ORAL FORMULATIONS COMPRISING OMEGA POLYENOIC FATTY ACIDS IN COMBINATION WITH NATURAL OR SEMI -SYNTHETI C STATINS

FIELD OF THE INVENTION The present invention relates to the field of formulations containing omega polyenoic fatty acids in combination with natural or semi-synthetic statins.

STATE OF THE ART

Omega polyenoic fatty acids are long chain polyunsaturated fatty acids with between

18 and 22 carbon atoms; among these, omega-3-polyenoic fatty acids, in which the first unsaturated bond is between the third and the fourth carbon atom, from the terminal methyl group, and omega-6-polyenoic fatty acids, in which the first unsaturated bond is between the sixth and the seventh carbon atom, are essential.

Among the omega-3-polyenoic fatty acids, in which fish oil is rich, the most widespread are eicosapentaenoic acid, generally indicated with the acronym EPA, and docosahexaenoic acid, indicated with the acronym DHA. Another important omega-3-polyenoic fatty acid, not of fish but of vegetable origin, is alpha-linolenic acid, indicated with the acronym ALA.

It has been widely proven that omega polyenoic fatty acids compete with arachidonic acid for binding to the enzymes cyclooxygenase and lipoxygenase, causing a reduction in blood triglyceride levels; moreover, they have an anti-aggregation and antithrombotic action due to their effect of reducing thromboxane A2 synthesis; they promote vasodilation and increase bleeding time .

Due to these valuable biological effects, omega polyenoic fatty acids are indicated in the prevention of recurrences after angioplasty surgery and for reducing angina attacks, as well as for treating hypertriglyceridemia, when combined with modified dietary regimens or also when the response to diets and other non-pharmacological measures alone has proved inadequate.

In the vast majority of cases food sources of omega polyenoic fatty acids are not in fact sufficient to achieve an adequate therapeutic or preventive response and to obtain an adequate source of daily administration these acids must be consumed in the form of pharmaceutical formulations or products intended for special nutritional uses, such as the one forming the subject matter of the present invention. In the pharmaceutical field, omega polyenoic fatty acids (fish oil esters) are in general combined with synthetic statins, such as simvastatin and other statins. Consumption of omega polyenoic fatty acids can allow cholesterol lowering drugs, such as statins (which can be of synthetic or natural origin) to function more effectively. The patent application PCT/EP2007/056344 by the same applicant describes formulations for the oral administration of omega polyenoic fatty acids in combination with active principles incompatible therewith, including synthetic statins (for example simvastatin). However, it must be considered that synthetic statins are considered a true drug, while in many cases the use of products of natural origin is more indicated, as these can also be used in the production of dietary supplements.

To date no formulations are known that contain the two components (omega polyenoic fatty acids and natural or semi-synthetic statins) and to obtain the effective benefits of their combination, it is necessary to administer several formulations, each containing only one of the components, due to technical prejudices and difficulties in the preparation of a single dose containing an oily liquid component and a powder component incompatible therewith. The advantages of instead being able to provide a single formulation for the simultaneous oral administration of omega polyenoic fatty acids and natural statins, especially in terms of patient compliance, are evident and the need was therefore felt to provide a formulation of this type. SUMMARY OF THE INVENTION

There are described pharmaceutical formulations for oral administration comprising omega polyenoic fatty acids in combination with natural or semi-synthetic statins, their preparation methods and their use. DETAILED DESCRIPTION OF THE INVENTION

With the present invention, these problems are overcome through a non- pharmaceutical formulation for the oral administration of omega polyenoic fatty acids in combination with natural or semi-synthetic statins. The polyenoic fatty acids according to the invention are preferably chosen in the group consisting of omega-3-polyenoic fatty acids, omega-6-polyenoic fatty acids, and their mixtures, more preferably mixtures of omega-3-polyenoic fatty acids. Particularly preferred according to the invention are mixtures of omega-3- polyenoic fatty acids containing EPA and DHA in quantities between 20 - 98% by weight calculated on the total weight of the mixture, and preferably in quantities equal to at least 60% by weight. In these mixtures the ratio by weight of EPA and DHA is, for example, between 0.05 and 2.5, and preferably between 0.9 and 1.5.

