WO2014095628A1

WO2014095628A1 - Oral formulation containing a statin in omega-3 polyunsaturated fatty acids (n-3 pufa)

Info

Publication number: WO2014095628A1
Application number: PCT/EP2013/076533
Authority: WO
Inventors: Mosè Santaniello; Maria Grazia Cima; Giuseppe Giannini
Original assignee: Sigma-Tau Industrie Farmaceutiche Riunite S.P.A.
Priority date: 2012-12-17
Filing date: 2013-12-13
Publication date: 2014-06-26

Abstract

The present application relates to a composition comprising a statin totally solubilized in a solvent system consisting of omega-3 polyunsaturated fatty acids (n- 3 PUFA), or their alkyl esters, and a ionic emulsifier selected between sodium docusate and a phosphatidylcholine enriched lecithin. The pharmaceutical composition according to the present invention can be used in the prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and all the pathologies related.

Description

Oral formulation containing a statin in omega-3 polyunsaturated fatty acids (n-

3 PUFA)

Field of the invention

The present application relates to the medical field, and in particular to a composition comprising a statin totally solubilized in a solvent system consisting of omega-3 polyunsaturated fatty acids (n-3 PUFA), or their alkyl esters, and a ionic emulsifier.

The pharmaceutical composition according to the present invention can be used in the prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and all the pathologies related.

Background of the invention

Hypercholesterolemia has been recognized as a major risk factor for coronary heart disease (CHD). In clinical trials, reducing serum LDL cholesterol has been demonstrated to decrease the incidence of CHD and to reverse atherosclerotic lesions. Coronary heart disease and, more generally, cardiovascular disease (CVD) represents the primary cause of mortality for men and women in developed countries globally. These premature deaths come at great cost to both the individuals and their families, as well as representing a huge burden to the health care system of the countries. The risk factors for coronary heart disease are well recognized and include: higher than average serum cholesterol, elevated levels of LDL; a low level of HDL in proportion to the LDL level; higher than average serum triglycerides; higher levels of lipid oxidation products creating plaques and streaks which cause blockages of coronary arteries. Reduction in these risk factors is effective to reduce the prevalence of coronary heart disease and its many costs. The medical protocols for the treatment of these pathologies are well known in the art, and include the use of several drugs or combination of the same.

The efficacy of the statins in the primary and secondary prevention of cardiovascular diseases has been demonstrated in a number of clinical studies. Several evidence suggests that the clinical benefit obtained with therapy with statins could be related to a reduction of systemic inflammatory markers (Ridker P.M., et al.; N. Engl, J. Med. 344: 1959-65, 2001) more than to the reduction of cholesterol level. Even though it has not been possible to prove that there is a direct relation of the antiinflammatory mechanism of statins in the reduction of cardiovascular events, some studies have shown that the treatment with statins improves plaque stability and reduces the arterial inflammatory reaction in patients subjected to endarterectomy (Crisby M., et. al.; Circulation 103:926-33, 2001 ). In addition, therapy with statins in experimental models determines the reduction of expressors of the inflammatory lesion, such as for example of the macrophage infiltration content (Van der Wal A.C., et a); Circulation 89:36-44, 1994), of the release of VCAM-1 , of interleukin- 1 and of tissue factor in the arteriosclerotic lesion (Sukhova GK, et al.; Arterioscler Thromb Vaso Biol 22: 1452-8, 2002 ).

Atorvastatin is used as a medicine in cardiology against all forms of cholesterol, prevention of cardiovascular events in people with diabetes. Atorvastatin selectively inhibits the liver enzyme HMG-CoA reductase, responsible for the synthesis of cholesterol in the liver. In this way, as do all the other statins, it lowers levels of total cholesterol, LDL (bad) cholesterol, apolipoprotein B (carrying the bad cholesterol) and triglycerides in patients with primary hypercholesterolemia, including family, or mixed hyperlipidaemia, i.e. with both high levels of triglycerides. Atorvastatin also has other side effects, it reduces inflammation, inhibits platelet aggregation, improves the function of blood vessels, especially the coronary vessels. Rosuvastatin has structural similarities with most other synthetic statins, but unlike other statins rosuvastatin contains sulfur. Rosuvastatin is a competitive inhibitor of the enzyme HMG-CoA reductase, having a mechanism of action similar to that of other statins. Its approximate elimination half life is 19 h and its time to peak plasma concentration is reached in 3-5 h following oral administration. Putative beneficial effects of rosuvastatin therapy on chronic heart failure may be negated by increases in collagen turnover markers as well as a reduction in plasma coenzyme Q10 levels in patients with chronic heart failure. Pitavastatin, like other statins, it is an inhibitor of HMG-CoA reductase, the enzyme that catalyses the first step of cholesterol synthesis and is usually administrated for the treatment of hypercholesterolaemia and for the prevention of cardiovascular disease. A 2009 study (J Atheroscler Thromb. 2009 Oct; 16(5) :654-61) showes that pitavastatin increases HDL cholesterol (24.6%), especially in patients with HDL lower than 40 mg/dl, in addition to greatly reducing LDL cholesterol (-31.3%) . Pitavastatin is most likely to be appropriate for patients with metabolic syndrome with high LDL, low HDL and diabetes mellitus.

Omega-3 polyunsaturated fatty acids (n-3 PUFA) have demonstrated a beneficial effect in the prevention of cardiovascular events (Bucher HC, et al.; Am. J.Med. 2002; 1 12:298-304 ), possibly by means of an antiinflammatory, antithrombotic and antiarrhythmic mechanism (Sethi S, et al.; Blood 2002: 100:-1340-6; Billman GE, et al.; Circulation 1999: 99:2452-7; My Svensson, et al. Clin J Am Soc Nephrol 2006, 1 : 780-786; Andy H Lee AH, Hiramatsu N. Nutrition and Dietary Supplements 201 1 :3 93-100). The hypolipidic effect was the first detected, so at first these drugs had been used for the treatment of dislipidemic disorders, while the antiinflammatory, antithrombotic, antiatherosclerotic and antiarrhythmogenic effects have been found later. GI SSI-Prevention trial (Lancet 1999 354: 447-55) was the first which demonstrated the efficacy and tolerability of n-3 PUFAs in post- myocardial infarction patients. According to the evidence in literature, today n-3 PUFAs are indicated for the primary and secondary prevention of ischemic cardiopathy and sudden cardiac death (SCD) (Mori TA, Beilin LJ. Long-chain omega- 3 fatty acids, blood lipids and cardiovascular risk reduction Curr Opin Lipidol 2001 ; 12: 1 1-7; Aarsetoey H. et al. Hindawi Publishing Corporation Cardiology Research and Practice, 2012, vol. 2012, 1- 15) .

