Oral pharmaceutical composition of pitavastatin and ezetimibe, method and uses thereof

Abstract

The present disclosure relates to a solid oral pharmaceutical composition comprising a therapeutically effective amount of pitavastatin or a pharmaceutically acceptable salt, an alkalizing agent and colloidal silicon dioxide. Furthermore, the present disclosure also relates to said composition further comprising a therapeutically effective amount of Ezetimibe.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to compositions comprising pitavastatin with improved stability and which are appropriate to be manufactured at an industrial scale, as well as to obtain fixed-dose compositions comprising pitavastatin and ezetimibe. The present disclosure further relates to the manufacturing process of those pharmaceutical compositions. BACKGROUND

[0002] Pitavastatin is the international non-proprietary name (INN) for (3R,5S,6E)-7-[2-Cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid which has the following chemical structure: OH OH O

[0003] Pitavastatin is an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, also known as a HMG-CoA reductase inhibitor. Pharmaceutical compositions of pitavastatin as its calcium salt form are registered and marketed under the trade names ALIPZA* and LIVAZO* for the treatment of high cholesterol in patients with primary hypercholesterolemia.

[0004] Pitavastatin compound temperature and pH sensitive and pharmaceutical formulations comprising pitavastatin, in particular tablets and / or capsules, showed limited stability in low pH.

[0005] Ezetimibe is the INN for (3R,4S)-l-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone which has the following chemical structure:

[0006] Ezetimibe is a selective cholesterol-absorption inhibitor. Pharmaceutical compositions of ezetimibe are registered and marketed under the trade name EZETROL* for the treatment of high cholesterol in patients with primary hypercholesterolemia by itself or concomitantly with an HMG-CoA reductase inhibitor.

[0007] Ezetimibe and pitavastatin combined products are registered in Korea under the trade name LIVALOZET*, film coated tablets.

[0008] WO2020178878, JP2021008432 and JP6937195 (Kowa) disclose conventional tablets comprising ezetimibe and pitavastatin, housed in airtight package.

[0009] CN 102451161 (Liyan Wang) discloses orodispersible tablets comprising ezetimibe and statins (namely ezetimibe and pitavastatin) and is focused on the dispersibility of the compositions and is silent on stability issues.

[0010] CN 112999178 (Lepu Pharma) discloses tablets comprising ezetimibe and pitavastatin - bilayer tablets with inappropriate dissolution properties and compositions comprising mixed granulates of both Active Pharmaceutical Ingredients (APIs).

[0011] US 20220047547A1 (Orient Pharma) discloses a manually filled gelatin capsule composition comprising pitavastatin granules or tablets or pellets and, ezetimibe granules or tablets or pellets - the granules or tablets' composition were explicitly filled manually and not using any industrial equipment. Furthermore, the finished capsule composition comprises an alkaline stabilizing agent selected from the group consisting of magnesium oxide, magnesium aluminometasilicate, potassium hydroxide, sodium bicarbonate, sodium carbonate, sodium hydroxide, calcium carbonate, ammonium hydroxide, diethanolamine and, an acidic stabilizing agent selected from the group consisting of citric acid, acetic acid, tartaric acid, lactic acid and sodium phosphate monobasic.

[0012] Ezetimibe is a labile molecule in water and alkali, whereas pitavastatin is stable under alkaline conditions.

[0013] The pitavastatin pharmaceutical formulation and the ezetimibe pharmaceutical formulation that are on the market have different compositions and comprise different excipients. Both, individually, are under the form of tablets, but due to chemical incompatibilities between excipients and / or between active ingredients and / or active ingredient / excipient, their combination in a single oral dose results in unstability and inadequate dissolution.

[0014] These facts are disclosed in order to illustrate the technical problems addressed by the present disclosure. GENERAL DESCRIPTION

[0015] In view of the drawbacks identified in the prior art, the technical problem underlying the present disclosure was to develop an oral pharmaceutical composition comprising pitavastatin showing improved stability and adequate properties to be manufactured at an industrial scale; also, the pitavastatin composition of the present disclosure may be combined with ezetimibe.

[0016] An aspect of the present disclosure relates to a stable solid oral pharmaceutical composition comprising a therapeutically effective amount of pitavastatin, an alkalizing agent and colloidal silicon dioxide and a therapeutically effective amount of Ezetimibe. It was surprisingly found a synergistic effect between pitavastatin (in particular, pitavastatin calcium) and ezetimibe. When combined in a fixed-dose composition, it was observed a significant improvement in the dissolution profile of ezetimibe.

[0017] In an embodiment for better results, at least around 80 % of the amount of each ezetimibe and pitavastatin are released in 15 min; preferably at least around 85% of the amount of each ezetimibe and pitavastatin are released in 15 min.

[0018] It was surprisingly found that a pharmaceutical composition comprising pitavastatin, an alkalizing agent and colloidal silicon dioxide allows an improved stability of the active ingredient pitavastatin in a pharmaceutical formulation, over various storage conditions and even in low doses.

[0019] Additionally, the pitavastatin calcium composition of the present disclosure and the preparation method thereof can not only stabilize the pitavastatin in the pharmaceutical composition, in particular a tablet, but also improve the content uniformity / assay of the small dose of pitavastatin in the composition. The pharmaceutical composition of the present disclosure, comprising pitavastatin, an alkalizing agent and colloidal silicon dioxide, is stable, shows an improved content uniformity, a high dissolution rate, and present a good stability and shelf-life and is suitable for industrial production.

[0020] The present disclosure describes a process for the preparation of a composition which ensures a good recovery by assay of the small dose of pitavastatin present in the composition.

[0021] An aspect of the present disclosure relates to a stable solid oral pharmaceutical composition comprising a therapeutically effective amount of pitavastatin or a pharmaceutically acceptable salt, an alkalizing agent and a colloidal silicon dioxide.

