EP1487425A2

EP1487425A2 - Use of a vanilloid as an anti-snoring element

Info

Publication number: EP1487425A2
Application number: EP03738193A
Authority: EP
Inventors: Daniel Jean; Léon Cariel
Original assignee: LMD SAS
Current assignee: LMD SAS
Priority date: 2002-03-25
Filing date: 2003-03-25
Publication date: 2004-12-22
Also published as: WO2003080036A2; US20050118287A1; WO2003080036A3; FR2837390A1; AU2003244710A8; WO2003080036B1; AU2003244710A1

Abstract

The invention relates to the use of a vallinoid to diminish, suppress or prevent snoring and in the production of a medicament for the treatment of sleep apnoea. Preferably, the vallinoid is selected from the group comprising capsaicin, piperine, gingerols and shogaols.

Description

TITLE: USE OF A VANILLOID AS ANTI-SNORING

The present invention relates to novel compositions useful against snoring and sleep apnea. It relates in particular to the use of a vanilloid to prevent, reduce or suppress snoring.

Except in cases of sleep apnea, snoring is not considered a health problem. In general it does not annoy the person who snores, but can considerably annoy those around him. Snoring is more common in men (20 to 32%) than women (8%) (Jennum P et al., J Sleep Res., 1992, 1, p.240-244 and Teculescu et al., Respiration 2001 , 68 (4 \ p.365- 370), and more in obese people than thin people. The typical noise of snoring occurs when the soft tissues of the upper respiratory tract vibrate with the passage of air, which can be caused by one or more of four different situations:

- tissues (including the soft palate) that relax more than the average, and react like a flag or a veil that flaps in the wind;

- excess weight (in obese people) which causes the throat to droop, which hinders the passage of air;

- polyps in the nasal passages (a polyp is a longiform growth which occurs on a mucous membrane);

- obstructions in the nasal passages due to a cold or allergy. Certain medications such as antihistamines or hypnotics can cause your throat muscles to relax too much and make snoring easier.

Sleeping on your back brings your tongue towards the back of the palate and reduces the air passageway, which can cause snoring.

Sleep apnea consists of more or less long, more or less followed respiratory stops, after which breathing resumes with noise. It is a problem that causes fatigue, mood swings, depression and even heart problems due to poor sleep and the dangerous drop in blood pressure. At the moment, snoring problems are mainly treated by surgery which aims to modify the topology of the upper airways (veloplasty, somnoplasty, somnoplasty by injection etc.). There are also various accessories supposed to come to the aid of snorers: pillows to better position the head, nasal orthosis to keep the air passage open etc. Some products to treat snoring problems are also available, in particular essential oils but without much success (WO 00/25588).

The Applicant has surprisingly discovered that a vanilloid can be used to prevent, suppress or decrease snoring and to treat sleep apnea.

The shogaols belonging to the vanilloid family, chemical substances related to vanillin, have already been described as having deodorant and / or antiseptic activity (FR 2758086). They are also known as aphrodisiacs (FR 01 02961). Certain shogaols are also known chemical constituents of plants of the genus Alpinia, such as qa 'Alpinia galanga or Alpinia officinarum or Zingiber, such as Zingiber officinalis, Zingiber cassumunar or Zingiber zerumbet, obtained by extraction from their rhizome.

Gingerol, another member of the vanilloid family, is also known to be a constituent of ginger belonging to the Zingiber officinalis family. Anti-snoring compositions comprising as main components an extract of Zingiber officinale and Dioscorea (Dioscorea villosa or Dioscoreaceae among others) have also been described (US 5,565,201, US 5,603,935, US 5,804,211). However, Zingiber officmale extract has never been described as having an action against snoring on its own. On the contrary, the presence of the second component seems essential (synergy of actions). In addition, given the quantity of chemical constituents present in these extracts, there is nothing to suggest that the vanilloids alone can be active anti-snoring.

