A corresponding European patent application has been filed with the Industrial Property Organization of Greece on 22 March 2019 (EP 19 386 018.6).

Field of the Invention

The present invention relates to a stable non-aqueous composition comprising the unique combination of three water-soluble extracts from olive fruit, Red Yeast Rice and Crocus sativus L stigmas and a method for preparing the same. This composition is suitable for encapsulation in soft capsules and is standardized in certain quantities of hydroxytyrosol, monacolin K and crocin, which act synergistically for the protection of blood lipids from oxidative stress.

Background of the Invention

Hydroxytyrosol (HT) is a phenolic compound naturally occurring in olive fruit and olive oil, and it was first discovered and extracted from the wastewater that resulted when green olives were rinsed in the process of making olive oil. Several studies have revealed the antioxidative and antidiabetic effect of olive oil polyphenols, including hydroxytyrosol. Recent studies on rats, following a model of diet-induced metabolic syndrome, high in carbohydrates and fat, showed that treatment with hydroxytyrosol decreased adiposity, improved impaired glucose and insulin tolerance and improved endothelial function with lower systolic blood pressure.

According to the Commission Regulation (EU) No 432/2012 on establishing a list of permitted health claims made on foods, olive oil polyphenols contribute to the protection of blood lipids from oxidative stress with a daily intake of at least 5 mg of hydroxytyrosol and its derivatives (e.g. oleuropein complex and tyrosol). These amounts, if provided by moderate amounts of olive oil, can be consumed in the context of a balanced diet (e.g. 20 g olive oil per day). However, taking into account that the concentrations in olive oils are not consistent, the consumption of this i smount of polyphenols is not standardized. Therefore, a composition providing regulated amounts of hydroxytyrosol on a daily basis is necessary.

Red Yeast Rice is the product of rice fermented with Monascus purpureus yeast. The active ingredient in Red Yeast Rice is Monacolin K. Monacolin K belongs in the family of statins and presents similar properties as the known statin Lova statin in the regulation of blood cholesterol levels. More specifically it inhibits hydroxyl methyl glutary I -Co A (HMG-CoA) reductase in liver from producing cholesterol, thus lowering its level in blood. According to the list of permitted health claims made on foods, a daily intake of 10 mg of monacolin K from Red Yeast Rise contributes to the maintenance of blood cholesterol levels. Commercial products of Red Yeast Rice are freely soluble in water and present variable contents of monacolin K, from 0.5% to more than 10%.

Crocus sativus L. (saffron) is a perennial spicy herb of Iridaceae family and is characterized by its strong aroma, its bitter taste and its orange-reddish pigment. These characteristics are due to more than 150 volatile (mainly terpenes) and non- volatile (mainly carotenoids) active components, and primarily due to four major bioactive compounds, namely, safranal, picrocrocin, crocetin and crocin. Saffron is regarded as tonic and antidepressant and has been used in various ancient cultures for strengthening digestion, relieving coughs, smoothing menstruation, relaxing muscle spasms, calming anxiety and improving mood. The stigmas of spice saffron are increasingly attracting attention because of their much functionality, such as in metabolic disorders, cardiovascular diseases, depression, anxiety and insomnia. Clinical studies in rats revealed the hypolipidemic effect of crocin on pancreatic lipase activity, rendering it a suitable candidate for use in a hypolipidemic treatment.

EP2170090 relates to nutritional and dietary products to be used as a source of hydroxytyrosol for preventing or treating cardiovascular diseases, plaque build-up in the arteries, arterial hypertension, and metabolic syndrome. The invention also relates to a process for preparing fortified oil-containing products with olive extract, i.e. for preparing so-called functional food. The process consists of mixing an aqueous solution of olive extract with olive oil in the presence of an emulsifier. Then, the mixture left to rest for at least 72 hours and the aqueous phase is decanted in order to obtain the fortified enriched oil. Furthermore the above-mentioned emulsion of olive extract in liquid form and edible oil was used to prepare soft gel capsules. The aforesaid method of enriching the edible oil with hydroxytyrosol is time- consuming due to the separation step of the aqueous from the oily phase.

W02010/069951 relates to pharmaceutical formulations for oral administration comprising omega-3 and omega-6 fatty acids and natural or semi-synthetic statins. The two active ingredients are kept isolated from each other inside the same dosage unit. The fatty acids are encapsulated in soft gelatin capsules, which are further nebulized with a suspension containing statins and other active ingredients. According to invention embodiments, the final product contains 500 mg of omega-3 fatty acids inside each capsule and 200 mg of fermented red rice, corresponding to 3 mg of statins, on the capsule coating.