[0022] In an embodiment for better results, the stable solid oral pharmaceutical composition of the present disclosure may comprise 1-2 mg of pitavastatin or a pharmaceutically acceptable salt; preferably 1 mg.

[0023] In an embodiment for better results, the weight ratio between pitavastatin or a pharmaceutically acceptable salt: colloidal silicon dioxide ranges from 1:1 to 1:5; preferably 1:1 to 1:3; more preferably 1:2.2 to 1:2.4; even more preferably 1:2.3.

[0024] In an embodiment for better results, the alkalizing agent is selected from the list consisting of: sodium carbonate, dipotassium hydrogen orthophosphate, magnesium hydroxide or mixtures thereof.

[0025] In an embodiment for better results, the alkalizing agent is sodium carbonate.

[0026] In an embodiment for better results, the weight ratio between pitavastatin or a pharmaceutically acceptable salt: alkaline agent is between 1:1 to 1:5.5; preferably between 1:1 to 1:3.4; more preferably 1:1.5 to 1:1.7.

[0027] In an embodiment for better results, the pitavastatin pharmaceutically acceptable salt is pitavastatin calcium.

[0028] In an embodiment for better results, the stable solid oral pharmaceutical composition of the present disclosure may comprise at least: a binder; a wetting agent; a filler, a disintegrant, a lubricant, or mixtures thereof.

[0029] In an embodiment for better results, the binder is selected from the list consisting of hypromellose, povidone, microcrystalline cellulose, hydroxypropylcellulose, hypromellose or polyvinylpyrrolidone, or mixtures thereof; preferably hypromellose and povidone.

[0030] In an embodiment for better results, the wetting agent is sodium lauryl sulfate.

[0031] In an embodiment for better results, the lubricant is selected from the list consisting of: sodium stearyl fumarate, magnesium stearate, stearic acid, talc, or mixtures thereof; preferably sodium stearyl fumarate.

[0032] In an embodiment for better results, the disintegrant is selected from the list consisting of sodium starch glycolate, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, croscarmellose sodium, crospovidone, or mixtures thereof; preferably sodium stearyl fumarate.

[0033] In an embodiment for better results, the filler is selected from the list consisting of microcrystalline cellulose, calcium phosphate, lactose, mannitol, starch, sorbitol, or mixtures thereof; preferably microcrystalline cellulose.

[0034] In an embodiment for better results, the composition is a compressed composition.

[0035] In an embodiment for better results, the stable solid oral pharmaceutical composition of the present disclosure may comprise comprising a therapeutically effective amount of Ezetimibe.

[0036] In an embodiment for better results, the therapeutically effective amount of Ezetimibe is in a form of solid dispersion granules of Ezetimibe.

[0037] In an embodiment for better results, the therapeutically effective amount of Ezetimibe is in a form of a compressed composition.

[0038] In an embodiment for better results, the amount pf Ezetimibe ranges from 5 to 10 mg.

[0039] In an embodiment for better results, the solid dispersion granules of Ezetimibe comprise Hypromellose and Lactose monohydrate-croscarmellose sodium.

[0040] In an embodiment for better results, the amount of colloidal silicon dioxide ranges from 1.2 to 5% w / w (w colloidal silicon dioxide / w total); preferably from 1.2 to 3 %w / w (w colloidal silicon dioxide / w total); more preferably the amount is 1.3 % w / w (w colloidal silicon dioxide / w total).

[0041] In an embodiment for better results, the amount of alkalizing agent ranges from 0.5 to 6.6 %w / w (w alkalizing agent / w total); preferably from 0.8 to 2 % (w alkalizing agent / w total); more preferably from 0.9 to 1.9 % (w alkalizing agent / w total).

[0042] Another aspect of the present disclosure relates to a method for obtaining the composition of the present disclosure comprising the following steps: weighing and sieving the pitavastatin, the colloidal silicon dioxide, the alkalinizing agent, the diluent, the disintegrant and the lubricant; mixing a first part of the diluent, a first part of the disintegrant, a first part of the lubricant and a first part of the colloidal silicon dioxide to obtain a pre-mixture; adding the pitavastatin, the alkalinizing agent, a second part of the diluent, a second part of the disintegrant, a second part of the lubricant and a second part of the colloidal silicon dioxide to the pre-mixture and mixing the to obtain a uniformed mixture; compressing the uniformed mixture to form a tablet; optionally coating the tablet to obtain a coated tablet.

[0043] In an embodiment for better results, the first part of the colloidal silicon dioxide is 20% to 60% of the total mass of the colloidal silicon dioxide; the first part of the diluent is 25 to 50 % of the total mass of the diluent; the first part of the disintegrant is 25 to 50 % of the total mass of the disintegrant; the first part of the lubricant is 25 to 50 % of the total mass of the lubricant.

[0044] In an embodiment for better results, the second part of the colloidal silicon dioxide is 40% to 80% of the total mass of the colloidal silicon dioxide; the second part of the diluent is 50 to 75 % of the total mass of the diluent; the second part of the disintegrant is 50 to 75 % of the total mass of the disintegrant; the second part of the lubricant is 50 to 75 % of the total mass of the lubricant;

[0045] Another aspect of the present disclosure relates to a fixed-dose composition of the present disclosure comprising at least one pitavastatin calcium compressed composition of the present disclosure and an ezetimibe compressed composition, preferably the fixed-dose composition is a capsule dosage form.

[0046] Another aspect of the present disclosure relates to a method for obtaining the solid dispersion granules of Ezetimibe of the present disclosure comprising the following steps: providing a suspension comprising an ethanolic solution of ezetimibe and an aqueous solution of hypromellose; adding the previous suspension to lactose monohydrate-croscarmellose sodium and mixing to obtain a uniform mixture; mixing and granulating the uniform mixture to obtain solid dispersion granules of Ezetimibe.

