FR3108036A1 - Pharmaceutical or dietetic composition containing the aqueous extract of lavender and usable as an antidiabetic - Google Patents

Abstract

Pharmaceutical or dietetic composition based on aqueous extracts of Lavender for use in treating metabolic syndrome and diabetes. According to the invention, this composition can also comprise an aqueous extract of at least one second plant from list 1.

Description

Pharmaceutical or dietetic composition containing the aqueous extract of lavender and usable as an antidiabetic.

The present invention relates to a new therapeutic or dietary use of the aqueous extract of Lavender as a hypoglycemic agent.

Some definitions.

To better understand this text, it is desirable to define a few words and terms used therein. The majority of all terms and words used are defined in the Illustrated Dictionary of Medical Terms by Garnier Delamare ^28th Edition.

Biological barriers : Set of structures that separate one biological compartment from another. Among the biological barriers, mention may be made of the intestinal barrier which separates the contents of the intestine (mucous compartment) and the blood (serous compartment). The most important biological barriers are: the intestine, the skin, the cornea, the blood-brain barrier and the alveolo-capillary barrier.

Excipient : It is a vehicle for a drug. It is a substance in which the active principles are incorporated to make them easily absorbable.

Nutrient: food substance which can be directly and completely assimilated, without having to undergo the modifications of digestion and which can be introduced by intravenous injection. Example: glucose, vitamins, mineral salts etc.

Drug: Substance or combination of substances presented as having curative or preventive properties with regard to human or animal diseases, as well as any product that can be administered to humans or animals in order to establish a medical diagnosis, restore, correct or modify their organic functions.

Essential drug: A drug that satisfies the priority health care needs of the population. These drugs are generally used for priority pathologies and are listed on the national list of essential drugs.

Xenobiotics : Chemical products, household or industrial, foreign to biological chemistry and behaving like a toxin or an allergen vis-à-vis the body.

The metabolic syndrome : The syndrome is a meeting of a group of signs (symptoms) which occur at the same time in a certain number of diseases. We mean in this context by metabolic syndrome, the association of symptoms of insulin resistance, hypertension and dyslipidemia. These symptoms are often seen in patients with type 2 diabetes, cardiovascular disease such as hypertension, and overweight (obesity).

Aqueous extract: We mean by aqueous extract, the extract using as solvent only water in liquid or vapor form.

Alpha amylase and alpha glucosidase : These are intestinal enzymes that transform starch and sugar chains into glucose.

OGTT stands for Oral Glucose Tolerance Test. This test involves giving oral glucose and measuring the amount of glucose in the blood to assess glucose tolerance.

The present invention relates to a new therapeutic or dietary use of the aqueous extract of the aerial part of Lavender as a hypoglycemic agent and as an inhibitor of the intestinal absorption of glucose. By lavender, we mean the different types of lavender (non-exhaustive) preferably the following types of lavender:

Lavandula angustifolia Mill,

Lavandula x intermedia Emeric ex Loisel,

Lavandula stoechas L ,

Lavandula dentata L ,

Lavandula pedunculata (Mill) Cav ,

Lavandula multifida L.

But the preferable species according to the invention is Lavandula pedunculata (Mill) Cav ,

The applicant has found, surprisingly, that an aqueous extract of lavender can be used in a pharmaceutical or dietetic composition to block or reduce the intestinal absorption of sugars. Consequently, the composition according to the invention can also be used as a medicine or a food supplement to combat diabetes, metabolic syndrome or weight gain.

The aqueous extract, according to the invention, may also contain one or more other natural substances such as the aqueous extracts (seed, seed, leaves, bark) of the following plants (list 1):

List 1

Nigella sativa (seed)

Hibiscus sabdariffa (calyx, leaves)

Catharanthus reeds (leaves);

Salvia officinalis (leaves);

Galega officinalis (leaves);

Juglans regia (leaves);

Eucalyptus globulus (leaves);

Trigonella foenum graecum (seed);

Phyllanthus amarus (leaves).

Scots pine or Pinus sylvestris L. buds or twig

Boscia senegalensis (bare seed)

Arbutus ( Arbutus unedo ) root bark or leaves

Pomegranate (fruit) or Punica granatum

African pyrethrum or Anacyclus pyrethrum.

