FR2878163A1 - Compositions, useful to treat anxiety, comprise active ingredients of Eschscholtzia extract with Valerian extract, in association with a vehicle for oral administration of distinct dosages and for day or night administration - Google Patents

Abstract

Compositions (I) (containing plant extracts), comprising active ingredients of Eschscholtzia extract associated with Valerian extract, in association with a vehicle for oral administration of distinct dosages and for administration either in day or night, are new. ACTIVITY : Tranquilizer; Hypnotic. No biological data given. MECHANISM OF ACTION : None given.

Description

Novel pharmaceutical compositions for phytotherapeutic purposes.

  The present invention relates to the field of san-té, and more particularly to the field of galenic pharmacy.

  More specifically, it relates to novel phytotherapeutic pharmaceutical compositions combining at least two plants, or plant extracts, in an improved dosage form.

  It specifically relates to new pharmaceutical compositions combining extracts of Eschscholtzia (California poppy) and Valerian (Valeriana officinalis), alone or in combination with other plants, or extracts of plants, for the treatment of anxiety or sleep loss, in a form suitable for separate administration day or night.

  In the context of the present invention, the term "separate delivery day or night" means different presentations as to the types of presentation, shape, color and / or taste which make it possible to modulate, differentiate or separate the different presentations depending on whether they are intended for daytime administration (morning and / or midday) or nighttime administration (at dinner or at bedtime).

  The active ingredients used are previously desiccated plant powders, or more conveniently aqueous or hydroalcoholic, dry, fluid or liquid extracts, which contain all the active ingredients of these two plants in a relatively concentrated form.

  The pharmaceutical compositions according to the invention therefore ferment separate presentations: - one intended for diurnal administration, based on the two aforementioned plants, and used to improve nervous dysfunction, such as anxiety and - the others for promote sleep during the night, thanks to different formulations and dosages.

  Extracts of Eschscholtzia, and especially hydroalcoholic extracts, are generally used to improve the sleep-induced sleep, and traditionally used to improve the symptomatic treatment of neurotonic states of adults and children, especially in cases of minor sleep disorders . They have already been associated with extracts of corydalis (USP 5,308,619). Thus, they are used to improve agitation states and nervous dysfunctions.

  Extracts of Valerianum, and particularly hydroalcoholic, fluid or dry extracts, find use in neuropsychiatry (Krystal A.D. and Coli CNS Spech, 2001 (October) 6 (10) 841-847).

  Preclinical tests have shown that these extracts have a sedative action, muscle relaxant and promote sleep. Other publications have confirmed these results (Malva S.O. and Coll Neurotox Res (2004) 6 (2) 131-140).

  The combination of these two plants, in a suitable dosage form, provides a synergistic effect that is manifested in states of nervousness and anxiety in stressed patients.

  It is also possible to add to the compositions according to the invention a third plant extract, such as Crataegus' extract (Crataegus monogyna or Crataegus livigata or Crataegus modopina or Crataegus oxyacantha or Hawthorn), which has interesting pharmacological properties on the flow of the myocardium and a hypotensive action, making it possible to improve the subjects in state of anxiety during the day.

  It is also possible to add to the compositions of the invention a melissa extract (Melissa officinalis), especially in the compositions for nocturnal administration which is capable of potentiating the sedative action of the other extracts, and of attenuating or reducing to improve digestive disorders.

  Preferably, the plants will be used in the form of aqueous, hydroalcoholic extracts, such as hydroethanol or hydrobutanolic extracts, alcoholic extracts, obtained by lixiio viation, maceration or by extraction in a supercritical fluid.

  The resulting extract can be dehydrated or desolvated by molecular sieve dehydration, zeodration, neoconcentration, spraying or lyophilization. These pulverulent extracts comply with the standards laid down by the various pharmacopoeias.

  Plants or plant extracts are stored under inert gas, protected from light and heat, before use.

  The properties of Valerian have been widely described in the literature. The activity, a moment related to the esters of borneol, was soon attributed to the Valpotriates. Experimental work conducted with iridoids on different animal species objectively showed a decrease in locomotor activity in mice, a spasmolytic effect, a decrease in aggression in cats; part of the pharmacological activity has also been attributed to valerene acid which binds to GABA and benzodiazepine receptors and prolongs sleep time.

