Pharmaceutical combinations of statins and fibrates for treatment and prevention of hyperlipidaemia and cardiovascular diseases

Abstract

To provide a solid stable immediate-release pharmaceutical composition comprising atorvastatin and fenofibrate or pharmaceutically acceptable salts thereof for the treatment of hyperlipidemia and the prevention of cardiovascular diseases, and to provide a method for producing the same.SOLUTION: A pharmaceutical composition comprises (a) a pharmaceutically acceptable amount of atorvastatin or an equivalent amount thereof in the range of 20±0.7 mg, (b) a pharmaceutically acceptable amount of micronized fenofibrate or micronized salts thereof in a range of 160 mg to 200 mg, and (c) a pharmaceutically acceptable amount of a pharmaceutically acceptable excipient and / or a pharmaceutically acceptable vehicle, wherein the micronized fenofibrate has a particle size distribution of less than 30 μm (100%), preferably less than or equal to 0.95 μm (d10), preferably less than or equal to 5.35 μm (d50), more preferably less than or equal to 11.28 μm (d90).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to pharmaceutical compositions for formulation in the field of the treatment of dyslipidemia and cardiovascular diseases.

Background Art

[0002] Patent Document 1 of WARNER LAMBERT COMPANY LLC (Patent Document 2 corresponding in Mexico) describes the active ingredient atorvastatin, pharmaceutical compositions containing it, and its use for manufacturing pharmaceutical products for alleviating hypercholesterolemia. However, their effectiveness ended in 2011 and 2010, respectively. Patent Document 3 of the same company describes crystalline Form I of atorvastatin hydrate having the following 2θ values measured using CuKα radiation in X-ray powder diffraction: at least one of 11.9 or 22.0. Crystalline Forms II and IV of atorvastatin are also described.

[0003] Other crystalline forms of atorvastatin and compositions containing them are described in Patent Document 4, Patent Document 5, Patent Document 6, Patent Document 7, Patent Document 8, and Patent Document 9 filed by DSM SINOCHEM PHARMACEUTICALS NETHERLANDS B.V.

[0004] Independently, Patent Document 10 of FOURNIER GMBH LAB describes the active ingredient fenofibrate. As a result, Patent Document 11 jointly owned by ALKERMES PHARMA IRELAND LIMITED and ABBOTT LABORATORIES, IRELAND, LIMITED describes, in its independent claims, a stable fenofibrate composition for oral administration containing fenofibrate particles having an effective average particle size of less than about 2000 nm.

[0005] However, with respect to the combination of these active ingredients, atorvastatin and fenofibrate, there is no description of dealing with their stability in the same pharmaceutical form, on the premise that they have different physicochemical properties and there are differences in the modes in which they are administered to reliably achieve a curative or preventive result. For example, atorvastatin shows sensitivity to humidity. Humidity risks impairing the stability of atorvastatin and, as a result, the composition or pharmaceutical form containing it. For example, pharmaceutical compositions have been proposed that incorporate these active ingredients in a single-dose solid dosage form, multilayer tablets, bilayer tablets or capsules, solutions, or separate entities of sachets containing the active ingredients in separate granules or pellets.

[0006] Patent Document 12 of ABBOTT LABORATORIES, IRELAND, LIMITED describes the use of a compound selected from fenofibrate, fenofibric acid and salts of fenofibric acid for the preparation of a pharmaceutical product for the treatment of obstructive sleep apnea or obstructive sleep apnea syndrome that may be associated with known hydroxymethylglutaryl coenzyme A reductase (HMG-CoA) inhibitors or statins including, but not limited to, atorvastatin.

[0007] Patent Document 13 of SARL GALENIX INNOVATIONS describes the process for manufacturing in tablet form a pharmaceutical composition containing one of the active ingredients fenofibrate or a derivative thereof, optionally in the form of an association of fenofibrate or a derivative thereof with a second active ingredient. The second active ingredient is selected from metformin, cobalamin, folic acid, betaine, n-acetylcysteine, vitamin E and HGM-CoA inhibitors. The process described in the claims includes only the granulation or compression steps carried out in a dry process.

[0008] In addition, Patent Document 14 of ABBOTT GMBH&CO.KG describes a preparation containing a fenofibric acid or a physiologically acceptable salt or derivative thereof and optionally other active substances (including atorvastatin in one embodiment), as well as a binder component containing at least one enteric binder and a physiologically acceptable excipient. The enteric binder is an enteric polymer selected from hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethylcellulose, cellulose acylate phthalate, cellulose acylate trimelittate, and sodium carboxymethylcellulose.

[0009] Separately from the above, Patent Document 15 mentions the formulation of a statin and any other lipid-lowering agent, and gives fenofibrate as an example. In this case, a wet granulation process is employed to form tablets, capsules or pellets.

[0010] Patent Documents 16 and 17 mention a solid dispersion process in which fenofibrate is melted together with other excipients and the liquid mixture is spread on a diluent. Atorvastatin-coated granules are further produced.

[0011] Patent Document 18 describes the production of a multilayer tablet by physically separating a part of a tablet containing fenofibrate from another part containing atorvastatin.

[0012] Patent Document 19 describes a co-solvent system consisting of poloxamer, polyethylene glycol, and diethylene glycol monoethyl ether used to achieve the elution of fenofibrate. This patent mentions that without an appropriate ratio of the co-solvent system, drug elution cannot be achieved. The co-solvent is in a ratio of 5 - 15%. The co-solvent is also characterized by a binder that can be HPMC, PVP, HPC, carboxymethyl cellulose, methocel, methacrylate, and mixtures thereof. These are confirmed at a weight ratio of 2 - 8%; the antistatic agent is selected from silicon dioxide and talc and mixtures thereof; the stabilizer contains calcium carbonate, silicated crystalline cellulose, calcium phosphate, and mixtures thereof at a ratio of 15 - 60%. Furthermore, the tablets may or may not be coated. In this Patent Document 19, fenofibrate is incorporated via an aqueous dispersion consisting of a co-solvent, surfactant, wetting agent, and binder. This dispersion is sprayed onto a mixture of diluent and disintegrant. It is dried and sieved. Atorvastatin, lubricant, stabilizer, antistatic agent, and compressible vehicle are added. In conclusion, this process is the wet granulation of fenofibrate. Elution is ensured by the co-solvent system. However, as described, atorvastatin is sensitive to moisture, and there is residual moisture in the wet granulation process that risks impairing the stability of atorvastatin and thus the stability of the tablets.