Preferably, the aqueous extract according to the invention contains between 1% and 80% by weight of the dry aqueous extract of lavender relative to the total weight of the composition or of the medicinal product. This composition or this medicinal product may also contain one or more aqueous extracts of plants from list 1 between 0.1% and 50% by weight relative to the total weight of the composition or the medicinal product.

Dosage forms

According to the invention, the composition can be presented in the form of tablets, capsules, granules, syrup, drinkable solution or any other form known to those skilled in the art comprising lavender extract.

Those skilled in the art know and use various excipients as binders or lubricants to manufacture powders, granules or other preparations. Examples of excipients which can thus be used according to the invention are: lactose, starch, dextrin, calcium phosphate, calcium carbonate, natural or synthetic aluminum silicate, magnesium oxide , hydrated aluminum hydroxide, magnesium stearate, sodium bicarbonate, rice starch. Other excipients not mentioned above but which are also suitable are described in "Remington's Pharmaceutical Sciences" by E.W. Martin, and can be used according to the invention.

In these various formulations, and for example those mentioned above, the composition can also be presented as a powder for dilution or syrup. This powder may contain only the active ingredients. This is obtained for example by atomization, drying, or freeze-drying from an aqueous extract, hydroalcoholic extract or the CO ₂ extract.

The object of the invention is therefore to propose a new pharmaceutical and/or dietary composition for blocking or reducing the intestinal absorption of sugar and total glycaemia and which can be used to combat type 2 diabetes, metabolic syndrome and overweight and as a hypoglycemic.

The applicant manages that the oral administration (per os) of an effective quantity of the mixture of an aqueous extract of lavender causes a reduction in the passage of sugars in the blood and hypoglycemia.

Implementation of the invention

The implementation of the invention can be done on the action of the composition according to the invention on the reduction or the inhibition of the passage of sugars in the blood when these sugars are administered orally at the same time as the composition pharmaceutical or diet according to the invention. The implementation of the invention can be done by measuring the total glycaemia in humans or laboratory animals such as rats and mice after oral absorption of a sufficient quantity of the preparation according to the invention.

An example of a simplified preparation of the invention is made by mixing the powder of the dry aqueous extract of lavender with or without association with a second plant from among the plants mentioned in list 1 and obtained by drying in the oven or by atomization or freeze-drying.

Materials and methods used

Chemical products

Phloridzin and glucose were purchased from Sigma (St Quentin-Fallavier, France). The pharmaceutical composition according to the invention of dry extracts was prepared by the TBC laboratories, Faculty of Pharmacy of Lille (France).

Tissue preparation

The 7-week-old mice (strain C57BL/6JRJ) were obtained from Janviers SA (France) and were fed standard laboratory food (UAR, Villemoisson s/Orge, France) until these studies were carried out. Food was removed 18 h before the experiments, but the animals had free access to drinking water. For electrophysiology studies, animals were killed by cervical dislocation after anesthesia and intestine segments from fasting animals were removed and rinsed of intestinal contents with fresh Ringer's solution. The stomachs of all the animals were found empty. The pieces of tissue were then opened along the mesenteric border and were mounted well flattened between the two acrylic Ussing half-chambers (Biomecatronics SAS, ZI de Ruitz, France).

Short-circuit current studies in Ussing chambers

The isotonic Ringer's solution used in the experiments is composed of (in mM) 115 NaCl, 25 NaHCO ₃ , 1.2 MgCl ₂ , 1.2 CaCl ₂ , 2.4 K ₂ HPO ₄ and 0.4 KH ₂ PO ₄ . The pH was 7.40 at 37°C.

An intestinal preparation is mounted between two Plexiglas half-chambers determining a mucous compartment and a serous compartment.

These half-chambers, whose opening is applied against the exposed surface of the intestinal tissue, are perforated into compartments containing Ringer's liquid which is a solution buffered at pH = 7.6 tempered at 37°C. The pH of Ringer's liquid and its oxygen saturation are constantly maintained by permanent bubbling of carbogen, a gaseous mixture composed of oxygen and carbon dioxide in the proportions of 95% O ₂ and 5% CO ₂ . The bubbling also ensures permanent mixing of the incubation medium in the two compartments.

