EP2504018A1

EP2504018A1 - Antidiabetic composition comprising a plant extract of englerina lecardii

Info

Publication number: EP2504018A1
Application number: EP10801273A
Authority: EP
Inventors: Aliou Mamadou Balde
Original assignee: Individual
Current assignee: Balde Aliou Mamadou
Priority date: 2009-11-23
Filing date: 2010-11-23
Publication date: 2012-10-03
Also published as: FR2952824B1; WO2011061725A1; US20120315327A1; US8703213B2; FR2952824A1

Abstract

The invention relates to a pharmaceutical antidiabetic composition containing, among the active ingredients thereof, a plant extract of Englerina lecardii, preferably a hydroalcoholic extract of Englerina lecardii leaves. The composition is preferably formulated in the form of microspheres produced using an extrusion and spheronisation method, and then grouped together in capsules. In particular, the composition is intended for cases of type 2 diabetes.

Description

ANTIDIABETIC COMPOSITION CONTAINING A VEGETABLE EXTRACT FROM ENGLERINA LECARDII

The present invention relates to the use of a vegetable extract Englerina lecardii for the manufacture of a pharmaceutical composition for the treatment of diabetes, more particularly for the treatment of type II diabetes.

Diabetes is a chronic condition that occurs when the pancreas does not secrete enough insulin, so-called type I diabetes, or when the body misuses the insulin it produces, so-called diabetes. II. Insulin is a hormone that regulates the concentration of sugar in the blood. Hyperglycemia, a high blood sugar concentration, is a common effect of diabetes which, over time, causes serious damage to many parts of the body, especially the heart, blood vessels, eyes, kidneys or nerves.

Type II diabetes accounts for 90% of the world's diabetes and is mainly caused by diet problems, overweight, lack of exercise and genetic factors. Fortunately, type I diabetes is a rare death and is rapidly fatal without the daily administration of insulin.

The World Health Organization (WHO) estimates that there are more than 180 million diabetics in the world, including 4 million in France alone, and that there will be more than double that in 2030. D ' after estimates, 1, 1 million people died of diabetes in 2005 and WHO predicts that deaths from diabetes will increase by more than 50% over the next 10 years if urgent action is not taken .

Diabetes and its complications also have important economic and social consequences for patients, their families, health systems and the nations concerned.

Nowadays, the most used treatment for diabetes is to administer a glucophage to the patient. It is usually metformin, a chemical obtained by semisynthesis from a plant called Galega.

The metformin molecule, usually used under form of tablets, has several disadvantages.

First, it has many medical contraindications. Metformin is particularly contraindicated in case of diabetes ketoacidosis, diabetic precoma, even moderate renal disorders (or pathologies causing them), liver disorders, explorations using iodinated contrast media, insufficiency cardiac or respiratory failure. It should not be given in children and lactating women and can only be taken under medical supervision by elderly and pregnant women. Finally, the prolonged use of metformin potentiates the risk of the appearance of its undesirable effects.

Metformin can also cause many side effects, including gastrointestinal symptoms such as nausea, vomiting, diarrhea, abdominal pain and loss of appetite. In some people, mild erythema, reduced vitamin B12 absorption with reduced serum levels and lactic acidosis have also been observed, with in the most severe cases acidotic dyspnea, abdominal pain, and hypothermia followed by coma.

Metformin, which is difficult to dose depending on each individual, can also cause, in case of overdose, an excessive drop in blood glucose, with consequences as serious as hyperglycemia.

In addition, metformin is an expensive drug, which poses a serious economic problem for diabetics from the poorest countries. Indeed, it should be remembered that almost 80% of diabetes deaths occur in low- and middle-income countries. However, the high cost of conventional diabetes treatments makes it difficult to access care in developing countries. Access to diabetes treatment is therefore limited to a very small proportion of those concerned.

Finally, metformin is a fragile molecule that requires strict conservation conditions, which is extremely problematic in hot and / or humid countries, particularly in Africa and Asia.

In these countries, particularly in Africa, it would be particularly interesting to have an effective treatment and much cheaper, obtained from local plants and in a form that does not pose conservation problems.

This is the goal of the invention whose objective is to provide an effective drug, generating much fewer side effects and whose cost would remain low compared to the cost of current drugs against diabetes.

