WO2018203195A1

WO2018203195A1 - Turmeric extracts based compositions

Info

Publication number: WO2018203195A1
Application number: PCT/IB2018/052928
Authority: WO
Inventors: Gabriele BILANCINI; Massimo BONUCCI
Original assignee: Bilancini Gabriele
Priority date: 2017-05-05
Filing date: 2018-04-27
Publication date: 2018-11-08
Also published as: IT201700048596A1

Abstract

Composition for oral intake comprising: curcuminoids; cyclodextrin, preferably B-cyclodextrin; a natural gelling agent. The composition the oral mucosa, in addition to the gastric system and the colon.

Description

Turmeric extracts based compositions

The present invention relates to turmeric-based compositions for food or pharmaceutical use.

Turmeric {Curcuma longa and other species) is a plant used widely as a spice. There are various known beneficial properties of turmeric and the curcuminoid-rich extracts thereof, of which the main extract is curcumin, which has lower percentages than other compounds, in particular demetoxycurcumin, bisdemetoxycurcumin, and cyclocurcumin.

The rhizome and extracts thereof are also widely used not only as a spice but also in traditional medicine. Various properties of curcuminoids have been described and include antioxidant, antiinflammatory, antiviral, antibacterial, antifungal, and anti-tumour effects, as a result of which curcumin has been proposed for the prevention and treatment of the most disparate diseases.

The insolubility of the compounds in question makes the administration thereof extremely difficult, in particular if one wishes to achieve high bioavailability, in order to obtain the relevant biological effects. Therefore, different formulations have been proposed (including therein for oral intake) of curcuminoid-based preparations, based, in particular, on plant extracts, in order to increase the bioavailability thereof (in particular through intestinal absorption of the said compounds) by increasing the solubility of the compounds.

Turmeric, especially at high doses or in highly concentrated extracts, poses considerable tolerability problems, for both the palate and the gastric system.

In fact, the said spice is particularly irritating and unpleasant in the oral cavity, and poorly tolerated in the gastric environment, especially on an empty stomach.

This fact greatly limits the feasibility of mouth-soluble products. Compositions have now been found which overcome the drawbacks described above and, surprisingly, guarantee a high absorption of the active ingredients, not only by the gastro-enteric mucosa, but also by the mucosa of the oral cavity, achieving extremely high bioavailability and minimising the unpleasant effects for both the palate and the gastric cavity.

The invention relates to mouth-soluble compositions for oral intake comprising:

curcuminoids;

cyclodextrin, preferably β-cyclodextrin;

a natural gelling agent, preferably chosen from guar gum, xanthan gum, gum arabic, pectin, glucomannan, yucca.

Preferably, the composition contains water, in order to form a gel. Preferably, the curcuminoids are present as natural turmeric extracts, preferably from the rhizome of Curcuma longa, for example: dry- sprayed dry extract, lyophilised dry extract, tindallised dry extract, alcoholic/hydroalcoholic extract, mother tincture, glycerin macerate, glycolic macerate, granulate, nanodispersion, lipophilic granules, mixtures of two or more of the previous forms, or extracts of any other kind. Turmeric powder may also be used. Curcuminoids from different sources may also be used and therefore the percentage ratios of the various curcuminoids may vary. Preferably, the majority is comprised of curcumin.

Curcuminoids, expressed as curcumin, preferably comprise from 1 to 70% of the composition, more preferably from 3 to 10%, with the percentages stated hereinafter in the present description being by weight, unless specified otherwise. They may be present in free form, or combined with other substances which protect them (dextrins, enzymes, natural or intermediate antioxidants), in liposomal or phytosomal forms, or as nanoemulsions.

Cyclodextrins, preferably β-cyclodextrins, are preferably present in percentages ranging from 2 to 70% of the composition, more preferably from 3 to 10%.

The natural gelling agent is preferably present in percentages ranging from 0.2 to 5%; they may be mixtures of several different compounds.

According to one aspect of the invention, the composition contains water, which may be present, according to a further aspect of the invention, in percentages ranging from 70 to 95%, more preferably between 80 and 90%, depending on the presentation of the final product and if a gel is desired or a product which must be further diluted.

According to a further preferred aspect of the invention, the composition may be prepared in gel form, which may be packaged in stick-packs or similar containers, or in bottles or any other type of packaging, in particular those used for pharmaceutical preparations or food supplements.