The transepithelial electric potential reflecting the asymmetry of the electric charges between the mucosal and serous side of the membrane, was measured by calomel electrodes connected (Biomecatronics SAS, France) by agarose bridges immersed in a KCl solution of 3 molars in 4% (w/v). These bridges have been placed on both sides of the fabric and are suitable for each half bedroom. Everything is connected to a high impedance voltmeter (Biomecatronics SAS, France).

The potential difference was short-circuited by a short-circuit current (Icc or Isc) via 3M KCl agarose bridges placed in each reservoir, adapted to the Ag-AgCl electrodes, the whole being connected to a system of voltage-Clamp (Biomecatronics SAS, France). Isc delivered and corrected for physiological fluid resistance, was recorded continuously on a computer using BioDaqsoft software (Biomecatronics SAS, France). Isc represents the sum of the net ion fluxes transported through the epithelium in the absence of an electrochemical gradient (mainly Na+, Cl ^- ₂ and HCO ^- ₃ ).

Oral Glucose Tolerance Test (OGTT)

OGTT is performed on Wistar rats. This test consists in measuring the glycaemia as a function of time in a live rat after having made it absorb the glucose beforehand, and after the oral administration or not of the preparation according to the invention. Then the results obtained are compared.

The principle consists in putting the rat on an empty stomach the day before for 17 hours (individual mesh cages, bottle of fresh water). On the day of the tests, the very clean 20% D-glucose solution is prepared (20g / 100 ml or 200 mg/ml, prepare 2 g in 10 ml). The preparation according to the invention is administered to the rat orally at the rate of 1 g of preparation per kg of body weight, then wait 30 minutes before administering 2 g/kg of D-glucose orally. Blood glucose levels are measured in the tail vein using Accu Check Active strips (Roche diagnostic).

Implementation and testing of the pharmaceutical composition

The invention is currently practiced under the name Lavandula pedunculata (Mill) Cav (LP)

In the context of the invention, it is possible to make a combination of the lavender extract, in whole or in part, with other plants providing such common or similar compounds. As shown below, this combination of LP and Nigella sativa, Boscia senegalensis, Trigonella foenum graecum, Punica granatum, Galega officinalis presents a synergy producing better results than the addition of the results obtained individually by each of these plants. This synergy is probably due to the presence of common or similar compounds between the aqueous extracts of these two plants.

The invention thus proposes a composition comprising, in addition to the aqueous extract of Lavender, an aqueous extract of at least a second plant from Table 1.

Example of preparation of the total aqueous extract

The aerial part of the dried lavender is preferably cold ground. The powder is mixed with water and left to macerate. The maceration is then filtered and then atomized to obtain a fine powder or first dried in the oven and then ground to obtain a fine powder.

The same process is used to obtain the powder from the aqueous extracts of the second plant. The two powders are mixed to obtain the active ingredient. By way of non-limiting examples but relating to an embodiment model of the formulation, the active principle of the LP can be produced with a concentration of the dry aqueous extract of lavender which varies between 0.1 to 80% and a concentration of the aqueous extract of another plant in list 1 above from 0.1 to 50%.

Effect of the (combined) active principles of lavender on the inhibition of intestinal glucose transport

After stabilization of the electrical parameters of the tissues, the pharmaceutical preparation according to the invention as well as D-glucose were introduced into the mucous compartment of the preparation (LP at different concentrations while glucose at 10 mM). To avoid the osmotic pressure generated by the introduction of D-Glucose into the mucous compartment, the same concentrations of mannitol (10 mM) were added to the serous side of the preparation. The variations of the electrical parameters are then noted and then recorded on the computer.

Statistics

The results, shown in the accompanying figures, are reported as the mean (M) of measurements plus the standard deviation (M ± SD). All determinations were made with an average of at least 7 tissue pieces (n). One-way analysis of variance was performed, followed by Dunnett's test using GraphPad Prism 5 software (GraphPad Software, Inc. CA 92037 USA). The comparisons of the action of Lavender on the activity of alpha amylase and alpha glucosidase was carried out by the student's t test.

Presentation of the invention

Effect of Lavender extract combined with another plant extract from list 1 for its hypoglycemic activity and inhibitor of intestinal glucose absorption.

