EP3829714A1

EP3829714A1 - Oral nutraceutical composition for use in the treatment of metabolic syndrome

Info

Publication number: EP3829714A1
Application number: EP19758812.2A
Authority: EP
Inventors: Mauro Rissa
Original assignee: Pharmanutrition R&d Srl
Current assignee: Pharmanutrition R&d Srl
Priority date: 2018-08-01
Filing date: 2019-08-01
Publication date: 2021-06-09
Also published as: IT201800007746A1; WO2020026186A1

Abstract

Oral composition comprising Berberis aristata with a minimum titre of 50% in berberine chloride, Cynara Scolimus extract with a minimum titre of 2.5% in caffeoylquinic acids, a polyoxyethylenate sorbitan ester, Piper nigrum extract with a minimum titre of 80% in pipeline content. This oral composition in particular in the form of a nutraceutical formulation is in particular suitable for the treatment of the metabolic syndrome.

Description

“Oral nutraceutieai composition for use in the treatment of metabolic syndrome”

DESCRIPTION

FIELD OF THE INVENTION

The present invention relates to a composition, in particular a nutraceutical formulation for the treatment of the metabolic syndrome.

STATE OF THE ART

Among the most effective substances and of high nutraceutical potential, but with poor oral bioavailability, berberine chloride (BERC), an alkaloid extracted from plants of the genus Berberis, characterized by the following formula, is certainly worth of consideration

Berberine chloride

It has shown interesting and well-documented anti-inflammatory and hypoglycaemic properties in the treatment of diseases such as the metabolic syndrome or in cardiovascular prophylaxis [1, 2, 3, 4, 5] BERC, net of its now unequivocal pharmacological and therapeutic potential, well documented in the literature, shows in the studies carried out on CACO-2 a high rate of expulsion from the enterocyte by the action of the P-gP pump [6, 7] This phenomenon seems to be the main cause of the poor oral bioavailability of BERC in humans [8]

Particularly interesting is the association of BERC with substances able to create pharmacological synergies in terms of reduction of plasma cholesterol fractions, in particular LDL and fasting glycaemia and to favour the restoration of a trophic state of the hepatic parenchyma, reducing steatosis and normalizing the secretion of intracellular enzymes such as GOT and GPT, indicators of hepatocytic cell damage during exotoxic liver diseases. In this context, the association between BERC and Cynara Scolimus extracts titrated in caffeoylquinic acids seems to have a particularly favourable pharmacological profile in the context of the mentioned therapeutic- nutraceutical objectives, with particular reference to the normalization of blood lipid parameters (total cholesterol and LDL, triglycerides) and normalization of liver parameters of liver damage [9]

In order to improve the bioavailability and bioaccessibility profile of BERC, in the light of the biotransformation phenomena and the lack of enterocytic internalization mentioned above, it is also necessary to provide a pharmaceutical form capable of interfering with the P-Gp enterocytic pump, reducing its expulsion rate towards the enteric lumen.

It is known that the black pepper pipeline acts as an inhibitor of the metabolization of pharmacological and nutraceutical active ingredients, in particular by inhibiting the enzyme UDP-glucuronyl transferase, responsible for enterocytic and hepatic glucuronidation [10] Polysorbate 80 (PS 80), a polyoxyethylene sorbitan ester with oleic acid, has been shown to favour the bioavailability of pharmacologically active ingredients and nutraceutical substances through a mechanism that increases their diffusibility through the mucopolysaccharide layer that coats the enteric epithelium (UWP) and by inhibiting P-gP [11]

WO 2014/044744 Al describes compositions for the treatment of the metabolic syndrome containing, as essential ingredients, the Cynara scolimus extract with a content of 30-45% in caffeoylquinic acid, extracts of Coffea spp with a content of caffeoylquinic acids ranging from 40 to 80% by weight and finally an Olea europaea extract.

JP 2013 237656 A reports that pipeline is used as an anti-dyslipidaemic agent, as it prevents the differentiation and maturation of cells in adipocytes.

US 2016/106793 Al describes a composition containing a combination of at least 3 extracts (including Cynara Scolimus , Chrysanttellum indicum and Vaccinium myrtillus) together with pipeline for the treatment of metabolic disorders.