The present invention therefore relates to the use of a vanilloid to reduce, suppress or prevent snoring. For the purposes of the present invention, the term vanilloid means any chemical molecule corresponding to any one of the following general formulas:

(I) (n) or

X represents a linear, saturated, mono-unsaturated or polyunsaturated, substituted or unsubstituted Cι-C ₄ alkyl group;

Y is chosen from the groups -N (H) C (O) -, -C (O) N-, and -C (O) -;

RI represents a linear, branched or cyclic chain, saturated, monounsaturated or polyunsaturated, substituted or unsubstituted C ₂ -C ₂₄ alkyl group.

Advantageously, the vanilloid is chosen from the group consisting of capsaicin, piperine, gingerols and shogaols. Advantageously, it is one or more shogaols.

Advantageously, the present invention relates to the use of a vanilloid for the manufacture of a medicament for treating sleep apnea. Advantageously, capsaicin corresponds to the following general formula:

Advantageously, it is obtained by percolation of the capsicum fruit powder and then purification of the capsicin thus obtained. It is also commercially available. Advantageously, the piperine is obtained by extraction of the pericarp from the black pepper. It is also commercially available. Advantageously, the shogaol (s) correspond (s) to the general formula (III):

(III) in which n is equal to 1, 2, 4, 6 or 8 and which are respectively named [3] - shogaol, [4] -shogaol, [6] -shogaol, [8] -shogaol and [10] -shogaol. Even more advantageously, it is [3] -shogaol.

In a particular embodiment, the shogaol (s) are in the form of a crude extract of a plant of the family Zingiberaceae, advantageously by a process which comprises the following step: a) preparation of crude extract from rhizomes, fresh or dried, of said plant, by maceration of a ground material of these rhizomes at a temperature between 10 and 35 ° C, followed by one or more reflux extractions of this ground material, or by subjecting a ground material of said rhizomes to percolation at a temperature between 10 and 35 ° C, each of these operations (maceration, reflux extractions and percolation) being carried out using an organic solvent or a mixture of appropriate organic solvents . The maceration of the ground rhizomes, prior to its extraction, has the main effect of improving the contacting of the plant tissues and the solvent during the extraction. Its duration can be between a dozen hours and a week depending on the state of freshness of the rhizomes used. For maceration, reflux extraction and percolation of the ground material, organic solvents are used which are miscible with water and have a relatively low boiling point so that they can be easily removed later by simple evaporation. , such as ethanol, methanol, acetone or their mixtures with water. However, since shogaols are soluble in many organic solvents, it is also other organic solvents such as ethyl acetate, ethyl ether, chloroform or methylene chloride can be used.

In another particular embodiment, the shogaol (s) are in the form of a purified extract of a plant of the family Zingiberaceae, advantageously obtained by a process which comprises, in addition to step a) described below above, the following additional steps: b) purification of the crude extract obtained in step a) by subjecting said extract, after elimination of the solvent or solvents which it contains and its recovery in water, to one or more several extractions against the current using an organic solvent or a mixture of organic solvents immiscible with water and, if desired, c) cliromatographic separation of the shogaols.

The water-immiscible organic solvent (s) useful for carrying out the counter-current extractions of the crude extract with a view to its purification are, in particular, chosen from ethyl acetate, ethyl ether, chloroform , methylene chloride and mixtures thereof.

Advantageously, the plant of the family Zingiberaceae is chosen from the species Alpinia galanga, Alpinia officinarum, Zingiber officinalis, Zingiber cassumunar and Zingiber zerumbet, even more advantageously, it is / Alpinia galanga.

For example, [3] -shogaol, [6] -shogaol and [8] -shogaol can be extracted from plants of the genus Alpinia such as Alpinia galanga or Alpinia officinarum, while [4] -shogaol and [10] -shogaol can be extracted from plants of the genus Zingiber such as Zingiber officinalis, Zingiber cassumunar or Zingiber zerumbet, in particular using the method as described above.

