ITMI20070339A1 - COMPOSITIONS FOR THE PREVENTION AND TREATMENT OF SLEEP DISORDERS ASSOCIATED WITH VARIATIONS OF THE TONE OF THE MOOD - Google Patents

Description

Description of the patent for industrial invention entitled:

"COMPOSITIONS FOR THE PREVENTION AND TREATMENT OF SLEEP DISORDERS ASSOCIATED WITH VARIATIONS IN MOOD TONE"

Summary of the invention

The present invention relates to compositions containing hypericum extract, melatonin and at least one other component with adaptogenic activity for the prevention and treatment of sleep disorders associated with mood changes, in controlled release micronized oral solid form.

Premise

Mood disorders, and the much more serious depression, are undoubtedly among the most widespread problems of today's society. The treatment of these ailments through the use of herbal remedies and / or plant derivatives dates back to several centuries ago. In the past, opium, belladonna, hashish, hyoscyamine and scopolamine were used for various reasons.

Conventional drug therapy instead began with the use of bromine (1826), codeine (1832), paraldehyde (1882) and barbiturates (early 1900s). This therapy was improved in 1957 with the introduction of the first tricyclic anti-depressants and the first MAO-inhibitors (imipramine and iproniazid). Currently there are no less than 40 different chemical compounds with anti-depressant and / or mood modulating action on the market. The common denominator of these products is unfortunately the low tolerability and a series of side effects which, at the level of the autonomic nervous system and the cardiovascular system, expose the user to particular ailments.

Today, however, it is possible to use a herbal derivative, the dry extract of Hypericum perforatum, effective in its anti-depressant action and totally free of side effects, used with great success in the treatment of mood disorders for several years now.

Hypericum perforatum, a plant known as St. John's wort, is one of the best known European medicinal plants and has been used in the treatment of psychiatric disorders for several centuries. However, it has only been for about 15 years that the scientific community around the world has realized the validity of this remedy in the treatment of mild depression and mood disorders.

To date, hypericum extract (in particular that standardized to 0.3% in hypericin but also containing the real active hyperforin) has been tested in 25 clinical studies (more than 2500 subjects) where it has shown comparable efficacy, and in some cases higher than that of the reference drugs and a total absence of side effects.

The extract was found to be active in depression (mild to moderate) and mood disorders and capable of inhibiting the clinical score of the various parameters associated with depression by 30% already after 4-6 weeks of treatment.

Insomnia (if we want to understand with this term sleep disorders of various types and etiologies united by the difficulty of falling asleep and / or early awakening) and, more generally, disorders related to the quality of sleep, is a rather common problem that it affects about 20% of the adult population.

The disorder becomes much more frequent if we consider the more advanced age groups: after the age of 60, in fact, the problem affects 50% of women and 30% of men with an easily understood socio-health impact.

As is well known, it is possible to tackle the problem of insomnia and / or poor sleep quality by resorting to classic anxiolytic and / or hypnotic drugs which, however, can cause the onset of unpleasant side effects (difficulty concentrating, driving problems , dry mouth, etc.).

Melatonin, (N-2-5-methoxy-1-H-indole-3-yl-ethylacetamide), is the main hormone of the epiphysis. Produced in all vertebrates and by some amphibians, it is also present in milk and (albeit in very low concentrations) in vegetables.

Melatonin is a substance involved in the regulation of the body's circadian rhythms and ultracircadian rhythms, such as those that regulate seasonal responses to variations in the duration of daily light in mammals (the so-called photoperiod responses).

Melatonin is synthesized in the epiphysis. Its precursor is the essential amino acid L-tryptophan, which is initially metabolized to 5-hydroxytryptophan, from which 5-hydroxytryptamine (serotonin) is then derived. This is then converted in two stages inside the epiphysis into real melatonin. The crucial step is the acetylation of hydroxytryptamine by a transferase known as AA-NAT.

Epiphyseal melatonin production shows an evident circadian rhythm which affects blood concentrations. The maximum secretion peak is the nocturnal peak.

The hypnotic and sleep-regulating or sleep-inducing effects are mediated by specific receptors, of which two forms have been identified: high-affinity receptors (ML1) and low-affinity receptors (ML2). The high affinity receptors are located in the pars tuberalis of the pituitary. Less clear is the distribution of low-affinity receptors. In any case, every biological action is mediated through a coupling with the G protein.

According to classical pharmacology, melatonin has a hypnotic, antioxidant and anti-apoptotic action. The hypnotic effect is mediated by the action of the hormone on the limbic system and the pars tuberalis. The antioxidant action, verified only at high dosages, is highlighted through the inhibition of the Fenton reactions catalyzed by metal ions.