[0013] Patent Document 20 generally describes a formulation of atorvastatin-fenofibrate at concentrations of 10 - 80 mg and 140 - 170 mg respectively, and a pharmaceutical form of tablets. Such a composition is manufactured without the need to add water or an aqueous medium, and at least 80% of the active substances (in this case, fibrate and statin) are present in the eluted form in the composition, which ensures appropriate bioavailability of both active ingredients upon oral administration.

[0014] However, in this Patent Document 20, the particulate material contains one or more fibrates and one or more statins as active substances, and at least 80% of the total amount of the active substances is eluted in a vehicle selected from the group consisting of hydrophobic, hydrophilic, and water-miscible vehicles. The active ingredient is eluted in the vehicle, and the active substance exists in the form of a solid solution in the particulate composition. The existence of the solid solution can be proven by DSC testing. However, during storage, partial crystallization of the active substance from the solid solution is expected. The vehicle has oil properties (adsorbent) with a maximum melting point of 25°C and a hydrophobic or hydrophilic vehicle with a melting point of 0 to 250°C, but an oil adsorbent needs to be added. These come into contact with a molten binder or a solid solvent. As an example, polyethylene glycol etc. are described. A mixture of PEG:poloxamer, specifically PEG6000, is described. As a regulator, a low-melting-point vehicle is preferred. The drug is eluted in a liquid vehicle, and the resulting solution is sprayed onto a solid diluent. Method options for melting the vehicle and eluting fenofibrate are mentioned, and the solution is sprayed onto a solid carrier capable of adsorbing the solution. Other method options for eluting a solid solution of fenofibrate in a vehicle are mentioned. As part of those manufacturing processes, the necessity of eluting the drug in a co-solvent is shown.

[0015] Separately from the above, Patent Document 21 describes a formulation of fenofibrate with improved oral bioavailability, simple design and manufacture, and no food effect. Fenofibrate is eluted in lipophilic and hydrophilic surfactants alone or together with a statin until a clear solution is obtained. It may contain a pH stabilizer, an antioxidant, a preservative, a coloring agent, a flavor, a buffer, and a thickening agent. It is characterized by containing 20 to 80% of polysorbate 80 and 10 to 20% of poloxamer, and the dosage form is a liquid contained in a capsule. This formulation may also contain 5 to 80 mg of atorvastatin. Furthermore, the present invention relates to the manufacturing process of the formulation and the dosage form including the formulation such as a soft gelatin capsule.

[0016] None of the prior art documents enable the formulation of atorvastatin and fenofibrate in a single solid, stable, immediate-release dosage form, without fully exploiting their physicochemical, fluidic, and particle size characteristics.

[0017] As described, for example, atorvastatin is sensitive to moisture, and in conventional granulation processes such as wet granulation, there is a risk of residual moisture that can impair the stability of atorvastatin and thus the stability of any pharmaceutical form manufactured in such a way that contains atorvastatin. In the present invention, the proposed composition and its manufacturing method overcome these major drawbacks and do not require the use of co-solvents to achieve the dissolution effect of the active ingredients.

[0018] Thus, the present invention proposes a formulation in a single-dose form of atorvastatin and fenofibrate, which are active ingredients at dosages of 20 ± 0.7 mg and 160 - 200 mg respectively, to solve a series of important technical problems due to differences in physicochemical properties and dosages, in order to ensure the achievement of stable products in the treatment of dyslipidemia and the prevention of cardiovascular diseases.

Prior Art Documents

Patent Documents

[0019]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Patent Document 9

Patent Document 10

Patent Document 11

Patent Document 12

Patent Document 13

Patent Document 14

Patent Document 15

Patent Document 16

Patent Document 17

Patent Document 18

Patent Document 19

Patent Document 20

Patent Document 21

Summary of the Invention

[0020] The present invention relates to a solid, stable immediate-release pharmaceutical composition comprising atorvastatin and fenofibrate or pharmaceutically acceptable salts thereof for the treatment of dyslipidemia and the prevention of cardiovascular diseases, and a method for producing the same. The method can obtain a pharmaceutical composition that is easy to administer in a single dose. The method includes a granulation step activated by heating with fenofibrate, an incorporation step of atorvastatin, and a compression step, and the steps are carried out while avoiding conditions that affect the stability of atorvastatin without containing water.

[0021] In one embodiment, fenofibrate is preferably micronized. The particle size distribution of micronized fenofibrate is less than 30 μm (100%), preferably 0.95 μm or less (d10), preferably 5.35 μm or less (d50), more preferably 11.28 μm or less (d90).

[0022] In another embodiment of the present invention, atorvastatin is preferably in the form of its calcium trihydrate.

[0023] In another embodiment of the present invention, dyslipidemia and cardiovascular diseases are selected from hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertension, angina pectoris, heart attack, aneurysm, and regulation of blood concentrations of LDL, HDL, and triglycerides.

[0024] One embodiment of the present invention includes a pharmaceutical composition comprising (a) a pharmaceutically acceptable amount of atorvastatin in the range of 20 ± 0.7 mg or an equivalent amount of its salt, (b) a pharmaceutically acceptable amount of micronized fenofibrate in the range of 160 mg to 200 mg or its micronized salt, and (c) a pharmaceutically acceptable amount of a pharmaceutically acceptable excipient and / or pharmaceutical vehicle. Pharmaceutically acceptable excipients and / or vehicles include binders, diluents, disintegrants, pH adjusters, surfactants, lubricants, solvents, and coatings. In a further embodiment of the present invention, the coating functions as a moisture barrier.

[0025] In other embodiments of the present invention, the composition is in the form of tablets, caplets, granules, pills, preferably in the form of biconvex tablets and / or coated tablets.

[0026] In other embodiments of the present invention, the dissolution profile of the formulation of this pharmaceutical formulation represents a comparison between the two dosages in order to demonstrate bioexemption. Since this is a study for the waiver of a bioequivalence test, the drug requiring the waiver of this test is called the test drug. The reference drug is that used in a comparative bioavailability test between drugs when administered in the same formulation with respect to both the co-administered reference drug and the separately administered reference drug.

[0027] In another aspect of the present invention, pharmacokinetic simulations were performed to predict the behavior of atorvastatin and fenofibric acid co-administered after following a dosing schedule of 1 tablet every 24 hours for 2 weeks. This makes it possible to demonstrate that the concentrations reached by both drugs are effective and safe and comparable to the concentrations reported in the literature.