  Valerian can advantageously be associated with flowers or flower heads of Hawthorn or alcoholic extracts of Hawthorn. It can also be associated with passionflower.

  Eschscholtzia (California poppy) is used as a powder of the aerial parts (French Phar, 10th Ed.) It owes its activity to the presence of many alkaloids. In addition to the majority and characteristics of the genus (Eschscholtzine, Californidine, etc.), protopine and aporphines (N-methyl laurotetanine) are isolated. Benzophenanthridines (Sanguinarine, chelerythrine) are present only in trace amounts.

  These active ingredients make it possible to confer sleep-inducing properties by: - an anxiolytic effect, - a decrease in the duration of sleep onset and - an improvement in the quality of sleep.

  The pharmaceutical compositions according to the invention may also contain other plants, or extracts of plants, forcing their sedative or tranquilizing action, such as the olive tree, the fume-terre, the ballotte, the Asa foetida, the Chasteberry , or sage, etc.

  Hawthorn has been analyzed to better understand the nature of its active ingredients. The preparations contain from 1 to 20% of flavonoids and from 2 to 3% of proanthocyanidols. The major constituent of the leaves is hyperoside (3-galactosidoquercetol) accompanied by spiréoside and rutoside, as well as vitexin, orientine and their 2 "-rhamnosylated derivatives.

  Clinical trials, performed in double blind, tend to confirm the pharmacological results obtained in the animal: -Improvement of the subjective symptoms, such as impression of shortness of breath, palpitations, slight heart in-sufficient, - decrease of the rhythm, improvement coronary flow and physical ability to exercise.

  It is also possible to associate, in the pharmaceutical compositions according to the invention, extracts of Corydalis (Corydalis 30 Cava) (see Arzneimittelforschung (1995) 45 (2) 124-126)) or ex-traits of Gattilier de China (Vitex agnus castus or Vitex negundo).

  The principle of the invention lies in the fact that, in order to facilitate the administration of these compositions, there is a clear distinction between formulations intended for diurnal or nocturnal administration, both by the composition, the dosage and the presentation of the compositions. forms. Forms for daytime administration will be in the form of colorless, light-colored tablets or dragees or capsules, with little dosage, while the forms for evening administration will be presented in the form of tablets, dragees or tablets. capsules more externally colored and having a higher content of active ingredients.

  It may also be that the compositions for daytime administration contain Eschscholtzia extract, Valerian extract and Hawthorn extract, while the overnight presentation contains extract of Eschscholtzia, Valerian extract and melissa extract. Hawthorn, in these formulations, can be replaced, for the day compositions, by passionflower extract and, in the night formulations, by melilot extract, infused with linden or lime. infused with chamomile.

  The blends for the manufacture of the dosage forms are made in the presence of inert excipients to achieve the desired dry pharmaceutical formulations.

  The invention also relates to the pharmaceutical forms according to the invention.

  For the day formulation, the concentration of the two active ingredients, in the pharmaceutical form, for a 450 mg tablet type will be between 5 and 20%, while the third extract, if present, will be 5 to 20%. at 30%.

  The role of the concentration of active ingredients in the formulation is essential for a use called Day / Night.

  The formulations according to the invention will be in the traditional forms of the oral route, such as tablets, dragees, soft capsules, pills, syrups or solutions.

  The concentrations of active ingredients for the day formulations according to the invention of the three different extracts vary from 5 to 20%, whereas those for the night formulations corresponding to one tablet before bedtime vary from 5 to 30%. These concentrations are based on the composition of the finished product, and are expressed in plant extracts for 450 mg tablets.

  According to the manufacturing practices, the percentages of dry extract Eschscholtzia and Valerian, in the night-time pharmaceutical form, of the 450 mg coated tablets type, will be between 5 and 30%, and the third extract will be chosen. among the list quoted between 5 and 30%.

  The tablets day and night will be film-coated and colored.

  One color differentiates tablets or tablets for the day from the one for the night. The formulations for the day will be light in color (white or pale blue); the formulations for the night will be dark in color (midnight blue).

  The dosage is one to two tablets morning, noon and night. These will be arranged on the same blister, so as to use them in rows: two rows day + one row night).