To solve this technical problem, the invention teaches the use of a vegetable extract Englerina lecardii for the manufacture of a pharmaceutical composition for the treatment of diabetes.

Advantageously, the composition according to the invention has no or very few side effects and is much less expensive than conventional diabetes medications. It is thus much better accepted by patients for long-term regular treatment.

It is particularly effective in type II diabetes, which is the most common type of diabetes.

It has a role of stimulation of the pancreas which allows the patient to secrete himself the sufficient amount of insulin necessary for his health. Studies have shown that the antidiabetic pharmaceutical composition of the invention makes it possible to treat diabetes from a level of 1.05 g / l of sugar in the blood.

Since the active principle of the antidiabetic pharmaceutical composition of the invention is directly derived from a natural plant extract, without chemical modification of its molecules, it is much better supported by the body and causes fewer side effects.

In addition, its effect is reinforced by the other components of the plant present in the plant extract and which are mixed with the active ingredient when the therapeutic composition is carried out.

In addition, and as is often the case with natural extracts of plants that are not chemically modified, the active principle of the antidiabetic pharmaceutical composition of the invention has very low risks of overdose, which considerably reduces the risk of excessive hypoglycaemia due to taking the medicine.

Other features and advantages of the invention will appear on reading the detailed description which follows. Englerina lecardii or Loranthus lecardii, whose vernacular name is sattaga bowal, is a sub-woody, hemiparasitic plant of the family Loranthaceae. It grows on savannah trees and is widely distributed in Senegal, Mali, Guinea-Bissau and Guinea. It has opposite or subopposed leaves, petiolate; and an ovate to elliptical or lanceolate leaf blade with cuneate base and acute to subacumine, glabrous and penninerve, with four to six pairs of lateral veins. Its flowers are golden yellow, showy, with a peduncle of 2.2 to 2.7 cm long, short pedicellate, grouped in pedunculate, axillary and perigonal umbels splitting on one side. It produces egg-shaped, egg-shaped fruits, 6-9 mm long, which are red when ripe.

To achieve the therapeutic composition according to the invention, a plant extract is used Englerina lecardii. This extract is preferably obtained from the leaves of Englerina lecardii and has a hypoglycemic activity, as well as an antioxidant and cytoprotective phytotherapeutic effect.

The fact of using the leaves of the plant to obtain the plant extract is advantageous, since the removal of these leaves does not destroy the plant, which can therefore continue to produce other leaves used to make the pharmaceutical composition of the plant. invention. However, other parts of the plant Englerina lecardii could also alternatively be used to make the composition according to the invention.

The leaf extract of Englerina lecardii contains many active ingredients, many of which have been identified. In order to study the chemical composition of this extract, a phytochemical screening was carried out by means of general tests and by thin layer chromatography. It revealed that the plant extract Englerina lecardii contains proanthocyanidins, saponosides, reducing compounds and carotenoids. Column chromatography revealed the presence of oligosaccharides and mainly polyphenols.

The plant extract Englerina lecardii used in the context of the invention is preferably a vegetable solution or a liquid plant extract and for example according to its concentration a mother tincture, an officinal dye or a liquid extract 6'Englerina lecardii.

This solution or liquid extract is obtained by any appropriate means and in particular by extraction, preferably aqueous, alcoholic or hydro-alcoholic, by maceration, infusion, decoction, digestion, leaching or the like.

According to a preferred embodiment of the invention, a liquid plant extract is prepared from Englerina lecardii leaves by means of hydro-alcoholic extraction by a stirring percolation technique. Its alcohol content is preferably between 30 and 70 °.

For example, Englerina lecardii mother tincture with an ethanol content of about 70% VA / was prepared from Englerina lecardii dry leaves by exhaustive cold percolation followed by concentration under vacuum. on the rotary evaporator.

The composition according to the invention can adopt different galenic forms. It can for example be in the form of tea bags containing for example about 5 grams of Englerina lecardii leaves roughly crushed.

It may also be in the form of tablets, preferably orodispersible, soft capsules, granules, capsules, powder, ampoules, syrup or any other appropriate dosage form, preferably oral, imaginable by the human being. job.

Preferably, the composition according to the invention is formulated in the form of microspheres, also called spheroids, preferentially grouped into capsules in an amount corresponding for example to a unit dose.