Figure 1. Effect of aqueous extract of lavender (LP) on inhibition of glucose uptake is dose-dependent. LP does not cause total inhibition of intestinal glucose absorption. This inhibition is partial

Figure 2 . Result of the oral glucose tolerance test (OGTT) on rats (A) and the area under the curve (B) obtained from A. This figure shows that the different herbal extracts can each decrease blood sugar on the fasting rat. CT= control, FGK= Trigonella foenum graecum , PG = Punica granatum, GO= Galega officinalis , LP= Lavandula pedunculata (Mill) Cav , MET= Metformin.

Figure 3 . Result of the oral glucose tolerance test (OGTT) on rats when two plants are associated (A) and the area under the curve (B) obtained from figure A. This figure shows that the different associations of Plant extracts may produce greater biological effects than individual extracts. For example, the association of LP+PG gives an effect similar to the reference drug Metformin (MET), whereas the effect of the association LP+FGK is greater than the individual effect of each of the plants used alone. CT=control, FGK= Trigonella foenum graecum , PG = Punica granatum, LP= Lavandula pedunculata (Mill) Cav , MET=Metformin.

According to the invention, the composition can be used: 1) as a medicament. 2) as a medicine for diabetes (antidiabetic). 3) as a medicine for metabolic syndrome. 4) as a drug against obesity. 5) As a non-therapeutic product as a dietary product to combat weight gain. 6) as a composition containing between 1% and 80% by weight of dry extract of lavender relative to the total weight of said composition. 7) as a composition presented in the form of a tablet or capsule and comprises between 30% and 80% by weight of dry extract of lavender relative to the total weight of said composition. 8) as a composition containing 0.1% to 50% by weight of the extract of at least one of the plants from list 1, of the following plants: Nigella sativa (seed), Hibiscus sabdariffa (calyx, leaves), Catharanthus reeds (leaves); Salvia officinalis (leaves); Galega officinalis (leaves); Juglans regia (leaves); Eucalyptus globulus (leaves); Trigonella foenum graecum (seed); Phyllanthus amarus (leaves); Scots pine or Pinus sylvestris L. buds or twig; Boscia senegalensis (bare seed); Arbutus ( Arbutus unedo ) root bark or leaves; Pomegranate (fruit) or Punica granatum ; African pyrethrum or Anacyclus pyrethrum relative to the total weight of said composition. 9) as a composition presented in the form of a tablet or capsule and comprises between 1% and 80% by weight of one of the plants from list 1 relative to the weight of Arbutus in said composition. 10) as a composition presented in the form of a powder for dilution or syrup, obtained by atomization or drying or freeze-drying from the aqueous extract.

Claims (10)

Composition, comprising an aqueous extract of lavender and an aqueous extract of at least one second plant from the following list I : Nigella sativa, Hibiscus sabdariffa, Catharanthus reeds, Salvia officinalis, Galega officinalis, Juglans regia, Eucalyptus globulus, Trigonella foenum graecum, Phyllanthus amarus, Pinus sylvestris L., Boscia Senegalensis, Arbutus unedo, Punica granatum, Anacyclus pyrethrum. Composition according to Claim 1, for its use as a medicament. Composition according to any one of Claims 1 or 2, characterized in that it comprises between 1% and 80% by weight of Lavender dry extract relative to the total weight of the said composition. Composition according to any one of Claims 1 to 3, characterized in that it is presented in the form of a tablet or capsule and comprises between 30% and 80% by weight of Lavender relative to the total weight of the said composition. Composition according to any one of Claims 1 to 4, characterized in that it comprises from 0.1% to 50% by weight of the extract of at least one of the plants from list 1 relative to the total weight of said composition. Composition according to any one of Claims 1 to 3 or 5, characterized in that it is presented in the form of a powder for dilution or syrup, obtained by atomization or drying or freeze-drying from the aqueous extract of Lavender. Composition according to Claim 2, for its use as a medicament against diabetes. Composition according to Claim 2, for its use as a medicament against obesity. Composition according to Claim 2, for its use as a medicament against the metabolic syndrome. Composition according to any one of Claims 1 and 3 to 6, for its non-therapeutic use as a dietetic product for combating weight gain