COMBINATION OF A LONG-ACTING HYPNOTIC AGENT AND A SHORT-ACTING HYPNOTIC AGENT AND THERAPEUTIC USE THEREOF
The invention relates to the combination of: a short-acting hypnotic agent which is selected from among a modulators of receptors GABA-A, a benzodiazepine, a phenothiazine, a melatonin derivative and a melatonin receptor agonist; and a long-acting hypnotic agent which is selected from among a modulator of receptors GABA-A, a benzodiazepine, an antagonist of receptors 5HT2A and a calcium ion modulator, for the treatment of sleep disorders. The invention also relates to galenic formulations containing said combinations.
1 . A combination of at least one short-acting hypnotic agent chosen from zolpidem, zopiclone, eszopiclone, zaleplon, melatonin, ramelteon, triazolam, etizolam, brotizolam and indiplon, or a salt, hydrate or solvate thereof, or a mixture in any combination thereof with eplivanserin or an addition salt, hydrate or solvate thereof.
2 . The combination as claimed in claim 1 , wherein the short-acting hypnotic agent is present in a galenical formulation suitable for immediate or sustained release, and eplivanserin or an addition salt, hydrate or solvate thereof is present in a galenical formulation suitable for immediate release.
3 . A pharmaceutical composition comprising, as active principle, zolpidem or a pharmaceutically acceptable salt thereof, and eplivanserin or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable excipient.
4 . The composition as claimed in claim 3 , wherein the short-acting hypnotic agent and eplivanserin or an addition salt, hydrate or solvate thereof are released immediately.
5 . The composition as claimed in claim 3 , wherein the short-acting hypnotic agent is released in a sustained manner and in that eplivanserin or an addition salt, hydrate or solvate thereof is released immediately.
6 . The composition as claimed in claim 3 , wherein it consists of a gel capsule comprising one or more immediate-release tablets containing the short-acting hypnotic agent and one or more immediate-release tablets containing eplivanserin or an addition salt, hydrate or solvate thereof.
7 . The composition as claimed in claim 3 , wherein it consists of a gel capsule containing one or more sustained-release tablets containing the short-acting hypnotic agent and one or more immediate-release tablets containing eplivanserin or an addition salt, hydrate or solvate thereof.
8 . The composition as claimed in claim 3 , wherein it consists of a gel capsule containing a mixture of immediate-release pellets of the short-acting hypnotic agent and of immediate-release pellets of eplivanserin or an addition salt, hydrate or solvate thereof.
9 . The composition as claimed in claim 3 , wherein it consists of a gel capsule comprising a mixture of sustained-release pellets of the short-acting hypnotic agent and of immediate-release pellets of eplivanserin or an addition salt, hydrate or solvate thereof.
10 . The composition as claimed in claim 3 , wherein it consists of a tablet containing immediate-release pellets of the short-acting hypnotic agent and of eplivanserin or an addition salt, hydrate or solvate thereof.
11 . The composition as claimed in claim 3 , wherein it consists of a tablet containing sustained-release pellets of the short-acting hypnotic agent and immediate-release pellets of eplivanserin or an addition salt, hydrate or solvate thereof.
12 . The composition as claimed in claim 3 , wherein it consists of a sustained-release enteric-coated tablet comprising immediate-release pellets of eplivanserin or an addition salt, hydrate or solvate thereof and immediate-release pellets of the short-acting hypnotic agent.
13 . The composition as claimed in claim 3 , wherein it consists of a multilayer tablet comprising:
(a) one or more immediate-release layers, each containing a dose of eplivanserin or an addition salt, hydrate or solvate thereof and optionally a dose of short-acting hypnotic agent,
(b) one or more sustained-release layers, each containing a dose of short-acting hypnotic agent, and optionally
(c) an inactive layer not containing any hypnotic agent.
14 . The composition as claimed in claim 3 , wherein it consists of a dry-coated tablet, which comprises an inner sustained-release core containing the short-acting hypnotic agent and in that the immediate-release coating layer contains eplivanserin or an addition salt, hydrate or solvate thereof.
15 . A method of treating a sleep disorder in a patient comprising administering to said patient a therapeutically effective amount of a combination consisting of at least one short-acting hypnotic agent chosen from zolpidem, zopiclone, eszopiclone, zaleplon, melatonin, ramelteon, triazolam, etizolam, brotizolam and indiplon, or a pharmaceutically acceptable salt, or a hydrate or a solvate thereof, and eplivanserin or a pharmaceutically acceptable salt, a hydrate or a solvate thereof.
16 . The method according to claim 15 , wherein the sleep disorder is dyssomnia, hypersomnia, parasomnia, sleep apnea, insomnia, primary insomnia, sleep maintenance insomnia, insomnia associated with a mental disease, and insomnia induced by caffeine, alcohol, amphetamines, opioids or anxiolytics.
17 . The method according to claim 16 , wherein the sleep disorder is sleep maintenance insomnia.
18 . The method according to claim 16 , wherein the short acting hypnotic is zolpidem or a salt thereof.