This has the many advantages of this dosage form, namely on the medical side a rapid release and high bioavailability of the active ingredients, and in practice a great ease of use for the patient and a little fragile and very stable form in the long run even under difficult storage conditions.

These microspheres can be made by different methods.

A first method consists for example in making a peripheral layer containing the plant extract Englerina lecardii around a neutral nucleus, formed for example of a mixture of sugar and starch or a crystal of sugar, mannitol or sorbitol.

The layer containing the plant extract Englerina lecardii can advantageously be made by coating, impregnation, spraying or spraying, the active ingredient being for this purpose preferably mixed with a mounting agent or a binder.

According to a second preferred method, the microspheres or spheroids can be formed by extrusion and spheronization.

For this purpose, the vegetable extract of Englerina lecardii is first mixed with an absorbent and adsorbent substance, preferentially of natural or synthetic polymer type, having plastic properties compatible with the extrusion and spheronization steps of the rest of the process.

It is for example microcrystalline cellulose, microfine cellulose, a weakly substituted hydroxypropyl cellulosic polymer, starch, modified starch, polysaccharides or any other suitable substance or mixture.

If the mixture is too dry, an aqueous or non-aqueous humidifying liquid may also be added to obtain a homogeneous, malleable paste that can undergo the next steps of the process.

The moistening liquid also serves as a vehicle for transporting and depositing the active ingredient to the heart of the absorbent and adsorbent substance in the microcavities of the polymer.

The manufacturing process then consists of extruding the wet mass through a die with calibrated orifices. This produces compact filaments of generally cylindrical and defined section, called "extrudates".

These "extrudates" are then placed in a cylindrical device called "spheronizer" containing in the lower part a fluted disc rotating at a variable and controlled speed. Under the effect of the centrifugal force exerted by the rotation of the rotating disk, the "extrudates" are fragmented regularly, then turn into spheres by a rolling-binding effect. The desired spheroids are thus obtained.

These two methods may further comprise at least one drying step and / or a calibration step. The drying can be done by light heating for example at a temperature between 30 and 40 ° C or by simple exposure to the open air for a sufficient time.

Finally, the resulting spheroids may optionally be coated on the periphery of an outer skin to protect for example external moisture, heat, aggressive body conditions or delayed effect.

The present inventors have found that the plant extract of leaves Englerina lecardii advantageously has, in addition to its antidiabetic properties, antibacterial, cytoprotective and antioxidant properties.

Biological studies have shown that the non-polar, chloroformic and / or ethyl acetate extract of Englerina lecardii leaves is active against Trypanosoma cruzi with a MIC (Minimum Inhibitory Concentration) of 2.05 to 2.91 g / ml and against T. brucei with a MIC of 2.18 g / ml. Plasmodium falciparum antiplasmodial activity was also noted (MIC = 16.91 μg / ml) and modest activity against Staphylococcus aureus (MIC = 29.1 μg / ml).

The polar methanol extract of Englerina lecardii leaves shows modest activity on Candida albicans with a MIC of 28.12 mg / ml.

With regard to the antidiabetic properties of the composition according to the invention, the present inventors have conducted two studies which have led to the conclusion of a significant decrease in blood glucose levels in diabetic patients treated with a decoction of leaves of Englerina lecardii. .

The first study is a preliminary ethno-therapeutic evaluation that was conducted in sixteen diabetic patients (nine men and seven women), aged 36 to 70 years.

These patients received daily, for eight weeks, three doses of Englerina lecardii plant extract, in the form of tea bags containing 5 g of coarsely crushed Englerina lecardii leaves.

This treatment resulted in a significant decrease in blood glucose level in thirteen patients. The progressive decreases in average blood glucose levels were as follows: 2.18 g / 1; 1.86 g / l; 1. 57 g / l; 1. 25 g / l and 1.11 g / l.

The second study is a clinical trial that was performed in the Endocrinology-Diabetology and Metabolic Diseases Department of the DONKA National Hospital in Conakry, Guinea. This controlled clinical trial has demonstrated the efficacy and good tolerance of a composition based on Englerina lecardii in the treatment of diabetes in adults. The details of this test are described below.

The patients included in the trial were treated with three strips of 5 g of Englerina lecardii leaves daily for three months.