Different patents have been published which describe pharmaceutical formulations of statins, such as for example: US 5, 180,589 or US 5,356,896 which describe pharmaceutical composition forms for the stabilization of statins at low pH.

US 6,235,311 describes a pharmaceutical composition combining a statin and aspirin.

US 5,225,202 describes a pharmaceutical composition of statins in the form of pellets with an enteric coating so as to protect the product at low pH.

WO2006045865 describes the microencapsulation of simvastatin in an oil phase constituted by diethyl esters of eicosapentaenoic acid and docosahexaenoic acid. WO2011 150505 discloses a solid phase containing the statin suspended in an oil phase containing PUFA.

WO2006096806 is related to a composition in unit dosage comprising a statin and fish oil enriched in diethyl esters of PUFA, the experimental data reported, however, are quite all relative to formulations containing simvastatin and no experimental data are reported relative to atorvastatin, rosuvastatin and pitavastatin.

WO00/76482, WO00/57918 and WO00/57859 describe pharmaceutical compositions formed by lipid regulating agents in oils or in surfactants.

WO2013072767 describes to compositions comprising n-3 PUFA and at least one salicylate in a form of a self-nanoemulsifying drug delivery system (SNEDDS), a self- microemulsifying drug delivery system (SMEDDS), or a self-emulsifying drug delivery system (SEDDS), in order to avoid unwanted oxidation of the double bonds in EPA and /or DHA which results in fixed dose combinations.

WO02/ 100394 and WO03/ 103640 describe pharmaceutical compositions formed by pure statin nanoparticles without any protective coating dispersed in pharmaceutically acceptable oils, however this type of formulations have stability problems for statins if the temperature of preparing the system exceeds 40 deg. C, as is the case for most oral preparations.

The studies are focused on finding a suitable method for the delivery of statins in a single dose with the oil phase. None of the studies mention the development of a method for the solubilization of atorvastatin in the oil phase. Atorvastatin, in fact, while proving to have an enhanced pharmacological activity in comparison to simvastatin, is almost insoluble in most of the oil phases used in the protocols for the preparation of medicines. Even the addition of certain emulsifiers and/or cosurfactant is not effective in achieving the desired purpose.

In vitro and in vivo, atorvastatin has been shown to possess activities additional to that strictly hypocholesterolemic, which contribute to the antiaterogenic action of the drug: 1) inhibition of proliferation and migration of vascular smooth muscle cells (Lea A.P., McTavish D., Drugs, 1997, 53 (5), 828); 2) reduction (67%) of the size of atherosclerotic lesions (lovastatin, pravastatin, simvastatin not show this property) (Bocan T.M.A. et el., Atherosclerosis, 1994, 11 1 , 127). In addition, the plasmatic half- life of atorvastatin is comprised between 14 and 20 hours, in respect to 2-3 hours of simvastatin cells (Lea A.P., McTavish D., Drugs, 1997, 53 (5), 828); this fact means that the pharmacological activity of atorvastatin is prolonged with respect to the others and that the administration of the medicament containing it can be reduced.

Rosuvastatin, has been shown to possess a number of advantageous pharmacological properties, including enhanced HMG-CoA reductase binding characteristics, relative hydrophilicity, and selective uptake into/ activity in hepatic cells. Cytochrome p450 (CYP) metabolism of rosuvastatin appears to be minimal and is principally mediated by the 2C9 enzyme, with little involvement of 3A4; this finding is consistent with the absence of clinically significant pharmacokinetic drug- drug interactions between rosuvastatin and other drugs known to inhibit CYP enzymes. Rosuvastatin has also been shown to be highly effective in reducing LDL- C, increasing high-density lipoprotein cholesterol (HDL-C), and producing favorable modifications of other elements of the atherogenic lipid profile in a wide range of dyslipidemic patients. The substantial LDL-C reductions and improvements in other lipid measures with rosuvastatin treatment should facilitate achievement of lipid goals and reduce the requirement for combination therapy in patients with severe hypercholesterolemia. Rosuvastatin is well tolerated alone, and in combination with fenofibrate, extended-release niacin, and cholestyramine, and has a safety profile similar to that of currently marketed statins (Olsson AG, McTaggart F, Raza A.; Cardiovasc Drug Rev. 2002 Winter;20(4) :303-28).

Pitavastatin is a highly potent 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor and an efficient hepatocyte low-density lipoprotein-cholesterol (LDL-C) receptor inducer. Its characteristic structure provides improved pharmacokinetics and significant LDL-C-lowering efficacy at low doses. The cyclopropyl group on the pitavastatin molecule appears to divert the drug away from metabolism by cytochrome P450 (CYP)3A4 and allows only a small degree of clinically insignificant metabolism by CYP2C9. As a result, pitavastatin is minimally metabolized; most of the bioavailable fraction of an oral dose is excreted unchanged in the bile and is reabsorbed by the small intestine ready for enterohepatic recirculation. This process probably accounts for pitavastatin 's increased bioavailability relative to most other statins and contributes to its prolonged duration of action. In addition to its potent LDL-C-lowering efficacy, a number of pleiotropic benefits that might lead to a reduction in residual risk have been suggested in vitro. These include beneficial effects on endothelial function, stabilisation of the coronary plaque, anti-inflammatory effects and anti-oxidation. With regard to the clinical safety and efficacy of pitavastatin, the Phase IV Collaborative study of Hypercholesterolemia drug Intervention and their Benefits for Atherosclerosis prevention (CHIBA study) showed similar changes in lipid profile with pitavastatin and atorvastatin in Japanese patients with hypercholesterolemia (Saito Y., Atheroscler Suppl. 2011 Nov; 12(3):271-6).