EP 2 810 941 Al describes piperine derivatives having anti-dyslipidaemic activity, PANAHI YUNES ET AL in "Lipid-modifying effects of adjunctive therapy with curcuminoids-piperine combination in patients with metabolic syndrome: Results of a randomized controlled t", COMPLEMENTARY THERAPIES IN MEDICINE, vol. 22, no. 5, pages 851-857, XP029080004,ISSN: 0965-2299, DOI:

10.1016/J.CTIM.2014.07.006 e in "Antioxidant and anti-inflammatory effects of curcuminoid-piperine combination in subjects with metabolic syndrome: A randomized controlled trial and an updated meta-analysis", CLINICAL NUTRITION, CHURCHILL LIVINGSTONE, LONDON, GB, vol. 34, no. 6, 7 January 2015 (2015-01-07), pages 1101-1108, XP029324349, ISSN: 0261-5614, DOI: 10.1016/J.CLNU.2014.12.019 disclose the activity of the association of curcumin and piperine to treat the metabolic syndrome.

SALEM MARYEM BEN ET AL in "Pharmacological Studies of Artichoke Leaf Extract and Their Health Benefits", PLANTS FOODS FOR HUMAN NUTRITION, KLUWER ACADEMIC PUBLISHERS, NL, vol. 70, no. 4, 27 August 2015 (2015- 08-27), pages 441-453, XP035929326,ISSN: 0921-9668, DOI: 10.1007/S11130-015- 0503-8[retrieved on 2015-08-27] are interested in the general health benefits of artichoke leaf extracts. NOMIKOS ET Al in "Boiled wild artichoke reduces postprandial glycemic and insulinemic responses in normal subjects but has no effect on metabolic syndrome patients", NUTRITION RESEARCH, ELSEVIER INC, XX, vol. 27, no. 12, 26 November 2007 (2007-11-26), pages 741-749, XP022361961, ISSN: 0271-5317, DOI: 10.1016/J.NUTRES.2007.09 .009 reports the activity of Cynara cardiunculus extracts (thistle or wild artichoke) in reducing blood glucose and postprandial insulin only on healthy subjects but not on individuals with metabolic syndrome.

JURGONSKI ADAM ET AL: in "Caffeoylquinic acid-rich extract from chicory seeds improves glycaemia, atherogenic index, and antioxidant status in rats", NUTRI, vol. 28, no. 3, 1 March 2012 (2012-03-01), pages 300-306,

XP009166712, ISSN: 1873-1244, DOI: 10.1016/J.NUT.2011.06.010 [retrieved on 2011-10-19] report that chicory extracts rich in caffeoylquinic acids are effective in the treatment of metabolic syndrome together with rutin, a quercetin derivative. TABESHPOUR JAMSHID ET AL: "A review of the effects of Berberis vulgaris and its major component, berberine, in metabolic syndrome", IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES, vol. 20, no. 5, 30 April 2017 (2017-04-30), pages 557-568, XP00951097 4 report the activity of Berberis vulgaris and in particular of berberine as an anti-dyslipidaemic.

WO 2018/189672 Al describes the association of the Cynara cordiunculus extract that, as noted above, is the common thistle, with an extract of another plant, Citrus aurantium bergamia, in the treatment of hepatic steatosis and in the treatment of dyslipidaemia.

SUMMARY OF THE INVENTION

An oral composition and an industrial method for its realization have been identified in order to achieve a pharmaceutical form able to maximize the effectiveness of BERC and of the extract. The applicant has in fact unexpectedly found that the second Cynara Scolimus extract titrated in caffeoylquinic acids acts, in synergy with Piperine and a polyoxyethylene sorbitan ester, preferably polysorbate 80, in the inhibition of P-gP, thus consolidating the effect of promoting absorption. In fact, confirming this, the applicant has furthermore found that the oral composition that is the object of the present invention and comprises Berberis aristata extract with a minimum titre of 50% in BERC, Cynara scolimus extract with a minimum title of 2.5% in caffeoylquinic acids, dispersed in a suspension of polysorbate 80 and Piper Nigrum extract with a minimum titre of 80% in piperine, shows a high efficacy, clinically documented, in normalizing the lipidic, glucidic and hepatic profile in patients with moderate hypercholesterolemia and compatible with the initial clinical signs of metabolic syndrome.

Therefore, the object of the present invention is an oral composition comprising

A) as the only active ingredients Berberis aristata with a minimum of 50% in berberine chloride, Cynara scolimus extract and possibly:

· a vitamin of the B group,

• folic acid and

• a pharmaceutically acceptable chromium salt,

B) as absorption promoters, a polyoxyethylenate sorbitan ester, Piper nigrum extract with a minimum titre of 80% in piperine, in which Cynara scolimus has a titre of 2.5% in caffeoylquinic acids and is present in an amount such that the caffeoylquinic acid content is between 0.5 and 5 mg.

