EP0957928A1

EP0957928A1 - Plant extract compositions, method of preparation, and pharmaceutical compositions containing them

Info

Publication number: EP0957928A1
Application number: EP97907160A
Authority: EP
Inventors: Ravi Shrivastava
Original assignee: Laboratoires Remilea
Current assignee: Laboratoires Remilea
Priority date: 1997-03-03
Filing date: 1997-03-03
Publication date: 1999-11-24
Also published as: US6254899B1; CA2283122A1; AU1930897A; WO1998039018A1; JP2001513803A

Abstract

The invention concerns a composition of salicoid (Salix alba extract) and parthenoid (Tanacetum parthenium extract), or of plants or plant extracts containing these two active principles, its use in a method for treatment of the human or animal body by therapy or for the preparation of a medicine in particular for treating migraine, and compositions particularly pharmaceutical containing them.

Description

PLANT EXTRACT COMPOSITIONS, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The present invention relates to new compositions of plant extracts, their preparation process, their application as medicaments and the pharmaceutical compositions containing them.

Migraine affects around 10% of the French population on a regular basis. This disease is predominantly female (two women for one man). Migraine treatments are essentially symptomatic; none are truly healing. Several reasons explain the lack of discovery of an effective anti-migraine drug. The major difficulty is not knowing exactly the intimate factors triggering migraine attacks. However, assumptions have been made regarding the role:

- neuronal receptors (serotonin, dopamine, histamine)

- prostaglandins,

- nor-adrenergic receptors (central and peripheral),

- stress, diet, the effects of pollution. All of these elements probably contribute to the onset of the migraine crisis but do not alone explain the phenomenon. In the absence of scientific data on the mechanism of migraine, treatment can only be symptomatic for the moment.

Dihydro-ergotamine, prostaglandin inhibitors (aspirin), analgesics (paracetamol), calcium channel blockers, beta blockers and other 5HT receptor inhibitor molecules such as sumatriptan are the symptomatic treatments for this disease.

These drugs, of chemical origin, are known to have undesirable or even toxic effects (for example hepatotoxic effect of paracetamol and aspirin), especially in chronic use. In addition, because of their efficacy and low toxicity, these new products are generally of high cost.

We are still looking for active compounds to fight migraine. In addition, products of natural origin are increasingly popular with the sick.

White willow barks (Salix alba) are used, especially in

France, for the oral treatment of mild fevers and flu, in case of pain, and orally and locally in painful joint manifestations, tendonitis and strains. The active ingredients in question are said to be salicoids.

The aerial part of the Chamomile (Tanacetum parthenium) is used for the oral treatment of painful periods and in the prevention of migraine attacks. The active ingredients at issue are parthenoids.

Now the Applicant has discovered with astonishment that compositions of salicoids and parthenoids, or of plants or plant extracts containing these two active principles, in particular associated with a metal preferably chosen from copper, zinc or magnesium to the trace element, or riboflavin, were endowed with remarkable anti-inflammatory, analgesic and anti-migraine properties.

This is why the present invention relates to a new composition of a salicoid and a parthenoid, or of plants or plant extracts containing these two active ingredients. A preferred composition comprises an extract of plants of the genus Tanacetum and an extract of plants of the genus Salix.

By “plant extract” is understood in the broad sense both plants and parts of plants, for example and preferably dried or dehydrated, and ground, or alternatively extracts of such plants or parts of plants obtained using at least one aqueous and / or organic solvent and which are in a form conventionally used in pharmacy or dietetics, liquid or in particular solid.

The plant of the genus Tanacetum can be for example Matricaria pyrethrum, Leucanthenum parthenium and preferably Tanacetum parthenium also called Matricaria chamomilla. The aerial parts of this plant are preferably used, dried and ground; such extracts are, for example, those sold by the company BIOSPHERE 99 (Vie le Comte - FRANCE) under the reference BIO 3010. The plant of the genus Salix, may for example be Salix cinerea, and preferably Salix alba. The bark of this plant is preferably used, dried and ground; such extracts are, for example, those sold by the company BIOSPHERE 99 under the reference BIO 3021.

A preferred composition above is characterized in that it additionally contains riboflavin, zinc, magnesium or preferably copper in the state of a trace element, that is to say that the metal is used in low or very low proportions, for example less than 1 part per 100, preferably less than 1 part per 300, particularly less than 1 part per 1000 relative to the weight of the other components. The copper used can be in particular in the form of copper salts, particularly cupric salts (Cu ⁺⁺ ), for example in the form of mineral salts such as copper sulphate, and very particularly salified in the form of organic salts, preferably in form of gluconates. The same is true for zinc or magnesium. More particularly, the above compositions are retained in which the plant of the genus Tanacetum is Tanacetum parthenium and the plant of the genus Salix is Salix alba.