[0047] In an embodiment for better results, the therapeutically effective amount of Ezetimibe is in a form of solid dispersion granules of Ezetimibe.

[0048] In an embodiment for better results, the solid dispersion granules of Ezetimibe comprise Hypromellose and Lactose monohydrate-croscarmellose sodium.

[0049] In an embodiment for better results, at least around 80 % of the amount of each ezetimibe and pitavastatin are released in 15 min; preferably at least around 85% of the amount of each ezetimibe and pitavastatin are released in 15 min.

[0050] In an embodiment for better results, the composition of the present disclosure may be used in the prevention or treatment of hypercholesterolemia.

[0051] In an embodiment for better results, the composition may be use for the manufacture of a medicament for the treatment of hypercholesterolemia.

[0052] In an embodiment for better results, the disclosure is also related to a method for treating or preventing hypercholesterolemia in a subject, the method comprising administering the composition of the present disclosure.

[0053] Another aspect of the present disclosure relates to the manufacturing process of those pharmaceutical compositions.

[0054] Another aspect of the present disclosure relates to a stable solid oral pharmaceutical composition that further comprises a therapeutically effective amount of ezetimibe.

[0055] Unexpectedly, the pharmaceutical composition of the present disclosure comprising pitavastatin also showed to be suitable to obtain pharmaceutical compositions combining pitavastatin and ezetimibe.

[0056] Ezetimibe powder was very unstable when mixed with pitavastatin powder and filled in capsules. The same instability of ezetimibe was observed when pitavastatin powder was filled in capsules with ezetimibe granules. Nonetheless, surprisingly such instability was not observed in the pharmaceutical composition of the present disclosure comprising a therapeutically effective amount of pitavastatin and ezetimibe, wherein the results obtained showed adequate stability of both the active ingredients, as well as adequate dissolution rates.

[0057] In an embodiment, the therapeutically effective amount of ezetimibe is in the form of a compressed composition.

[0058] In a preferred embodiment, the compressed composition comprises a solid dispersion of ezetimibe and from 0.0001 to 5 mg of a solubilizing agent.

[0059] In a preferred embodiment, the ezetimibe compressed composition further comprises a hydrophilic agent, which is, preferably, hypromellose.

[0060] The ezetimibe compressed composition does not contain an alkalinizing excipient, an acidifying excipient nor a buffer.

[0061] The stable solid oral pharmaceutical composition of the present disclosure surprisingly exhibits suitable stability, cost effectiveness, and process robustness (good uniformity, good flowability, good compact ability / compressibility, mass uniformity, and adequate hardness). At the same time, such composition exhibits dissolution and pharmacokinetics comparable to the respective marketed product (reference composition) containing one of the active substances (pitavastatin or ezetimibe) (in the present disclosure, the composition may be a stable solid oral pharmaceutical composition comprising pitavastatin, or the combination of two stable solid oral pharmaceutical compositions, each one comprising separately ezetimibe and pitavastatin). BRIEF DESCRIPTION OF THE DRAWINGS

[0062] The following figures provide preferred embodiments for illustrating the disclosure and should not be seen as limiting the scope of invention.

[0063] Figure 1: Dissolution profile of pitavastatin on composition XIII (Fixed dose composition of pitavastatin lmg and ezetimibe 10 mg).

[0064] Figure 2: Dissolution profile of ezetimibe on composition XIII (Fixed dose composition of pitavastatin 1 mg and ezetimibe 10 mg). DETAILED DESCRIPTION

[0065] In a first aspect, the present disclosure relates to improved stability and dissolution rate compositions of pitavastatin comprising colloidal silicon dioxide as glidant.

[0066] In a second aspect, the present disclosure relates to the manufacturing process of the improved stability and dissolution rate compositions of pitavastatin comprising Colloidal Silicon Dioxide as glidant.

[0067] In the present disclosure, colloidal silicon dioxide is particularly used as an excipient in the pitavastatin composition. It was surprisingly found that when colloidal silicon dioxide is used, the pitavastatin calcium is prevented from degrading with time (formation of a related substance), so that a pitavastatin -containing composition, preferably a pitavastatin calcium-containing composition, having excellent stability can be produced.

[0068] In consideration of the dose of the active ingredient and the handleability of the composition, the compounding amount of colloidal silicon dioxide (silica, colloidal anhydrous) can be selected, for example, in the range of 1 to 5 parts by weight with respect to 1 part by weight of pitavastatin calcium, preferably, in the range of 1 to 3 parts; more preferably, in the range of 2.2 to 2.3 parts.

[0069] As an alkalinizing agent, it is preferable to use Sodium Carbonate Anhydrous, Dipotassium Hydrogen-orthophosphate or magnesium hydroxide, in the range of 1 to 5 parts by weight with respect to 1 part by weight of pitavastatin calcium, preferably in the range of 1 to 3.3 parts and, more preferably, in the range of 1.5 to 1.7 parts by weight with respect to 1 part by weight of pitavastatin calcium.

[0070] The pitavastatin containing composition of the present invention may further comprise other excipients, such as, diluents, binders, lubricants and / or disintegrants.

[0071] The filler may be selected from microcrystalline cellulose, calcium phosphate, lactose, mannitol, starch, and sorbitol, and may be used singly or in combination; preferably the diluent is microcrystalline cellulose.

[0072] The binder may be selected from microcrystalline cellulose, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, starch slurry, water, various concentrations of ethanol solution, and may be used singly or in combination.

[0073] The lubricant may be selected from sodium stearyl fumarate, magnesium stearate, stearic acid and talc, and they may be used singly or in combination; preferably the lubricant is sodium stearyl fumarate.

[0074] The disintegrant may be selected from sodium starch glycolate, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, croscarmellose sodium and crospovidone, and they may be used singly or in combination; preferably the disintegrant is sodium starch glycolate.