It is also possible, if deemed appropriate, to prepare compositions with a lower water content, which may be mixed with water or with specific solutions at the time of administration. To this end, bottles suitable for containing the preparation in powder form and a separate solution may be used, wherein the contents are mixed by breaking a divider, which is preferably part of the cap, as it common practice. The compositions may also be in the form of granulates, chewable tablets or sweets, or any other form deemed suitable.

Other components may be present, for example mineral salts, to increase bioavailability and/or solubility and/or aggregation and/or chelation and/or palatability (Fe, Cu, Zn, Mg, Mn, K, Ca, Na), which may be taken individually or in combination with each other, or with other active ingredients, such as, for example, vitamins such as ascorbyl palmitate or tocopheryl acetate. Natural or artificial aromas and sweeteners, and preservatives may be present, such as, for example, citric acid, ascorbic acid, potassium sorbate, sodium benzoate and other commonly used excipients, for example maltodextrin, hydroxypropyl methylcellulose, and colloidal silica. It has been found that, unlike with other existing turmeric-based compositions, the compositions according to the present invention provide significant absorption within the oral cavity.

Curcuminoids may be understood as compounds present in natural turmeric, precursors thereof, or active metabolites thereof, salts or any other pharmaceutically acceptable form.

Example

A gel was made with the following composition:

Water: 87.576 %

β-cyclodextrin: 5.000%

ULTRASOL CURCUWIN turmeric: 3.600%

Arjuna BCM-95® turmeric (Water Dispersible) Product code: CW-

050: 2.000%

Xanthan gum: 0.800%

Citrus aroma: 0.400%

Citric acid: 0.400%

Potassium sorbate: 0.200%

Sucralose: 0.024%

The total of Turmeric dry extract titrated with Curcumin in the complex is therefore, overall, 5.60%, 2.62% of which is Curcumin, given the nature of the preparations containing other components, such as maltodextrin and tocopherol. Oral absorption

The (5g) formulation was exposed to saliva and oral absorption was assessed using a reconstructed human oral mucosa model (HOE, SkinEthic). Briefly, the well has two compartments, the apical or oral cavity part and the basolateral or serosal part, separated by a porous membrane. The in vitro model used features the morphological and functional characteristics typical of oral mucosa cells.

The formulation was added to the apical part (oral cavity), while HBSS (Hanks' Balanced Salt Solution) was added to the basolateral (serosal) compartment. After 30 seconds, 1 minute, and 3 minutes of exposure, and the relative transit time, the apical and basolateral fractions were recovered and the curcuminoid content thereof was determined by HPLC analysis. The titre of the curcuminoids was determined by liquid chromatography coupled with a UV detector, in accordance with Pharmacopeia method USP36-NF31 "Powdered Turmeric Extract". Chromatographic separation was performed with a CI 8 reverse phase column in isocratic elution with mobile phase tetrahydrofuran- water 4:6 + 1 mg/ml citric acid. For detection, the UV detector was set at 420 nm. Quantification was achieved through calibration with external standards.

Bioavailability is stated as the absorption percentage, the amount of active ingredient absorbed per unit of amount of active ingredient, and the apparent permeability (Papp). Barrier integrity and cell viability

The impact of the formulation on the in vitro model used was assessed by determining cell viability with MTS assay, based on the ability of viable cells to metabolise the yellow tetrazolium salt with mitochondrial succinate dehydrogenase. The barrier properties were analysed by determining the trans-epithelial electrical resistance (TEER) of the monolayer, and the paracellular passage of the Lucifer yellow marker. The apparent permeability coefficient (Papp, cm/min) was calculated according to the following formula:

Papp = (AC V)/(At A CO)

where AC/At is the flow rate of the amount of the molecule transported, over the incubation time, through the monolayer (mM/s), V is the volume of the basolateral chamber (cm³), A is the surface area of the membrane (cm²), and CO is the initial concentration of molecule present in the apical chamber.

Oral absorption of curcuminoids

Oral absorption was assessed by exposing the epithelium for 30 seconds, 1 minute, and 3 minutes, and monitoring the passage of the active ingredient over time. In order to determine the bioavailability of the active ingredient, the apical fluid (oral cavity) and basolateral fluid (serosal) were collected for quantification of the titre of curcuminoids by HPLC. The absorption is expressed as:

(i) absorption percentage; (ii) amount of active ingredient absorbed per unit of amount of active ingredient; (iii) apparent permeability (Papp).

