WO2015066784A1

WO2015066784A1 - Pharmaceutical composition, oral pharmaceutical form, capsule, bilayer tablet, uses, method of treating hypercholesterolemia, hypertriglyceridemia and/or mixed dyslipidemia, and method of preventing atherosclerosis, diabetes or secondary prevention of other cardiovascular diseases

Info

Publication number: WO2015066784A1
Application number: PCT/BR2014/050008
Authority: WO
Inventors: Walker Magalhães LAHMANN; Hilton Oliveira dos SANTOS FILHO; Iara Silvia Brauer MANTOVANI; Cristiano Martins VELOSO; Simone Batista de OLIVEIRA; Fabiana Lima CARVALHO
Original assignee: Hypermarcas S.A.
Priority date: 2013-11-08
Filing date: 2014-11-07
Publication date: 2015-05-14
Also published as: BR102013028912A2

Abstract

20 ABSTRACT The present invention relates to a pharmaceutical composition comprising at least a fibrate or pharmaceutically acceptable salts thereof, and at least a statin or pharmaceutically acceptable salts thereof. The present invention relates to specific oral pharmaceutical forms, uses and related 5 methods of treatment.

Description

PHARMACEUTICAL COMPOSITION, ORAL PHARMACEUTICAL FORM, CAPSULE, BILAYER TABLET, USES, METHOD OF TREATING

HYPERCHOLESTEROLEMIA, HYPERTRIGLYCERIDEMIA AND/OR MIXED DYSLIPIDEMIA, AND METHOD OF PREVENTING ATHEROSCLEROSIS, DIABETES OR SECONDARY PREVENTION OF OTHER CARDIOVASCULAR

DISEASES

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising at least a fibrate or pharmaceutically acceptable salts thereof, and at least a statin or pharmaceutically acceptable salts thereof. The present invention relates to specific oral pharmaceutical forms, uses and related methods of treatment.

BACKGROUND OF THE INVENTION

There are clinical situations where the monotherapeutic lipid-lowering treatment with statins is inadequate or inappropriate for achieving the goals.

Thus, in certain cases, there is a need to associate medicines for optimizing the lipid levels and subsequently reducing the cardiovascular risk of these individuals.

One of the most frequently used associations on lipid-lowering therapy is the combination of statins with fibrates, which would be recommended in cases where intolerance to higher doses of statins occurs, and in situations of important hypertriglyceridemia.

In general, fixed dose associations provide increased convenience for the patient, insofar as they allow the ingestion of only one tablet instead of two different ones, as is the case with conventional treatments to control cholesterol and lipid levels.

Usually, the treatment with a fibrate is prescribed in combination with a statin. Preferably, fenofibrate is used, due to its effects in the reduction of triglyceride and increase of HDL-C levels, while statins are used due to their positive effects in reducing LDL-C and increasing HDL-C levels.

However, nowadays such combination therapy can be currently achieved only by the use of two separate products, that is, the patient needs to take, for example, a tablet or capsule containing fibrate, along with another tablet or capsule containing statin.

Generally, this association is very well tolerated, however, some patients may develop liver and/or muscle toxicity, at various degrees. Regarding the toxic effects on the skeletal musculature, the most serious complication observed with the use of these medicines is rhabdomyolysis, a syndrome characterized by muscle necrosis, elevation of creatine phosphokinase, followed by muscle pain, myoglobinuria and generally being life-threatening due to renal failure.

Additionally, fixed dose combinations or associations of any active pharmaceutical principles face difficulties in the production of certain pharmaceutical forms, especially related to:

a) Different solubility;

b) Different dissolution profiles;

c) Incompatibility of excipients;

d) Different stability conditions;

e) Incompatibility of active principles.

In view of the difficulties above, a common problem is to maintain the performance that active principles have individually, when they are combined in the same pharmaceutical form, comprising two active principles and excipients.

Thus, there is still the need for provision of fibrates and statins in a single dosage form.