Advantageously, the crude extract from Alpinia galanga contains an amount of [3] - shogaol comprised by weight between approximately 1 to 5% of the dry weight of said extract. According to the invention, this extract is obtained from rhizomes, fresh or dry, of said plant. Advantageously, the purified extract & Alpinia galanga contains an amount of [3] -shogaol at least equal by weight to 75% of the dry weight of said extract. The present invention also relates to the use of a vanilloid for the preparation of an anti-snoring composition.

Advantageously, the anti-snoring composition is formulated for oral administration, for example, in the form of powders, solutions or oral suspensions, syrups, tablets or capsules.

Advantageously, the composition is formulated in the form of a nasal or oral spray.

Physiologically acceptable excipients can be used in this type of composition. These excipients are conventional and well known to those skilled in the art.

Advantageously, the vanilloid is used at a daily dose corresponding to 20 mg of vanilloid taken in the form of plant extract or pure vanilloid. Advantageously, it is in this case shogaol.

The following examples of preparation of extracts containing shogaols are given only by way of illustrations of the subject of the invention of which they do not in any way constitute a limitation.

Example 1: Preparation of a crude extract of rhizomes of Alpinia galanga

A kilo of fresh rhizomes tf Alpinia galanga is coarsely ground, taking care not to cause excessive heating of the ground parts. The water content of the ground product thus obtained is determined and it is macerated in 7 liters of ethanol, the title of which is chosen so that, taking into account the water content of the ground material, the maceration solvent is 50% ethanol.

After 24 hours of maceration at approximately 20 ° C., the ground material is extracted at reflux with the maceration solvent for 30 minutes. This solvent is removed and replaced with an equal weight of 50% ethanol, and the ground material is again extracted at reflux for 30 minutes. The operation is repeated once. The 3 extracts obtained are combined (thus constituting a volume of about 19 liters), filtered on paper, then evaporated to dryness under reduced pressure.

A residue is obtained which weighs approximately 50 g, ie an approximate yield of 30% relative to the dry weight of the rhizomes. This extract contains the different shogaols present in the rhizomes of Alpinia galanga ([3] -shogaol, [6] -shogaol and [8] -shogaol) and its [3] -shogaol content is generally between 1 and 5% (w / w) depending on the rhizomes used.

EXAMPLE 2 Preparation of a Purified Extract of Rhizomes from Alpinia galanga

50 g of a crude extract, prepared in accordance with Example 1, are taken up in 1 liter of distilled water and the whole is brought to the boil for 1 minute with constant stirring. Stirring is continued until a complete homogenization of this extract is obtained and it is allowed to cool. It is then subjected to 4 successive countercurrent extractions each carried out with 100 ml of ethyl ether.

The ethereal solutions are united; they are added with anhydrous sodium sulphate to remove the water which they contain; they are filtered on paper and evaporated to dryness under reduced pressure. A residue is thus obtained which weighs 6.8 g, ie a yield of approximately 4% relative to the dry weight of the rhizomes. This extract, which mainly contains [3] -shogaol, has a [3] -shogaol content which is generally greater than 75%.

(W / w) -

Example 3: Obtaining [3] -shogaol

[3] -shogaol can be obtained from Alpinia galanga rhizomes by preparing a crude extract of these rhizomes in accordance with Example 1, then purifying this extract in accordance with Example 2 and then subjecting the extract thus purified by successive elutions on columns of silica gel, for example in the following manner. 10 g of a purified extract, prepared in accordance with Example 2, are added with 100 g of silica gel G60 and 500 ml of chloroform with constant stirring. As soon as this mixture is homogeneous, it is evaporated to dryness under reduced pressure so as to obtain a powder. This powder is deposited at the top of a column 10 cm in diameter and 50 cm in height, also containing G60 silica gel in petroleum ether. First eluted with petroleum ether until the residue is less than 0.1% (approximately 10 liters of petroleum ether necessary to reach this stage), then with 12 liters of benzene and , finally, per 8 liters of chloroform. The chloroform phase is evaporated to dryness under reduced pressure, leaving room for a residue of approximately 2.3 g. This residue is then subjected to preparative chromatography on a column 5 cm in diameter and 20 cm in height, filled with Cl 8 silica gel, and using a water / acetonitrile mixture (70/30) as elution gradient. . The fraction containing [3] -shogaol is eluted in a time between 5 and 7 minutes for a flow rate of 30 ml / min.