Brief Description of the Drawings

[0028]

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Mode for Carrying Out the Invention

[0029] Definition Pharmaceutically acceptable salts: The term pharmaceutically acceptable salts of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and are not undesirable biologically or otherwise (P. Heinrich Stahl and Camille G. Wermuth (Eds.) Pharmaceutical Salts Properties, Selection, and Use (International Union of Pure and Applied Chemistry), Wiley-VCH; 2 a nd revised edition (May 16, 2011)). Pharmaceutically acceptable base addition salts can be prepared from inorganic bases or organic bases. Salts derived from inorganic bases include, by way of example only, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Specific examples of suitable amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucosamine, theobromine, purine, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0030] Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids or organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0031] Excipients are raw materials that are part of the pharmaceutical composition. Excipients can be, inter alia, diluents, disintegrants, lubricants, coatings, absorbents.

[0032] Stability. It is the ability of a pharmaceutical product to maintain its chemical, physical, microbiological, and biopharmaceutical properties within specific limits throughout its shelf life.

[0033] The present invention relates to a solid, stable, immediate-release, synergistically effective dissolution-maintaining, and bioavailable pharmaceutical composition of a statin and a fibrate, which are orally administered in a single pharmaceutical form as therapeutic agents for the treatment of dyslipidemias selected from hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertension, angina pectoris, heart attack, aneurysm, and regulation of blood concentrations of LDL, HDL, and triglycerides, and for the prevention of cardiovascular diseases.

[0034] The present invention also relates to the manufacture of the above composition of a statin and a fibrate for oral administration. In particular, atorvastatin is selected for the statin and fenofibrate is selected for the fibrate. The method enables the obtaining of a pharmaceutical composition that is easy to administer in a single dose.

[0035] The combination of atorvastatin and fenofibrate poses a series of important technical challenges in the development of a pharmaceutical composition due to the appropriate selection of the physicochemical properties of the drugs, excipients, and manufacturing conditions, as well as the differences in dosages to ensure a stable product, and plays a very important role regarding the drug release, absorption rate, and amount absorbed by the body.

[0036] The composition of the present invention comprises (a) a pharmaceutically acceptable amount of atorvastatin in the range of 20 ± 0.7 mg, (b) a pharmaceutically acceptable amount of fenofibrate in the range of 160 mg to 200 mg, and (c) a pharmaceutically acceptable amount of a pharmaceutically acceptable excipient and / or pharmaceutical vehicle. The pharmaceutical composition can be used in the manufacture of a pharmaceutical product useful in the treatment of dyslipidemias and the prevention of cardiovascular diseases.

[0037] In one embodiment, the composition of the present invention contains atorvastatin or an equivalent amount of its salt, preferably in the form of its calcium trihydrate, and 21.65 mg of atorvastatin calcium trihydrate corresponds to 20 mg of atorvastatin.

Chemical formula

[0038] In a preferred embodiment, the pharmaceutically acceptable amount of the active ingredient atorvastatin is adjusted by titration.

[0039] In other embodiments, the composition of the present invention preferably contains fenofibrate in micronized form.

Chemical formula

[0040] Those skilled in the art can recognize that various methods of particle micronization exist in the prior art such as Remington Pharmaceuticals.Gennaro AR, editor.20th Edition.Tome I.Buenos Aires:Editorial Medica(e with accent mark)Panamericana; Lachman L, Lieberman HA, Kanig JL.The theory and practice of industrial pharmacy 3ed.Philadelphia:Lea-Febiger, 1986:333;and Pharmacopoeias:USP, British Pharmacopoeia. It is obvious to those skilled in the art to solve and execute the processes of micronization, reduction and particle size distribution according to existing pharmaceutical documents or in combination with them, and numerous variations are possible in the realization of this process to ensure the proper functionality of the product and meet the required quality characteristics without departing from its gist and scope.

[0041] Measurement of the particle size distribution of micronized fenofibrate by laser beam diffraction was performed using the DPS module in a particle size analyzer.

[0042] The particle size distribution of the micronized fenofibrate is less than 30 μm (100%), preferably the particle size distribution of the micronized fenofibrate is 0.95 μm or less (d10), preferably 5.35 μm or less (d50), more preferably 11.28 μm or less (d90) (Figure 1).

[0043] The pharmaceutical composition of the present invention includes pharmaceutically acceptable excipients and / or vehicles including, but not limited to, binders, diluents, disintegrants, pH adjusters, surfactants, lubricants, solvents, and coatings.

[0044] Examples of pharmaceutically acceptable binders are various grades of polyethylene glycol, glyceryl behenate, microcrystalline wax, and stearoyl polyoxyglyceride. In one embodiment, the binder is preferably a pharmaceutically acceptable amount of poloxamer 188 in the range of 5-10%.

[0045] Examples of pharmaceutically acceptable diluents, the functions of which are well-known in the prior art and include adjusting and maintaining a certain tablet weight, include, but are not limited to, cellulose derivatives such as PH102 microcrystalline cellulose, phosphate derivatives such as dibasic calcium phosphate, starch derivatives such as pregelatinized starch and corn starch, and mannitol, xylitol, maltitol, lactitol, sorbitol, sucrose, or combinations thereof. In one embodiment, the diluent is preferably a pharmaceutically acceptable amount of lactose monohydrate in the range of 5-90%. In a further embodiment, the diluent is also preferably a pharmaceutically acceptable amount of magnesium aluminum silicate in the range of 5-90%.

[0046] Pharmaceutically acceptable disintegrants include, but are not limited to, cellulose derivatives such as crosscarmellose, hydroxypropyl cellulose, carboxymethyl cellulose, microcrystalline cellulose, povidone derivatives such as crospovidone, starch derivatives such as pregelatinized starch, sodium starch glycolate, and corn starch. In one embodiment, the disintegrant is preferably a pharmaceutically acceptable amount of sodium starch glycolate in the range of 2 to 8%, and sodium starch glycolate is selected in the present invention for its high performance of rapidly taking in water and increasing its volume.

[0047] Examples of pH adjusters for imparting formulation stability include alkali and alkaline earth metal salts such as calcium phosphate, sodium hydroxide, sodium carbonate, sodium bicarbonate, calcium hydroxide. In one embodiment, the pH adjuster is preferably a pharmaceutically acceptable amount of magnesium oxide in the range of 0.5 to 5%.

[0048] Pharmaceutically acceptable surfactants can be, for example, poloxamer, polyoxyethylene castor oil derivatives, benzalkonium chloride, benzethonium chloride, polyoxyethylene alkyl ether, and polyoxyethylene sorbitan fatty acid esters. In one embodiment, the surfactant is preferably a pharmaceutically acceptable amount of sodium lauryl sulfate in the range of 1 to 2.5%.