BRIEF DESCRIPTION OF THE INVENTION

It is proposed in this invention the fixed dose association of (a) a fibrate or pharmaceutically acceptable salts thereof and (b) a statin or pharmaceutically acceptable salts thereof, wherein (a) is in physical contact with (b), but the active principles are isolated from each other by a coating (b) with inert polymer.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 presents the dissolution profile of capsules containing 20 mg of atorvastatin, having immediate release profile in accordance with the present invention, in phosphate buffer medium, at pH 6.8, using apparatus 2 (paddle) rotating at 75 rpm, at 37°C, in 900 ml_. Figure 2 presents the comparative dissolution profile of a tablet containing 20 mg of atorvastatin in phosphate buffer, at pH 6.8, using apparatus 2 (paddle) rotating at 75 rpm, at 37°C in 900 ml_. - curve obtained with the reference medicine containing only this active ingredient, marketed under the brand name Citalor®, by Pfizer group (20 mg/cp. Batch No. 10437003B).

Figure 3 presents the dissolution profile of capsules containing 250 mg of fenofibrate, having controlled release profile in accordance with the present invention, in sodium lauryl sulfate 0.1 M solution, using apparatus 2 (paddle) rotating at 120 rpm, at 37°C, in 1 ,000 ml_.

Figure 4 presents the comparative dissolution profile of fenofibrate capsules containing 250 mg in the form of controlled release in sodium lauryl sulfate 0.1 M solution, using apparatus 2 (paddle) rotating at 120 rpm, at 37°C, in 1 ,000 mL - curve obtained with the reference medicine containing only this active ingredient, marketed under the brand name Lipanon®, by Farmasa (250 mg/capsule, Batch No. B12H0074).

DETAILED DESCRIPTION OF THE INVENTION

In order to solve the inconveniences and difficulties of the state of the art, a single pharmaceutical form capable of carrying fibrates and statins effectively was developed, overcoming the incompatibility among its constituents (stability) and keeping the solubility profile adequate to treatments (bioavailability) and, surprisingly, preventing adverse effects of muscle and/or liver toxicity, particularly rhabdomyolysis.

Thus, in a first aspect, the invention relates to an oral pharmaceutical form comprising (a) a fibrate or pharmaceutically acceptable salts thereof and (b) a statin or pharmaceutically acceptable salts thereof, wherein (a) is in physical contact with (b), but the active principles are isolated from each other by a coating of (b) with inert polymer.

Statins appropriate to the invention are one or more from atorvastatin, simvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, cerivastatin and pharmaceutically acceptable salts thereof. Atorvastatin, and pharmaceutically acceptable salts thereof, are particularly used. More particularly, atorvastatin is used in the form of a calcium compound, in amorphous or crystalline form. It relates to a white to yellowish white crystalline powder, insoluble in aqueous solutions of pH equal to or less than four. It is slightly soluble in distilled water, phosphate buffer pH 7.4 and acetonitrile, slightly soluble in ethanol and very soluble in methanol.

Calcium atorvastatin has the following structural formula:

Statins are known as HMG-CoA inhibitors (wherein HMG-CoA is an acronym for "3-hydroxy-3-methylglutaryl-coenzyme A"), an enzyme of the liver tissue that produces mevalonate, a small molecule used in the synthesis of cholesterol and other mevalonate derivatives. Its inhibition reduces the amount of cholesterol produced which, in turn, reduces the total amount of LDL ("low density lipoprotein") cholesterol. As high levels of LDL cholesterol are associated with morbidity and mortality from cardiovascular and cerebrovascular events, the effect of constant use of statins is particularly suitable to prevent such events.

It is known that statins have poor stability in acid medium, thus, particularly, the compositions of the present invention proposed have a matrix pH close to neutrality to minimize its degradation, moreover, it was detected that the use of antioxidants has an important role in the molecule stabilization. Thus, particularly, the statins according to the present invention can be stabilized by one or more antioxidants, for example, sodium metabisulfite, potassium metabisulfite, sodium sulfite, not being limited to these.

The alkaline environment favors the dissolution of this active principle, thus enabling the adequate absorption by the gastrointestinal tract.