Furthermore, recent studies increased the already perceived necessity to obtain a single formulation containing two or more compound for the prevention of the cardiovascular pathologies, showing that the simultaneous administration improves the compliance. In Thorn S. et al. JAMA September 4, 2013 , 310 (9), p. 918-929 a fixed dose combination of aspirin, simvastatin and lisinopril is used in the long term therapy showing advantages with respect to the traditional protocols.

Considering the advantages in the employment of atorvastatin, rosuvastatin and pitavastatin in the prevention and treatment of pathologies related to hypercholesterolemia and hypertriglyceridemia, it becomes more and more noticeable the need to find a method for the solubilization of these three statins in the oil phase.

Summary of the invention

It has now surprisingly been found that creating a solvent system consisting of an ionic emulsifier (a deoiled phosphatidyl choline enriched lecithin or sodium docusate) and omega-3 polyunsaturated fatty acid (n-3 PUFA) it's possible to obtain a complete solubilization of atorvastatin, rosuvastatin or pitavastatin.

It is therefore the object of the present invention a composition which comprises a solvent system consisting of omega-3 polyunsaturated fatty acid (n-3 PUFA), or their alkyl esters, and a ionic emulsifier selected between a deoiled phosphatidyl choline enriched lecithin and sodium docusate; and a statin, selected between of atorvastatin, rosuvastatin or pitavastatin, wherein the statin is completely dissolved in the solvent system in the solvent system.

A non limiting example of the lecithin according to the present invention is the one sold under the trade name "Epikuron™ 200".

The composition according to the invention can also comprise other useful elements, without this substantially impairing the activity.

Another object of the present invention is a pharmaceutical composition containing the above-mentioned elements, optionally in a mixture with one or more pharmaceutically acceptable vehicles or excipients.

The compositions of the invention, together with a conventionally employed adjuvant, carrier, diluent or excipient may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use.

The compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavours and the like.

The above described components for orally administered are merely representative. Further materials as well as processing techniques and the like are set out in Part 5 of Remington's Pharmaceutical Sciences, 20th Edition, 2000, Merck Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

The composition according to the present invention can also be formulated as a food supplement or dietary supplement, which constitutes a further object of the invention.

Other objects of the present invention are the uses of the above mentioned composition as a medicament, particular for the prevention and treatment of diseases related to hyperlipidemias, hypercholesterolemia and hypertriglyceridemia. The medicament according to the invention can be used to treat the individual disease states or to exert a preventive or protective action against them, or to treat a complex pathological picture that includes one or more of the therapeutic aspects seen above. Detailed description of the invention

The composition according to the present invention comprises active ingredients which are known in the medical field and already used in clinical practice. Therefore, they are very easy to procure, inasmuch as they are products which have been on the market for some time and are of a grade suitable for human or animal administration .

The statins are a known class of drugs used for lowering cholesterol levels. Statins are available on the market or can be prepared according to known methods described in the literature. For the purposes of the present invention atorvastatin and rosuvastatin are particularly preferred. The effective dose currently used for the statins is in an amount between 5 and 80 mg, the most common dose is 20 mg. The term "omega-3 polyunsaturated fatty acids" (here abbreviated as "n-3 PUFA") relates to a family of long-chain polyunsaturated fatty acids, generally C16-C24, in particular those having a C20-C22 chain, that have in common a carbon-carbon double bond in the n-3 position, i.e. the third bond from the methyl end of the fatty acid. Examples of the most common omega-3 polyunsaturated fatty acids found in nature are reported in the Table below together with the assigned names.

Lipid

Common name Chemical name

name

16:3

- all-cis-7, 10, 13-hexadecatrienoic acid

(n-3)

18:3

a-Linolenic acid (ALA) aZZ-cis-9, 12, 15-octadecatrienoic acid

(n-3)

18:4

Stearidonic acid (STD) all- cis- 6,9, 12, 15-octadecatetraenoic acid

(n-3)

20:3

Eicosatrienoic acid (ETE) all- cis- 11 , 14, 17-eicosatrienoic acid

(n-3)

20:4

Eicosatetraenoic acid (ETA) all-cis-8, 1 1, 14, 17-eicosatetraenoic acid

(n-3)

20:5

Eicosapentaenoic acid (EPA) all- cis- 5,8, 11 , 14, 17-eicosapentaenoic acid

(n-3)

Docosapentaenoic acid (DPA), 22:5 all-cis-7, 10, 13, 16, 19-docosapentaenoic Clupanodonic acid (n-3) acid

22:6 aZZ-cis-4,7, 10, 13, 16, 19-docosahexaenoic

Docosahexaenoic acid (DHA)

(n-3) acid

24:5 all- cis-9, 12, 15, 18,21 -docosahexaenoic

Tetracosapentaenoic acid

(n-3) acid

Tetracosahexaenoic acid 24:6

all-cis-6,9, 12, 15, 18,21-tetracosenoic acid (Nisinic acid) (n-3)

The ones most preferred are cis-5, 8, 1 1 , 14, 17-eicosapentaenoic acid (EPA) and cis- 4,7, 10, 13, 16, 19-docosahexaenoic acid (DHA).

Preferably the n-3 PUFA according to the invention is a mixture of fatty acids having a high content in EPA and DHA, for example with a content in EPA and DHA higher than 25% by weight, preferably from about 30% to about 100% by weight, in particular about between 75% and 95%, and more preferably at least 85% by weight on the total fatty acid weight. Preferably the total content of n-3 PUFA according to the invention is a mixture of fatty acids having at least 90% of n-3 PUFA by weight on the total fatty acid weight.