[0075] The lubricant includes sodium stearyl fumarate, magnesium stearate, stearic acid and talc, and they may be used singly or in combination; preferably the lubricant is sodium stearyl fumarate.

[0076] Other excipients such as coloring agents, sweeteners, flavoring agents, may also be added if desired.

[0077] According to the present invention, the pitavastatin composition is a oral solid dosage form.

[0078] In a preferred embodiment, the tablet may be coated. Preferably, the weight of the film coating material is from 1 to 3%.

[0079] In an embodiment, the pitavastatin calcium tablet core components are as follows: 1.0 to 2.0 mg of pitavastatin calcium; 40.0 to 76.0 parts by weight of filler (in relation to the amount of pitavastatin calcium); 0.5 to 1.5 parts of disintegrant; 0.5 to 1.5 parts of lubricant; 1.5 to 5.5 parts of alkalizing agent; 1 to 5 parts by weight of colloidal silicon dioxide (all in relation to the amount of pitavastatin calcium).

[0080] The pharmaceutical composition comprising pitavastatin calcium tablets may be prepared through a process comprising the following steps: - the raw materials are weighed and passed through a 0.5 mm sieve; - a first part of the diluent, a first part of the disintegrant and a first part of the lubricant are mixed with a first part of the colloidal silicon dioxide to obtain a pre-mixture; - then, the pitavastatin calcium, the a I ka I in izing agent, the second part of the diluent, the second part of the disintegrant, the second part of the lubricant and the second part of the colloidal silicon dioxide are added to the pre-mix and the mixture is uniformly mixed; - compressing (tableting) the mixture obtained to form a tablet; - optionally coating.

[0081] The first part of the colloidal silicon dioxide is 20% to 60% of the total mass of the colloidal silicon dioxide, and the remaining colloidal silicon dioxide is 40% to 80% of the total mass of the colloidal silicon dioxide.

[0082] The first part of diluent, the first part of the disintegrant and the first part of the lubricant is 25 to 50% of the total mass of the diluent, of the total mass of the disintegrant or of the total mass of the lubricant, respectively, and the remaining diluent, disintegrant or lubricant is 50 to 75% of the total mass of the diluent, disintegrant or lubricant, respectively. Example 1 - Tablets comprising pitavastatin Table 1 - Qualitative and quantitative composition of compositions l-IV. Composition I (comparative) Composition II Composition III Composition IV (mg) % (w / w) (mg) % (w / w) (mg) % (w / w) (mg) % (w / w) Pitavastatin Calcium 1.050 1.31 1.050 1.31 1.050 1.31 1.050 1.31 Microcrystalline cellulose 75.749 94.742 74.242 92.851 72.475 90.643 70.708 88.435 Colloidal Silicon Dioxide 1.578 1.974 1.547 1.934 1.510 1.888 1.473 1.842 Sodium starch glycolate 0.947 1.184 0.928 1.161 0.906 1.133 0.884 1.105 Sodium stearyl fumarate 0.631 0.790 0.618 0.774 0.604 0.755 0.590 0.737 Sodium carbonate anhydrous - - 1.570 1.96 3.410 4.26 5.250 6.57 Total 79.955 100.00 79.955 100.00 79.955 100.00 79.955 100.00 Table 2 - Qualitative and quantitative composition of compositions V-VIL Composition V Composition VI Composition VII (mg) % (w / w) (mg) % (w / w) (mg) % (w / w) Pitavastatin Calcium 1.050 1.31 1.050 1.31 1.050 1.31 Microcrystalline cellulose 74.088 92.660 72.476 90.645 70.709 88.435 Colloidal Silicon Dioxide 1.544 1.930 1.509 1.887 1.473 1.842 Sodium     starch glycolate 0.926 1.158 0.906 1.133 0.884 1.105 Sodium     stearyl fumarate 0.617 0.772 0.604 0.755 0.589 0.737 Dipotassium hydrogenorthophosphate 1.730 2.16 3.410 4.26 5.250 6.57 Total 79.955 100.00 79.955 100.00 79.955 100.00

[0083] Description of the manufacturing process of the Composition I to Composition VII: a) Part (34%) of the colloidal silicon dioxide, part of microcrystalline cellulose (33%), part of sodium starch glycolate (33%) and part of sodium stearyl fumarate (33%), all previously sieved, were introduced in a mixer of suitable capacity and firstly pre-mixed; b) More colloidal silicon dioxide (22%) was further added to the previous pre-mixture and mixed; WO 2025 / 186786                                   PCT / IB2025 / 052491 c) Then, pitavastatin calcium and the rest of colloidal silicon dioxide (44%), the rest of microcrystalline cellulose (67%), the rest of sodium starch glycolate (67%) and the rest of sodium stearyl fumarate (67%), all previously sieved, were added to the mixture of b) and mixed together; e) for compositions comprising an alkalizing agent (Compositions II to VII), it was further added and mixed; f) Then, the sieved mixture obtained in step c) was compressed to obtain a tablet. Stability and Assay studies

[0084] Each composition I to VII was analysed for Assay and Related Substances using a High Performance Liquid Chromatography system with a UV detector at 244 nm. For the samples analysis was used a validated and stability indicating methodology, and the quantification was performed using a characterized working standard to quantify lactone impurity, which is the prevalent impurity of pitavastatin and the total of impurities.

