Cosmetic or pharmaceutical composition on the basis of plant extracts having an effect on the capillary fragility.

The present application relates to a new composition, capable of being used in the cosmetic or pharmaceutical field, containing plant extracts and having an action on the capillaries by reducing their permeability and by increasing their resistance.

Extracts of Ruscus aculeatus L associated or not with a vitamin factor have already been proposed for the treatment of functional disorders linked to venous insufficiency and capillary fragility.

Furthermore, fractions enriched in saponins from stabilized rhizomes of Ruscus aculeatus L have been described as having therapeutic activity in particular in the case of venous diseases, varicose veins, ulcers, hemorrhoids and various disorders of the capillary system such as purpura, epistaxis, frostbite or gynecological conditions.

These compositions of the prior art are mainly described in French patent n ° 77.01290 as well as in BSM n ° 3.994.M.

After various studies on the extracts of Ruscus aculeatus L, it was found quite surprisingly that it was possible to obtain a remarkable synergy of action and complementarity in the reduction of the permeability of the capillaries and in the increase their resistance, by combining extracts of Ruscus aculeatus L with extracts of sage or Salvia

Officinalis L.

It has also been found that by combining these extracts, an extract of passionflower or Passiflora incarnata, the synergistic effect is more appreciably increased, the action being more constant over time.

The subject of the present invention is therefore, as a new industrial product, a composition for cosmetic or pharmaceutical use, having an action on the capillaries by reducing their permeability and increasing their resistance, this composition containing in a vehicle suitable for cosmetic application. or pharmaceutical, a combination of plant extracts consisting of:<ul id="ul0001" list-style="none"><li>(i) a bitter extract (Ruscus aculeatus L), and</li><li>(ii) a sage extract (Salvia officinalis L).</li></ul>

According to the invention, this combination of plant extracts is present in the composition at the following concentrations, expressed as dry matter:<tables id="tabl0001" num="0001"><img file="EP0147331A2_D0001.tif" /></tables>

According to a particular embodiment, the composition also contains a soft extract of passion flower (Passiflora incarnata) at a concentration<tables id="tabl0002" num="0002"><img file="EP0147331A2_D0002.tif" /></tables>

The vasoprotective effect of these associations as well as their synergy of action have been demonstrated using the petechiae method which will be referred to below.

The dry extract of fragon or Ruscus aculeatus L, used in the compositions according to the invention, is obtained from rhizomes previously ground and extracted using an aqueous-alcoholic solution of an alcohol having 3 to 6 atoms of carbon, preferably using n-butanol saturated with water.

Mention may be made, as an extraction process, of those described in French patents Nos. 1,377,453, 69,23,340 and 71,29,817, the latter patent having the particular object of purifying the extracts obtained in order to enrich them with saponins.

The extracts of Ruscus aculeatus L obtained by these processes are in the form of a beige powder soluble at 2% in water and in alcohol at 60 °. These extracts are essentially characterized by a saponin content greater than 65% and preferably between 70 and 80 X.

The dry extract of sage or Salvia officinalis L is an extract obtained from the dried leaves and flowering tops. The extraction can be carried out hot using water, the extraction juices are then filtered, concentrated under vacuum and then spray-dried.

It is also possible to use, according to the invention, hydro-alcoholic extracts, tinctures containing 60 or 40% alcohol, alcoholic (30%) or propylene glycol extracts (40%).

The dry extract of sage is essentially characterized by the presence of ursolic acid, flavonoids (luteolin and apigenin glucosides), rosmarinic acid, picrosalvin as well as various terpene products such as tujone, borneol, salvene, pinene, bornyl acetate and linolyl.

The dry extract is in the form of a fine powder, yellowish brown to brown in color, soluble up to 1% in water and slightly soluble in alcohol at 60 ° and sparingly soluble in alcohol at 95 °.

The soft extract of passionflower or Passiflora incarnata is obtained by aqueous or hydroalcoholic extraction from the aerial parts of the plant, then concentration in order to obtain a pasty mass having a solids content greater than 60% and preferably about 80 %.

The extract, which is in the form of a very dark brown paste, contains as active principles of vitexin, isovitexin, orientin and isoorientin.

A 2% solution in 50% ethanol (by volume) is clear or slightly opalescent.

When the compositions are intended for a cosmetic application, these are preferably in the form of an emulsion, a cream, a milk, a gel, a lotion, a poultice or a '' aerosol foam.

These compositions applied to the skin have a slimming and anti-cellulite action, in particular when they are combined with other plant extracts and / or with other active ingredients such as water-soluble organic compounds derived from monomethyltrisilanol such as for example monomethyltrisilanol manuronate. sold by the company EXYMOL under the name of "Algisium" (aqueous solution containing 1% of monomethyltrisilanol manuronate) or the lactate sold by the same Company under the name of "Lasilium" (aqueous solution containing 1% of monomethyltrisilanol lactate).

The latter compounds can be present at a concentration of between 2 and 20% of the 1% solutions, ie between 0.02 and 0.2% by weight expressed as active material.