The terms "PUFA" and "n-3 PUFA", as used here, are intended to encompass their corresponding C 1-C3 alkyl esters, preferably ethyl esters, and/or from their salts with pharmaceutically acceptable bases such as sodium hydroxide, lysine, arginine or aminoalcohols such as choline. The ethyl esters are the most widely used and preferred according to the invention.

The composition of the invention is administered preferably orally, in particular in the form of soft gelatin capsules. For oral use, the unit dose generally comprises 100- 1000 mg of polyunsaturated fatty acids of the omega-3 series, preferably 500- 1000 mg or 300-500 mg, the total dose being usually around 0.1-3.0 g per day or per alternate day, according to the case concerned, and preferably 0.3-2.0 g per day and in particular 1.0 g per day.

This amount of product may be administered in the form of several daily divided doses or preferably as a single dose, in order to reach the desired blood level. Of course, the clinician may vary the amount of product (or mixture with another therapeutic agent) to be administered, basing on the patient's conditions, age and weight.

Other types of formulation for oral administration are also suitable for the purposes of the invention; for example hard capsules or tablets, in which the polyunsaturated fatty acids are adsorbed on solid supports. It is also possible to use emulsions, granulates in dispersing excipients, syrups, droplets, etc., and other forms of administration able to ensure systemic absorption of the drug, such as sterile solutions or emulsions and the like, suitable for parenteral use and the like, as evaluated by the expert of the art, on the basis of the severity of the pathology.

Those compositions illustrated in the European Pharmacopea 2000 (EuPh. 2000), containing quantities greater than or equal to 80 wt% of mixtures of EPA and DHA ethyl esters and a total of omega-3 polyunsaturated fatty acid ethyl esters greater than or equal to 90 wt% are also suitable for the purposes of the present invention. The pharmaceutical composition suitable for use according to the present invention generally comprise at least one pharmaceutically acceptable vehicle and/ or one diluent and/ or one surfactant and/ or one thickener and /or one binder and/ or one lubricant and /or one aromatizer and/ or one colorant and /or one stabilizer and the like, which can easily be selected by the expert of the art.

The most preferred ratio between EPA and DHA is about 0.6- 1.1 / 1.3- 1.8; in particular is comprised between 0.9 and 1.5.

Preferably the content of EPA (as ethyl ester) is comprised between 40 and 51% by weight and the content of DHA (as ethyl ester) is comprises between 34 and 45% by weight on the total fatty acids weight.

Specific drugs containing n-3 PUFA that meet the above specifications, as active ingredient and that can be used according to the present invention, are already available on the market.

Phosphatidyl cholines (PC) are a class of phospholipids that incorporate choline as a head group. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources such as egg yolk or soy beans from which they are mechanically extracted or chemically extracted using hexane. They are also a member of the lecithin group of yellow-brownish fatty substances occurring in animal and plant tissues. In an embodiment of the present invention the ionic emulsifier is a deoiled and purified soy lecithin containing from at least 30% of phosphatidyl choline (Epikuron™ 130 ) to at least 92% phosphatidyl choline (Epikuron™ 200). In a preferred embodiment a deoiled and purified soy lecithin enriched with at least 92% of phosphatidyl choline is used. Further examples of suitable ionic emulsifiers are Epikuron™ 145 V and Epikuron™ 170.

It is known in the art that soy lecithin is endowed with an anticholesterolemic activity. Therefore another advantage of the present invention is that said soy lecithin in combination with the omega-3 fatty acid and the statin will increase, in an additive manner, the anticholesterolemic activity of the composition of the invention.

Sodium docusate is often used as an emulsifying, wetting, and dispersing agent. It is an anionic surfactant, a substance that lowers the surface tension of water. It is used in symptomatic treatment of constipation, and in painful anorectal conditions such as hemorrhoids and anal fissures for people avoiding straining during bowel movements.

In one embodiment the composition according to the present invention comprises:

• n-3 PUFA in an amount comprised between 0.5 and 1.0 g, preferably between 0.8 and 0.9 g, more preferably 0.9 g;

• Deoiled phosphatidyl choline enriched lecithin in an amount comprised between 0.01 and 0.8 g, preferably between 0.05 and 0.6 g, more preferably 0.1 g; and

• Atorvastatin in an amount comprised between 0.01 and 0.09 g, preferably between 0.02 g and 0.08 g.

In another embodiment the composition according to the present invention comprises:

• Rosuvastatin in an amount comprised between 0.01 and 0.09 g, preferably between 0.02 and 0.04 g.

• Deoiled phosphatidyl choline enriched lecithin in an amount comprised between 0.01 and 0.8 g, preferably between 0.05 and 0.6 g, more preferably 0.1 g; and • Pravastatin in an amount comprised between 0.01 and 0.09 g, preferably between 0.02 and 0.04 g.

· n-3 PUFA in an amount comprised between 0.5 and 1.0 g, preferably between 0.8 and 0.9 g, more preferably 0.9 g;

• Sodium docusate in an amount comprised between 0.05 and 0.2 g, preferably 0.1 g; and

• Atorvastatin in an amount comprised between 0.01 and 0.09 g, preferably 0.03 g.

· Sodium docusate in an amount comprised between 0.05 and 0.2 g, preferably 0.1 g; and

· Pravastatin in an amount comprised between 0.01 and 0.09 g, preferably between 0.02 and 0.06 g.

In another embodiment the composition according to the present invention comprises: • n-3 PUFA in an amount comprised between 0.5 and 1.0 g, preferably between 0.8 and 0.9 g, more preferably 0.9 g;

• Deoiled phosphatidyl choline enriched lecithin in an amount comprised between 0.01 and 0.8 g, preferably between 0.05 and 0.6 g, more preferably 0.09 g; and

• Sodium docusate in an amount comprised between 0.005 and 0.2 g, preferably 0.01 g; and

• Atorvastatin in an amount comprised between 0.01 and 0.09 g, preferably between 0.02 and 0.04 g.

• Pitavastatin in an amount comprised between 0.01 and 0.09 g, preferably between 0.02 and 0.04 g.