Fibrates appropriate to the invention are particularly chosen from fenofibrate, bezafibrate, clofibrate and ciprofibrate, and salts pharmaceutically acceptable thereof. Fenofibrate, and pharmaceutically acceptable salts thereof, are particularly used.

Fenofibrate is a white solid insoluble in water. The melting point is from 79 to 82 °C. Its chemical name is 2-[4-(4-chlorobenzoyl]-2-methyl-propanoic acid 1 -methylethyl ester and has the following structural formula:

Fenofibrate is derived from fibric acid effective in the treatment of types lla, lib, III, IV and V dyslipidemias. Fenofibrate is a prodrug quickly hydrolyzed into its pharmacologically active form, fenofibric acid.

Fenofibric acid increases the activity of lipoprotein lipase between 33 and 37%. This enzyme catalyzes the lipolysis of the core of triglycerides present in chylomicrons and the catabolism of very low density lipoproteins (VLDL), respectively, reducing the synthesis and increasing the degradation of triglycerides. As a result, the levels of triglycerides in blood are reduced between 40 and 50%. Lipoprotein lipase also promotes the increase in HDL- cholesterol levels.

Additionally, fenofibric acid also interferes with the synthesis of cholesterol in the liver and, consequently, 30 to 50% reduction in the synthesis of bile may occur, probably resulting from the reduction of hepatic cholesterol necessary for the formation of bile acids. The secretion of cholesterol in bile also increases, although the mechanism is unknown. The reduction of plasma cholesterol is, therefore, due to a reduction of the amount of LDL and VLDL fractions.

Thus, fenofibrate has a regulatory activity on the lipid balance, by increasing levels of HDL-cholesterol and improving the total cholesterol/HDL cholesterol ratio which, by its turn, is considered an atherogenic risk marker.

A particular embodiment of the invention comprises a capsule containing 100 to 300 mg of fenofibrate, preferably about 250 mg of fenofibrate, or its pharmaceutically acceptable salts thereof, and from 10 to 80 mg of atorvastatin, preferably about 20 mg of atorvastatin, or its pharmaceutically acceptable salts thereof.

In an even more particular embodiment of the invention, the capsule contains (a) pellets of fenofibrate, or pharmaceutically acceptable salts thereof, where these pellets are in the form of controlled/extended release, in amounts sufficiently adequate to treatment (250 mg); and (b) granulates and/or coated mini tablets containing atorvastatin and/or its pharmaceutically acceptable salts thereof, wherein (a) is in physical contact with (b), but the active principles are isolated from each other by the coating (b) with an inert polymer.

"Controlled/extended release pellets" are understood as an agglomeration of fine powders containing one or more active substances and in small spheroid units. These spheroidal units produced by spheronization or addition are independent units that do not necessarily contain the required entire dose of the active principle, but the set of pellets has the required dose.

In another embodiment, the present invention also comprises bilayer tablets as a dosage form, in which said tablets comprise a layer of fibrate (a) and, in another layer, a statin (b), further comprising the same dosages of active ingredients and the same delivery systems of said capsules described.

According to the present invention, controlled/extended release is defined as a pharmaceutical form which features modified release, wherein the active substance is gradually released from the pharmaceutical form for an extended period of time.

Some studies teach that the association of fibrates with statins may potentialize an adverse effect that deserves special attention, named myopathy syndrome. This is due to the fact that these drugs compete for the same glicuronisyltransferases that metabolize most of statins and fibrates and, as a result, the levels of both drugs may be increased when they are coadministered. However, some literatures also state that fenofibrate undergo glucuronidation by enzymes that are not involved in the glucuronidation of statins, therefore, the combinations of fenofibrate and statins are less likely to cause myopathy than therapy with other fibrates.