These compositions can also contain other conventional ingredients such as, for example, perfumes, dyes, preservatives, thickeners, solvents, etc.

According to a preferred embodiment, the compositions are intended for pharmaceutical use in cases of venous or capillary insufficiency.

In particular, these compositions find an application in phlebology, in particular in syndromes of venous origin such as those known under the expression of "Heavy Legs", leg ulcers., Phlebitis, frostbite, in gynecology in the case certain dysmenorrhea, and in proctology in the treatment of simple hemorrhoids and hemorrhoidal anites.

Pharmaceutical compositions intended for systemic application can be prepared, for example, by adding the extracts as defined above as active substance, to inert non-toxic, solid or liquid carriers, generally used in this type of composition.

These compositions can be administered enterally, parenterally or topically. For enteral administration, the compositions are in the form of tablets, granules, capsules, dragees, syrups, suspensions, solutions or suppositories.

The dosage is of course a function of the route of administration and the activity sought.

In proctology, for example, suppositories can contain, per unit, in an excipient consisting of semi-synthetic glycerides of:<ul id="ul0002" list-style="none"><li>- 0.01 to 0.05 g of sage extract,</li><li>- 0.01 to 0.03 g of dry broom extract, and optionally of:</li><li>- 0.01 to 0.03 g of soft extract of passionflower.</li></ul>

The pharmaceutical compositions can contain inert or optionally pharmacodynamically active additives. The tablets or granules can contain, for example, binders, fillers, carriers or diluents. The liquid compositions can be present for example in the form of a sterile and water-miscible solution. In addition to the extracts, the capsules may contain a filler or a thickener. Oral pharmaceutical compositions may also contain flavor enhancers and substances commonly used as preservatives, stabilizers, regulators and emulsifiers.

The supports and diluents as listed above can consist of organic or mineral substances, for example by gelatin, lactose, starch, magnesium stearate, talc, gum arabic or polyalkylene glycols . When the pharmaceutical compositions are intended for topical application, these are in the form of ointments, ointments, tinctures, creams, solutions, lotions, sprays or suspensions.

Ointments or ointments are preferred and are prepared by mixing the extracts according to the invention as active constituents with inert non-toxic supports suitable for topical treatment.

For example, a cream for the treatment of heavy legs; periplebitis, hypodermitis or frostbite, contains in an excipient suitable for 100 g,<ul id="ul0003" list-style="none"><li>- 0.3 to 3.5 g of a dry sage extract, and</li><li>- 0.3 to 2.5 g of a dry extract of broom, and optionally of:</li><li>- 0.2 to 1.5 g of a soft passionflower extract.</li></ul>

Measurement of activity on capillary fragility by the petechiae method

This commonly used method for determining capillary fragility has been described in the article by JL PARROT and P. CANU, "Factors which increase the resistance of capillaries" Arch. Int. Pharmaco dyn. n ° 1, p.152 (1964).

However, the principle and the method will be recalled below.

The principle consists, using a vacuum chamber, of causing the appearance of petechiae on a part of the dorsal skin of rats which allows the measurement of the capillary resistance to time - 0. We then apply, on an adjacent and delimited area of ​​the skin, the composition to be tested which causes a variation in this resistance, a variation which is recorded on different parts of the treated skin at regular time intervals (30 min, 1 hr, 1 hr 30 min, 2 hr, and 2:30).

The experiment is terminated by a final measurement on a portion of the untreated skin in order to verify that the control measurement has not varied.

The apparatus allowing the measurement is derived from that described by R. CHARLIER, A. HOOSLET and M. COLOT, "Experimental investigations on vascular fragility" Arch. Int. de Physiologie et de Biochimie, 71, (1), 1963, it includes a vacuum pump connected to a vacuum tank itself connected to a manometer which allows to measure the depression expressed in mm of Hg. A second bottle is inserted between the vacuum tank and the pressure gauge and serves as a buffer. A cell connected to a glass tube controlled by a tap allows the pressure to be applied to the skin. The cell has a diameter of approximately 5 mm and has flat edges so as to avoid deformation of the skin.

For each composition to be tested, the measurements. Capillary resistance was carried out on 16 white male WISTAR rats (weight 360 - 400 g), the lower dorsal part of which was clipped and shaved, the animals being left for 48 hours before the experiment. at rest.

At the start of the experiment, the threshold of capillary resistance for each rat is measured by applying a depression of 350 mm Hg for 15 seconds and then increasing this depression by 5 to 5 mm Hg until the appearance of petechiae (4 to 5 petechiae).

This measurement being carried out, the composition to be tested is then applied (2 mg / cm²) on an adjacent and delimited part of the skin and the depression necessary to reveal the petechiae is measured every 30 min., at different locations. The experiment is stopped after the 6th measurement, i.e. after 2h30.

It is then checked, on an untreated part, that the capillary resistance measured at time t = 0 has not undergone any significant variation.