[0049] Examples of pharmaceutically acceptable lubricants include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, stearic acid, monostearate, stearyl fumarate, talc, and sulfated derivatives such as magnesium lauryl sulfate. In one embodiment, the lubricant is preferably a pharmaceutically acceptable amount of magnesium stearate in the range of 0.25 to 5%.

[0050] On the one hand, the composition of the present invention may include coatings that can be in explicit and non-limiting forms selected from cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polyvinyl derivatives such as polyvinyl alcohol, polyethylene glycol, all grades of povidone K, and their derivatives, and water-repellent coatings. In one embodiment, the water-repellent coating is preferably Opadry such as pharmaceutically acceptable amounts of Opadry AMB II blue in the range of 0.5 to 6%.

[0051] The composition of the present invention also includes a solvent that is pharmaceutically acceptable or in sufficient amount (q.s.), such as water, and preferably water. The present invention also describes an optimized method that enables the compounding and manufacturing of the active ingredients atorvastatin and fenofibrate in a single solid, stable, immediate-release pharmaceutical form. Atorvastatin is preferably in the form of its calcium trihydrate, and 21.65 mg of atorvastatin calcium trihydrate corresponds to 20 mg of atorvastatin.

[0052] The solid pharmaceutical composition is selected from the group consisting of tablets, single-layer tablets, granules, caplets, or pills. Preferably, it is in the form of tablets and / or coated tablets. The biconvex tablets enable the efficient execution of the coating process and achieve a stable product with good physical and chemical properties.

[0053] The most preferred pharmaceutical form of the present invention is a "tablet" due to its dosing accuracy. It is also the most acceptable pharmaceutical form for easy administration, and different from capsules, it enables the dosing of high-concentration drugs. In the case of tablets, the volume of the powder can be reduced, making their handling and administration easy.

[0054] The present invention also relates to both a pharmaceutical composition and a manufacturing method for obtaining it. The method enables the obtaining of a pharmaceutical composition that is easy to administer in a single dose.

[0055] The production process of the composition in tablet form lies in the selection of unit operations, sequences, and execution times that control the different physicochemical properties of the drug. The technical problem lies in the formulation of two drugs with very low water solubility and low fluidity. In the case of fenofibrate, since a preferably micronized material is used, considering the high concentration of the active ingredient, it is necessary to carry out a granulation process for manufacturing tablets. Atorvastatin also exhibits important stability problems, being susceptible to humidity, acidic pH, and high temperature.

[0056] In the melt granulation process, the binder solution of the standard wet granulation process is replaced by a soluble binder. This binder can be added in a molten state, but can also be added in its solid state if the technology employed allows it.

[0057] However, in the present invention, since the process does not reach the melting point of the binder, it is not melt granulation. Thermal activation granulation is a process in which heating is used to trigger granulation (i.e., agglomeration) in the presence of a binder at a glass transition temperature that can be controlled without reaching the melting point. The glass transition temperature (Tg) is the temperature at which, above it, a reversible transition occurs in the amorphous regions of the polymer from a glassy state (hard and brittle) to a state of viscoelasticity with a significant loss of hardness. It is associated with the onset of movement of a long range of polymer chains due to the temperature factor. By raising the temperature above the glass transition temperature, the viscoelastic behavior of the polymer is achieved, i.e., the polymer in its solid state exhibits mechanical properties intermediate between those of its liquid state and solid state.

[0058] The challenge of granulation activated by heating is to achieve densification of the powder mixture so as to improve fluidity, compressibility, and drug elution.

[0059] Poloxamer 188 has a melting point of 52 °C to 57 °C and a reported glass transition temperature of about 50 °C. The process is operated at a product temperature of 47 °C, at which temperature the polymer achieves the adhesion of smaller particles (fine powders) to form larger particles (granules or aggregates).

[0060] Temperature control is important because it is only necessary to densify the powder mixture as described. Managing the product temperature at the melting point of the polymer means a greater agglomerating effect of the particles, i.e., the granules formed are larger and harder, which is a significant factor in drug elution.

[0061] Among the properties of fenofibrate, a negative electrostatic charge is confirmed, and since it is dissipated by the incorporation of magnesium oxide, better handling and overall incorporation of the drug are ensured in subsequent handling steps.

[0062] Fenofibrate exhibits low solubility, photosensitivity, elastic deformability, and moderate cohesiveness. Magnesium oxide, as already described, dissipates the charge of fenofibrate, but also achieves higher particle lubricity and reduces the cohesiveness of the drug.

[0063] Magnesium aluminum silicate is employed as a diluent, and it improves the hydrodynamic properties of fenofibrate by reducing the electrostatic charge without affecting the flow properties together with magnesium oxide, so it is not employed as a moisture adsorbent.

[0064] Therefore, in the present invention, it is determined to perform a granulation step activated by heating with fenofibrate and incorporate atorvastatin while avoiding conditions that can contain water and affect the stability of the drug. Since atorvastatin is sensitive, the production was carried out pursuing the maintenance of a water-free process. The properties of the fenofibrate powder do not allow a process by direct compression, so a granulation step is required.

[0065] In another embodiment of the present invention, the dissolution rate of the active ingredient was measured. The dissolution profile of this pharmaceutical formulation represents a comparison between the two doses demonstrating exemption.

[0066] With the innovations made in the processes and formulations of drugs, it has become possible to obtain products with proven stability through research in accordance with current regulations. In those products, the quality attributes were met during the evaluation period. Stability testing is a means of comparing various formulations, packaging materials, or manufacturing processes in short-term experiments. As soon as the final formulation and manufacturing process are set, the manufacturer conducts a series of stability tests to predict the stability of the product or drug in this case and determine its shelf life and storage conditions.

[0067] The initial and early results for the measurement of the stability of the compositions of the present invention for the manufacture of pharmaceutical products useful for the treatment of dyslipidemia and the prevention of cardiovascular diseases under the conditions of 40°C / 75%RH, 25°C / 60%RH, and 30°C / 75%RH are shown in Examples 10 to 15 (Tables 20 to 61) below. The pharmaceutical compositions for the pharmaceutical products are shown at dosages of 20 / 160 mg and 20 / 200 mg for atorvastatin / fenofibrate, respectively.

[0068] The technology development included a series of evaluations that defined the formulations and processes as described below. Those skilled in the art should understand that multiple variations and modes in the implementation of the present invention are possible without departing from the gist and scope of the present invention so as to ensure the proper functions of the products and meet the required quality characteristics.

Example

[0069] Example 1. Particle Size Distribution of Fenofibrate The measurement of the particle size distribution by laser beam diffraction was performed on micronized fenofibrate by placing 0.5 g of the raw material in the sample holder and obtaining an ambiguity of 4 to 7% using the DPS module in the particle size analyzer. The measurement was performed in duplicate.