In another embodiment of the present invention the composition has a unitary form, in which the active ingredients are present in a single pharmaceutical form, particularly soft gelatin capsules. The compositions according to the present invention optionally contain, along with the active ingredient, at least one pharmaceutically acceptable vehicle or excipient.

The pharmaceutical composition according to the present invention can be formulated in soft capsules for oral administration. Said soft gelatin capsules preferably have an enteric coating. In order to demonstrate the substantial advantage and unexpected effect of the present invention, the present invention is carried out according to following examples, but not limited to these examples.

EXAMPLES

Materials and Methods:

For the purpose of the present invention the following materials have been used:

• the omega-3 polyunsaturated fatty acids (n-3 PUFA) are a mixture of ethyl esters of polyunsaturated fatty acids with a content in EPA and DHA greater than 85%, in a ratio EPA/DHA comprised between 0.9 and 1 .5, and is a product provided by Pronova Biopharma Norge AS Norway

• the atorvastatin used is atorvastatin calcium amorphous furnished by Biocon (India) ;

• the polyoxyethylene(20)sorbitan monooleate, also known under the trade name Tween 80^®, used is furnished by Sigma- Aldrich;

· the polyoxyethylenglyceroltrihydroxystearate, also known under the trade name Cremophor EL^®, used is furnished by BASF Italia Sri;

• the polyethyleneglycol(15)hydroxystearate, also known under the trade name Solutol HS 15^®, used is furnished by BASF Italia Sri;

• the mixture of glyceryl and polyethylene glycol esters, also known under the trade name Labrasol^® used is furnished by GATTEFOSSE' ITALIA, S.r.l (Milan, Italy);

• the hydrogenated phosphatidyl choline, also known under the trade name Epikuron™ 200 SH and the deoiled phosphatidyl choline enriched lecithin, also known under the trade name Epikuron™ 200 used are both furnished by Cargill;

• the solid natural lecithin, also known under the name Lipoid S PC-3, used is furnished by Lipoid GmbH;

• the sodium docusate used is furnished by Sigma-Aldrich;

• the 2-(2-ethoxyethoxy)ethanol, also known under the trade name Transcutol P^®, used is furnished by GATTEFOSSE' ITALIA; • the rosuvastatin used is rosuvastatin calcium amorphous furnished by Biocon (India);

• the pitvastatin used is pitavastatin calcium furnished by MSN Laboratories Pvt. Ltd (India);

• the propylene glycol monolaurate, also known under the trade name Lauroglycol 90™, used is furnished by GATTEFOSSE' ITALIA, S.r.l (Milan, Italy). HPLC Analysis:

The same method was applied to the preliminary solubility tests and to all the formulations in which the solution was clear at a first sight. The solution to be analyzed is left under mechanical centrifugation and then the supernatant is separated trough filtration on PTFE (polytetrafluoroethylene) filter (size pore 0.22μπι) and analyzed by HPLC, using a COLUMN Intersil ODS-3 4.6x250mm, a solution of CH3CN/H2O 70/30 + 0.1% of CF3COOH as eluent, a flow of lml/min and a UV/VIS Detector.

Preliminary solubility tests

As a starting point the solubility of the statins in omega-3 polyunsaturated fatty acids (n-3 PUFA) was tested in the following way: to n-3 PUFA (1 ml) an increasing amount of statin was added so as to reach a point, in which a precipitate was formed. The mixture thus obtained was then let under agitation for 18 hours and then analyzed by HPLC with the method described. The results are summarized in Table 1, from which the maximum amount of statin dissolved in n-3 PUFA may be observed. Table 1

Formulations with non-ionic emulsifiers (Comparative Examples)

The emulsifier was dissolved directly into the n-3 PUFA and left under mechanical stirring, then the atorvastatin was added and the appearance of the solution was evaluated. The emulsifiers used were those already known in the medical field, available on the market and currently used for similar compositions .

In some cases a cosurfactant was added in a second step to further enhance the solubility of atorvastatin, the cosurfactant used was Transcutol P^®.

Formulation 1

1. 0.9 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.1 g polyoxyethylene(20)sorbitan monooleate (Tween 80^®)

3. 0.02 g atorvastatin

Tween 80^® was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 3 hours at 25°C and 75% RH (relative humidity); a clear solution was observed. After the addition of atorvastatin, the formation of a floating fluid was observed. Transcutol P^® in an amount of 0.02 g was added, but no change in the clearness of the solution was observed. The atorvastatin was not solubilized. Formulation 2

1. 0.9 g omega-3 polyunsaturated fatty acids (n-3 PUFA) 2. 0.1 g Polyoxyethylenglyceroltrihydroxystearate (Cremophor EL^®)

3. 0.02 g atorvastatin

Cremophor EL^® was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a solution with opalescence was observed. After the addition of atorvastatin a precipitate was observed. The atorvastatin was not solubilized.

Formulation 3

1. 0.9 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.1 g polyethylene glycol( 15) hydroxy stearate (Solutol HS 15^®)

3. 0.02 g atorvastatin

Solutol HS 15^® was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear solution was observed. After the addition of atorvastatin a clear solution was observed, but a waxy precipitate was observed after few minutes. The atorvastatin was not solubilized.

Formulation 4

1. 0.9 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.1 g mixture of glyceryl and polyethylene glycol esters (Labrasol^®)

3. 0.02 g atorvastatin

Labrasol^® was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 3 hours at 25°C and 75% RH; a solution with opalescence was observed. After the addition of atorvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a white solid suspension was observed. The atorvastatin was not solubilized.

Formulation 5

1. 0.9 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.1 g mixture of glyceryl and polyethylene glycol esters (Labrasol^®)

3. 0.02 g atorvastatin 4. 0.02 g Transcutol P^®

Labrasol^® was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 3 hours at 25°C and 75% RH; a solution with opalescence was observed. Transcutol P^®was added, no changing in the clearness of the solution was observed. After the addition of atorvastatin a large precipitate was observed. The atorvastatin was not solubilized.