WO2012114133 relates to a process for the enrichment of olive oil with biologically active substances obtained by the extraction of powder and stigmas of plant Saffron {Crocus sativus L) in alcohol or water. All enriched solutions present higher antioxidant capacity than the originals, thus revealing the synergistic effect of the combination active ingredients coming from dried extracts of Crocus sativus L and olive oil. However, the content of the active ingredients (crocin, crocetin, safranal) in the Crocus sativus L extract and therefore in the enriched olive oil is not specified.

A stable non-aqueous composition consisting of the unique combination of three water-soluble extracts, namely, Olive fruit extract, Red Yeast Rice extract and Crocus sativus L. extract, standardized in hydroxytyrosol, monacolin K and crocin, respectively, all dispersed in an edible vegetable oil, is not reported in the prior art.

The present invention is based on the discovery that these three water-soluble extracts provide a synergistic effect in terms of the antioxidant efficacy of the active ingredients comprised in the extracts.

A stable non-aqueous composition suitable for inclusion in a soft capsule should, however, meet certain criteria. Thus, it is important that such composition is stable and provides a homogenous distribution of reactive ingredients in, for instance, soft capsules. The applicant has undertaken significant efforts to this end. Nevertheless, fol lowing conventional wisdom, it appeared difficult to avoid the formation of large aggregates in the suspension of the active ingredients in an edible oil (see experimental section of this application).

Summary of the Invention Accordingly, a first object of the invention relates to a nutritional product in the form of a soft capsule, suitable for oral administration, which provides the unique combination of the active ingredients hydroxytyrosol, monacolin K and crocin. The composition of this invention combines the unique properties of three components, which can act synergistically in the maintenance of blood cholesterol levels in a subject, by protecting blood lipids from oxidative stress.

A second object of the invention relates to a non-conventional but feasible method of preparing a non-aqueous homogeneous composition comprising of hydroxytyrosol, monacolin K and crocin. In this context, the invention solves the problem of keeping the active ingredients isolated from each other in the same preparation. Description of the invention

The invention relates to a nutritional product in the form of a soft capsule, suitable for oral administration, which provides the unique combination of active ingredients hydroxytyrosol, monacolin K and crocin in a regular daily dosage.

In a preferred embodiment, hydroxytyrosol is in the form of an olive fruit extract standardized to at least 7% of hydroxytyrosol and its analogues. Such extracts are commercially available and come from the extraction of olive fruits and olive fruit waste waters under known methods. The assay of hydroxytyrosol in a standardized olive fruit extract is evaluated with the aid of high-performance liquid chromatography (HPLC) at 280 nm. In a preferred embodiment, monacolin K is in the form of Red Yeast Rice extract standardized to at least 4% of monacolin K. Water-soluble Red Yeast Rice extracts containing up to 25% monacolin K are known in the prior art and are commercially available. The assay of monacolin K in a standardized Red Yeast Rice extract is evaluated with the aid of high-performance liquid chromatography (HPLC) at 237 nm.

In a preferred embodiment, crocin is in the form of Crocus sativus L (saffron) extract standardized to at least 25% of crocin. GR1008908 refers to a process of making stable water-soluble extracts from the stigmas of Crocus sativus L, rich in crocin and suitable for prevention of atherosclerosis. This patent is incorporated herein by reference in its entirety. The assay of crocin in a standardized extract from the stigmas of Crocus sativus L. is evaluated with the aid of high-performance liquid chromatography (HPLC) at 440 nm. In a preferred embodiment the dosage unit relates to a soft capsule having a weight between 600 and 1200 mg, said capsule contains a stable non-aqueous composition comprising of: 5-8 % w/w of an olive fruit extract standardized to at least 7 % of hydroxytyrosol, 10-30% w/w of Red Yeast Rice extract standardized to at least 3% monacolin K, 10-20% w/w Crocus sativus L dried extract standardized to at least 25% of crocin, 25-50% w/w edible oil and a suitable emulsifier.

In a preferred embodiment, the quantity of olive fruit extract, standardized in 7% hydroxytyrosol, is in the range of 30 to 70 mg per dosage unit, which corresponds from 2 to 5 mg of pure hydroxytyrosol per dosage unit.