[0070] The particle size distribution of micronized fenofibrate is less than 30 μm (100%), preferably 0.95 μm or less (d10), preferably 5.35 μm or less (d50), more preferably 11.28 μm or less (d90) (Figure 1).

[0071] Example 2. Manufacturing process for producing tablets The manufacturing process for the preparation of tablets containing the pharmaceutical composition of the present invention is as follows: - A granulation step activated by heating with fenofibrate, preferably micronized fenofibrate - A step of incorporating atorvastatin - A compression step The process is carried out without including water and avoiding conditions that affect the stability of atorvastatin.

[0072] In this regard, the various steps include the following. 1. 70% magnesium oxide is added to micronized fenofibrate and manually mixed to eliminate powder static electricity. 2. The above mixture is sieved through a mesh (0.64 mm, i.e., 0.025 inches) together with poloxamer 188, 20% lactose monohydrate DCL-11, and 80% magnesium aluminum silicate. 3. The powder is filled into granulation equipment having a heating system and the temperature is set to 47 °C with a constant operation. 4. When the temperature is reached, heating is stopped and the obtained granules are left to cool to 25 - 30 °C. 5. The granules obtained in step 3 are subjected to a particle size reduction operation (1.27 mm, i.e., 0.050 inches). 6. Atorvastatin and 20% magnesium aluminum silicate are added to a diffusion mixer and mixed for 3 minutes. 7. Sodium starch glycolate, 30% magnesium oxide, and 80% lactose monohydrate DCL-11 are sieved through a mesh (1.27 mm, i.e., 0.050 inches). 8. The sieved product according to step 5 and the powder according to step 7 are added to the mixer according to step 6 and mixed for 5 minutes. 9. Sodium lauryl sulfate and magnesium stearate are sieved through a mesh (1.27 mm, i.e., 0.050 inches). 10. The powder from Step 9 is added to the mixer from Step 8 and mixed for 3 minutes. 11. The final powder mixture is compressed into a 600 ± 30 mg core with a hardness of 6.0 - 13.0 Kp and a disintegration time of less than 9 minutes. 12. The core is coated with Opadry AMB II with a 3.23% weight gain.

[0073] Example 3. Pharmaceutical composition of atorvastatin formulated with fenofibrate

Table 1

[0074] Sufficient water (q.s.) for the formulation, including the water for coating, is up to 0.08 mg / tablet without affecting the manufacturing process and stability of the pharmaceutical composition of the present invention.

[0075] Example 4. Preferred pharmaceutical composition of atorvastatin formulated with fenofibrate

Table 2

[0076] Sufficient water (q.s.) for the formulation, including the water for coating, is up to 0.08 mg / tablet without affecting the manufacturing process and stability of the pharmaceutical composition of the present invention.

[0077] Example 5. Preferred pharmaceutical composition of atorvastatin formulated with fenofibrate

Table 3

[0078] Statins and fenofibric acid derivatives (fibrates) are widely used in the treatment of hypercholesterolemia and hypertriglyceridemia, respectively, and when administered together, they have shown efficacy in the treatment of mixed dyslipidemia.

[0079] It is important to verify that a stable condition is ensured through a manufacturing process incorporating granulation activated by heating and compression without the intervention of water, and that a stable immediate-release dosage form of a single solid is obtained when the active ingredients, atorvastatin and fenofibrate, are formulated at dosages of 20 / 200 mg and 20 / 160 mg, respectively. For this purpose, the dissolution and pharmacokinetic tests and profiles are shown below.

[0080] Example 6. Dissolution Test The dissolution test (in vitro test) measures the rate (amount / time) and extent (total amount) at which a drug is released from a dosage form. In the case of a dissolution profile, it corresponds to the quantification of the drug dissolved at various times under standardized conditions. The importance of the dissolution test is as follows. a) It serves as a guide for the development of new formulations during product development, and it enables the evaluation of the potential interference of excipients or manufacturing processes on drug release. b) Process control and quality assurance: It helps to ensure the continuous quality and optimization of the product after manufacturing, formulation, changes in the manufacturing site, and scale-up of the process. c) In vivo development indicator: It is an indicator of bioavailability and enables the establishment of a correlation between in vitro parameters and bioavailability results.

[0081] The dissolution profile was performed on atorvastatin / fenofibrate tablets 20 / 200 mg (reference drug) and atorvastatin / fenofibrate tablets 20 / 160 mg (test drug). Both drug lots (reference and test) are the property of Laboratorios Silanes S.A.de C.V.

[0082] The conduct, execution, and obtaining of results of the test were carried out according to the following criteria and specifications established in the Official Mexican Standard NOM-177-SSA1-2013. The comparison of the dissolution profiles was performed using the f 2 similarity factor method. In the case of atorvastatin, the similarity factor f2 = 68.03 was confirmed, and for fenofibrate, similarity factor f 2 = 59.91 was confirmed. As established by the Mexican official standard NOM - 177 - SSA1 - 2013, when the similarity factor is 50 or more, the elution profiles are considered similar.

[0083] For sample analysis, two elution methods were carried out. One is to quantify atorvastatin in the elution profile sample by HPLC based on the guidelines described in the United States Pharmacopeia USP, Ed.41, 2018. This method was verified according to NOM - 177 - SSA1 - 2013.

[0084] Agilent Technologies' model 708 - DS elution tester using 0.05M phosphate buffer pH 6.8 as the elution medium and Agilent Technologies' model 1200 chromatograph were employed.

[0085] For fenofibrate, another method was carried out to quantify the elution profile sample by HPLC as described in the United States Pharmacopeia USP, Ed.41, 2018. This method was verified according to NOM - 177 - SSA1 - 2013. Agilent Technologies' model 708 - DS elution tester using 0.05M sodium dodecyl sulfate solution as the elution medium and Agilent Technologies' model 1200 chromatograph were employed.

[0086] The dissolution rate of atorvastatin in its respective elution medium for both the reference drug and the test drug was higher than 80% on average within the first 15 minutes and higher than 90% on average within 20 minutes. Therefore, these results indicate that the evaluated products can be accepted as equivalents. See Tables 4 - 5 and Figures 2 - 3.

[0087]

Table 4

[0088]

Table 5

[0089] For both the control agent and the test agent, the dissolution rate of fenofibrate in their respective dissolution media was higher than 40% on average within the first 20 minutes and higher than 80% on average within 60 minutes. Therefore, these results indicate that the products evaluated can be accepted as equivalents. See Tables 6 - 7 and Figures 4 - 5.