Out of 31 subjects initially included, 25 subjects (nine men and sixteen women, mean age: 49 years) participated in the trial to completion. Four patients were lost to follow-up and two patients stopped participating in trials for personal convenience. In three cases, intermediate laboratory data (transaminases, bilirubin, venous glucose) were not collected for material reasons (samples not analyzed for lack of electricity).

Efficiency

Glucose averages before inclusion and after six and twelve weeks of treatment are shown in Table I below.

In this table, it can be seen that fasting blood glucose decreased on average by 80 mg / dl (205 mg / dl on average at baseline versus 125 mg / dl on average after 12 weeks of treatment, p <0.001). Table I: Changes in averages after 6 and 12 weeks of treatment with Englerina lecardii and comparison after 12 weeks of treatment with Englerina lecardii with parameters evaluating efficacy (n = 25 subjects)

6 12 Difference

Variables Inclusion p ** wk. wk. absolute (%) *

Weight (Kg) 77.28 77.32 76.81 -0.47 (-0.61%) 0.41

Body mass index (Kg / m ² ) 28.94 28.98 28.70 -0.24 (-0.83%) 0.53

Systolic Blood Pressure (mm Hg) 128.8 125.6 123.2 -5.6 (-4.35%) 0.07

Diastolic Blood Pressure (mm Hg) 83.2 82.8 80.8 -2.4 (-2.88%) 0.27

Fasting blood glucose (g / l) 2.05 1, 51 1, 25 -0.80 (-39.02%) <0.001 ^* Between baseline and observed values after 12 weeks of treatment ^** Comparison by t Test.

Tolerance

In addition to the efficacy of the treatment, its tolerance was also assessed in this trial, both clinically and biologically.

Clinically, ten patients (40% of the subjects tested) reported side effects: diarrhea in four cases (16%), bitterness to ingestion in two cases (8%), increased polyuria in one case (4%), a dry mouth in one case (4%), daytime sleepiness and a feeling of "lightness" without concomitant hypoglycemia in one case (4%).

Biologically, biological tolerance monitoring parameters were measured at baseline and after six and twelve weeks of treatment. The evolution of these parameters is presented in Table II below. Table II: Evolution of the averages after 6 and 12 weeks of treatment with Englerina lecardii and comparison after 12 weeks of treatment with Englerina lecardii parameters assessing tolerance (n = 25 subjects)

6 12 Difference

Variables Inclusion p ** wk. wk. absolute (%) *

ALT (Ul / I) 7.15 6.42 6.47 -0.68 (-9.51%) 0.73

ASAT rate (UI / I) 7.43 12.47 7.57 0.14 (+1, 88%) 0.89

Bilirubin (mmol / l) 13.26 1 1, 77 1 1, 16 -2.10 (-15.84%) 0.31

Creatinine (mmol / l) 72.1 1 67.08 88.80 +16.69 (+ 23.15%) 0.38 * Between the baseline and the 12 weeks of treatment.

** Comparison by t Test.

No abnormalities in blood counts were observed during the trial. There was a slight increase in creatinine (72.1 mmol / l at baseline versus 88.8 mmol / l after 12 weeks of treatment) with no associated proteinuria. The following parameters: weight, waist circumference and hip circumference, systolic and diastolic arterial pressures, transaminases (ASAT and ALT) and bilirubin, did not change significantly.

In sum, no major adverse events were reported. The majority of reported clinical side effects are gastrointestinal (diarrhea) or are likely related to the mode of administration (bitterness to ingestion). The symptoms of polyuria (6%) and dry mouth (6%) may be related to hyperglycemia itself. The daytime sleepiness and the feeling of "lightness" reported by a subject were not explained, especially since they could not be related to hypoglycaemia.

From a biological point of view, blood creatinine levels increased compared to baseline levels (21% for subjects at the end of the trial and 18% for subjects at half the time of treatment). However, no subject has reached a level of creatinine likely to cause renal toxicity. Transaminase levels remained within normal limits, while mean bilirubin levels increased after 6 weeks of treatment before decreasing after 12 weeks. weeks of treatment.

Therefore, a decrease of about 0.8 g / l in blood glucose level can be observed due to the administration of Englerina lecardii, which appears clinically interesting. The hypoglycemic effect suggested during the ethnotherapeutic preliminary study is thus confirmed. The decrease in blood glucose is progressive and is observed without weight gain.