The association of polysorbate 80 - piperine has not been described yet, at least in the form of intimate mixing of the second in the first, as foreseen in the process to prepare the aforementioned formulation in order to obtain an enteric absorption promoter capable of simultaneously improving the diffusion of the active ingredient through the UWP and the inhibition of UDP-glucuronyl transferase in the enterocyte. The further object of the present invention, namely the industrial method for the preparation of the aforementioned oral composition, preferably in the form of a gastro-resistant tablet, comprises in particular the following steps:

1) dispersing the extract of Piper nigrum titrated in pipeline in the polyoxyethylenate sorbitan, until obtaining a uniform and stable suspension over time;

2) intimately mixing Cynara scolimus and Berberis aristata in the form of powders, until a uniform powder is obtained;

3) wetting the powder coming from step b) with the liquid suspension of step a);

4) merging the obtained wet powder coming from step c) with possible excipients such as calcium phosphate, microcrystalline cellulose and magnesium stearate in order to obtain a dry, smooth and compressible powder;

5) compressing the powder obtained in step d;

6) coating the tablets obtained in the previous step with gastro-resistant film comprising hydroxypropyl cellulose and crospovidone or polymers of methacrylic acid commercially available under the tradenames Eudragit, Eudragard.

This process is characterized by the wetting of the powder mixture composed of Berberis aristata extract and Cynara scolimus extract titrated in caffeoylquinic acids into the suspension of the polyoxyethylenate sorbitan ester and Piperine, prepared in step a. The intimate mixing of the two active principles with the aforementioned absorption promoters achieved in the step c of the process of the invention allows obtaining a final powder, which is subsequently compressed and coated with a film that ensures the overcoming of the gastric transit and the subsequent disaggregation in the first enteric tract (3 hours), considerably increases the effectiveness of the absorption promotion system thus favouring an increased clinical response compared to the mere association of the active ingredients. Moreover, the action of Cynara scolimus titrated in caffeoylquinic acids is responsible for a cholesterol-lowering effect synergistic to that of BERC and of a hepato-trophic and detoxifying effect, responsible for the normalization of the plasma enzyme profile (GOT, GPT).

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, the definition "comprising" before a list of components, as in the case of the oral composition object of the invention or of steps as in the process, further object of the invention, does not exclude the presence of further components or steps besides those listed.

In the oral composition according to the present invention, the Berberis aristata extract preferably has a titre of 98% in berberine chloride.

Preferably, the Berberis aristata is present in the formulations object of the invention in such a content that the berberine chloride is present in a variable amount between 250 and 500 mg.

In the oral composition according to the present invention, the Cynara scolimus extract is present in amounts such as to have a caffeoylquinic acid content of between 0.5 and 5 mg.

Polysorbate 80, also known as PS80, is preferably used as sorbitan polyoxyethylenate ester. The sorbitan polyoxyethylenate ester content can vary from a minimum of 1% to a maximum of 10% by weight of the weight of the oral composition.

Preferably, for the purposes of the present invention, the Piper nigrum extract has a piperine titre between 95 and 98%.

Preferably, in the oral composition according to the present invention, the Piper nigrum is present in such amounts that the piperine content varies between a minimum of 0.1% by weight to a maximum of 2% of the total weight of said composition. Oral compositions may also contain as an active ingredient a vitamin belonging to B vitamins and a pharmaceutically acceptable chromium salt to further promote the normalization of glycaemia.

According to preferred solutions, the oral composition object of the present invention comprises picolinate chromium as pharmaceutically acceptable chromium salt, and as B vitamins, the oral composition object of the invention contains vitamin Bl and folic acid to assist the hypoglycaemic effect. According to a particularly preferred embodiment, the oral composition according to the present invention comprises chromium picolinate, vitamin Bl and folic acid.

The oral compositions object of the present invention can be in the form of granulates or gastro-resistant tablets, even if as mentioned above, the latter are particularly preferred.

The oral compositions according to the present invention are preferably in the form of nutraceutical formulations and are in particular suitable for the treatment of the metabolic syndrome.

For the purposes of the present invention, a nutraceutical is, in its original definition, a food, or part of a food with proven beneficial and protective effects on both the physical and psychological health of the individual, according to what reported in the review entitled NUTRACEUTICA: DEFINIZIONE, REGOL AMENT AZIONE E APPLICAZIONI by A. Pirillo and A.L. Catapano and published in Giornale Italiano di Farmacoeconomia e Farmacoutilizzazione 2014; 6 (4): 23-30.