As an example of the foregoing, it is verified that fenofibrate and gemfibrozil are significantly different, since they are metabolized by different hepatic enzymes in their glucuronidation (UGT 1 A9 and 2B7 for fenofibrate and UGT 1 A1 and 1 A3 for gemfibrozil). These differences have significant clinical implications, since most statins are glucoronized by the same family of enzymes of gemfibrozil, thus competing in the conversion of statins, from the open to lactone form, which is metabolized by the liver and is subsequently catalyzed by cytochrome. Fenofibrate is a mild inhibitor of CYP2C9, while gemfibrozil is a potent inhibitor of CYP2C9 and CYP2C8. Statins are known as carriers (or transporters), which are carriers of anionic organic carrier polypeptides, and the interaction between gemfibrozil and statins could result from interaction with hepatic carriers, leading to decreased uptake by the liver.

These differences seem to explain the greater interaction of statins with gemfibrozil, compared with fenofibrate. Gemfibrozil increases the area under the curve of the concentration of all statins (there are no reports that atorvastatin has been assessed), while fenofibrate does not significantly increase the area under the curve of concentrations of simvastatin, cerivastatin, pravastatin or rosuvastatin.

Thus, the need to develop a different composition in relation to the state of the art or to what has been already proposed, with greater safeness to patients, has been verified.

The composition particularly proposes how the association of fenofibrate and atorvastatin (or its pharmaceutically acceptable salts thereof), is less likely to cause myopathy than therapy with other fibrates, since fenofibrate has less potential for interaction with atorvastatin metabolism.

Additionally, the composition of this invention presents a great advantage as regards to the release of active principles, since the release of atorvastatin occurs immediately (in about 30 minutes) and the release of fenofibrate occurs in a controlled/extended manner (in about 14 hours), starting to be released only after 1 hour, thus preventing any competition that would occur during absorption/metabolism of fenofibrate, since when it starts its dissolution stages, atorvastatin has already been virtually absorbed, keeping the concentrations of both drugs at safe levels, and consequently further reducing the possibility of occurrence of myopathy syndrome.

It is further known that this syndrome may be related to concentration of drugs, from the release control of fenofibrate, there is modulation of the release and, consequently, of the plasma concentration of active ingredient, thus avoiding the presence of high doses capable of triggering said pathology.

Another aspect of considerable relevance of the present invention lies in the fact that some studies have shown that fenofibrate must be taken preferably along with the main meal to better absorb the active component and, on the other hand, there are reports that the absorption of atorvastatin is impaired when it is in the presence of food. Thus, the proposed releases of active ingredients (immediately for atorvastatin and controlled/extended for fenofibrate) are advantageous, since it indicates to the patient (e.g. in the package insert) the dosage of a daily intake one hour before the main meal which, in turn, will favor the absorption of both active principles.

It is derived from this the fact that atorvastatin, for its immediate release, will be available and absorbed within this first time, i.e. before the meal, while fenofibrate will start to be dissolved in the fed state, i.e., after this first hour (along the main meal).

The controlled/extended release pellets containing fibrate and the immediate release granules and/or coated mini tablets containing statin are produced separately. Thus, the specific aspects related to the stability of each active principle are advantageously respected, enabling the best use of their features and preventing an active principle from impairing the stability of the other.

Thus, in another aspect, the present invention comprises a pharmaceutical preparation in the pharmaceutical form of capsule, which contains in its interior fibrate pellets and coated mini tablets containing a statin.

In an embodiment of the present invention, the amount of mini tablets can range from one to ten, being particularly two.

The mini tablets may can contain a variety of excipients, such as disintegrants, diluents, stabilizers, glidants and others. Among the disintegrants, those with a great expansion coefficient may be used, such as crospovidone, croscarmellose and starch glycolate, without limitation. Diluents can be sucrose, dextrose, mannitol, sorbitol, starch, microcrystalline cellulose and lactose, among others.

Examples of lubricants and glidants that can be used for in the production of tablets are, without limitation, hydrogenated vegetable oils, magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silica, talc or mixtures of the excipients above. A preferred lubricant is magnesium stearate, or mixtures of stearate with colloidal silica.

The compression can be done in rotary compressors, and the shape and size of the mini tablets may vary.

The coat of the mini tablet aims to preserve stability of the active ingredient by protection provided by core isolation from the external environment. Preferably, the coating is hydrophilic, permeable to water and to the moist environment of the gastrointestinal tract.