Formulations with ionic emulsifiers

The emulsifier was dissolved directly into the n-3 PUFA and left under mechanical stirring, then the atorvastatin was added and the appearance of the solution was evaluated. The emulsifiers used were natural or synthetic lecithin derivatives already known in the medical field, available on the market and currently used for similar composition. In some cases also a cosurfactant was added in a second step to further enhance the solubility of atorvastatin, the cosurfactant used was Transcutol P^®.

Formulation 6 (comparative example)

1. 0.9 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.1 g hydrogenated phosphatidyl choline (Epikuron™ 200 SH)

3. 0.02 g atorvastatin

Epikuron™ 200 SH was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a single phase solution was not obtained. The Epikuron™ 200 SH was not solubilized in the oil. Formulation 7 (comparative example)

1. 0.9 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.1 g solid natural lecithin (Lipoid S PC-3)

3. 0.02 g atorvastatin

Lipoid S PC-3 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a single phase solution was not obtained. The Lipoid S PC-3 was not solubilized in the oil. Formulation 8

1. 0.9 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.1 g deoiled phosphatidyl choline enriched lecithin (Epikuron™ 200)

3. 0.02 g atorvastatin

Epikuron™ 200 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C e 75% RH; a clear yellow solution was observed. After the addition of atorvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C e 75% RH; a clear solution was visible to the naked-eye. The complete solubilization of atorvastatin was confirmed analyzing the solution by HPLC with the method described.

At least 90% of the atorvastatin in the composition at an initial measurement time was maintained after 6 month at 5°C and 80% of RH.

Other formulations with different amount of the components were tested in order to evaluate the maximum amount of atorvastatin that can be solubilized. These formulations, from No. 9 to No. 1 1, are hereunder reported.

Formulation 9

1. 0.95 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.05 g Epikuron™ 200

3. 0.03 g atorvastatin

Epikuron™ 200 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear yellow solution was observed. After the addition of atorvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C e 75% RH; a clear solution was visible to the naked-eye. The complete solubilization of atorvastatin was confirmed analyzing the solution by HPLC with the method described.

Formulation 10

1. 0.9 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.1 g Epikuron™ 200 3. 0.06 g atorvastatin

Epikuron™ 200 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear yellow solution was observed. After the addition of atorvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear solution was visible to the naked-eye. The complete solubilization of atorvastatin was confirmed analyzing the solution by HPLC with the method described.

Formulation 11

1. 0.8 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.2 g Epikuron™ 200

3. 0.09 g atorvastatin

Different formulations using another ionic emulsifier, the sodium docusate, were also prepared and tested. The results are the following:

Formulation 12

1. 0.9 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.1 g sodium docusate

3. 0.02 g atorvastatin

The sodium docusate was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours 25°C and 75% RH; a clear pale yellow solution was observed. After the addition of atorvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear solution was visible to the naked-eye. The complete solubilization of atorvastatin was confirmed analyzing the solution by HPLC with the method described.

Formulation 13

1. 0.9 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.1 g sodium docusate

3. 0.03 g atorvastatin

The sodium docusate was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear pale yellow solution was observed. After the addition of atorvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear solution was visible to the naked-eye. The complete solubilization of atorvastatin was confirmed analyzing the solution by HPLC with the method described.

Formulation 14

1. 0.9 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.09 g Epikuron™ 200

3. 0.01 g sodium docusate

4. 0.02 g atorvastatin

The sodium docusate was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH. After the addition of Epikuron™ 200 the solution was left again under mechanical stirring at 600 rpm for 18 hours at 25°C. After the addition of atorvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH and a clear solution was visible to the naked-eye. The complete solubilization of atorvastatin was confirmed analyzing the solution by HPLC with the method described.

For an easier reference the results obtained for all previous formulations are summarized in Table 2. Table 2

Oil Emulsifier Surfactant Statin

Formul Amount Amount Amount Amount Solubility

Component Component Component Component

No. (g) (g) (g) (g)

1 n-3 PUFA 0.9 Tween 80 ^® 0.1 Transcutol P^® 0.02 Atorvastatin 0.02 Not soluble

2 n-3 PUFA 0.9 Cremophor EL^® 0.1 - - Atorvastatin 0.02 Not soluble

3 n-3 PUFA 0.9 Solutol HS 15^® 0.1 - - Atorvastatin 0.02 Not soluble

4 n-3 PUFA 0.9 Labrasol^® 0.1 - - - 0.02 Not soluble

5 n-3 PUFA 0.9 Labrasol^® 0.1 Transcutol P^® 0.02 Atorvastatin 0.02 Not soluble

6 n-3 PUFA 0.9 Epikuron™ 200SH 0.1 - - Atorvastatin 0.02 Not soluble

7 n-3 PUFA 0.9 Lipoid S PC-3 0.1 - - Atorvastatin 0.02 Not soluble

8 n-3 PUFA 0.9 Epikuron™ 200 0.1 - - Atorvastatin 0.02 Soluble

9 n-3 PUFA 0.95 Epikuron™ 200 0.05 - - Atorvastatin 0.03 Soluble

10 n-3 PUFA 0.9 Epikuron™ 200 0.1 - - Atorvastatin 0.06 Soluble

1 1 n-3 PUFA 0.8 Epikuron™ 200 0.2 - - Atorvastatin 0.09 Soluble

12 n-3 PUFA 0.9 Sodium docusate 0.1 - - Atorvastatin 0.02 Soluble

13 n-3 PUFA 0.9 Sodium docusate 0.1 - - Atorvastatin 0.03 Soluble

Epikuron™ 200 0.09

14 n-3 PUFA 0.9 - - Atorvastatin 0.02 Soluble

Sodium docusate 0.01

Formulation 15

1. 4.5 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.5 g polyoxyethylene(20)sorbitan monooleate (Tween 80^®)

3. 0.02 g rosuvastatin

Tween 80^® was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH (relative humidity); an opalescent solution was observed. After the addition of rosuvastatin to 1 ml of the solution obtained, the solution was left under mechanical stirring at 600 rpm for 24 hours at 25°C a precipitate was observed. The rosuvastatin was not solubilized. Formulation 16

1. 4.5 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.5 g Polyoxyethylenglyceroltrihydroxystearate (Cremophor EL^®)

3. 0.02 g rosuvastatin

Cremophor EL^® was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 2 hours at 25°C and 75% RH (relative humidity); a clear solution was observed. After the addition of rosuvastatin to 1 ml of the solution obtained, the solution was left under mechanical stirring at 600 rpm for 24 hours at 25°C a precipitate was observed. The rosuvastatin was not solubilized.