In a preferred embodiment, the quantity of the standardized in 7% hydroxytyrosol olive fruit extract is 35 mg per dosage unit, which corresponds to 2.5 mg of pure hydroxytyrosol per dosage unit.

In a preferred embodiment, the quantity of Red Yeast Rice extract, standardized in 4% monacolin K, is in the range of 50 to 200 mg per dosage unit, which corresponds from 2 to 8 mg of monacolin K per dosage unit. In a preferred embodiment, the quantity of Red Yeast Rice extract, standardized in 4% monacolin K, is 125 mg per dosage unit, which corresponds to 5 mg of monacolin K per dosage unit. In a preferred embodiment, the quantity of Crocus sativus L. extract, standardized in 25% crocin, is in the range of 70 to 200 mg per dosage unit, which corresponds from 17.5 to 50 mg of crocin per dosage unit.

In a preferred embodiment, the quantity of Crocus sativus L. extract, standardized in 25% crocin, is 100 mg per dosage unit, which corresponds to 25 mg of crocin per dosage unit.

In a preferred embodiment, olive fruit extract, Red Yeast Rice extract and Crocus sativus L extract are dispersed in an edible vegetable oil, selected from coconut oil, corn oil, cotton seed oil, olive oil, palm oil, peanut oil, rape seed oil, safflower oil, sesame oil, soy bean oil, and sunflower oil.

In a preferred embodiment, the dispersion of olive fruit extract, Red Yeast Rice extract and Crocus sativus L extract takes place in an edible vegetable oil, the quantity of which is in the range from 200 mg to 400 mg per dosage unit, more preferably is 240 mg per dosage unit. In a preferred embodiment, olive fruit extract, Red Yeast Rice extract and Crocus sativus L extract are dispersed in olive oil, which is also rich in polyphenols, and acts synergistically with the above-mentioned three extracts in the protection of blood lipids from oxidative stress.

In a preferred embodiment, the composition further comprising of a suitable emulsifier, preferably lecithin, the quantity of which is in the range from 80 mg to 160 mg per dosage unit, more preferably is 100 mg per dosage unit.

In a preferred embodiment the dosage unit is in the form of a soft capsule, each capsule comprising of the ingredients of the capsule shell and encapsulates the composition of the invention comprising of 2.5 mg hydroxytyrosol, 5 mg monacolin K, 25 mg crocin, 240 gr of an edible oil and 100 gr of lecithin.

In a preferred embodiment the dosage unit is in the form of a soft capsule, each capsule comprising of the ingredients of the capsule shell and encapsulates the composition of the invention comprising of 35 mg olive fruit extract, 125 mg Red Yeast Rice extract and 100 mg Crocus sativus L. extract, 240 gr of an edible oil and 100 gr of lecithin.

The invention also relates to a method of preparing a stable non-aqueous composition comprising the unique combination of a dried olive fruit extract, a Red Yeast Rice extract and a Crocus sativus L dried extract presenting a synergistic effect in the regulation of blood cholesterol levels in a subject.

It was proved difficult to prepare a homogeneous dispersion following common procedures from the prior art i.e. by preparing a blend of the three water-soluble solid extracts and subsequently dispersing the solid blend into a hydrophobic matrix with the aid of stirring or agitation and optionally with the aid of heating. Experiments carried out following a well-established procedure, where dried extracts of olive fruit, Red Yeast Rice and Crocus sativus L are mixed together and the mixture is blended using a drum mixer of 50 L capacity, at 7 rpm rotating speed for 120 min. Blend uniformity tests performed on 3 samples from different positions of the drum mixer. Major uniformity deviations observed in the final blend, especially in terms of hydroxytyrosol assay even after 240 min of blending time (Tables 1 and 2).

Table 1: Uniformity results of the solid mixture of the three extracts after blending for 120 min

Table 2: Uniformity results of the solid mixture of the three extracts after 240 min blending

It was supposed that these deviations would decrease during the dispersion of the blend into the edible oil under agitation with the aid of heating and in the presence of an emulsifier. In this context, 24 Kg of edible oil mixed with 10 kg of lecithin in an enameled reactor at 600 rpm and at 60 °C. The blend of the three extracts gradually added in the above oily suspension and the whole mixed under the same conditions. However, large aggregates formed in the oily suspension, which were not homogenized even after stirring for 120 min and after passing through a colloidal mill (300 Lt/h).