The materials that form the coating are, e.g., mixtures of polyvinylpyrrolidone or polyvinylpyrrolidone-polyvinyl acetate copolymer with hydroxypropylmethylcellulose (HPMC) or polyvinyl alcohol, without limitation to these. These polymers are dispersed in ethyl alcohol, water or hydroalcoholic mixtures to constitute the application vehicle, without being limited to these. Pigments, talc or wetting agents, plasticizers, opacifiers and others can be added to the polymer solution in water or alcohol.

Particularly, the coating is made with a polymer, like polyvinyl alcohol, dispersed in aqueous solution with the addition of opacifiers and plasticizer agents, such as polyethylene glycols.

The coating forming material may be sprinkled on the mini tablet as a dispersion, using perforated coating equipments.

The process of producing pellets, known as pelletizing, consists in the agglomeration of fine powders of the active substance and excipients in small spherical units, so-called pellets. These spherical units differ from the product obtained in the classical process of granulation not only in relation to the process by which they are produced, but also by the presented physical characteristics. The excipients used in the pellet composition are typically those used in the obtainment of tablets or capsules. Considerations should be made concerning the physical-chemical properties of excipients and the active substance intended for the composition.

In another embodiment, the present invention contemplates the use of the pharmaceutical composition in the treatment of hypercholesterolemia, hypertriglyceridemia and/or mixed dyslipidemia, as well as atherosclerosis, diabetes or secondary prevention of other cardiovascular diseases, without causing the adverse effects of liver and/or muscle toxicity, particularly rhabdomyolysis. The present invention further comprises the use of the pharmaceutical composition for preparing a medicine, particularly in the form of capsule or bilayer tablet, which is useful in the treatments or preventions described.

In another embodiment, the present invention further comprises methods for the therapeutic treatment of hypercholesterolemia, hypertriglyceridemia and/or mixed dyslipidemia, as well as atherosclerosis, diabetes or secondary prevention of other cardiovascular diseases, without causing the adverse effects of liver and/or muscle toxicity, particularly rhabdomyolysiswhich consists in providing to a patient in need thereof, one hour before the meal, an effective amount of the pharmaceutical composition according to the present invention.

Merely illustrative examples are presented below, without imparting any limitations to the scope of this invention beyond those expressed in the attached claims.

EXAMPLE 1

PHARMACEUTICAL COMPOSITION ACCORDING TO THE

INVENTION

The following is an exemplary embodiment of this invention, related to the coated mini tablet. Such example is merely illustrative of a particular embodiment of the invention, and for this reason, it does not represent any limitation beyond the restrictions set forth by set of claims below.

Capsules containing two mini tablets of calcium atorvastatin and fenofibrate pellets were prepared. TABLE 1

STATIN MINI TABLET ACCORDING TO THE INVENTION

TABLE 2

FIBRATE PELLETS ACCORDING TO THE INVENTION

EXAMPLE 2

PREPARATION PROCESS

The process of producing pellets, known as pelletizing, can be carried out by one of the following manners: 1 ^st agglomeration of fine powders of the active substance and excipients in small spherical units (inert pellets); 2^nd granulation of a portion of the active substance with a binder solution, which is dried and standardized in an adequate mesh, and the production of such pellets by applying concentric layers of the remaining active component and diluent on the granules previously prepared above in a coating bucket; or 3^rd granulation of the active substance and diluent with a binder solution, sequentially submitted to extrusion/spheronization.

For the preparation of mini tablets, the following raw materials in the amounts indicated in table (I) above, were passed through an appropriate mesh: cellulose, amorphous calcium atorvastatin and crospovidone. Then, the raw materials were transferred to a mixer and mixed. Afterwards, sodium metabisulfite and lactose, pre-sieved in an appropriate mesh, were added and mixed.

Finally, magnesium stearate was added to the previous mixture, passing through an appropriate mesh, which was mixed and sent to the compression step in a rotary compressor.

After compression, the coating was carried out through a circular equipment with perforated bucket.

The coating used was a mixture comprised by polyvinyl alcohol, polyethylene glycol, talc and titanium dioxide.