Among the compositions of the invention, there may also be mentioned those in which the extracts used are dry extracts of plant parts, dried and ground, especially those in which the extracts used are the aerial parts of Tanacetum parthenium, dried and ground and those in which the extracts used are the bark of Salix alba, dried and ground. A preferred composition above is characterized in that it contains, if reference is made to extracts of the above type and taking into account only said extracts, from 10 to 90% by weight of extract of Tanacetum parthenium and from 10 to 90% by weight of Salix alba extract.

The compositions which are the subject of the present invention have very advantageous pharmacological properties. They are endowed in particular with remarkable anti-inflammatory, analgesic and antimigraine properties.

These properties are illustrated below in the experimental part. They justify the use of the compositions described above, as a medicament.

This is why the invention also relates to the compositions of an extract of plants of the genus Tanacetum and of an extract of plant of the genus Salix, for their use in a method of therapeutic treatment of the human or animal body, ie that is, as a medicine. The medicaments according to the present invention find their use for example in both curative and preventive treatment of rheumatism, anti-inflammatory pathologies, vascular pathologies in particular hypertension or vascular spasms and cardiac pathologies, in particular tachycardias. They also find their use in both curative and preventive treatment of migraines.

The usual dose, which varies depending on the subject treated and the condition in question, can be, for example, from 100 mg to 1000 mg per day orally in humans of aerial parts, dried and ground, of Tanacetum parthenium with 300 mg to 1000 mg of bark, dried and crushed, of Salix alba and with 0.05 mg to 2.50 mg of copper as cupric ions, for 7 to 30 days for curative treatment or preventive of migraines.

A subject of the invention is also pharmaceutical compositions which contain at least one aforementioned composition, as active ingredient.

In these compositions, the active principle is advantageously present at physiologically effective doses; the aforementioned compositions contain in particular an effective anti-migraine dose of at least one active ingredient above. As medicaments, the above compositions can be incorporated into pharmaceutical compositions intended for the digestive tract.

These pharmaceutical compositions can be, for example, solid or liquid and can be presented in the pharmaceutical forms commonly used in human medicine, such as for example simple or coated tablets, capsules, granules, caramels, suppositories; they are prepared according to the usual methods. The active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

The present invention also relates to a process for the preparation of a composition described above, characterized in that the active ingredient (s) are mixed, according to methods known in themselves, with acceptable excipients, in particular pharmaceutically acceptable .

A subject of the invention is also the use of a above composition, for obtaining a medicament intended for use as as anti-migraine, that is to say for the treatment of migraine, as well as for obtaining a medicament intended for use as an anti-inflammatory.

A composition described above can also be in the form of a food supplement or a dietetic or phytotherapeutic product. In these forms, it can be in the common forms of pharmaceutical compositions, in particular those intended for “general public” use.

All of the above compositions can advantageously be combined with another active ingredient chosen from the group consisting of analgesics, antipyretics, antibiotics, anti-inflammatories, corticoids, antivirals and drugs for cardiovascular pathologies.

The following examples illustrate the present invention.

EXAMPLE 1

We prepared capsules corresponding to the formula

Freeze-dried powder of hydro-alcoholic extract of white willow bark

(origin BIOSPHERE 99 reference BIO 3021) 100 mg Lyophilized powder of hydro-alcoholic extract of aerial parts of Feverfew

(origin BIOSPHERE 99 reference BIO 3010) 100 mg

Copper gluconate 1, 428 mg

Copper gluconate contains 14% of Cu ⁺⁺ ions or 0.20 mg of Cu ⁺⁺ .

EXAMPLE 2

We prepared capsules corresponding to the formula

Freeze-dried powder of hydro-alcoholic extract of white willow bark

(origin BIOSPHERE 99 reference BIO 3021) 100 mg Freeze-dried powder of hydro-alcoholic extract from aerial parts of Chamomile

(origin BIOSPHERE 99 reference BIO 3010) 100 mg

Zinc gluconate 2,000 mg Magnesium gluconate 150 mg

EXAMPLE 3

Tablets with the formula have been prepared

Lyophilized powder of hydroalcoholic extract of white willow bark (origin BIOSPHERE 99 reference BIO 3021) 150 mg