  Colors can be, for example, light blue for day and night blue tablets for night tablets; or the day tablets may be colored with a certain color (for example: white) and the night tablets may be colored in another color (for example: yellow or orange).

  For the other forms, expressed in mg, the amounts of extracts will be 50 to 100 mg for the day formulations and 100 to 200 mg for the night formulations, and in particular of 50 to 100 mg of Eschsholtzia extract and of 80 to 200 mg for Valerian extract in day formulations.

  The following examples illustrate the invention without, however, limiting it.

  EXAMPLE I: Core Formulas Day / Night, for one tablet

KERNELS DAY mg

  Valerian Extract 75 14,42 Eschscholtzia Extract 50 9,61 Hawthorn Extract 50 9,61 Avicel 102 312 60 Starlac 20,80 4 Aerosil 200 1,80 0, 36 Vegetable Magnesium Stearate 10,40 2 tal For nuclei of 450 mg, the staining for film coating will deposit between 5 to 10% of a suspension of the following composition: Day formulation: SEPPIC coloring N 65 (light blue) Sepifilm LP 014 7.2% - Sepisperse dry 1514 blue 4.8% - water 88% io

NIGHT CORNERS

  mg 0/0 Valerian extract 150 28.85 Eschscholtzia extract 120 23.08 Melissa extract 150 28.85 Avicel 102 71.60 13.76 Starlac 15.60 3, 00 Aerosil 200 2.40 0.46 Stearate Magnesium magnesium 10.40 2.00 tal For nuclei of 450 mg, the staining for lamination will deposit between 5 and 10% of a suspension of the following composition: Night formulation: SEPPIC coloring N 67 (midnight blue ) Sepifilm LP 014 7.2% Sepisperse dry 1036 blue 4.8% Water 88%

KERNEL DAY mg%

  Valerian Extract 100 - Eschscholtzia Extract 75 - Hawthorn Extract 75 - Avicel 102 168 - Starlac 20 - EXAMPLE II: Core Formulas Day / Night, for a tablet 0/0 Aerosil 100 2 - Vegetable Magnesium Stearate 10 - For nuclei of 450 mg, the staining for the coating will deposit between 5 to 10% of a suspension of the following composition: Day Formulation: SEPPIC stain Na 65 (light blue) Sepifilm LP 014 7.2 Sepisperse dry 1514 Blue Water 4.8%

KERNEL NIGHT mg%

  Valerian Extract 135 - Extract of Eschscholtzia 125 - Melissa Extract 135 - Avicel 102 25 - Starlac 15 - Aerosil 100 3 - Vegetable Magnesium Stearate For nuclei of 450 mg, the coloring for film coating will deposit between 5 at 10% of a suspension of the following composition: Night Formulation: coloring SEPPIC N 67 (midnight blue) Sepifilm LP 014 7.2% - Sepisperse dry 1036 blue 4.8% - Water 88% -

EXAMPLE III

  Formula day for one capsule, size 1 5 (dosage of 1 capsule morning and noon)

DAY mg

  Eschscholtzia extract 75 Valerian extract 75 Hawthorn extract 50 Aerosil 200 2 Lactose 48 Night formula for two capsules, size 1 (dosage of 2 capsules night, evening)

NIGHT mg

  Extract of Eschscholtzia 80 Extract of Valerian 80 Extract of Melissa 80 Aerosil 200 2 Lactose 8

EXAMPLE IV

  Day formula for a soft capsule, (ref 10 oval) Light blue color

DAY mg

  Extract of Eschscholtzia 80 Extract of Valerian 75 Hawthorn extract 50 Vegetable oil qs 600 Night formula for a soft capsule (ref 10 oval) Color blue night

NIGHT mg

  Extract of Eschscholtzia 100 Extract of Valerian 140 Extract of Melissa 160 Vegetable oil qs 600 He

EXAMPLE V

Formula day for one capsule

DAY mg

  Extract of Eschscholtzia 80 Extract of Valerian 60 Extract of Passionflower 90 Lactose 60 Aerosil 200 4 Formula night for a capsule

NIGHT mg

  Extract of Eschscholtzia 90 Extract of Valerian 40 Extract of Melilot 100 Lactose 60 Talc 5

