FORMULATIONS BASED ON ASTRAGALOSIDE IV OR EXTRACTS CONTAINING IT FOR THE PREVENTION AND TREATMENT OF INSOMNIA AND JET-LAG-RELATED DISORDERS

The present invention relates to formulations based on astragaloside IV or extracts containing it for the prevention and treatment of insomnia and jet-lag-related disorders.

Prior art

Jet lag is a syndrome involving numerous variables (biological, environmental and climatic). It is mainly caused by a lack of synchronisation between the circadian rhythms to which the body is used, and the new cycles of light and darkness typical of the destination.

Disorganisation of the internal biological clock (which also regulates the sleep-waking cycle) as a result of new light/dark periods gives rise to a series of disorders collectively called "jet-lag syndrome". Said disorders include daytime asthenia (tiredness and fatigue during the day), loss of appetite, general malaise, nausea, headache, aching muscles, sleep disorders associated with a melatonin secretion imbalance, excessive drowsiness, insomnia, and difficulty falling asleep; reduced physical and mental performance, difficulty in concentrating or performing normal activities, low or altered mood, irritability, agitation, alterations in gastrointestinal functionality, digestive problems, stomach disorders, constipation or diarrhoea.

Astragalus membranaceus is an oriental plant which is highly prized in both traditional and allopathic medicine. The root of this species, which is rich in high- molecular-weight polysaccharides, possesses tonic, adaptogenic and immuno- modulating properties.

In addition to the activities described above, astragalus extract has also been proposed for preventing or combating insomnia and/or sleep quality disorders. Description of the invention

It has now been discovered that astragaloside IV boosts the sedative effect of melatonin to a surprising extent. The synergic effect is particularly evident when the weight ratio between astragaloside and melatonin is between 20: 1 and 5:1.

The present invention therefore relates to compositions containing melatonin and astragaloside IV or Astragalus membranaceus extracts containing it, typically aqueous or water-alcohol extracts.

A 20: 1 weight ratio between astragaloside IV and melatonin is preferred.

The unit doses of melatonin range from 0.5 to 5 mg, preferably from 0.5 to 3 mg, and more preferably from 0.5 to 1 mg.

The doses of astragaloside IV (or the equivalent in extracts containing it) range from 2.5 mg to 100 mg, preferably from 5 to 75 mg, and more preferably from 5 to 20 mg.

According to a preferred aspect of the invention, astragaloside IV can be in free form or phospholipid-complexed, in particular with soya distearoyl- phosphatidylcholine or phosphatidylserine, in terclathrate form or co-ground with beta-cyclodextrins. Similarly, the extract containing astragaloside, preferably a dried extract, may be in free form, phospholipid-complexed, in terclathrate form or co- ground with beta-cyclodextrins. Suitable carriers include oils, lipids and/or amino acids.

The formulations according to the invention can also contain other ingredients able to exercise a psychotropic, sedative, tranquil Using and anti-anxiety action such as St. John's Wort, kawakawa, passion fruit, chamomile, valerian, lemon balm and linden derivatives or extracts, and ingredients with an antioxidant action (which therefore stabilise the formula) can be added, such as polyphenols, vitamins ^" A, C and E, ubidecarenone, glutathione, selenium, lipoic acid and derivatives thereof.

The compositions according to the invention can be formulated in a way suitable for oral administration, and will be prepared by conventional methods well known in pharmaceutical technology, such as those described in "Remington's Pharmaceutical Handbook", Mack Publishing Co., N.Y., USA, using excipients, diluents, fillers, anti-caking agents, flavourings and sweeteners acceptable for their final use.

In particular, the compositions according to the invention can be formulated as conventional, film-coated, multilayer, differentiated-release or gastroprotected tablets, soft or hard gelatin capsules, granulates, sachets, suspensible or effervescent powder, medicated gummy lozenges, effervescent tablets or orodispersible powder.

Pharmacological tests

The effect of the association according to the invention has been demonstrated in a sedation model developed in the Sprague-Dawley rat (Simonsen Laboratories Inc., Gilford, CA), wherein the kinetic activity of the animals was monitored for 24 hours with a photoelectric cell that counts the movements of the animals in the cage.

It was observed that the sedative action of melatonin only appears if an astragalus extract containing astragaloside IV combined with melatonin is administered to the animal. In fact, neither the administration of astragalus extract only, with or without astragaloside, nor the administration of astragalus extract with astragaloside but without melatonin, produces a sedative effect compared with the control group. Conversely, the administration of astragalus extracts with astragaloside or of pure astragaloside combined with melatonin produces a highly significant sedative effect. This phenomenon appears at melatonin doses described as totally ineffective in terms of sedation in the rat. To obtain the same sedation with melatonin only, a dose of melatonin 20 times higher would have to be administered to the animal (see table 1).

Table 1. Effect of various pharmacological treatments, measured cumulatively by photocell in the 24 hours after treatment, on the spontaneous locomotor activity of SD rats (N=8/cage).

Treatment no. of counts/ P

24 hours

Control 8037

Astragalus extract 0% astragaloside IV (os) 100 mg/rat 8122

Astragalus extract 20% astragaloside IV (os) 100 mg/rat 8097

Astragaloside IV (os) 20 mg/rat 7986

Melatonin 2.0 mg/kg (os) 8210

Melatonin 40 mg/kg (os) 4354 <0.01

Astragalus extract 0% astragaloside IV (os) 100 mg/rat +

Melatonin 2.0 mg/kg (os) 8189

Astragalus extract 20% astragaloside IV (os) 100 mg/rat +

Melatonin 2.0 mg/kg (os) 4523 O.01

Astragaloside IV (os) 20 mg/rat +

Melatonin 2.0 mg/kg (os) 4366 O.01

Some examples of formulations are set out below.

EXAMPLE 1 : FILM-COATED TABLETS

Melatonin: 1 mg/dose

Astragalus extract (10% astragaloside IV): 200 mg/dose

EXAMPLE 2: THREE-LAYER TABLETS

1st fast-release layer

Astragalus extract (titrated to 20%): 100 mg/dose

Melatonin: 1 mg/dose

2nd normal-release layer

Astragalus extract (titrated to 20%): 100 mg/dose

Melatonin: 1 mg/dose

3rd slow-release layer Salvia miltiorrhiza extract: 25 mg/dose

Melatonin: 1 mg/dose EXAMPLE 3: GASTROPROTECTED TABLETS

Astragaloside IV: 20 mg/dose

Melatonin: 1 mg/dose EXAMPLE 4: OROSOLUBLE SACHETS

Astragaloside IV: 20 mg/dose

Melatonin: 1 mg/dose EXAMPLE 5: SOFT GELATIN CAPSULES

Astragaloside IV: 10 mg/dose Melatonin: 0.5 mg/dose