Surprisingly, it was found that a non-aqueous, oily, homogeneous and stable dispersion consisting of the extracts from olive fruits, Red Yeast Rice and Crocus sativus L obtained by following the next steps: a) Each of the dried extracts was separately sieved through a 60 mesh sieve to obtain a particle size of less than 250 pm.

b) the sieved olive fruit extract is mixed with an edible oil and an emulsifier, at a temperature in the range of 45 °C and 75 °C. c) the sieved Red Yeast Rice extract is dispersed in the oily mixture of the second step, following by stirring at the same temperature for a time period between 1 and 3 hours.

d) the oily mixture of the third step is cooled down to a temperature in the range between 25 °C and 35 °C and then homogenized by passing through a colloidal mill (300 Lt/h).

e) the sieved Crocus sativus L dried extract is dispersed in the homogenous oily dispersion of the third step, following by stirring at a temperature between 25 °C and 35 °C for a time period between 1 and 3 hours. f) the final oily non-aqueous mixture is cooled down to room temperature, more preferably at 25 °C and further homogenized by passing through a colloidal mill (300 Lt/h).

Uniformity tests performed in order to evidence that the final oily non-aqueous composition is homogeneous. Table 3 presents the quantity of the active ingredient of each extract in the blend and its assay in each sample.

Table 3: Uniformity results of the oily non-aqueous composition as obtained following the steps a) to f).

Uniformity tests summarized in Table 3 show that the composition obtained following the steps a) to f) is homogeneous and fully retains the percentages of the active ingredients, namely, hydroxytyrosol, monacolin K and crocin, as those evaluated by high-pressure liquid chromatography (HPLC). The composition of the invention remain stable after 3 and 6 months storage at normal and accelerated conditions of temperature and relative humidity.

Table 4. Stability studies of the oily non-aqueous composition of the invention after storage at normal and accelerated conditions.

The stable non-aqueous composition of the invention, comprising the unique combination of dried solid extracts from olive fruits, Red Yeast Rice and Crocus sativus L stigmas, is suitable for encapsulation in soft capsules, and can be consumed as a dietary supplement for oral administration.

In a preferred embodiment, the soft capsule shell is manufactured from gelatin, a plasticizer, preferably glycerin and purified water according to known in the state of - li the art methods. The process for producing gelatin comprise of mixing the components at a high temperature, preferably between 60 °C and 80 °C, under vacuum, for a time period between 3 and 4 hours, preferably 4 hours.

In a preferred embodiment, the soft capsule shell is manufactured from non-animal ingredients including water-soluble polysaccharides, cellulose, micro-crystalline starch derivatives and/or carrageenan extracts, according to known methods. The as prepared soft capsules are intended for use by subjects following a vegetarian diet.

The soft capsule of gelatin or non-gelatin origin can be shaped in various forms, optionally, oval, or oblong or spherical. Examples

In a preferred embodiment, the edible olive oil is heated to 50 °C and then the emulsifier is added in portions under agitation. The sieved through a 60 mesh sieve olive fruit extract standardized in hydroxytyrosol is dispersed in the oily mass gradually under stirring, preferably at 600 rpm, maintaining the same temperature. Subsequently, the sieved through a 60 mesh sieve Red Yeast Rice extract is gradually added and the oily mixture is stirred for 120 minutes keeping the temperature at 50 °C. The oily mixture is then cooled to 30 °C and passes through a colloidal mill (300 Lt/h). The sieved through a 60 mesh sieve extract of Crocus sativus L is then added to the homogenous mixture and the oily mixture is stirred at 600 rpm for an additional 2 hours at 25 °C. The final mixture, which consists of the filling mass of the soft capsules, passes through a colloidal mill (300 Lt/h) for optimal homogenization. The mixture is then encapsulated in soft gelatin capsules of oval shape, which subsequently dried in rotating bins with air flow at 20 °C in a low humidity atmosphere, preferably 25% RH, and simultaneous mechanical cleaning of the capsules from the lubricating oil (paraffin oil) with lint-free towels for about 24 hours.