Freeze-dried powder of hydro-alcoholic extract from aerial parts of Chamomile

(origin BIOSPHERE 99 reference BIO 3010) 150 mg

Copper gluconate 1,500 mg

EXAMPLE 4

We prepared drinkable ampoules corresponding to the formula

Lyophilized powder of hydro-alcoholic extract of white willow bark (origin BIOSPHERE 99 reference BIO 3021) 1% w / v

Freeze-dried powder of hydro-alcoholic extract from aerial parts of Chamomile

(origin BIOSPHERE 99 reference BIO 3010) 1% w / v

Excipient qs 10 ml

EXAMPLE 5

We prepared a cream with the formula

Freeze-dried powder of hydro-alcoholic extract of white willow bark

(origin BIOSPHERE 99 reference BIO 3021) 1% w / v Freeze-dried powder of hydro-alcoholic extract from aerial parts of Chamomile

(origin BIOSPHERE 99 reference BIO 3010) 1% w / v

0.05% copper gluconate Excipient qs 10 ml

PHARMACOLOGICAL STUDY

1. Test of anti-inflammatory activity Podal edema induced by carrageenan was used to evaluate the anti-inflammatory activity of the products tested.

Operating procedure :

The products were tested on male and female Ico rats (Sprague Dawley) weighing approximately 250 g supplied by the company IFFA-CREDO. The products tested were suspended in hydroxypropyl methyl cellulose (HPMC).

The animals were administered orally at a volume of 5 ml per kg of body weight, according to the protocol in the table below.

Control animals received either placebo (T +), ie HPMC alone, or indomethacin (T-) orally.

The treatment took place two hours before the experiment. One hour after oral administration of the test product, all the animals received by injection 0.2 ml of a 2% solution of carrageenan (Satia) in a 0.9% sodium chloride solution in the right hind leg (T ₀ ).

The podal volume of each rat was measured using a plethysmometer. The podal edema of each animal was measured at times T _0l T ₀ + 60 minutes, T ₀ + 120 minutes, T ₀ + 240 minutes.

The results were expressed as average percentages of inflammation compared to control values (T +) before treatment and at each measurement time as well as as a percentage reduction in edema versus a control before treatment and at each time. of measurement.

The results obtained are as follows:

RESULTS

% inflammation after 1h, 2h and 4h of treatment

(% compared to control (T +))

"-" means that the inflammation has been reduced

"+" Means increased inflammation

Conclusions

Salix alba extract alone has no effect on inflammation caused by carrageenan.

Tanacetum parthenium extract alone slightly reduces inflammation (only during the first two hours after administration, but this effect gradually fades).

Unexpectedly, the administration of Salix alba (50%) and Tanacetum parthenium (50%) in the presence of metal significantly reduces the edema induced by carrageenan from the second hour after treatment. The anti-inflammatory activity manifests itself after the first hour of treatment and continues beyond the four hours of the duration of the test, which shows lasting activity over time.

2. Study of the anti-migraine activity The anti-migraine properties of the compositions of the present application were evaluated by studying the capacity of the product to bind to the β receptors involved in the migraine process. The binding of the products tested to the β receptors was evaluated according to the technique described by Abrahamson et al. in "Biochemical Pharmacology, Vol. 37, No. 2, pages 203-208, (1988).

Cell membranes were prepared using a piece of rat heart tissue for analysis of β1 receptors and guinea pig lung tissue for β2 receptors. The tissues were homogenized in a centrifuge at 45,000 rpm for 5 minutes. After centrifugation, the membrane pellet was diluted in 20 mM Tris buffer (Tris-HCl in 154 mM NaCI and 2 mM MgCI ₂ , pH 7.5 at 4 ° C) to obtain a protein concentration of 0.6 mg / ml to 2 mg / ml for the suspensions used in the experiment with radioligands in the presence of 100 μl of Guanosine Triphosphate.

The reference compound for the β1 receptor was atenolol and for the β2 receptor the compound ICI 118.551. The radioligand used for both the β1 receptor and the β2 receptor was [ ³ H] (-) CGP 12.177 at the concentration of 0.5 nM for the first and 0.4 nM for the second., And the ligand non-specific alprenolol (50 μM). The incubation time was 20 min at 25 ° C in both cases.

Operating protocol: The procedure was as follows:

100 mg of lyophilized extract of S. alba and T. parthenium were mixed with 1 ml of distilled water (dilution 1:10) and prepared in duplicate. The tubes were centrifuged at 500 xg for 5 minutes. The supernatants were collected and used as a stock solution for the following experiments. The solution of the combination of S. alba and T. parthenium + copper was prepared by mixing 0.5 ml of S. alba solution with 0.5 ml of T. parthenium solution and with 0.933 mg of gluconate of copper and everything was mixed. To continue the studies, all the solutions were diluted to 10% for use (final dilution 1/100). All the experiments were carried out in duplicate.