In the process object of the present invention in the step d) the possible excipients are selected from at least one of the following: calcium phosphate, microcrystalline cellulose and magnesium stearate in order to obtain a dry, smooth and compressible powder. An example of an oral composition according to the present invention in the form of a gastro-resistant tablet is reported below for illustrative purposes.

EXAMPLE 1

The clinical study proving the efficacy of the oral compositions according to the present invention is reported below.

EXAMPLE 2

2.1. Premise

Despite the progress in scientific knowledge about the prevention of cardiovascular diseases, they still represent the most frequent cause of death in the world today, causing the death of about 4 million people every year in Europe alone. In particular, cardiovascular diseases related to atherosclerosis are responsible for 42% of deaths in women and 38% in men under 75 [12]

Several known risk factors contribute to the development of cardiovascular diseases; classically they are divided into factors that can be modified with lifestyle changes or a pharmacological treatment (e.g. hypercholesterolemia, hypertension, smoking, diabetes mellitus) and non-modifiable factors (age, male sex, familiarity). Among the modifiable factors, high concentrations of LDL cholesterol represent one of the main independent cardiovascular risk factors [13]

From the available data, it can be concluded that a 1% reduction in LDL cholesterol corresponds to a relative risk reduction for cardiovascular events of about 1% [14] Thus, a reduction in LDL cholesterol by 20%, compatible with a correction of eating habits and nutritional supplementation with effective nutraceuticals, would have the potential to reduce cardiovascular risk by about 20%.

The lipid-lowering nutraceuticals described in the literature are numerous and their use is supported by different levels of scientific evidence and efficacy [15] The single most effective (and even best-selling) nutraceutical is fermented red rice extract, whose active ingredient is monacolin K, a substance produced by fermentation of common rice by the fungus Monascus purpureus. Monacolin K is very effective, as it has the same chemical structure as synthetic lovastatin [16] However, this analogy has its disadvantages, because it is associated with the same side effects of statins (although attenuated by the dosage limitations provided for by the law) and the same risk of drug interactions, for which some European Union states are proposing employment restrictions.

The aim of this study was the evaluation of the short-term metabolic effect of the combination of other cholesterol-lowering nutraceuticals with a different action from statins such as dry extracts of artichoke and berberis in patients suffering from moderate hypercholesterolemia in primary prevention for cardiovascular diseases.

2.2. Materials and methods

For this double-blind, placebo-controlled, parallel-group randomized clinical trial, we consecutively enrolled 40 patients with the following characteristics:

- Primary prevention for cardiovascular diseases

- LDL-C = 130-190 mg/dL and TG <400 mg/dL

- Willingness to participate in the study

- Adherence to a globally correct diet

Patients in primary prevention with high cardiovascular risk (estimated according to ESC guidelines) and secondary prevention (including patients with moderate to severe renal insufficiency and type 1 and 2 diabetes mellitus), obese (BMI> 30 mg/dL) were excluded, as well as those with known liver diseases. The test was conducted in accordance with the principles of the Helsinki Declaration and enrolled patients signed an ad hoc informed consent.

After a 15-day run-in period aimed at standardizing eating habits with correction of the most macroscopic errors, the enrolled patients were then randomized to receive one tablet at night before going to bed whose formulation is the one shown in Example 1 or a placebo (indistinguishable in shape and volume), for a duration of 8 weeks, in association with a standardized Mediterranean diet.

All the laboratory tests were performed using standardized methods [17] by trained personnel at the lipidology laboratory belonging to the Department of Medical and Surgical Sciences of the Alma Mater Studiorum ETniversity of Bologna. Cholesterolaemia LDL and non-HDL have been calculated with standard formulas. Cholesterolaemia LDL was also dosed by direct method, to avoid that the effect of the diet on triglyceridemia altered the perception of reduced LDL cholesterol level dosed with the Friedewald formula.

All data were statistically analysed with the help of SPSS 21.0 for Windows. After a descriptive analysis, inferential comparative analyses were conducted for dependent and independent samples, using non-parametric tests to compare symptom intensities (Mann-Whitney test for non-parametric data). A "p" level below 0.05 was chosen as the significance threshold for all tests.

2.3 Results

The characteristics of the patients enrolled in the baseline are summarized in Table 1. All patients completed the study and no one complained of side effects. In particular, no patient showed increases in serum CPK or complained of myalgia or cramps. Anthropometric variations (body weight, waist circumference, body mass index) were not observed in both groups.

In particular, none of the 5 patients enrolled in the group treated with the tested nutraceutical, previously intolerant to low-dose statins or fermented red rice, reported side effects.