The final composition and the capsule shell components are briefly described in the following table: Quantity (mg) per

Ingredients

dosage unit

Crocus sativus L Extract (25% in Crocin) 100

Olive fruit extract (7% in hydroxytyrosol) 35

Red Yeast Rice Extract (4% in Monacolin K) 125

Edible olive oil 240

Lecithin 100

Ingredients of soft capsule shells

Gelatin Pharma 195 bloom 132

Glycerin 48

Purified water 20

In a preferred embodiment, the edible olive oil is heated to 50 °C and then the emulsifier is added in portions under agitation. The sieved through a 60 mesh sieve olive fruit extract standardized in hydroxytyrosol is dispersed in the oily mass gradually under stirring, preferably at 600 rpm, maintaining the same temperature. Subsequently, the sieved through a 60 mesh sieve Red Yeast Rice extract is gradually added and the oily mixture is stirred for 120 minutes keeping the temperature at 50 °C. The oily mixture is then cooled to 30 °C and passes through a colloidal mill (300 Lt/h). The sieved through a 60 mesh sieve extract of Crocus sativus L is then added to the homogenous mixture and the oily mixture is stirred at 600 rpm for an additional 2 hours at 25 °C. The final mixture, which consists of the filling mass of the soft capsules, passes through a colloidal mill (300 Lt/h) for optimal homogenization. The mixture is then encapsulated in soft non-gelatin capsules of spherical shape, which subsequently dried in rotating bins with air flow at 20 °C in a low humidity atmosphere, preferably 25% RH, and simultaneous mechanical cleaning of the capsules from the lubricating oil (paraffin oil) with lint-free towels for about 24 hours.

The final composition and the capsule shell components are briefly described in the following table: Quantity (mg) per

Ingredients

dosage unit

Crocus sativus L Extract (25% in Crocin) 100

Olive fruit extract (7% in hydroxytyrosol) 35

Red Yeast Rice Extract (4% in Monacolin K) 125

Edible olive oil 240

Lecithin 100

Ingredients of soft capsule shells

Microcrystalline Starch 46

Iota-carrageenan 20

Glycerin 46

Disodium Phosphate 2

Purified water 86

The composition of the invention provides a regulated delivery of the three active ingredients, namely, hydroxytyrosol, monacolin K and crocin to a subject, through a standardized dosage unit on a daily base. Each dosage unit, in the form of a single soft capsule, contains 2.5 mg of hydroxytyrosol in the form of olive fruit extract, 5 mg of monacolin K in the form of Red Yeast Rice and 25 mg of crocin in the form of a Crocus sativus L extract. The daily consumption of two soft capsules of Examples 1 and / or 2 provides the claimed amounts of hydroxytyrosol and monacolin K, according to Commission Regulation (EU) No 432/2012 and further provides an enriched to crocin extract, all present a beneficial effect on the maintenance of blood cholesterol levels.

It is within the ability of a skilled person to adjust the quantities of the extracts and prepare compositions according to the invention comprising of different strengths of the active ingredients. Antiradical scavenging activity tests.

The model of scavenging stable radical 2,2-diphenyl-l-picrylhydrazyl radical (DPPH) is a widely used method to evaluate antioxidant capacities of natural products, and it has been used for olive oil and other vegetable oils, as well as for individual antioxidants (Brand-Williams, W. et al. Lebensm.-Wiss. u. -Techno! . 1995, 28, 25-30). The spectrophotometric method for assessing the total antioxidant activity is based on the absorbance decrease monitoring of the DPPH· radical in the presence of antioxidants. DPPH- is characterized as a stable free radical due to the delocalization of the spare electron over the molecule. Thus, the molecule cannot dimerize, as would happen with other free radicals. The delocalization gives rise to a deep violet color characterized by an absorption band at about 515 nm. When a DPPH· solution is mixed with a substance which can donate a hydrogen atom, the reduced form is generated, accompanied by the loss of the violet color.

The DPPH radical scavenging activity of the three active components, namely hydroxytyrosol from olive fruit extract, monacolin K from red yeast rice extract and crocins from Crocus sativus L extract and their combination in a composition suitable for oral administration, is measured, in order to reveal the synergism for the three components.

Experimental Method for DPPH radical scavenging test.

A solution of DPPH 10 ^~3 M was prepared by dissolving 0.0394 g of the radical DPPH in 100 mL methanol. The volumetric flask was wrapped in foil and stirred in a vortex apparatus. The solution obtained had a deep purple color and was left in the refrigerator for 2 h in order for the absorbance to be stabilized. A calibration curve of concentration versus absorbance of DPPH was prepared as follows: The 10 ^~3 M solution of DPPH was diluted with the addition of methanol to prepare DPPH solutions in the range of 5 to 1000 mM (10 ⁴ M, 5xl0 ⁵ M, 10 ⁵ M, and 5xl0 ⁶ M). These solutions were vortexed, left in darkness and their absorbance was measured in a UV-Vis spectrophotometer (Varian Cary 300) at A _max = 515 nm and 630 nm.