In addition to the vegetable extract Englerina lecardii, the composition according to the invention may contain one or more other suitable compounds or excipients such as for example extracts of one or more other plants, vitamins, minerals, trace elements , compounds increasing the effectiveness of the active ingredient, protecting it or assisting in its rapid release, flavorings, mounting agents, binding compounds, slippery compounds, lubricating compounds, surfactants, sugars, lactose, sorbitol, mannitol, modified starches or starches, maltodextrins, carbonates, citrates, gelatin, polyvinylpyrrolidone, polysaccharides, cellulose derivatives, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, microfine cellulose , low substituted hydroxypropyl cellulosic polymers or any other suitable compound.

The following example will better illustrate the invention. Spheroids were made by the extrusion and spheronization process described above, from a hydroalcoholic extract of Englerina lecardii leaves, prepared according to the European Pharmacopoeia, with an ethanol content of 70% VA / and a residue. dry about 10%. These spheroids were collected in capsules of 350 mg.

Example:

For a capsule of 350 mg:

• extract Englerina lecardii 350 ml equivalent dry residue 35 mg

• microcellulose q.s.

The spheroids obtained were grouped into capsules of 350 mg corresponding to a unit dose of composition, for a preferred dosage of three capsules per day.

It is specified here that one can add chromium to the formula in variable proportions acceptable and tolerable by the human body according to the guidelines of the WHO World Health Organization.

This trace element is a facilitator that activates the fight against diabetes.

This incorporation can be carried out in various ways including the simple addition to the extract or the microcrystalline cellulose powder or even in the wetting liquid.

Obviously, the invention is not limited to the preferred embodiments described above, the skilled person can make many modifications and imagine other variants without departing from the scope or the scope of the invention defined by the claims.

Claims

1. Use of a plant extract 6'Englerina lecardii for the manufacture of a pharmaceutical composition for the treatment of diabetes.

2. Use of a plant extract Englerina lecardii according to the preceding claim for the manufacture of a pharmaceutical composition for the treatment of type II diabetes.

3. Use of a vegetable extract Englerina lecardii according to claim 1 or 2 characterized in that the plant extract of Englerina lecardii is obtained from leaves of Englerina lecardii.

4. Use of a vegetable extract Englerina lecardii according to claim 3, characterized in that the vegetable extract Englerina lecardii is a hydro-alcoholic extract of leaves Englerina lecardii.

5. Use of a vegetable extract of Englerina lecardii according to claim 4, characterized in that the plant extract of Englerina lecardii is a mother tincture of Englerina lecardii with an ethanol content of about 70% V / V .

6. Use of a vegetable extract Englerina lecardii according to any one of claims 1 to 5, characterized in that the pharmaceutical composition further contains one or more compounds or excipients selected from plant extracts, vitamins, minerals, trace elements, compounds increasing the effectiveness of the active ingredient, protecting it or assisting in its rapid release, flavorings, mounting agents, binding compounds, slippery compounds, lubricating compounds, surfactants, sugars, lactose, sorbitol, mannitol, modified starches and starches, maltodextrins, carbonates, citrates, gelatin, polyvinylpyrrolidone, polysaccharides, cellulose derivatives, crosslinked sodium carboxymethylcellulose, microcrystalline cellulose, microfine cellulose and weakly substituted hydroxypropyl cellulosic polymers.

7. Use of a plant extract of Englerina lecardii according to any one of claims 1 to 6, characterized in that the pharmaceutical composition is in an oral dosage form.

8. Use according to any one of the preceding claims, characterized in that chromium is added in amounts tolerable by the human body.

9. Use of a vegetable extract Englerina lecardii according to any one of claims 1 to 7, characterized in that the pharmaceutical composition is in a dosage form of infusettes, microspheres, tablets, orodispersible tablets, soft capsules, granules, capsules, powder, ampoules or syrup.

10. Use of a vegetable extract of Englerina lecardii according to claim 9, characterized in that the pharmaceutical composition is in a dosage form of infusettes containing about five grams of Englerina lecardii leaves coarsely ground.

1 1. Use of a vegetable extract of Englerina lecardii according to Claim 9, characterized in that the pharmaceutical composition is in a galenical form of microspheres produced by an extrusion and spheronization process.

12. Use of a vegetable extract of Englerina lecardii according to claim 1 1, characterized in that the microspheres are grouped into capsules.