In the placebo group there was a significant reduction in total cholesterol, LDL and non-HDL as well as in triglyceridemia compared to baseline, demonstrating the effectiveness of the dietary approach set (Table 2).

Regarding efficacy, the combined nutraceutical significantly reduced levels of total cholesterol, LDL (calculated and dosed) and non-HDL cholesterol, triglycerides, basal glycaemia, GOT and GPT compared to baseline, while cholesterolaemia HDL has increased compared to baseline (Table 2). The values of total cholesterol, LDL (calculated and dosed) and non-HDL cholesterol decreased significantly even compared to placebo (Table 2). Table 1- Baseline clinical and laboratory values in the two treatment groups

Table 2 - Anthropometric, lipidic and safety parameters in subjects treated with BBR ART or placebo (values reported as average ± SD)

* p<0.05 vs. baseline ; ** p<0.0l vs. baseline ; ^L r<0.01 vs. placebo

There is a growing interest in the study of nutraceuticals with cholesterol-lowering action confirmed in controlled clinical studies [18] In our study the pre-established association of dry extract of artichoke and berberine, pharmaceutically modified so as to allow a better bioavailability (and therefore a lower number of daily administrations in order to improve persistence in therapy), has led to a significant reduction in plasma levels of total cholesterol (-19%), LDL cholesterol (-16%), non- HDL cholesterol (-19%) and triglyceridemia (-15%), in association with a standardized stabilization diet.

In conclusion, the pre-established association of artichoke extract and berberine proved to be an effective cholesterol-lowering agent apparently devoid of side effects.

Bibliography

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Claims

1. Oral composition comprising:

A) as the sole active ingredients Berberis aristata with a minimum content of 50% in berberine chloride, Cynara scolimus extract, and optionally:

• a B vitamin,

• folic acid and

• a pharmaceutically acceptable chromium salt,

B) as enteric absorption promoters, a sorbitan polyoxyethylenate ester and Piper nigrum extract having a minimum content of 80% in pipeline,

wherein the Cynara scolimus extract has a titre of 2.5% in caffeoylquinic acids and is present in such an amount that the content in caffeoylquinic acids ranges from 0.5 to

5 mg.

2. An oral composition according to claim 1, wherein the Berberis aristata extract has a content of 98% in berberine chloride.

3. An oral composition according to claim 1 or 2, wherein Piper nigrum has a piperine content ranging from 95 to 98%.

4. An oral composition according to any one of claims from 1 to 3, wherein Berber is Aristata is present in a content such that berberine chloride is present in an amount ranging between 250 and 500 mg.

5. An oral composition according to any one of claims from 1 to 4, wherein the sorbitan polyoxyethylenate ester is polysorbate 80.

6. An oral composition according to any one of claims from 1 to 5, wherein the sorbitan polyoxyethylenate ester may vary from a minimum of 1% by weight to a maximum of 10% by weight of the weight of the oral composition.

7. An oral composition according to any one of claims from 1 to 6, wherein the Piper nigrum extract is present in such amounts that the piperine content ranges from a minimum of 0.1% by weight to a maximum of 2% by weight of the total weight of said composition.

8. An oral composition according to any one of claims from 1 to 7, wherein said optional pharmaceutically acceptable chromium salt is chromium picolinate.

9. An oral composition according to anyone of claims from 1 to 8, wherein the B vitamin is selected from vitamin Bl and folic acid.

10. An oral composition according to any one of the claims from 1 to 9 in the form of granulates or gastro-resistant tablets.

11. An oral composition according to any one of the claims from 1 to 10 in the form of a nutracetic formulation.

12. An oral composition according to any one of the claims from 1 to 11 for use in the treatment of the metabolic syndrome.

13. Process for preparing the oral composition according to any one of the claims from 1 to 12 in the form of gastroresistant tablets comprising the following steps: a. dispersing the Piper nigrum extract titrated in pipeline into the sorbitan polyoxyethylenate, until obtaining a uniform and stable suspension over time;

b. intimately mixing Cynara scolimus and Berber is aristata in the form of powders, until obtaining a uniform powder;

c. wetting the powder from step b) with the liquid suspension from step a);

d. merging the wet powder from step c) with any excipients preferably selected among at least one of the following: calcium phosphate, microcrystalline cellulose and magnesium stearate;

e. compressing the powder obtained in step d;

f. coating the tablets obtained in the previous step with a gastro-resistant film, preferably comprising hydroxypropyl cellulose and crospovidone or methacrylic acid-derived polymers.