[0085] The short-term accelerated stability study was carried out on HDPE (high density polyethylene) open bottles and closed bottles for 2 months at 40°C / 75% HR. Table 3 - Assay and Impurities results when storage at 40°C / 75% HR for compositions l-IV. HDPE closed bottles Comp. I (comparative) Comp. II Comp. Ill Comp. IV Time (months) 0 2 0 2 0 2 0 2 Assay (%) 89.64 87.16 90.26 89.49 90.45 88.56 91.68 92.03 Lactone impurity (%) 0.08 0.94 0.00 nd nd 0.13 nd Nd Total impurities (%) 0.20 1.55 0.29 0.46 0.38 1.77 0.62 0.70 HDPE open bottles Comp. I (comparative) Comp. II Comp. Ill Comp. IV Time (months) 0 2 0 2 0 2 0 2 Assay (%) 89.64 85.73 90.26 89.61 90.45 87.83 91.68 88.81 Lactone impurity (%) 0.08 1.54 0.00 nd nd nd nd nd Total impurities (%) 0.20 2.58 0.29 1.18 0.38 2.08 0.62 2.99 Table 4 - Assay and Impurities results when storage at 40°C / 75% HR for compositions V-VII. HDPE closed bottles Comp. V Comp. VI Comp. VII Time (months) 0 2 0 2 0 2 Assay (%) 90.98 89.48 89.05 85.76 88.51 86.93 Lactone impurity (%) 0.03 0.35 0.03 0.15 0.02 0.14 Total impurities (%) 0.19 0.96 0.17 1.07 0.17 0.64 HDPE open bottles Comp. V Comp. VI Comp. VII Time (months) 0 2 0 2 0 2 Assay (%) 90.98 87.47 89.05 86.24 88.51 85.54 Lactone impurity (%) 0.03 0.48 0.03 0.43 0.02 0.20 Total impurities (%) 0.19 1.79 0.17 1.68 0.17 1.40 Table 5- Assay and Impurities results when storage at 25°C / 60% RH for compositions l-IV. HDPE closed bottles Comp. I Comp. II Comp. Ill Comp. IV Time (months) 0 2 0 2 0 2 0 2 Assay (%) 89.64 88.72 90.26 91.39 90.45 88.58 - - Lactone impurity (%) 0.08 0.23 0.00 nd. nd nd - - Total impurities (%) 0.20 0.45 0.29 0.34 0.38 0.50 - - HDPE open bottles Comp. I Comp. II Comp. Ill Comp. IV Time (months) 0 2 0 2 0 2 0 2 Assay (%) 89.64 87.97 90.26 91.13 90.45 89.83 91.7 90.32 Lactone impurity (%) 0.08 0.44 0.00 nd nd nd nd nd Total impurities (%) 0.20 0.69 0.29 0.48 0.38 0.57 0.62 0.76 Table 6- Assay and Impurities results when storage at 25°C / 60% RH for compositions V-VIL HDPE closed bottles Comp. V Comp. VI Comp. VII Time (months) 0 2 0 2 0 2 Assay (%) 90.98 89.65 89.05 88.70 88.51 86.22 Lactone impurity (%) 0.03 0.16 0.03 0.08 0.02 0.12 Total impurities (%) 0.19 0.43 0.17 0.37 0.17 0.40 HDPE open bottles Comp. V Comp. VI Comp. VII Time (months) 0 2 0 2 0 2 Assay (%) 90.98 89.23 89.05 87.49 88.51 86.24 Lactone impurity (%) 0.03 0.21 0.03 0.12 0.02 0.09 Total impurities (%) 0.19 0.65 0.17 0.55 0.17 0.54 Example 2 -Tablets comprising Pitavastatin and different amounts of Colloidal Silicon Dioxide

[0086] Further tablets (Composition VIII to Composition X) were prepared, using different amounts of colloidal silicon dioxide.

[0087] The manufacturing process of Compositions VIII to X follow the process described in Example 1. Furthermore, Composition XI is film coated according to the methods described in the art. Table 7 - Qualitative and quantitative compositions Comp. I (comparative) Comp. VIII Comp. IX Comp. X Constituents Mass (mg) % (w / w) Mass (mg) % (w / w) Mass (mg) % (w / w) Mass (mg) % (w / w) Pitavastatin Calcium 1.050 1.31 1.050 1.31 1.050 1.31 1.050 1.31 Microcrystalline cellulose 75.749 94.742 74.981 93.782 73.445 91.862 73.517 91.901 Colloidal Silicon Dioxide 1.578 1.974 2.362 2.954 3.930 4.915 2.332 2.915 Sodium starch glycolate 0.947 1.184 0.937 1.172 0.918 1.148 0.919 1.149 Sodium stearyl fumarate 0.631 0.790 0.625 0.782 0.612 0.766 0.612 0.765 Sodium carbonate anhydrous - - - - - - 1.57 1.96 Total 79.955 100.00 79.955 100.00 79.955 100.00 80.00 100.00 Table 8 - Assay results. TO Comp. 1 (with 1.974% w / w of Colloidal silicon dioxide) Comp. VIII (with 2.954% w / w of Colloidal silicon dioxide) Comp. IX (with 4.915% w / w of Colloidal silicon dioxide) Assay (%) 89.6 98.1 98.3

[0088] Surprisingly, compositions VIII and IX, comprising an amount of colloidal silicon dioxide above 2.5 % (w / w) (preferably around 2.8 - 2.9 (w / w)), showed a significantly improved assay result comparing with composition I comprising an amount of colloidal silicon dioxide of 1.974% w / w (inferior to 2 % (w / w)).

[0089] Composition VIII comprises a weight ratio between pitavastatin calcium: colloidal silicon dioxide of 1:2.2 and composition IX comprises a weight ratio between pitavastatin calcium: colloidal silicon dioxide of 1:3.7. Example 3 - fixed-dose composition of Pitavastatin and Ezetimibe

[0090] An aspect of the present disclosure relates to a fixed-dose composition comprising pitavastatin and Ezetimibe, having surprisingly improved stability and improved dissolution rates. Said fixed dose composition preferably comprises one to four pitavastatin tablets and one ezetimibe tablet. The present disclosure also relates to the manufacturing process of said fixed-dose composition.