The anti-apoptotic action was shown only in in vitro and vivo experimental models with apoptosis mediated by dexamethasone.

From a pharmacokinetic point of view, melatonin is absorbed in the small intestine. From there, it is metabolized in the liver to 6-hydroxymelatonin. After glucuronidation or sulfation, the metabolite is excreted in the urine. All the non-metabolized instead interacts with the various receptors placed in the tissues. The half-life of melatonin administered varies between 35 and 50 minutes.

The main clinical use of melatonin is aimed at the treatment of some forms of non-severe insomnia or the treatment and prevention of some common sleep disorders. Another very common application supported by the judgments of the various European and American ministries of health is in the symptomatic treatment of jet lag syndrome, that is, the malaise linked to the change of time zone.

NSAIDs and beta-blockers have been reported to decrease piasmatic concentrations of melatonin. On the contrary, some anti-depressants increase their oral bioavailability. Benzodiazepines and some antihistamines seem to increase the action of melatonin, as well as the co-administration of kava-kava or valerian.

From a toxicological point of view, melatonin did not induce signs of toxicity up to prolonged administration of 30 g / day. Despite this, the recommended dose varies according to the scientific literature between 0.3 and 3.0 mg / day. The intake is preferable in the evening before going to bed.

Since the endogenous production of melatonin is related to the quantity of L-tryptophan available in the diet, the administration of this amino acid supports the endogenous epiphyseal share, preventing its potential fall linked to the exogenous administration of melatonin.

Description of the invention

It has now been surprisingly found that the association of hypericum and melatonin extracts with other adaptogenic components is extremely effective in dealing with the problem of mood loss when this is associated with a poor quality of sleep understood as difficulty falling asleep with subsequent continuous nocturnal awakenings. .

Therefore, the present invention relates to compositions containing:

a) Hypericum perforatum,

b) Melatonin,

c) at least one adaptogen component of plant or synthetic origin, for the prevention and treatment of sleep disorders associated with changes in mood.

From the data that emerged from the pharmacological experimentation, the critical character of the presence of the three components mentioned above emerges for the purpose of optimal effectiveness of the final formulation. Furthermore, it has also been observed that the effect obtained with the compositions of the present invention is superior to that obtained from the sum of the effects obtained following the separate administration of the individual components of the association itself: apparently this superior effect is due to a synergy between the various components.

Examples of adaptogenic components, i.e. components known for their activity of increasing the body's resistance to stressful conditions, include extracts of Avena sativa, Chamomile, Hawthorn, Rhodiola rosea, Passiflora, Eleuterocco, Valeriana, Melissa, Calendula, Griffonia, tryptophan, serotonin. Avena sativa extract is particularly preferred.

The compositions in accordance with the invention may possibly contain a mixture of said adaptogenic components, for example a phytotherapeutic extract (Avena sativa extract, Chamomile, Lemon balm, etc.) associated with synthetic or natural sources of tryptophan, serotonin.

The phytotherapeutic extracts of Hypericum and adaptogenic plants are widely known and commercially available or else they can be prepared with methods known to those skilled in the art starting from the appropriate plant material.

According to a preferred aspect of the invention, the compositions will contain:

a) Hypericum perforatum extract in quantities ranging from 0.1 mg to 3600 mg;

b) melatonin in quantities ranging from 0.1 mg to 30 mg; And

c) Avena sativa extract in quantities ranging from 1 mg to 2000 mg. According to a preferred aspect of the invention, the compositions will contain hypericum extract standardized at 0.3% in hypericin. The hypericum extract used may also contain a second standardization parameter: hyperforin (between 0.5 and 15%).

According to a further preferred aspect of the invention, the compositions will also contain L-tryptophan (or the Griffonia simplicifolia extract that contains it).

According to another preferred aspect of the invention, the compositions will be in micronized oral solid form with controlled release of the active components. These compositions, thanks to the micronization process to which the mixture of active ingredients is subjected before the final compression step, provide an increase in the "wettability" characteristic of the active ingredients and consequently their relative oral bioavailability which is increased by approximately 35%.

Furthermore, the compositions of the invention provide an optimal therapeutic effect, allowing the active ingredients to be distributed kinetically throughout the time span affected by the disorder. In the case of the treatment of "sleep disturbances", the optimum is reached when permanent activity is ensured during the hours of rest. Since these are generally eight (8), a “retard” form has been developed capable of distributing the active principles and their piasmatic absorption in the 8 hours following administration.

In accordance with the invention, this "retard" form releases a first 30% of assets during the first hour, then a further 10% during the following hour, another 20% within the fourth hour, another 20% within the sixth and a last remaining share within the octave.