EXAMPLE VI

  Day formula for a white candy

DAY mg

  Extract of Eschscholtzia 60 Extract of Valerian 30 Extract of Fumitory bulbous 70 (corydalis cava) Night formula for a dragee to filming blue night

NIGHT mg

  Eschscholtzia extract 120 Passionflower extract 50 Ballot extract 80

Claims (18)

  1) Pharmaceutical compositions based on plant extracts characterized in that they have the active ingredients Eschscholtzia extract, combined with Valerian extract, in combination with a suitable vehicle for oral administration to dosages that are distinct and suitable for administration either during the day or at night.   2) Pharmaceutical compositions according to claim 1, characterized in that they contain, as active ingredients, Eschscholtzia extract, combined with Valerian extract, in admixture or in combination with a vehicle or a suitable diluent, for oral administration, and at doses adapted for nighttime diurnal administration.   3) Pharmaceutical compositions according to claim 1 and claim 2, wherein are added the active ingredients of at least one plant or plant extract selected from the group consisting of Melissa, Hawthorn, Passionflower, Olivier, Melilot, Black Ballot, Chaste Tree, Sage and Asa foetida.   4) Pharmaceutical compositions according to claim 1, characterized in that the compositions for diurnal administration contain, as active ingredients, Eschscholtzia extract and Valerian extract.   5) Pharmaceutical compositions according to claim 4, characterized in that the compositions for daytime administration contain 50 to 100 mg of Eschscholtzia extract and 80 mg to 200 mg of Valerian extract.   6. Pharmaceutical compositions for diurnal administration according to claim 4, characterized in that they contain, in addition, Melissa extract.   7) Pharmaceutical compositions according to claim 1 and claim 4, characterized in that in the compositions for daytime administration, the plant extracts are present in an amount ranging from 5 to 20% by weight for each extract.   8) Pharmaceutical compositions according to claim 1 and claim 4, characterized in that, in formulations for daytime administration, Hawthorn extract is present in an amount ranging from 50 to 75 mg per unit dose.   9) Pharmaceutical compositions according to claim 4 and claim 5, characterized in that the compositions for daytime administration are in the form of film-coated or coated tablets, or colored or white capsules, preferably light blue in color.   10) Pharmaceutical compositions according to claim 1 or claim 2, characterized in that the pharmaceutical compositions for the night-time administration contain, as active ingredients, Eschscholtzia extract and Valerian extract.   11) Pharmaceutical compositions for nocturnal administration according to claim 10, characterized in that they contain, in addition, passionflower extract and / or melilot extract and / or camomile extract.   12) Pharmaceutical compositions according to claim 1 and claim 10, characterized in that in the compositions for the nightly administration, the plant extracts are present at a concentration ranging from 5 to 30% for each extract.   13) Pharmaceutical compositions according to claim 1 and claim 10, characterized in that they contain, in the formulations with nocturnal administration a quantity of Valerian extract which is 40, 80, 135, 140 or 150 mg, and an amount of Eschscholtzia extract which is 80, 90, 120, 125 mg per unit dose.   Pharmaceutical compositions according to claim 1 or claim 10, characterized in that, in the formulations intended for nocturnal administration, the Melissa extract is present in an amount which is 80, 135, 150 or 160 mg per unitary catch.   15) Pharmaceutical compositions according to claim 4 and claim 10, characterized in that the compositions for the night-time administration are in the form of film-coated or coated tablets or colored dragees, the dye or the coating or the film-coating is different of that used for compositions intended for daytime administration.   16) Pharmaceutical compositions according to claim 4 or claim 10, characterized in that the compositions for the night-time administration are in the form of film-coated or coated tablets, or in the form of dragees, capsules or soft capsules of dark color, especially of midnight blue color.   17) Pharmaceutical forms containing the pharmaceutical compositions according to claim 1 and claim 2, characterized in that to obtain in the same package, in blister form, the pharmaceutical compositions for diurnal administration, in the form of two rows and arrange the compositions for the nightly administration as a single row on the same blister.   18) Use of the pharmaceutical compositions according to claim 1 or claim 2, one or two doses in the morning and / or at noon, and two taken at night for the treatment of anxiety, and disturbances in the sleep.