After coating, two 10 mg mini tablets of atorvastatin were "filled" in a hard gelatin capsule No. 00, together with the fenofibrate pellets in the amount required to achieve the fenofibrate concentration of 250 mg. A capsuller was used in this process.

EXAMPLE 3

SOLUBILITY TEST

Comparative tests show that solubility profiles of both mini tablets and the pellets are suitable. The results are shown in the graphs of figures 1 to 4.

The atorvastatin compositions were evaluated in order to show a similar immediate release in vitro profile.

Figure 1 presents the dissolution profile of capsules containing 20 mg of atorvastatin, having immediate release profile in accordance with the present invention, in phosphate buffer medium, at pH 6.8, using apparatus 2 (paddle) rotating at 75 rpm, at 37°C, in 900 mL.

Figure 2 presents the comparative dissolution profile of a tablet containing 20 mg of atorvastatin in phosphate buffer, at pH 6.8, using apparatus 2 (paddle) rotating at 75 rpm, at 37°C in 900 mL. - curve obtained with the reference medicine containing only this active ingredient, marketed under the brand name Citalor®, by Pfizer group (20 mg/cp. Batch No. 10437003B).

The comparison between the curves of the mini tablet dissolution profiles, according to the present invention, and the state of the art product, exhibits a similar in vitro performance. It is further verified that the curves show a very fast dissolution behavior of the product, that is, more than 85% release in 15 minutes, exempting the calculation of the similarity factor/F2, suitable to the objectives of the present invention.

Fenofibrate compositions were compared in order to demonstrate, in vitro, the controlled/extended release profile of the composition, according to the present invention.

Figure 3 presents the dissolution profile of capsules containing 250 mg of fenofibrate, having controlled release profile in accordance with the present invention, in a sodium lauryl sulfate 0, 1 M solution, using apparatus 2 (paddle), rotating at 120 rpm, at 37°C, in 1000 ml_.

The comparative study of the profiles, according to figures 3 and 4, show that the state of the art product versus the product of this invention presents a similar in vitro performance.

EXAMPLE 4

STABILITY TEST

Stability study under the following conditions: 40 °C/75% RH, during 6 months (accelerated stability) and 30 °C/75% RH, during 12 months (long term stability), where during the period all tests indicative of stability are evaluated, as well as all possible impurities of the associated product, as described in the official textbooks for the isolated products, especially USP (Atorvastatin: related compound H (lactone) and other specific and non-specific impurities/fenofibrate: related compound B and other non-specific impurities). This ensures a more stable and, consequently, a safer composition for human use.

EXAMPLE 5

IN VIVO STUDY OF THE EVALUATION OF PHARMACOKINETICS OF THE ASSOCIATION FENOFIBRATE + ATORVASTATIN IN HEALTHY PATIENTS UNDER FASTING AND FED CONDITIONS

The purpose of this clinical, randomized and cross-over study is to evaluate the pharmacokinetic profile of the capsule according to the present invention (atorvastatin 20 mg + fenofibrate 250 mg) in comparison with the reference medicines (Citalor® containing only atorvastatin, available from Pfizer group, and Lipanon, containing only fenofibrate, available from Farmasa), by comparing the serum concentration of the unchanged analyte atorvastatin (AT) and the fenofibric acid metabolite in healthy individuals.

The pharmacokinetic profile of the medicine is also evaluated by comparing the serum concentration of the following active metabolite: O- hydroxy atorvastatin (2-hidroxy atorvastatin, O-HAT).

Inclusion criteria

1 . voluntary participation;

2. age between 18 and 55 years, regardless of sex, clinically healthy and presenting normal laboratory parameters;

3. BMI≥ 18.5 and≤ 30.

Exclusion criteria

1 . Participation in clinical trials in 12 months preceding the survey; 2. Clinical history of hypersensitivity reactions to atorvastatin and fenofibrate, and/or any other medicine component;

3. Presence of alterations in clinical and laboratory examinations that interfere in the study results;

4. Presence of lung, cardiovascular, neurological, endocrine, gastrointestinal or genitourinary diseases, or of other systems;

5. Acute disease within 7 days prior to the beginning of the study;

6. Chronic disease that determines medicine administration, such as arterial hypertension, diabetes or any other that requires continuous use of any medicine, including the use of vitamins, mineral supplements and over-the- counter (OTC) medicines;

7. Use of medicines that interact with any medication of the association;

8. History of current use of tobacco, or within the last 12 months;

9. Current or past (less than 12 months) medical history of use of illicit drugs;

Estimated number of researched individuals: 72 people, 24 in each arm. Feed study design: prospective, randomized, open and crossed-over (3 sequences, 3 periods) controlled by a feed active comparative.