[0091] Ezetimibe powder was very unstable when mixed with pitavastatin powder and filled in capsules. The same instability of Ezetimibe was observed when pitavastatin powder was filled in capsules with Ezetimibe granules. Nonetheless, surprisingly such instability was not observed in the pharmaceutical composition of the present disclosure comprising a therapeutically effective amount of pitavastatin, an alkalizing agent and colloidal silicon dioxide, and a therapeutically effective amount of ezetimibe.

[0092] Formulation experiments were performed to evaluate the impact on the assays, dissolution rates and stability of the fixed-dose composition of pitavastatin and Ezetimibe, when silica colloidal anhydrous is present in the pitavastatin composition. Table 9 - Qualitative and quantitative composition of Pitavastatin tablets of composition XI. Comp. XI Constituents Mass per tablet (mg) % (w / w) Pitavastatin Calcium 1.05 1.27 Sodium carbonate anhydrous 1.57 1.90 Microcrystalline cellulose 73.517 89.117 Silica Colloidal Anhydrous (colloidal silicon dioxide) 2.332 2.827 Sodium starch glycolate 0.919 1.114 Sodium stearyl fumarate 0.612 0.742 Film coating (Opadry® amb II) 2.5 3.03 Total 82.50 100 Table 10 - Pitavastatin assay results TO (0 month) Comp. II Comp. XI Assay (%) pitavastatin 90.26 100.6 Table 11 - Qualitative and quantitative composition of Ezetimibe tablet (Composition XII) which is filled into a hard capsule with the Pitavastatin tablet (Composition XI) Comp. XII Constituents Mass per tablet (mg) % (w / w) Ezetimibe 10.000 10.000 Lactose monohydrate 39.010 39.010 Hypromellose 4.000 4.000 Croscarmellose sodium 3.370 3.370 Sodium lauryl sulphate 2.000 2.000 Microcrystalline Cellulose 40.620 40.620 Sodium stearyl fumarate 1.000 1.000 Total 100.000 100

[0093] The compressed ezetimibe composition XII is prepared according to the following process: a) Lactose monohydrate and Croscarmellose sodium powders were added into a fluid granulator, mixed and preheated at 45 °C. WO 2025 / 186786                                   PCT / IB2025 / 052491 b) Then the mixture was granulated with a granulation suspension prepared by the combination of an ethanolic solution of Ezetimibe and an aqueous polymer solution. c) The obtained granules were dried at 45 °C inlet air with suitable volumetric flow rate and calibrated by a 0.7 mm sieve aperture. d) The granules were mixed with microcrystalline cellulose, croscarmellose sodium and sodium lauryl sulphate and, then lubricated with sodium stearyl fumarate and thereafter compressed. Stability and Assay studies of Composition XI

[0094] A tablet according to Composition XI was analysed for Assay and Related substances using a High-Performance Liquid Chromatography system with a UV detector at 244 nm for pitavastatin quantification. For the samples analysis was used a validated and stability indicating methodology, and the quantification was performed using a characterized working standards to quantify specified impurities and the total impurities.

[0095] A Dissolution test was also performed. In the dissolution test of the disclosed examples the dissolutions were performed in 900 mL of dissolution medium at 37 °C ± 0.5°C, using USP Apparatus 1 (baskets) method at a rotation speed of 75 rpm for pitavastatin. Samples are removed after 15 minutes from test initiation and analysed for dissolved pitavastatin using a suitable HPLC method at 242 nm. A pH 6.8 phosphate buffer medium had been used dissolution medium, with adequate discrimination ability. The reported dissolution results are average values from six tablets.

[0096] The stability study was conducted in container closure system selected for proposed for packaging, storage and distribution. The long term and accelerated storage conditions were evaluated after 9 and 12 months. Table 12 - Stability and assay study results at 25°C / 60% RH and at 30°C / 75%RH for Composition XI in PVC / PVDC / aluminum. 0 months 9 months 12 months 25°C / 60%RH 30°C / 75%RH 25°C / 60%RH 30°C / 75%RH Assay (%) Pitavastatin 100.6 102.2 99.9 100.1 101.4 Related Comp. (%) Cis-lsomer n.d. <0.1 <0.1 n.d. <0.1 Pitavastatin Lactone n.d. <0.1 <0.1 <0.1 <0.1 5-Ketomer n.d. <0.1 0.17 <0.1 0.18 Unspecif. Impurities 0.14 <0.1 <0.1 <0.1 <0.1 Total impurities 0.14 b.q.l. 0.17 b.q.l. 0.18 Dissolution (%) Pitavastatin Q=80% 15 minutes 98 94 89 91 84 b.q.l: below quantification limit; n.d.; not detected Stability, Assay and dissolution studies of fixed-dose Compositions

[0097] Fixed-dose compositions in the form of hard gelatine capsules filled with one Ezetimibe tablet of composition XII and one, two or four pitavastatin tablets of composition XI were prepared.

[0098] Fixed-dose composition XIII relates to a fixed-dose compositions in the form of hard gelatine capsules filled with one Ezetimibe tablet of composition XII and one pitavastatin tablet of composition XI.

[0099] Fixed-dose composition XIV relates to a fixed-dose compositions in the form of hard gelatine capsules filled with one Ezetimibe tablet of composition XII and four pitavastatin tablets of composition XI.

[00100] Each capsule according to the Fixed-dose Compositions XIII and XIV was analysed for Assay and Related substances using a High-Performance Liquid Chromatography system with a UV detector at 244 nm for pitavastatin quantification and 235 nm for ezetimibe quantification. For the samples analysis was used a validated and stability indicating methodology, and the quantification was performed using a characterized working standards to quantify specified impurities and the total impurities.

