11. A method of treating a subject for at least one disease, symptom and/or disorder associated with sleep cycle dysfunction comprising administering a composition according to claim 1 to the subject.

12. The composition for use according to claim 11, wherein said composition is for use in a method for preventive and/or curative treatment of at least one disease, symptom and/or disorder associated with sleep cycle dysfunction in a subject in need.

13. The method of claim 11, wherein said at least one disease, symptom and/or disorder is selected from among insomnia, inability to fall asleep, difficulty in falling asleep, early awakening, interruption of deep sleep by one or more nocturnal awakenings, and excessive daytime sleepiness.

14. The method of claim 11, wherein said subject has at least one disorder of the NON-REM stage of sleep and at least one disorder of the REM stage of deep sleep.

15. The method of claim 11, wherein said (b.1) saffron comprises safranal at a % by weight comprised in a range from 0.01% to 1.5% with respect to the total weight of (b.1), preferably comprised from 0.05% to 1%, more preferably comprised from 0.1% and 0.5%; preferably said saffron is a dry extract of Crocus sativus stigmas.

16. The method of claim 11, wherein said (b.2) extract of Magnolia officinalis and/or Magnolia champaca comprises honokiol at a % by weight comprised in a range from 0.1% to 10% with respect to the total weight of (b.2), preferably comprised from 1% to 5%, more preferably comprised from 1.5% to 2.5% preferably said (b.2) is a dry extract of Magnolia officinalis and/or Magnolia champaca bark, leaves and/or flowers, preferably dry extract of bark.

17. The method of claim 11, wherein said (I) mixture further comprises (c) magnesium, preferably magnesium oxide.

18. The method of claim 11, wherein said (I) mixture comprises or, alternatively, consists of: (a) extract of Eucommia ulmoides, preferably dry extract of bark; (b.1) saffron comprising safranal at % by weight comprised from 0.1% to 0.5% with respect to the total weight of (b.1), preferably saffron such as dry extract of Crocus sativus stigmas; (b.2) extract of Magnolia officinalis and/or Magnolia champaca comprising honokiol at % by weight comprised from 1.5% and 2.5% with respect to the total weight of (b.2), preferably dry extract of bark; and, optionally, (c) magnesium, preferably magnesium oxide.

19. The method of claim 11, wherein the composition is in solid form for oral administration and it comprises: (i) a first delayed release formulation comprising said (a) extract of Eucommia ulmoides, wherein said extract (a) is released into the intestinal tract of a subject in a range comprised from 1.5 hours to 8 hours after administration of the composition to said subject, preferably comprised from 2 hours to 7 hours, more preferably comprised from 2.5 hours to 6 hours; (ii.i) a second immediate release formulation comprising: sa id (b.1) saffron, comprising safranal at % by weight comprised from 0.01% to 1.5% with respect to the total weight of (b.1), preferably comprised from 0.05% to 1%, more preferably comprised from 0.1% to 0.5%; wherein said (b.1) is released into the gastric mucosa in a range comprised from 5 minutes to 45 minutes or from 5 minutes to 20 minutes after the administration of the composition to said subject, preferably from 5 minutes to 15 minutes, more preferably from 5 minutes to 10 minutes; (ii.ii) a third intermediate release formulation comprising said (b.2) extract of Magnolia officinalis and/or Magnolia champaca, comprising honokiol at a % by weight comprised from 0.1% to 10% with respect to the total weight of (b.2), preferably comprised from 1% to 5%, more preferably comprised from 1.5% to 2.5%; wherein said extract (b.2) is released in the first intestinal tract within a time comprised in a range from 20 minutes to 120 minutes or from 20 minutes to 90 minutes after the administration of the composition to said subject, preferably comprised from 20 minutes to 60 minutes, more preferably comprised from 20 minutes to 45 minutes.

20. The method of claim 18, wherein the composition in solid form for oral administration comprises: (i) said first delayed release formulation comprising said (a) extract of Eucommia ulmoides such as dry extract of Eucommia ulmoides bark; and (ii.i) said second immediate release formulation comprising said (b.1) saffron such as dry extract of Crocus sativus stigmas comprising safranal at % by weight comprised from 0.1% to 0.5% with respect to the total weight of (b.1); and (ii.ii) said third intermediate release formulation comprising said (b.2) dry extract of Magnolia officinalis bark comprising honokiol at a % by weight comprised from 1.5% to 2.5% with respect to the total weight of (b.2).

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