The calibration curve of absorbance {Abs) versus concentration Cone) of DPPH is expressed by the following equations:

l = 515 nm: Abs = 0.00557* Cone - 0.00070; R = 0.99994 l = 630 nm: Abs = 0.00192* Cone - 0.00298; R = 0.99997

For the antioxidant test, all extracts/compositions tested were dissolved in methanol at the corresponding concentrations (please refer in Tables 1 and 2). Briefly, stock solutions of all extracts were prepared in methanol as following: olive fruit extract 3.60 mg/mL, red yeast rice extract 11.60 mg/ml_, Crocus sativus L extract 10.52 mg/mL. The final solutions resulted from dilutions of the stock solutions. Olive fruit extract solution prepared with 1 mL of corresponding stock solution diluted to 5 mL with methanol, red yeast rice extract solution prepared with 2 mL of corresponding stock solution diluted to 5 mL with methanol, Crocus sativus L. extract solution prepared with 2 mL of corresponding stock solution diluted to 5 mL with methanol, and the Olive fruit / Red Yeast Rice / Crocus sativus L extracts composition was prepared by mixing 1, 2, and 2 mL of the corresponding stock solutions. The absorbance of the DPPH 10 ⁴ M solution was measured at t = 0 (A ₀ ), against methanol as blank. For each of the tested pure extracts/compositions, 50 pL of their methanolic solution was pipetted in a cuvette and subsequently 3.0 mL of DPPH 10 ^~4 M solution were added and the solution was gently mixed. The absorbance (AT) was measured after 60 min (the value reached a plateau after 40 min). For each measurement, a solution of the corresponding extract/combination in methanol was used as the blank (50 pL of sample methanolic solution mixed with 3.0 mL methanol). For each of the samples tested for its radical scavenging activity the % reduction in DPPH absorbance was estimated as (A ₀ - A _T ) * 100 / A ₀ .

The values in the Tables are expressed as the mean values of at least five determinations. All experiments were repeated in duplicate. The SD is estimated to be below 10% for all experiments.

Table 1. Results of DPPH absorbance before and after the addition of Olive fruit /Red Yeast Rice Extracts Composition and its bioactive constituents at A _ma x = 515 nm.

Ao, initial DPPH absorbance.

A _T , final DPPH absorbance in the reaction medium (steady state).

Table 2. Results of DPPH absorbance before and after the addition of Olive fruit /Red Yeast Rice / Crocus sativus L. Extracts Composition and its bioactive constituents at A _max = 630 nm.

AQ, initial DPPH absorbance. A _T , final DPPH absorbance in the reaction medium (steady state).

Due to high absorbance of Crocus sativus L extract at 515 nm, the DPPH antiradical scavenging activity test also performed at 630 nm, where DPPH also presents a linear calibration curve in the concentration range of 5 to 1000 mM.

In this context, Table 1 reveals the synergistic effect of the combination of Olive fruit and Red Yeast rice extracts as expressed by the % DPPH reduction of the combination of the two extracts compared to the sum of the % DPPH reduction of each one. Most importantly, a representative embodiment of the invention with the combination of the three extracts reduces the absorbance of a 10 ⁴ M DPPH solution in a greater degree compared to the corresponding reduction from each extract, furthermore, it presents a greater performance than the combined sum of the three individual extracts, thus, indicating that the unique combination of Olive fruit, Red Yeast Rice and Crocus sativus L. extracts act synergistically in the % absorbance reduction of DPPH and therefore present a synergistic antioxidant activity.

Literature

EP2170090: Hydroxytyrosol fortified oils and their uses

WO2010/069951: Oral formulations comprising omega polyenoic fatty acids in

combination with natural or semi -synthetic statins

WO2012114133: Production of an olive oil with increased antioxidants properties, enriched with the extraction of saffron ( Crocus sativus L)

GR1008908: Method for the cool extraction and production of stable solid water- soluble extracts taken from the stigmas of the Greek Crocus sativus L plant - use of said extracts for the prevention and/or treatment of arteriosclerosis.

Brand-Williams, W.; Cuvelier, M.E.; Berset, C. Use of a Free Radical Method to Evaluate Antioxidant Activity. Lebensm.-Wiss. u. -Techno!., 28, 25-30 (1995)