[0090]

Table 6

[0091]

Table 7

[0092] Example 7. Dissolution Profile The calculation of the average dissolution rate and similarity factor of each agent (control agent and test agent) at the sampling times executed is shown in the form of comparison tables and graphs for atorvastatin (Tables 8 - 9) and fenofibrate (Tables 10 - 11). See Figures 6 and 7.

[0093]

Table 8

[0094]

Table 9

[0095]

Table 10

[0096]

Table 11

[0097] Under the conditions evaluated for atorvastatin, it can be seen that both drugs have more similar dissolution profiles. The comparison was made by examining the average value of the first four sampling times from the first sampling time until up to one maximum sampling time after the reference drug reached 85% of the drug dissolution. The similarity factor was f 2 = 68.03. The Official Mexican Standard NOM-177-SSA1-2013 states that when the similarity factor is 50 or more, the dissolution profiles are considered similar.

[0098] Under the conditions evaluated for fenofibrate, it can be seen that the dissolution profiles tend to be similar. The comparison of the dissolution profiles was made by calculating the similarity factor f 2 . In this case, five sampling times were examined. The similarity factor was f 2 = 59.91. Therefore, the profiles are considered similar as established by the Official Mexican Standard NOM-177-SSA1-2013.

[0099] Example 8. Pharmacokinetic Simulation of Atorvastatin and Fenofibrate at Steady State Based on international standards, it is acceptable to conduct an examination of clinical pharmacokinetic interactions with a single dose to characterize the association between atorvastatin and fenofibrate, and to predict or represent in silico the bioavailability that can be obtained according to a multiple-dose schedule until steady state is reached (FDA, 2020).

[0100] Pharmacokinetic simulations were performed to predict the behavior of atorvastatin and fenofibric acid (the active metabolite of fenofibrate) when administered simultaneously after a dosing schedule of one tablet every 24 hours for two weeks. This demonstrated that the concentrations achieved for both drugs were consistent with those reported in the literature for fenofibric acid (3.17 - 30 μg / mL; Back, 2018; Moffat, 2011) and atorvastatin (2.5 - 50.1 ng / mL; Chou, 2013), being effective, safe, and without contradiction.

[0101] Plasma concentration data over time for atorvastatin and fenofibric acid (the active metabolite of fenofibrate), on which the steady-state simulations are based, correspond to those obtained from studies conducted in healthy volunteers under fasting conditions and demonstrate no pharmacokinetic interaction between 20 mg of atorvastatin and 200 mg of fenofibrate when administered at fixed doses (pharmaceutical product characteristics of Laboratorios Silanes, S.A.de C.V.) relative to the individual control agents indicated by the Federal Commission for Protection against Sanitary Risks (COFEPRIS).

[0102] The product under study corresponds to that manufactured by Laboratorios Silanes as described below. Test agent (Treatment B) Generic name: Atorvastatin / Fenofibrate Pharmaceutical form: Tablet Formulation: Each tablet contains 20 mg of atorvastatin / 200 mg of fenofibrate Dosing regimen: 20 mg of atorvastatin / 200 mg of fenofibrate (one tablet) Batch: 19A081G1

[0103] Pharmacokinetic simulation at steady state (atorvastatin) The mean plasma concentration profiles and descriptive statistics of the main pharmacokinetic parameters of atorvastatin after administration as a single oral dose of the fixed combination of atorvastatin 20 mg / fenofibrate 200 mg are shown below (Tables 12 and 13).

[0104] [Table 12]

[0105] [Table 13]

[0106] Compartment pharmacokinetic modeling of atorvastatin Simulations of plasma concentrations at steady state were performed by fitting the data to the best compartment pharmacokinetic model using Phoenix / Winnonlin version 8.2 software. In this regard, the plasma concentration of atorvastatin has a better correlation with a two-compartment model, represented schematically (Figures 8, 9, and 10) and mathematically (Tables 14 and 15). [Number]

[0107] [Table 14]

[0108] [Table 15]

[0109] Based on the above results, the accumulation ratio was calculated using Equation 2 below. [Number]

[0110] R is the accumulation rate, beta is the elimination constant in the two-compartment model, and τ is the dosing interval (24 hours in the simulation). A value of R = 1.10 means that there is no significant accumulation (10%) of atorvastatin at steady state when administered once daily.

[0111] Simulated steady-state pharmacokinetics (fenofibric acid) The mean plasma concentration profiles and descriptive statistics of the main pharmacokinetic parameters of fenofibric acid (the main active metabolite of fenofibrate) after administration as a single oral dose in a fixed combination of atorvastatin 20 mg / fenofibrate 200 mg are shown below (Tables 16 and 17).

[0112] [Table 16]

[0113] [Table 17]

[0114] Compartmental pharmacokinetic modeling of fenofibric acid Simulations of plasma concentrations at steady state were performed by fitting the data to the best compartmental pharmacokinetic model using Phoenix / Winnonlin version 8.2 software. In this regard, the plasma concentration of fenofibric acid correlates best with a one-compartment model represented graphically (Figures 11, 12, and 13) and mathematically (Tables 18 and 19). [Table]

[0115] [Table 18]

[0116] [Table 19]

[0117] Based on the above results, the accumulation rate was calculated using the following Equation 4.

Equation

[0118] The value of R indicates an accumulation 2.57 times the plasma concentration of fenofibric acid at steady state when administered once daily.

[0119] In conclusion, the prediction for steady state complements the results obtained in the study of the interaction when both drugs are administered as single doses, and essentially provides sufficient pharmacokinetic information considering the following reasons. · The pharmacokinetic parameters of atorvastatin are not significantly different when compared to single and multiple dosing over two weeks in hemodialysis patients (Lins, 2003) or single and multiple dosing over 90 days in patients taking grapefruit juice daily (Reddy, 2011). · Atorvastatin does not show accumulation at steady state with a once-daily dosing schedule. · The extent and concentration of atorvastatin absorption increase proportionally with the dose (Lipitor, 2020). · Atorvastatin and fenofibrate (fenofibric acid) do not have time-dependent pharmacokinetics (e.g., autoinhibition or autoinduction). · The processes responsible for the elimination of atorvastatin from the systemic circulation are CYP3A4, P-gp, and OATP2 (OATP1B1), but fenofibrate and fenofibric acid are not metabolized via cytochrome P450, do not significantly inhibit transport via P-gp, and do not have the potential to cause clinically significant drug-drug interactions due to inhibition of OATP1B1 (Wong, 2006, Yamazaki, 2005).