Formulation 17

1. 4.5 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.5 g mixture of glyceryl and polyethylene glycol esters (Labrasol^®)

3. 0.02 g rosuvastatin

Labrasol^® was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 2 hours at 25°C and 75% RH; a clear solution was observed. After the addition of rosuvastatin to 1 ml of the solution obtained, the solution was left under mechanical stirring at 600 rpm for 24 hours at 25°C a precipitate was observed. The rosuvastatin was not solubilized. Formulation 18

1. 0.9 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.1 g Epikuron™ 200

3. 0.02 g rosuvastatin

Epikuron™ 200 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear yellow solution was observed. After the addition of rosuvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear solution was visible to the naked-eye. The complete solubilization of rosuvastatin was confirmed analyzing the solution by HPLC with the method described.

Formulation 19

1. 0.9 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.1 g sodium docusate

3. 0.02 g rosuvastatin

The sodium docusate was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours 25°C and 75% RH; a clear pale yellow solution was observed. After the addition of 20 mg of rosuvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear solution was visible to the naked-eye. The complete solubilization of rosuvastatin was confirmed analyzing the solution by HPLC with the method described.

For an easier reference the results obtained for all previous formulations are summarized in Table 3 Table 3

The maximum amount of rosuvastatin that can be solubilized with the several emulsifiers employed in Formulation 15 to 19 was measured and the results are reported in Table 4.

Table 4

Formulation 20

1. 0.9 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.1 g Epikuron™ 200 3. 0.02 g pitavastatin

Epikuron™ 200 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH. After the addition of the solution was left again under mechanical stirring at 600 rpm for 24 hours 25°C. A clear solution was visible to the naked-eye. The complete solubilization of pitavastatin was confirmed analyzing the solution by HPLC with the method described.

Formulation 21

1. 0.9 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.1 g sodium docusate

3. 0.02 g pitavastatin

The sodium docusate was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH. After the addition of 20 mg of pitavastatin the solution was left under mechanical stirring at 600 rpm for 24 hours 25°C. A clear solution was visible to the naked-eye. The complete solubilization of pitavastatin was confirmed analyzing the solution by HPLC with the method described.

Formulation 22

1. 0.9 g omega-3 polyunsaturated fatty acids (n-3 PUFA)

2. 0.09 g Epikuron™ 200

3. 0.01 g sodium docusate

4. 0.02 g pitavastatin

The sodium docusate was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH. After the addition of Epikuron™ 200 the solution was left again under mechanical stirring at 600 rpm for 18 hours 25°C; a clear solution was observed. After the addition of 20 mg of pitavastatin the solution was left under mechanical stirring at 600 rpm for 18 hours 25°C. A clear solution was visible to the naked-eye. The complete solubilization of pitavastatin was confirmed analyzing the solution by HPLC with the method described.

For an easier reference the results obtained for all previous formulations are summarized in Table 5.

Table 5

The maximum amount of pitavastatin that can be solubilized with the Formulation 20 to 22 was measured and the results are reported in Table 6.

Table 6

Further Solubility Tests

In order to show substantial characteristics and unexpected results of the present invention, a series of tests had been carried out comparing two compositions disclosed in WO2006096806 replacing simvastatin with atorvastatin and rosuvastatin, demonstrating the inefficiency of the composition described in said patent application in the solubilization of atorvastatin. The formulation were prepared with the same method described in WO2006096806, specifically:

Formulation 23 (corresponding to formulation 7 of WO2006096806):

80 mg of Transcutol P^® were added to 20 mg of atorvastatin and stirred well manually until the solid was wet; after 20 min a clear solution was obtained. The n- 3 PUFA was added to the solution ad a white precipitate was observed.

Formulation 24

80 mg of Transcutol P^® were added to 20 mg of rosuvastatin and stirred well manually until the solid was wet; after 20 min a clear solution was obtained. The n- 3 PUFA was added to the solution ad a precipitate was observed.

Formulation 15 (corresponding to formulation 15 of WO2006096806) : 50 mg of Lauroglycol 90™ was added to 20 mg of atorvastatin and stirred well manually until the solid was wetted then n-3 PUFA was added and the solution was left under mechanical stirring at 600 rpm for 10 min at 25°C and 75% RH; even after this stage the atorvastatin remained insoluble. Lastly the remaining 70 mg of Lauroglycol 90™ were added and a part of atorvastatin was solubilized while the other remained dispersed, giving an opalescent solution.

Formulation 26

50 mg of Lauroglycol 90™ was added to 20 mg of rosuvastatin and stirred well manually until the solid was wetted then n-3 PUFA was added and the solution was left under mechanical stirring at 600 rpm for 24h at 25°C and 75% RH; even after this stage the rosuvastatin remained insoluble. Lastly the remaining 70 mg of Lauroglycol 90™ were added and a part of rosuvastatin was solubilized while the other remained insoluble, giving a precipitate.

The results are summarized in Table 7. These results show that the composition described in the patent application to solubilize simvastatin cannot be applied to atorvastatin and rosuvastatin, because they are not soluble in the same solvent system.

Table 7

Stability test:

In order to evaluate the stability of the formulations prepared according to the present invention the amount of degradation products after 1 , 3 and 6 month were calculated. A suitable amount of the formulation to be analyzed was diluted wit methanol and left under mechanical centrifugation; supernatant is separated trough filtration on PTFE (polytetrafluoroethylene) filter (size pore 0.22μιτι) and analyzed by HPLC, using a COLUMN Intersil ODS-3 4.6x250mm, a solution of CH3CN/H2O 70/30 + 0.1% of CF3COOH as eluent, a flow of lml/min and a UV/VIS Detector.