According to the invention, the term natural or semi-synthetic statins is intended as fermented red rice, garlic and artichoke extracts and polyphenols from vitis vinifera. Particularly preferred is fermented red rice having a content of Lovastatin and Monacolin K higher than 1.5% by weight. The fermented red rice is obtained from fermentation of the common cooking rice {Oryza sativa), by means of a particular yeast, called Monascus purpureus or red yeast . This rice, which owes its name to its characteristic colour, is a conventional component of Chinese phytotherapy but is also widely known in the Western world for its valuable hypolipidemic effects. The enormous scientific and economic interest surrounding red rice is linked to the presence of Monascus purpureus; during its fermenting activity, this yeast is in fact enriched by a group of substances, called monacolins, which have been scientifically associated with marked hypocholesterolemizing activity. Among these, monacolin K stands out, as it reflects the chemical structure and pharmacological action of lovastatin (a drug belonging to the statin category). Similarly to these pharmaceutical products, the monacolin K of red rice is capable of inhibiting HMG-CoA reductase, which represents a key enzyme in the biosynthesis of cholesterol. As its plasma levels depend above all on this biosynthetic pathway (and only to a lesser extent on diet): integration with fermented red rice has proved effective in normalizing total cholesterol, LDL cholesterol and triglyceride levels.

In this sense, fermented red rice is more effective with respect to the administration of equivalent dosages of lovastatin, proving that its properties reflect a combination of actions that cannot be attributed solely to monacolin K. Also for this reason, besides its well-documented hypolipidemizing activity, fermented red rice seems to reduce cardiovascular risk due to antiatheroschlerotic activities of other type (antinflammatory, vasodilating and reductive effect on lipoprotein A levels). Controlled fermentation in the laboratory can also slightly vary the composition of Monascus purpureus and allow the selection of strains rich in Monacolin K or other substances having particular pharmacological actions.

Natural or semi-synthetic statins - preferably fermented red rice - are present in the formulation of the invention in the quantities permitted for nutraceutical formulations, in particular up to 3 mg.

Preferably, according to the invention, the two active principles - fatty acids on the one hand and one or more natural or semi-synthetic statins on the other - are kept isolated from each other inside a same dosage unit. Preferably, the active principle present in the higher dosage, i.e. the fatty acid, is encapsulated, in a soft or hard gelatin capsule, while the second active principle, possibly in combination with one or more other active principles, is uniformly distributed on the capsule.

Among the active principles as defined above we can, for example choose: Vitamin E, Ascorbic acid and their mixtures. Besides supplying a vitamin, these components act as stabilizers for the formulation of the invention.

According to the invention, the present formulations typically contain, inside the capsule, from 100 to 1 ,500 mg of fatty acids, preferably around 1 ,000 mg. Natural or semi-synthetic statins are applied to the capsule with one or more film- coating agents and possibly one or more inert substances, using appropriate solvents.

One or more further film coatings without said active principles and comprising one or more appropriate film-coating agents, possibly in admixture with at least an inert subtance, can be applied to the filmed coating containing the second active principle. Among the film-coating agents that can be used according to the invention, film-coating agents chosen among hydroxy propyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol / polyethylene glycol copolymers, and their mixtures are preferred; while the possible inert substance is chosen among lactose monohydrate, polyalcohols and other substances permitted for products intended for particular nutritional uses. The following examples are given by way of non-limiting illustration of the invention. EXAMPLE 1

10,600 soft gelatin capsules were prepared, containing 500 mg of omega-3-polyenoic fatty acids per capsule with a minimum EPA-DHA content of 30%. These capsules were placed in a coating pan equipped with automatic spray, product and air inlet temperature control system and nebulized with a suspension having the following composition, in order to obtain a fermented red rice content of

200 mg per capsule equal to 3 mg of statins: Fermented red rice 1.5% 2,375 g

Ascorbic acid 382 g

Vitamin E 191 g

Polyvinylpyrrolidone 687 g

Ethano 2,748 g Acetone 6,106 g

Processing was performed by setting the following operating parameters on the equipment:

Coating pan revolutions: 8 rpm

Inlet air temperature: 52 °C Nozzle: 1 mm hole

Nebulization pressure: 0.5 bar

Pump speed: 15-25 rpm

The capsules obtained were film-coated with a solution having the following composition: Hydroxy propyl methylcellulose 109 g

Acetone 930 g

Ethanol 930 g

Water 21 O g

The film-coating process was performed setting the following operating parameter on the equipment:

Coating pan revolutions: 8 rpm

Inlet air temperature: 45 °C

Nozzle: 1 mm hole

Nebulization pressure: 1 bar Pump speed: 15-25 rpm

At the end of the film-coating process and subsequent drying the capsules were analyzed and packed in polythene bottles to perform a stability study at 25 °C and 60% relative humidity and at 40 °C and

75% relative humidity, obtaining the following results in relation to fermented red rice content:

25 °C 60% RH 40 °C 75% RH Time (0) 198.9 mg/capsule 198.9 mg/capsule

3 months: 206 mg/capsule 196.3 mg/capsule

EXAMPLE 2

In the same operating conditions described in Example 1 , a suspension, having the following composition, was nebulized onto 10,600 soft gelatin capsules containing approximately 500 mg of the mixture of fatty acids of Example 1 :

Fermented red rice 3% 1 ,18O g

Lactose monohydrate 1 ,18O g

Ascorbic acid 382 g

Vitamin E 191 g Polyvinylpyrrolidone 687 g

Ethanol 2,748 g

Acetone 6,106 g

The capsules obtained were film-coated in the same operating conditions described in Example 1 with a coating solution having the following composition: Hydroxy propyl methylcellulose 109 g

Acetone 930 g

Ethanol 930 g

Water 21 O g

The capsules were analyzed and packed in polythene bottles to perform a stability study at 25 °C and 60% relative humidity and at 40 °C and 75% relative humidity, and were found to have the same stability as the capsules of

Example 1 with regard to the fermented red rice content.

EXAMPLE 3

10,600 soft gelatin capsules were prepared, containing 1000 mg of omega-3- polyenoic fatty acids per capsule with a minimum EPA-DHA content of 70%.

These capsules were placed in a coating pan equipped with automatic spray, product and air inlet temperature control system and nebulized with a suspension having the following composition in order to obtain a fermented red rice content of 200 mg per capsule equivalent to 3 mg of statins:

Fermented red rice 1.5% 2,375 g

Ascorbic acid 382 g Vitamin E 191 g

Polyvinylpyrrolidone 687 g

Ethanol 2,748 g

Acetone 6,106 g

Processing was performed by setting the following operating parameters on the equipment:

Coating pan revolutions: 8 rpm

Inlet air temperature: 52 °C

Nozzle: 1 mm hole

Nebulization pressure: 0.5 bar Pump speed: 15-25 rpm

The capsules obtained were film-coated with a coating solution having the following composition:

Hydroxy propyl methylcellulose 109 g

Acetone 930 g Ethanol 930 g

Water 21 O g

The film-coating process was performed by setting the following operating parameters on the equipment:

Coating pan revolutions: 8 rpm Inlet air temperature: 45 °C

Nozzle: 1 mm hole

Nebulization pressure: 1 bar

Pump speed: 15-25 rpm

The capsules were analyzed and packed in polythene bottles to perform a stability study at 25 °C and 60% relative humidity and at 40 °C and 75% relative humidity, and were found to have the same stability as the capsules of

Example 1 with regard to the fermented red rice content. EXAMPLE 4

In the same operating conditions described in Example 1 , 2,800 soft gelatin capsules, containing approximately 500 mg of mixture of fatty acids, were nebulized with a suspension having the following composition: Fermented red rice 1.5% 630 g

Polyvinylpyrrolidone 189 g

Ethanol 2,220 g

Water 100 g

The capsules obtained were film-coated in the same operating conditions described in Example 1 with a coating solution having the following composition:

Hydroxy propyl methylcellulose 50 g

Acetone 425 g

Ethanol 425 g

Water 100 g The capsules were analyzed obtaining a fermented red rice content equal to 205 mg/capsule.

EXAMPLE 5

In the same operating conditions described in Example 4, 2,800 soft gelatin capsules, containing approximately 500 mg of the mixture of fatty acids, were nebulized with a suspension having the following composition:

Fermented red rice 1.5% 630 g

Polyvinyl alcohol / polyethylene glycol copolymer 280 g

Ethanol 1 ,260 g

Water 1 ,260 g The capsules obtained were film-coated in the same operating conditions and with the same coating solution as Example 4, obtaining at the end of the analytical tests a fermented red rice content equal to 200 mg/capsule.