According to this method, the capillary resistance was determined using the following compositions:<ul id="ul0004" list-style="none"><li>1) Placébo = excipient with the following composition:<img file="EP0147331A2_D0003.tif" /></li></ul><ul id="ul0005" list-style="none"><li>2) Cream P = Excipient + 0.5% of soft passionflower extract</li><li>3) Cream S = Excipient + 0.5% dry sage extract</li><li>4) Cream F = Excipient + 1% dry broom extract</li><li>5) FP cream = Excipient + 1% dry bitter extract + 0.5% soft passionflower extract</li><li>6) PS cream = Excipient + 0.5% of passionflower soft extract + 0.5% of sage sage extract</li><li>7) FS cream = Excipient + 1% dry bitter extract + 0.5% dry sage extract</li><li>8) FSP cream = Excipient + 1% dry bitter extract + 0.5% sage dry extract + 0.5% passionflower soft extract</li></ul>

The results observed are collated in Table A below. The values ​​obtained (mm / Hg) correspond to an average of the measurements recorded on the 16 rats treated for each of the creams.<tables id="tabl0003" num="0003"><img file="EP0147331A2_D0004.tif" /></tables>

Results analysis

<ul id="ul0006" list-style="none"><li>1) Placébo has no effect on capillary resistance.</li><li>2) The soft extract of passionflower only very slightly increases the capillary resistance (maximum approximately 3% obtained after 2 hours then rapid fall).</li><li>3) The dry sage extract has a maximum similar to passionflower extract but remains constant after 2 hours.</li><li>4) The dry bitter extract has a significant action on capillary resistance (approximately 4.5% between 1:30 and 2 hours after application).</li><li>5) The association of broom extract and passionflower extract exerts an action on capillary resistance, the latter passing to approximately 10% after 2 h - 2 h 30 after application.</li><li>6) The association of the soft extract of passionflower and the dry extract of sage also shows an effect on the capillary resistance but is less accentuated (6% only after 2:30).</li><li>7) The association of the dry extract of broom and the dry extract of sage has a significant synergistic effect on the capillary resistance compared to the dry extract of broom on the one hand and the dry extract of sage on the other hand (increase in capillary resistance of about 20%).</li><li>8) The association of dry bitter extract, dry sage extract and soft passionflower extract induces a very strong increase in capillary resistance.</li></ul>

If, to the means recorded for each of the creams, the method of multiple comparison of the means of NEWMAN and KEULS (analysis of variance) is applied, the rankings given below are obtained.

For a given time, the averages recorded for each cream are classified in ascending order.

The means underlined by the same solid line are not significantly different from each other, otherwise, the difference is significant with a risk of 5%.<tables id="tabl0004" num="0004"><img file="EP0147331A2_D0005.tif" /></tables><tables id="tabl0005" num="0005"><img file="EP0147331A2_D0006.tif" /></tables><tables id="tabl0006" num="0006"><img file="EP0147331A2_D0007.tif" /></tables><tables id="tabl0007" num="0007"><img file="EP0147331A2_D0008.tif" /></tables>

It follows from these classifications that the FS cream according to the invention is significantly less than the FSP cream after 1 hour 30 minutes, but is significantly better than the other creams after 2 hours.

After 2:30, FS and FSP creams are not significantly different from each other but are significantly superior to other creams.

We will now give by way of illustration and without any limiting character several examples of compositions based on plant extracts according to the invention.

EXAMPLE 1 Slimming cream

<tables id="tabl0008" num="0008"><img file="EP0147331A2_D0009.tif" /></tables>- Plant extracts:<tables id="tabl0009" num="0009"><img file="EP0147331A2_D0010.tif" /></tables>

EXAMPLE 2 Relaxing body milk for "heavy legs"

<tables id="tabl0010" num="0010"><img file="EP0147331A2_D0011.tif" /></tables>- Plant extracts:<tables id="tabl0011" num="0011"><img file="EP0147331A2_D0012.tif" /></tables>

EXAMPLE 3: Anti-fatigue gel for "heavy legs"

<tables id="tabl0012" num="0012"><img file="EP0147331A2_D0013.tif" /></tables>

- Plant extracts<tables id="tabl0013" num="0013"><img file="EP0147331A2_D0014.tif" /></tables>

EXAMPLE 4 Cream for Rosacea

<tables id="tabl0014" num="0014"><img file="EP0147331A2_D0015.tif" /></tables>- Plant extracts:<tables id="tabl0015" num="0015"><img file="EP0147331A2_D0016.tif" /></tables>

EXAMPLE 5 Ointment for Varicose Veins

<tables id="tabl0016" num="0016"><img file="EP0147331A2_D0017.tif" /></tables>- Plant extracts:<tables id="tabl0017" num="0017"><img file="EP0147331A2_D0018.tif" /></tables>

- Plant extracts<tables id="tabl0018" num="0018"><img file="EP0147331A2_D0019.tif" /></tables><tables id="tabl0019" num="0019"><img file="EP0147331A2_D0020.tif" /></tables>