[00101] A Dissolution test was also performed. In the dissolution test of the disclosed examples the dissolutions were performed in 900 mL of dissolution medium at 37 °C ± 0.5°C, using USP Apparatus 1 (baskets) method at a rotation speed of 100 rpm for ezetimibe and 75 rpm for pitavastatin. Samples are removed after 15 minutes from test initiation and analysed for dissolved Ezetimibe and pitavastatin using WO 2025 / 186786                                   PCT / IB2025 / 052491 a suitable HPLC method at 242 nm. A 0.1N hydrochloric acid + 0.15% SDS (Sodium dodecyl sulfate) had been used as dissolution medium for Ezetimibe and a pH 6.8 phosphate buffer medium for pitavastatin, with adequate discrimination ability. The reported dissolution results are average values from six capsules.

[00102] The stability study was conducted in container closure system selected for proposed for packaging, storage and distribution. The long term and intermediate stability were evaluated after 6 and 12 months, and accelerated storage conditions after 6 months.

[00103] Figure 1 and Figure 2 shows the dissolution profile of pitavastatin and ezetimibe, respectively, on composition XIII (fixed dose composition of pitavastatin 1 mg and ezetimibe 10 mg). Table 13 - Stability and assay study results at 25°C / 60% RH, 30°C / 75% RH and at 40°C / 75%RH for Fixed-dose Composition XIII (hard gelatine capsule with one 10 mg ezetimibe tablet and one 1 mg pitavastatin tablet) in oriented polyamide (OPA) sealed with aluminum sheet. 0 months 6 months 12 months 25°C / 60%R H 30°C / 75%R H 40°C / 75%R H 25°C / 60%R H 30°C / 75% RH Assay (%) Ezetimibe 101.4 101.9 102.3 102.3 101,7 101, 5 Pitavastatin 99.2 102.4 101.2 100.9 101,1 100, 5 Related Comp. (%) Ezetimib e RRS-lsomer n.d. n.d. n.d. n.d. n.d. n.d. EZT-Ketone <0.05 <0.05 < 0.05 <0.05 <0.05 0.05 Cyclic Ether n.d. n.d. n.d. n.d. n.d. n.d. Unspecif. Impurities <0.05 <0.05 < 0.05 <0.05 n.d. n.d. Total impurities b.q.l. b.q.l. b.q.l. b.q.l. b.q.l. b.q.l. Pitavast atin Cis-lsomer n.d. n.d. n.d. n.d. n.d. n.d. Pitavastatin Lactone 0.18 0,18 0,17 < 0.1 0.10 <0.1 5-Ketomer n.d. n.d. n.d. n.d. n.d. n.d. Unspecif. Impurities <0.1 0.13 < 0.1% <0.1 0.14 0.10 Total impurities 0.18 0.31 0.17 b.q.l. 0.25 0.10 Dissolution (%) Ezetimibe Q=75% 15 minutes 100 88 90 89 94 86 Pitavastatin Q=80% 15 minutes 97 96 87 98 99 99 b.q.l: below quantification limit; n.d.; not detected WO 2025 / 186786                                   PCT / IB2025 / 052491 Table 14 - Stability and assay study results at 25°C / 60% RH, 30°C / 75% RH and at 40°C / 75%RH for Fixed-dose Composition XIV (hard gelatine capsule with one 10 mg ezetimibe tablet and four 1 mg pitavastatin tablets) in OPA sealed with aluminum sheet. 0 months 6 months 12 months 25°C / 60%R H 30°C / 75%R H 40°C / 75%R H 25°C / 60%R H 30°C / 75% RH Assay (%) Ezetimibe 100.0 101.8 102.7 102.6 101.0 101. 9 Pitavastatin 100.0 99.7 99.2 99.1 100.0 100. 4 Related Comp. (%) Ezetimib e RRS-lsomer n.d. n.d. n.d. n.d. n.d. n.d. EZT-Ketone <0.05 <0.05 <0.05 <0.05 <0.05 <0.0 5 Cyclic Ether n.d. n.d. n.d. <0.05 n.d. n.d. Unspecif. Impurities <0.05 <0.05 <0.05 <0.05 <0.05 <0.0 5 Total impurities b.q.l. b.q.l. b.q.l. b.q.l. b.q.l. b.q.l. Pitavast atin Cis-lsomer n.d. n.d. n.d. n.d. n.d. n.d. Pitavastatin Lactone 0.16 0.14 0.12 0.23 0.22 0.23 5-Ketomer n.d. n.d. n.d. <0.1 n.d. n.d. Unspecif. Impurities <0.1 0.11 0.11 0.21 0.13 0.16 Total impurities 0.16 0.25 0.23 0.44 0.35 0.39 Dissolution (%) Ezetimibe Q=75% 15 minutes 89 85 88 84 94 92 Pitavastatin Q=80% 15 minutes 98 100 97 93 100 101 b.q.l: below quantification limit; n.d.; not detected Table 15. Dissolution profile of pitavastatin and ezetimibe on composition XIII (fixed dose composition of pitavastatin 1 mg and ezetimibe 10 mg). Time (min.) Composition XIII Ezetimibe Pitavastatin 0 0 0 10 91 91 15 100 96 20 105 97 30 107 98 45 106 - 60 107 - Example 4 - Ezetimibe compressed compositions

[00104] The Ezetimibe compressed composition of the present invention may comprise excipients, such as, diluents, binders, disintegrants, lubricants, solubilizing agents and / or wetting agents.

[00105] The Ezetimibe composition optionally comprises one or more diluents, preferably selected from a list consisting of lactose (anhydrous or monohydrate) and microcrystalline cellulose, or mixtures thereof.

[00106] The Ezetimibe composition optionally comprises one or more binders, preferably selected from the list consisting of Hypromellose and povidone, or mixtures thereof.

[00107] The Ezetimibe composition optionally comprises one or more disintegrants, preferably selected from the list consisting of croscarmellose sodium, crospovidone, povidone and hydroxipropylcellulose, or mixtures thereof.

[00108] The Ezetimibe composition optionally comprises one or more lubricants, preferably selected from the list consisting of sodium stearyl fumarate and magnesium stearate, or mixture thereof.