Fast study design: prospective, randomized, open and crossed-over (3 sequences, 3 periods) controlled by a fast active comparative.

Considering a cross-study, with 3 periods, each medicine (text, comparative 1 and comparative 2) is orally administered once (a medication in every study period).

Primary pharmaco-kinetic parameters:

The primary pharmacokinetic parameters, for comparability purposes, will be the dosages of the unchanged analyte (AT) and of the fenofibrate active metabolite (fenofibric acid), assessed by AUC, Tmax, Cmax and T1/2.

Secondary pharmaco-kinetic parameters:

The secondary pharmaco-kinetic parameters will be the dosage of active metabolite O-HAT, assessed by AUC, Tmax, Cmax and T1/2.

Studies were conducted in a small number of healthy volunteers, with the main objective of determining the in vivo pharmacokinetics and/or pharmacodynamics, as well the initial safety data.

Claims

1 . PHARMACEUTICAL COMPOSITION characterized in that it contains (a) at least a fibrate or pharmaceutically acceptable salts thereof, carried in a controlled/extended release form with pharmaceutically acceptable excipients and (b) at least one statin, or pharmaceutically acceptable salts thereof, in an immediate release form with pharmaceutically acceptable excipients.

2. COMPOSITION, according to claim 1 , characterized in that the fibrate (a) is selected from fenofibrate, bezafibrate, clofibrate and ciprofibrate, and pharmaceutically acceptable salts thereof.

3. COMPOSITION, according to claim 2, characterized in that the fibrate

(a) is fenofibrate and pharmaceutically acceptable salts thereof.

4. COMPOSITION, according to claim 3, characterized in that it contains 100 to 300 mg of fenofibrate as fibrate (a).

5. COMPOSITION, according to claim 4, characterized in that it contains about 250 mg of fenofibrate as fibrate (a).

6. COMPOSITION, according to claim 1 , characterized in that the statin is selected from one or more among atorvastatin, simvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, cerivastatin and pharmaceutically acceptable salts thereof.

7. COMPOSITION, according to claim 1 , characterized in that the statin

(b) is atorvastatin and pharmaceutically acceptable salts thereof.

8. COMPOSITION, according to claim 7, characterized in that the statin (b) is amorphous calcium atorvastatin.

9. COMPOSITION, according to claim 8, characterized in that the amount of statin (b) varies between 10 and 80 mg.

10. COMPOSITION, according to claim 9, characterized in that the amount of statin (b) is 20 mg.

1 1. COMPOSITION, according to claim 6, characterized in that the statin (b) is stabilized with an antioxidant agent.

12. COMPOSITION, according to claim 1 1 , characterized in that the antioxidant agent is selected from one or more of sodium metabisulfite, potassium metabisulfite and sodium sulfite.

13. COMPOSITION, according to claim 1 , characterized in that the pharmaceutically acceptable excipients used in (a) comprise a binder and a diluent.

14. COMPOSITION, according to claim 1 , characterized in that the pharmaceutically acceptable excipients in the mini tablet used in (b) comprise disintegrants, diluents, antioxidants, lubricants and glidants.

15. COMPOSITION, according to claim 14, characterized in that the disintegrant is selected from one or more of crospovidone, croscarmellose and starch glycolate, the diluent is selected from one or more of sucrose, dextrose, mannitol, sorbitol, starch, cellulose and lactose, the antioxidant is selected from one or more of sodium metabisulphite, potassium metabisulphite and sodium sulphite, and lubricant and glindant is selected from one or more of hydrogenated vegetable oils, magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium lauryl sulphate, colloidal silica and talc.