As shown in Table 1, oral absorption of curcuminoids from the formulation is greater after a 30-second exposure (0.17% equivalent to 1.71 μg absorbed/mg of active ingredient and to a Papp permeability of 0.00012 cm/min).

Table 1

Impact of the formulation on membrane integrity and viability of the in vitro oral epithelium model

The impact of the formulation on barrier integrity and on cell viability was assessed at different times by determining the apparent permeability (Papp) of Lucifer yellow, measuring trans-epithelial electrical resistance (TEER), and performing an MTS assay (Figures 2, 3, and 4). The Curcumin gel-95 formulation does not induce significant alterations in barrier properties and cell viability.

It has emerged that oral curcuminoid absorption is around 0.17% corresponding to 1.71 μg of active ingredient per unit of amount of active ingredient, with a higher permeability in the first minute of exposure. Exposure to the formulation does not induce alterations in the barrier properties of the in vitro epithelium or in the viability. Anti-TNFa effect

This trial examined a number of patients, aged between 25 and 65 years, presenting a somewhat high inflammatory state. At the first examination, a blood sample was taken to detect inflammatory cytokines IL-6 (interleukin 6) and Tnfa (tumour necrosis factor a). These 2 molecules were examined to monitor the level of systemic inflammation present.

Each patient was assigned treatment with the aforesaid product, with a daily dosage of 5g.

At the subsequent check-up, which was carried out after, on average, one and a half months of supplementation, new venous sampling was carried out again to check the new IL-6 and Tnfa values. The results are summarised in Table 2.

The best effect was observed in the Tnfa inflammatory cytokine: as can be observed in the table, in fact, at the check-up (tl), the substance was no longer found in the patients' blood, even when the original levels were somewhat high in some cases (patients 3 and 8). As regards IL-6, meanwhile, a reduction in this molecule was observed in 60% of patients, indicating that curcumin also affects this inflammatory marker.

In conclusion, the study demonstrated a direct short-term efficacy on the inflammatory cytokine Tnfa and a positive indirect influence, in more than half of the cases, on interleukin-6.

Table 2

Anti-inflammatory effect

In the present study, the systemic anti-inflammatory activity of the curcuminoids absorbed following oral exposure to the formulation was assessed.

The monocytic/macrophage THP-1 in vitro model was used for this purpose. The THP-1 model was exposed to the bioavailable fraction of curcuminoids, and the anti-inflammatory activity was assessed by determining II- 1 β and TNF-α release.

In accordance with the previous study, orally, the formulation shows a maximum absorption peak (0.17%) within the first 30 seconds without inducing adverse effects on cell viability and barrier properties in the in vitro oral epithelium model.

The bioavailable fraction of curcuminoids has an anti-inflammatory action, as evidenced by the decrease in the release of proinflammatory cytokines 11 -β (Figure 5) and TNF-a (Figure 6) by the inflamed monocytic/macrophage model.

In conclusion, the formulation provides rapid and significant absorption by the oral epithelium and a suitable bioavailability to guarantee an effective anti-inflammatory action systemically after just a single administration.

Claims

1. Composition for oral intake comprising

curcuminoids;

cyclodextrins;

a natural gelling agent.

2. Composition according to claim 1, wherein the dextrins preferably are β-cyclodextrins.

3. Composition according to claim 1 or 2, wherein the gelling agent comprises one or more of guar gum, xanthan gum, gum arabic, pectins, glucomannan, yucca.

4. Composition according to any of the preceding claims, comprising from 70 to 95 %, in particular from 80 to 90 % by weight, in particular from 80 to 90 % by weight of water.

5. Composition according to any of the preceding claims, wherein curcuminoids are present as natural extracts of turmeric.

6. Composition according to any of the preceding claims, wherein curcuminoids constitute from 1 to 70 %, in particular from 3 to 10 %, by weight.

7. Composition according to any of the preceding claims, wherein dextrins constitute from 2 to 70 %, in particular from 3 to 10 %, by weight.

8. Composition according to claim 1 or 2, wherein the gelling agent constitutes from 0.2 to 5% by weight.