[0120] Example 9. Comparison of the dissolution profiles of fenofibrate and atorvastatin A comparison of the fenofibrate dissolution profiles was carried out between a commercially available fenofibrate tablet (control), a composition described in the prior art (Mexican Patent Application Publication No. a / 2013 / 006332), and the composition of fenofibrate and atorvastatin of the present invention (test) (Figure 14).

[0121] A comparison of the atorvastatin dissolution profiles was also carried out between a commercially available atorvastatin tablet (control), a composition described in the prior art (Mexican Patent Application Publication No. a / 2013 / 006332), and the composition of fenofibrate and atorvastatin of the present invention (test) (Figure 15). As observed, the dissolution profile of the fenofibrate-atorvastatin composition of the present invention is better than those of the individual active ingredients and the formulations described in the prior art.

[0122] Example 10. Stability of the pharmaceutical composition of atorvastatin and fenofibrate 20 / 160 mg tablets Results of accelerated stability analysis (40°C ± 2°C / 75% RH ± 5% RH)

[0123] [Table 20]

[0124] [Table 21]

[0125] [Table 22]

[0126] [Table 23]

[0127]

Table 24

[0128]

Table 25

[0129]

Table 26

[0130] Example 11. Stability of Pharmaceutical Composition of Atorvastatin and Fenofibrate 20 / 160 mg Tablets Results of Accelerated Stability Analysis (25°C ± 2°C / 60% RH ± 5% RH)

[0131]

Table 27

[0132]

Table 28

[0133]

Table 29

[0134]

Table 30

[0135]

Table 31

[0136]

Table 32

[0137]

Table 33

[0138] Example 12. Stability of Pharmaceutical Composition of Atorvastatin and Fenofibrate 20 / 160 mg Tablets Accelerated Stability Analysis Results (30°C ± 2°C / 75% RH ± 5% RH)

[0139]

Table 34

[0140]

Table 35

[0141]

Table 36

[0142]

Table 37

[0143]

Table 38

[0144]

Table 39

[0145]

Table 40

[0146] Example 13. Stability of Pharmaceutical Composition of Atorvastatin and Fenofibrate 20 / 200 mg Tablets Accelerated Stability Analysis Results (40°C ± 2°C / 75% RH ± 5% RH)

[0147]

Table 41

[0148]

Table 42

[0149]

Table 43

[0150]

Table 44

[0151]

Table 45

[0152]

Table 46

[0153]

Table 47

[0154] Example 14. Stability of Pharmaceutical Composition of Atorvastatin and Fenofibrate 20 / 200 mg Tablets Accelerated Stability Analysis Results (25°C ± 2°C / 60% RH ± 5% RH)

[0155]

Table 48

[0156]

Table 49

[0157]

Table 50

[0158]

Table 51

[0159]

Table 52

[0160]

Table 53

[0161]

Table 54

[0162] Example 15. Stability of Pharmaceutical Composition of Atorvastatin and Fenofibrate 20 / 200 mg Tablets Accelerated Stability Analysis Results (30°C ± 2°C / 75% RH ± 5% RH)

[0163]

Table 55

[0164]

Table 56

[0165]

Table 57

[0166]

Table 58

[0167]

Table 59

[0168]

Table 60

[0169]

Table 61

[0170] Effects and Uses of the Present Invention Solid dosage forms are excellent in their high physical, chemical and biological stability, dosing accuracy, drug release controllability and low cost.

[0171] Oral liquid forms usually exhibit several advantageous effects such as higher bioavailability, lower irritation to the gastric mucosa, and easy intake compared to solid forms. The high potential for contamination and the potential instability in the elution of drugs are the main disadvantages. The sign of solution instability is that the solution can crystallize. This is because the medium in which they are identified promotes the change to their basic state, which becomes less soluble, which can also reduce the bioavailability of the drug.

[0172] The present invention describes an optimized method that enables the compounding and manufacturing of a single solid, stable, immediate-release dosage form at dosages of 20 / 200 mg and 20 / 160 mg of atorvastatin and fenofibrate, respectively, which are the active ingredients. Atorvastatin is preferably in the form of its calcium trihydrate. Therefore, the present invention performs a granulation step activated by heating with fenofibrate, incorporates atorvastatin while avoiding conditions that contain water and can affect the stability of the drug, and conducts the manufacturing.

[0173] Therefore, the present invention solves a series of important technical problems due to the differences in physicochemical properties and dosages, and ensures obtaining a stable product that was impossible to obtain or formulate.

[0174] The composition of the present invention is also aimed at, among other things, the treatment and control of a selected group of symptoms of dyslipidemia, hyperlipoproteinemia, and hypercholesterolemia, the prevention and control of cardiovascular diseases such as hypertension, angina pectoris, heart attack, and aneurysm, and the regulation of blood concentrations of LDL, HDL, and triglycerides.

[0175] References Back HM, Song B, Pradhan S, Chae JW, Han N, Kang W, Chang MJ, Zheng J, Kwon KI, Karlsson MO, Yun HY. A mechanism-based pharmacokinetic model of fenofibrate for explaining increased drug absorption after food consumption. BMC Pharmacology and Toxicology (2018) 19:4, pp1-10 Chou YC, Wang YK, Charng MJ, Ueng YF. Determination of serum atorvastatin concentrations in lipid-controlling patients with and without myalgia syndrome. Journal of Food and Drug Analysis, Volume 21, Issue 2, June 2013, Pages 147-153 Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), Clinical Drug Interaction Studies - Cytochrome P450 Enzyme - and Transporter - Mediated Drug Interactions Guidance for Industry. January 2020 Clinical Pharmacology Lins RL, Matthys KE, Verpooten GA, Peeters PC, Dratwa M, Stolear JC, Lameire NH. Pharmacokinetics of Atorvastatin and Its Metabolites After Single and Multiple Dosing in Hypercholesterolaemic Haemodialysis Patients. Nephrol Dial Transplant. 2003 May;18(5):967-76 LIPITOR (registered trademark) (atorvastatin calcium tablets), Product monograph 10mg, 20mg, 40mg, and 80mg atorvastatin. Lipid metabolism regulator. Submission Control No: 237270. (registered trademark) Pfizer Ireland Pharmaceuticals Upjohn Canada ULC, Licensee (copyright) Upjohn Canada ULC, 2020. Date of Revision: April 30, 2020; page27 Moffat AC, Osselton MD, Widdop B. Clarke’s Analysis of Drugs and Poisons in pharmaceuticals, body fluids and postmortem material. Fourth edition, Pharmaceutical Press 2011:42 Reddy P, Ellington D, Zhu Y, Zdrojewski I, Parent SJ, Harmatz JS, Derendorf H, Greenblatt DJ, Browne J. Serum concentrations and clinical effects of atorvastatin in patients taking grapefruit juice daily. British Journal of Clinical Pharmacology (copyright) 2011, 72:3 / 434-441 Wong B.A. Focus on Statin Research. Nova Biomedical Books, New York, 2006: 112 - 130 Yamazaki M, Li B, Louie SW, Pudvah NT, Stocco R, Wong W, Abramovitz M, Demartis A, Laufer R, Hochman JH, Prueksaritanont T, Lin JH. Effects of Fibrates on Human Organic Anion-Transporting Polypeptide 1B1-, Multidrug Resistance Protein 2- And P-glycoprotein-mediated Transport. Xenobiotica. 2005 Jul; 35(7): 737 - 53