16. COMPOSITION, according to claim 1 , characterized in that it comprises a coating layer in (b) of an inert polymer.

17. COMPOSITION, according to claim 16, characterized in that the inert polymer is selected from one or more from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone copolymer, polyvinyl acetate, hydroxypropylmethylcellulose or polyvinyl alcohol.

18. COMPOSITION, according to claim 17, characterized in that the coating layer in (b) comprises polyvinyl alcohol dispersed in aqueous solution with opacifiers and a plasticizing agent of polyethylene glycol type.

19. COMPOSITION, according to claim 1 , characterized in that the immediate release occurs within 30 minutes of ingestion and the controlled/extended release begins after 1 hour, and occurs within 14 hours from ingestion.

20. ORAL PHARMACEUTICAL FORM, characterized in that it comprises the pharmaceutical composition set forth in one of claims 1 to 19, wherein (a) at least a fibrate or pharmaceutically acceptable salts thereof is conveyed in controlled/extended release pellets and (b) at least one statin or pharmaceutically acceptable salts thereof is conveyed in immediate release mini tablets and/or granules, wherein (a) is in physical contact with (b), but the active principles are isolated from each other by means of the coating (b) with an inert polymer.

21. ORAL PHARMACEUTICAL FORM, according to claim 20, characterized in that it is capsule comprising pellets inside (a) and 1 to 10 mini tablets (b).

22. ORAL PHARMACEUTICAL FORM, according to claim 21 , characterized in that the capsule comprises 2 mini tablets (b).

23. CAPSULE, characterized in that it comprises the pharmaceutical composition set forth in one of claims 1 to 19, wherein the fibrate (a) is conveyed in controlled/extended release pellets and the statin (b) is conveyed in immediate release mini tablets and/or granules, wherein (a) is in physical contact with (b), but the active principles are isolated from each other by means of the coating (b) with an inert polymer.

24. CAPSULE, according to claim 23, characterized in that it comprises 1 to 10 mini tablets.

25. CAPSULE, according to claim 24, characterized in that it comprises 2 mini tablets.

26. BILAYER TABLET, characterized in that it comprises the pharmaceutical composition set forth in one of the claims 1 to 19, in which a layer contains the fibrate (a) and the other the statin (b).

27. USE of a pharmaceutical composition set forth in one of claims 1 to 19, characterized in that it is used in the preparation of a medicine useful in the treatment of hypercholesterolemia, hypertriglyceridemia and/or mixed dyslipidemia or atherosclerosis, diabetes or secondary prevention of other cardiovascular diseases, which is less likely to cause adverse effects of liver and/or muscle toxicity.

28. ORAL PHARMACEUTICAL FORM, characterized in that it comprises fibrate (a) with controlled/extended release and statin (b) of immediate release, decreasing the possibility of interaction/competition for the same metabolism enzymatic groups, with subsequent reduction of the likelihood of causing muscle and/or liver toxicity.

29. ORAL PHARMACEUTICAL FORM, according to claim 28, characterized in that it has controlled/extended release in (a), modulating the release of the active ingredient and avoiding the presence of high doses that may cause myopathy syndrome.

30. METHOD OF TREATING HYPERCHOLESTEROLEMIA, HYPERTRIGLYCERIDEMIA AND/OR MIXED DYSLIPIDEMIA, characterized in that it comprises providing a therapeutically effective amount of the pharmaceutical composition to a patient in need thereof, which is set forth in any of claims 1 to 19 one hour before the meal.

31. METHOD OF PREVENTING ATHEROSCLEROSIS, DIABETES OR SECONDARY PREVENTION OF OTHER CARDIOVASCULAR DISEASES, characterized in that it comprises providing a therapeutically effective amount of the pharmaceutical composition to a patient in need thereof, which is set forth in any of claims 1 to 19 one hour before the meal.

32. METHOD, according to ant of claims 30 or 31 , characterized in that it less prone to adverse effects of liver and/or muscle toxicity.