[3] -shogaol can be identified by high pressure liquid chromatography (HPLC) coupled with mass spectrometry.

Example 4 Preparation of an Anti-Snoring Composition in Oral Form

1 kg of raw extract, prepared in accordance with Example 1, was intimately mixed with 1 kg of maltodextrin in a knife mill in order to ensure better homogeneity in the mixture and to obtain a non-sticky mobile powder.

This powder was then distributed in No. 0 capsules so as to obtain a unit dosage of 250 mg of crude extract.

Likewise, capsules can be made from [3] -shogaol to obtain a unit dosage of 25 mg of [3] -shogaol.

Example 5: activity of shogaol on snoring:

Daily doses corresponding to 20 mg of shogaol taken in the form of an extract according to Example 1 or 2 or of pure shogaol according to Example 3 were administered to a panel of men and women. The effects appear after 48 hours of treatment and persist 48 hours after stopping it.

Shogaol significantly reduces snoring in users.

Without being bound by theory, it seems that the effect of this molecule and of the other vanilloids is to be linked to their involvement in the emission by certain nociceptive neurons of a neurotransmitter, substance P.

Claims

1. Use of a vanilloid corresponding to any of the following general formulas:

or

X represents a linear Cι-C alkyl group, saturated, monounsaturated or polyunsaturated, and substituted or unsubstituted;

Y is chosen from the groups -N (H) C (O) -, -C (O) N-, and -C (O) -;

RI represents a linear, branched or cyclic chain, saturated, monounsaturated or polyunsaturated, substituted or unsubstituted C ₂ -C ₄ alkyl group.

for the manufacture of a medicament intended to reduce, suppress or prevent snoring.

2. Use according to claim 1 characterized in that the vanilloid is chosen from the group consisting of capsaicin, piperine, gingerols and shogaols, advantageously, it is one or more shogaols.

3. Use according to claim 2, characterized in that the shogaol (s) corresponds (s) to the general formula (III):

(In) in which n is equal to 1, 2, 4, 6 or 8, advantageously 1.

4. Use according to any one of claims 2 or 3, characterized in that the (s) shogaol (s) is in the form of a crude extract of a plant of the family Zingiberaceae, advantageously obtained by a process which comprises the following stage: a) preparation of crude extract from rhizomes, fresh or dried, of said plant, by maceration of a ground material of these rhizomes at a temperature between 10 and 35 ° C, followed by one or more reflux extractions of this ground material, or by subjecting a ground material of said rhizomes to percolation at a temperature between 10 and 35 ° C., each of these operations (maceration, reflux extraction and percolation) being carried out by means of an organic solvent or a mixture of suitable organic solvents.

5. Use according to any one of claims 2 or 3, characterized in that the (s) shogaol (s) is in the form of a purified extract of a plant of the family Zingiberaceae advantageously obtained by a process which comprises step a) as described in claim 3 and the following additional steps: b) purification of the crude extract obtained in step a) by subjecting said extract, after removal of the solvent or solvents which it contains and its recovery in water, at one or more countercurrent extractions using an organic solvent or a mixture of organic solvents immiscible with water and, if desired, c) chromatographic separation of the shogaols.

6. Use according to any one of claims 4 or 5, characterized in that the plant of the family Zingiberaceae is chosen from the species Alpinia galanga, Alpinia officinarum, zingiber officinalis, zingiber cassumunar and zingiber zerumbet, advantageously it is from Y Alpinia galanga.

7. Use according to any one of the preceding claims, characterized in that the vanilloid is formulated for oral administration or in the form of a nasal or buccal spray.

8. Use of a vanilloid for the manufacture of a medicament intended to treat sleep apnea.