Claims

1. (a) a pharma- ceutically acceptable amount of atorvastatin or an equivalent amount of a salt thereof in the range of 20±0.7 mg; (b) a pharma-ceutically acceptable amount of micronized fenofibrate or a micronized salt thereof in the range of 160 mg to 200 mg; and (c) a pharma-ceutically acceptable amount of a pharma-ceutically acceptable excipient and / or a pharma-ceutically acceptable vehicle, further in a solid stable immediate release form; The micronized fenofibrate has a particle size distribution of 100% less than 30 μm, preferably 0.95 μm or less (d10), preferably 5.35 μm or less (d50), more preferably 11.28 μm or less (d90); The particle size distribution of the pharmaceutical composition is measured by laser beam diffraction using a DPS module in a particle size analyzer.

2. 2. The pharmaceutical composition of claim 1, wherein the atorvastatin is preferably in the form of its calcium salt trihydrate in an amount of 21.65 mg, which corresponds to 20 mg of atorvastatin.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the pharma- ceutically acceptable excipients and / or vehicles include binders, diluents, disintegrants, pH adjusters, surfactants, lubricants, solvents and coatings.

4. 4. The pharmaceutical composition of claim 3, wherein the binder is preferably Poloxamer 188 in a pharma- ceutically acceptable amount ranging from 5 to 10%.

5. The pharmaceutical composition of claim 3, wherein the diluent is lactose monohydrate, preferably in a pharma- ceutically acceptable amount ranging from 5 to 90%.

6. 4. The pharmaceutical composition of claim 3, wherein the diluent is magnesium aluminum silicate in a pharma- ceutically acceptable amount, preferably in the range of 5-90%.

7. The pharmaceutical composition according to claim 3, wherein the disintegrant is sodium starch glycolate, preferably in a pharma- ceutically acceptable amount ranging from 2 to 8%.

8. 4. The pharmaceutical composition of claim 3, wherein the pH adjusting agent is magnesium oxide, preferably in a pharma- ceutically acceptable amount ranging from 0.5 to 5%.

9. 4. The pharmaceutical composition of claim 3, wherein the surfactant is sodium lauryl sulfate, preferably in a pharma- ceutically acceptable amount ranging from 1 to 2.5%.

10. The pharmaceutical composition of claim 3, wherein the lubricant is preferably magnesium stearate in a pharma- ceutically acceptable amount ranging from 0.25 to 5%.

11. The pharmaceutical composition of claim 3 , wherein the coating is a water-blocking coating.

12. The water barrier coating is preferably AMB II Opadry in a pharma- ceutically acceptable amount ranging from 0.5 to 6%; 12. The pharmaceutical composition of claim 11, wherein the AMB II Opadry comprises the following combination: a) polyvinyl alcohol, talc, titanium dioxide, glyceryl monocaprylocaprate, sodium lauryl sulfate, Blue No. 2 / aluminum lake and indigo carmine, or b) polyvinyl alcohol, talc, titanium dioxide, glyceryl monocaprylocaprate and sodium lauryl sulfate.

13. 4. The pharmaceutical composition of claim 3, wherein the solvent is preferably water in a pharma- ceutically acceptable amount.

14. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the solid pharmaceutical form is selected from the group consisting of tablets, caplets, granules, and pills.

15. 15. A pharmaceutical composition according to claim 14, preferably in the form of a biconvex tablet or a coated tablet.

16. a heat activated granulation step with fenofibrate, preferably micronized fenofibrate; Atorvastatin incorporation step; A compression stage; and is carried out without water and avoiding conditions that may affect the stability of the atorvastatin; The heat activated granulation step comprises: a) adding 70% magnesium oxide to the micronized fenofibrate and mixing by hand to remove static electricity from the powder; b) sieving the above mixture through a mesh (0.64 mm or 0.025 inch) along with Poloxamer 188, 20% lactose monohydrate and 80% magnesium aluminum silicate; c) the powder is charged into a granulator having a heating system and a temperature of 47° C. in constant operation; d) once said temperature is reached, said heating is stopped and the resulting granules are allowed to cool to 25-30°C; 16. A method for producing a pharmaceutical composition according to any one of claims 1 to 15, comprising: e) carrying out a particle size reduction operation on the granules obtained in step c) by means of a mesh (1.27 mm, i.e. 0.050 inch).

17. The step of incorporating atorvastatin comprises: f) adding the atorvastatin and 20% magnesium aluminum silicate to a diffusion mixer and mixing for 3 minutes; g) Sifting the sodium starch glycolate, 30% magnesium oxide and 80% lactose monohydrate through a sieve (1.27 mm or 0.050 inch); h) adding the sieved material from step e) and the powder from step g) to the mixer of step f) and mixing for 5 minutes; i) Sieve the sodium lauryl sulfate and magnesium stearate through a mesh (1.27 mm or 0.050 inch); 17. The method of claim 16, comprising: j) adding the powder of step i) to the mixer according to step h) and mixing for 3 minutes.

18. The compression step comprises: k) compressing the final powder blend into 600±30 mg kernels; l) coating the core with Opadry AMB II at a weight gain of 3.23%, 17. The method of claim 16, wherein the AMB II Opadry comprises the following ingredients: a) polyvinyl alcohol, talc, titanium dioxide, glyceryl monocaprylocaprate, sodium lauryl sulfate, Blue No. 2 / aluminum lake and indigo carmine; or b) polyvinyl alcohol, talc, titanium dioxide, glyceryl monocaprylocaprate and sodium lauryl sulfate.

19. 20. Use of a pharmaceutical composition according to any one of claims 1 to 15 for the manufacture of a pharmaceutical product useful for the treatment of dyslipidemia and the prevention of cardiovascular diseases.

20. 20. The use according to claim 19, wherein the dyslipidemia and cardiovascular diseases are selected from hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertension, angina, heart attack, aneurysm, and regulation of blood levels of LDL, HDL and triglycerides.

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