The therapeutic advantage obtained with the retard formulation of the invention is to maintain a high quality of sleep even in the last 3-4 hours of rest, a phase very often disturbed by early awakenings. Obviously, this effectiveness does not affect the times of falling asleep, as the tablet is technologically structured in such a way as to release, through the quick-release layer, and to absorb 50% of the product at a piasmatic level within the first half hour of administration.

The compositions of the invention allow the mixture of the 3 active ingredients to be released in a time-dependent manner. 50% of these is in fact released very quickly and thus determines the rapid action of the product on the body. The remaining 50% is instead released in a delayed but time-controlled manner over the next 8 hours. This allows the product to continue to be effective throughout 1 night (as regards the quality of sleep) and for the early hours of the next morning as regards the mood profile.

The compositions of the present invention can be suitably formulated according to conventional methods well known in the pharmaceutical technique, such as those described in "Remington's Pharmaceutical Handbook", Mack Publishing Co., N.Y., USA, using excipients, diluents, bulking agents, anti-caking agents acceptable for the their final use.

Some examples of formulations of the invention are reported below.

Formative examples

1) Type 1 capsules

Hypericum extract 7 mg Melatonin 3 mg Avena sativa extract 30 mg Microcei 41 mg Vegetable magnesium stearate 7 mg Aerosil 10 mg 2) Film-coated tablets of 750 mg

Hypericum extract 7 mg Melatonin 3 mg Avena sativa extract 30 mg Microcei 340 mg Dicaphos 333 mg Vegetable magnesium stearate 10 mg Aerosil 8 mg Explocel 18 mg Sepifilm 22.8 mg Shellac 7 mg Dye 0.2 mg 3) Double-layer tablets a Scheduled Release of 750 mg STRATO FAST RELEASE

Hypericum extract 3.5 mg Melatonin 1.5 mg Avena sativa extract 15 mg Dicaphos 304 mg Explocel 15 mg Aerosil 3 mg Vegetable magnesium stearate 6 mg Dye 1 mg STRATO SLOW RELEASE

Hypericum extract 3.5 mg Melatonin 1.5 mg Avena sativa extract 15 mg Metholose 80 mg Aerosil 2 mg Vegetable magnesium stearate 3 mg Microcei 80 mg Dicaphos 164 mg 4) Sachets 2500 mg

Hypericum extract 7 mg Melatonin 3 mg Avena sativa extract 30 mg Fructose 1976 mg Aerosil 15 mg Orange aroma 180 mg Mandarin aroma 40 mg Citric acid 220 mg Acesulfame k 25 mg E102 2 mg 5) Gold-Dispersible formulation 1800 mg

Hypericum extract 7 mg Melatonin 3 mg Avena sativa extract 30 mg Sorbitol 160 mg Orange flavor 20 mg Tangerine flavor 5 mg Acesulfame k 2 mg Aerosil 5 mg Fructose 1566 mg 6) Discoid Gummy 1235 mg

Hypericum extract 7 mg Melatonin 3 mg Avena sativa extract 30 mg Base gum 800 mg Aspartame 2 mg Menthol 2 mg Acesulfame 1 mg Levilite 20 mg Talc F.U. 20 mg Vegetable magnesium stearate 18 mg Shellac 12 mg Xylitol 250 mg Gum arabic 6 mg Titanium dioxide 6 mg Carnauba wax 0.2 mg

Claims (8)

CLAIMS 1. Compositions comprising hypericum extract, melatonin and at least one other component with adaptogenic activity. 2. Compositions according to claim 1 in which the other component with adaptogenic activity is selected from extracts of Avena sativa, Chamomile, Hawthorn, Rhodiola rosea, Passiflora, Eleuterocco, Valerian, Lemon balm, Calendula, Griffonia, tryptophan, serotonin. 3. Compositions according to claim 1 or 2 wherein the component with adaptogenic activity is extract of Avena sativa. 4. Compositions according to claim 3, containing: a) Hypericum perforatum extract in quantities ranging from 0.1 to 3600 mg; b) melatonin in quantities ranging from 0.1 to 30 mg; And c) Avena sativa extract in quantities ranging from 1 to 2000 mg. 5. Compositions according to any one of claims 1 to 4, containing 0.3% standardized hypericum extract in hypericin. 6. Compositions according to any of claims 1 to 5, also containing L-tryptophan (or the Griffonia extract that contains it). 7. Compositions according to the preceding claims, in controlled release micronized oral solid form. 8. Use of: a) Hypericum perforatum, b) Melatonin, e c) Avena sativa extract or other adaptogenic components for the preparation of compositions for the prevention and treatment of sleep disorders associated with changes in mood.