The degradation of n-3 PUFA was not significant, the results on Formulation 8 are reported in the table below.

Table 8

The main degradation product of the statin was the lattonic form. Stability tests on Formulation 8 and Formulation 12, were performed; the results obtained and summarized in Table 9 demonstrate that both the formulation have a good stability at 5°C

Table 9

% lattonic form after % lattonic form % lattonic form

Formulation Temperature

1 month after 3 months after 6 months

8 5°C 0 0.64 1.65

12 5°C 0 1.20 3.35 Discussion of the results:

The experimental data reported in this application show that the solvent system used allows to achieve the objective of the complete solubilization of a significant amount of active substances such as atorvastatin, rosuvastatin and pitavastatin that are otherwise not soluble in n-3 PUFA. This solubilization, as demonstrated by the comparison data, cannot be achieved with similar compositions present in the state of the art. The solubility of atorvastatin in n-3 PUFA alone (0.1 mg/ml) thus increases by 600 times, reaching a maximum of 60 mg/ml in the formulations which use sodium docusate, and even to 90 mg/ml for formulations that use the Epikuron™ 200; that of pitavastatin is a bit higher than atorvastatin in n-3 PUFA alone (2.3 mg/ml) but it reaches a maximun amount of solubilization of more than 60 mg/ml. Even more advantageous is the increase of the solubility of rosuvastatin, which, as shown in formulations 18- 19 is completely solubilized in an amount of 0.02 g per gram of solvent system, and reach the maximum of the solubility with sodium docusate, arriving at 40 mg/ml of solvent, as showed in table 4, and having a starting point of solubility lower than atorvastatin and pitavastatin, as can be seen from results in Table 1.

As for the sodium docusate , it assembles the characteristics of the emulsifier and the property of symptomatic treatment of constipation, which is a common adverse effect that occurs in patients treated with statins, and in particular with atorvastatin.

Medicaments can be prepared according to the formulations described in the present invention, using atorvastatin, rosuvastatin and pitavastatin, which, as is known in the art, have a pharmaceutical efficacy superior to that of simvastatin; such formulations therefore allow to use compounds with a lower minimum effective dose obtaining the same or better results. Consequently, assuming an equal estimated efficacy, side effects on the patient are reduced, thus demonstrating further effectiveness of the solution proposed by the present invention compared to the prior art. The stability demonstrated by the solutions prepared makes them useful in the of preparation of pharmaceutical compositions for oral administration, for use in the treatment of pathologies related to hyperlipidemia and hypertriglyceridemia, hypercholesterolemia, pathologies for which the individual components are already used in standard treatment protocols known in the art.

The bioavailability of the formulation described in the present invention was tested with standard methods known in the art and was found not significantly different from that of the single elements; this result assure that the formulation according to the present invention avoid any problem of overdose. Furthermore, the process of preparation of the present compositions is simple and particularly suitable for industrial applicability.

Claims

A composition in unit dose form, comprising:

1) a solvent system consisting of:

a) omega-3 polyunsaturated fatty acids (n-3 PUFA), or their alkyl esters;

b) a ionic emulsifier selected between a deoiled phosphatidyl choline enriched lecithin and sodium docusate; and

2) a statin, selected between atorvastatin, rosuvastatin and pitavastatin; wherein the statin is completely dissolved in the solvent system.

The composition according to claim 1 , further comprising 2-(2- ethoxyethoxhy)ethanol.

The composition according to claim 1 , characterized in that the omega-3 polyunsaturated fatty acids (n-3 PUFA) are selected from the group consisting of eicosapentaenoic acid, the docosahexaenoic acid or mixtures thereof.

The composition according claim 3, characterized in that the ratio between eicosapentaenoic acid and docosahexaenoic acid is comprised between 0.5 and 2.

The composition according to claim 1 , characterized in that the omega-3 polyunsaturated fatty acids (n-3 PUFA) are a mixture of fatty acids having a content in EPA and DHA comprised between 75% and 95% by weight, preferably at least 85%, on the total fatty acids weight, and wherein the total content of n-3 PUFA is at least 90% by weight on the total fatty acids weight. The composition according to claim 1 , wherein the omega-3 polyunsaturated fatty acids (n-3 PUFA) are a mixture of ethyl esters of EPA and DHA in a ratio comprised between 0.9 and 1.5 and the content of EPA ethyl ester is comprised between 40 and 51 % and the content of DHA ethyl ester is comprised between 34 and 45% by weight on the total fatty acids weight.

7. The composition according to claim 1 , characterized in that the alkyl ester of omega-3 polyunsaturated fatty acids (n-3 PUFA) are selected from the group consisting of ethyl, methyl, propyl, butyl esters or mixtures thereof.

8. The composition according to claim 1, in which the omega-3 polyunsaturated fatty acids (n-3 PUFA) are in an amount comprised between 0.5 and 1.0 g, preferably between 0.8 and 0.9 g, more preferably 0.9 g.

9. The composition according to claim 1 , in which the statin is in an amount comprised between 0.02 and 0.09 g.

10. The composition according to claim 1 characterized in that the ionic emulsifier is a deoiled phosphatidyl choline enriched lecithin in which the content of phosphatidyl choline is greater than 92%.

1 1. The pharmaceutical composition according to claim 1 , in which the deoiled phosphatidyl choline enriched lecithin is in an amount comprised between 0.01 and 0.8 g, preferably between 0.05 and 0.6 g, more preferably 0.2 g.

12. The composition according to claim 1, in which the sodium docusate is in an amount comprised between 0.05 and 0.2 g, preferably 0.1 g.

13. A pharmaceutical composition comprising the composition according to claims 1-12, further comprising at least one pharmaceutically acceptable vehicle or excipient.

14. The pharmaceutical composition according to claim 13 for use in the prevention and treatment of pathologies related to hyperlipidemia, hypercholesterolemia and hypertriglyceridemia.

15. The pharmaceutical composition according to claims 13 or 14 characterized in that is encapsulated by soft gelatin capsules, optionally having an enteric coating, for oral administration.