The percentage of inhibition of specific radioligands, obtained for the receptor studied, was determined and expressed as the percentage of inhibition in comparison with atenolol (β1) and with ICI-118551 (β2) which represent the compounds of reference.

RESULTS

Conclusions

The S. alba extract has some affinity for the β1 (-48%) and β2 (-42%) receptors. The extract of T. parthenium shows a greater affinity for the β1 (-86%) and β2 (-95%) receptors. The solution containing the combination of S. alba and T. parthenium with copper strongly inhibits the β1 receptors (-

93%) and β2 (-97%).

The association of S. alba and T. parthenium with the metal has the capacity to almost 100% inhibit the β receptors, involved in the pathophysiology of migraine.

3. Analgesic activity test 50 male mice of 20-24 g supplied by the company IFFA-CREDO (France) were divided into 5 batches. The products studied were administered:

- orally thirty minutes before the injection of phenylbenzoquinone (PBQ): (PBQ 20 mg + alcohol 5 ml + water qs 100 ml). - intraperitoneally at a rate of 0.20 ml per mouse.

The products to be tested were suspended in the excipient HPMC (Hydroxy Propyl Methyl Cellulose).

The animals were treated as below:

Aspirin has been used as the reference analgesic product.

PBQ induces abdominal cramps indicating the intensity of pain. The number of cramps per mouse was measured 1 h and 2 h after the administration of the test product (30 min and 1 h 30 after the injection of the PBQ).

RESULTS

The results are expressed as a percentage:

Number of cramps in the control batch - Number of cramps in the treated batch x 100 Number of cramps in the control batch Results table: number of cramps over a 10-minute period

Conclusions

- Aspirin used as a reference analgesic product reduces abdominal cramps induced by the injection of PBQ by 33% and 55%

5 respectively 60min. and 120 min. after administration.

- The Salix alba extract alone at a dose of 150mg / kg slightly reduces the number of cramps (by 13% and 15% respectively after 1h and 2h).

- The extract of Tanacetum parthenium alone has no effect during the first hour of treatment; on the other hand it shows a slight analgesic activity (of

10 11%) at T = 2h.

- the combination of Salix alba extract (50%), Tanacetum parthenium extract (50%) and copper provides a strong increase in the analgesic effects of the two extracts tested alone.

These results show that, although Salix alba alone or Tanacetum parthenium 15 alone have no analgesic activity, their association with copper (Cu ⁺⁺ ) provides an interesting analgesic effect.

4. Toxicological study

The acute toxicity of the combination White willow bark extract (S. alba) - Fever chamomile dry extract (T. parthenium) - 20 Copper gluconate was evaluated in the following proportions: 15g - 15g - 142.8 mg (5g in 20 ml of water) in the Ico rat (Sprague Dawley) orally at the dose of

2 ml / kg administered as a single dose. Morbidity examinations have been carried out

15 min, 1, 2 and 4 hours after intubation then daily until day

14. 25 The lethal dose 50 (LD 50) of the test product is greater than 2 g / kg orally in the rat.

Claims

1. A composition of a salicoid and a parthenoid, or of plants or plant extracts containing these two active ingredients.

2. A composition according to claim 1 characterized in that it additionally contains a metal chosen from copper, zinc or magnesium in the state of trace element, or riboflavin.

3. A composition according to claim 1 or 2 characterized in that it contains a plant of the genus Tanacetum and a plant of the genus Salix.

4. A composition according to one of claims 1 to 3, characterized in that the extracts used are dry extracts of plant parts, dried and ground.

5. A composition according to claim 1, for its use in a method of therapeutic treatment of the human or animal body.

6. A composition according to one of claims 2 to 4, for its use in a method of therapeutic treatment of the human or animal body.

7. A pharmaceutical composition characterized in that it contains, as active principle, a composition as defined in claim 1, as well as a pharmaceutically acceptable excipient.

8. A pharmaceutical composition characterized in that it contains, as active principle, at least one of the compositions as defined in any one of claims 2 and 3, as well as a pharmaceutically acceptable excipient.

9. Use of a composition as defined in claim 1 for the preparation of a medicament intended for the treatment of migraine.

10. Use of a composition as defined in one of claims 2 to 4 for the preparation of a medicament intended for the treatment of migraine.