[00109] The Ezetimibe composition optionally comprises a wetting agent, preferably the wetting agent is sodium lauryl sulphate.

[00110] The Ezetimibe composition optionally comprises one or more solubilizing agents, preferably selected from the list consisting of purified water and ethanol, or mixtures thereof.

[00111] The method of preparing the Ezetimibe compressed composition comprises the following steps: - Lactose monohydrate and croscarmellose sodium are mixed in a fluid bed granulator; - A suspension formed by the ethanolic solution of ezetimibe and the aqueous solution of hypromellose are added to the Lactose monohydrate-croscarmellose sodium mixture and the mixture is granulated; - The ezetimibe solid dispersion granules obtained are dried and sieved; - Sodium lauryl sulfate, croscarmellose sodium, microcrystalline cellulose and a lubricant (magnesium stearate or sodium stearyl fumarate) are added to the granules. The granules and powders are mixed and compressed into tablets. Table 16 - Ezetimibe tablets (compressed composition). Composition El Composition E2 Component Amount (mg) % (wt / wt) Amount (mg) % (wt / wt) Ezetimibe 5.000 10.00 5.000 10.00 Lactose monohydrate 19.505 39.01 27.500 55.00 Hypromellose 2.000 4.00 2.000 4.00 Croscarmellose sodium 1.685 3.370 4.000 8.00 Sodium lauryl sulphate 1.000 2.00 1.000 2.00 Microcrystalline cellulose 20.310 40.62 10.000 20.00 Sodium stearyl fumarate 0.500 1.00 - - Magnesium stearate - - 0.500 1.00 Water, purified * * * * Ethanol, anhydrous * * * * Total (mg) 50.000 100 50.000 100 * Purified water and ethanol anhydrous were evaporated by drying and were not included in the composition calculations.

[00112] Comparative examples of ezetimibe compressed composition were prepared.

[00113] Comparative compositions El to E3 are alternative ezetimibe compressed compositions wherein the active ingredient is not in solid dispersion form.

[00114] Comparative composition El was prepared by mixing in a fluid bed granulator ezetimibe, croscarmellose sodium, lactose monohydrate, sodium lauryl sulfate and microcrystalline cellulose. The previous mixture was then granulated with water. The granulate that was formed was dried, lubricated with magnesium stearate and compressed.

[00115] Comparative composition E2 was prepared by mixing croscarmellose sodium, lactose monohydrate, sodium lauryl sulfate and microcrystalline cellulose in a fluid bed granulator. The previous mixture was then granulated with ezetimibe dissolved in ethanol. The granules that were formed were dried, lubricated with magnesium stearate and compressed.

[00116] Comparative composition E3 was prepared by mixing croscarmellose sodium, lactose monohydrate, sodium lauryl sulfate and microcrystalline cellulose in a fluid bed granulator. The previous mixture was then granulated with a granulation suspension of ezetimibe and hypromellose in ethanol. The granules that were formed were dried, lubricated with magnesium stearate and compressed.

[00117] Table 17 shows the breakdown of the quantity of each component forming comparative compositions El, E2 and E3. Table 17 - Ezetimibe compressed compositions (comparative examples) Comparative composition El Comparative composition E2 Comparative composition E3 Component Amount (mg) % (wt / wt) Amount (mg) % (wt / wt) Amount (mg) % (wt / wt) Ezetimibe 5.000 10.00 5.000 10.00 5.000 10.00 Lactose monohydrate 27.500 55.00 27.500 55.00 27.500 55.00 Croscarmellose sodium 4.000 8.00 4.000 8.00 4.000 8.00 Povidone 2.000 4.00 2.000 4.00 - - Hypromellose - - - - 2.000 4.00 Microcrystalline Cellulose 10.000 20.00 10.000 20.00 10.000 20.00 Sodium lauryl sulfate 1.000 2.00 1.000 2.00 1.000 2.00 Magnesium stearate 0.500 1.00 0.500 1.00 0.500 1.00 Water, purified * * - - - - Ethanol, anhydrous - - * * * * Total (mg) 50.000 100.00 50.000 100.00 50.000 100.00 * Purified water or ethanol anhydrous were evaporated by drying and were not included in the composition calculations.

[00118] The dissolution test was performed comparing the ezetimibe compressed compositions El -E2 and the comparative compositions El to E3. The dissolution test was performed in 1000 mL of dissolution medium at 37 °C ± 0.5 °C, using USP Apparatus 2 (paddles) method at a rotation speed of 50 rpm. Samples are removed after 5, 10, 15, 30, 45 and 60 minutes from test initiation and analyzed for dissolved ezetimibe using a suitable HPLC method at 240 nm. 0.1N HCI + 0.15% SDS was used as dissolution medium, with adequate discrimination ability. The reported dissolution results are the average values of six tablets. The similarity factor ( / 2) is a measurement of the similarity in percentage of dissolution between two curves. Two dissolution profiles are considered similar when the / 2 value is > 50. The results are summarized in Table 18. WO 2025 / 186786                                   PCT / IB2025 / 052491 Table 18 - Data related to the dissolution profiles of disclosed compositions El and E2 (table 15) and comparative (comp.) compositions El to E3 (table 16) and Ezetrol® tablets. Time (min.) Ezetrol ® Comparativ e Comp. El Comparative Comp. E2 Comparativ e Comp. E3 Comp. El Comp. E2 0 0 0 0 0 0 0 5 46 39 50 45 54 50 10 75 53 60 57 66 63 15 81 60 66 65 73 69 30 88 72 73 77 82 80 45 89 77 76 81 87 86 60 90 79 79 84 89 89 f2(%) (vs Ezetrol®) Ref 33 44 44 55 51

[00119] As depicted in Table 18, comparative compositions El to E3 do not constitute compositions with dissolution behaviour similar to the ezetimibe reference product Ezetrol*. On the other side, it was surprisingly found that compositions El and E2 show a dissolution profile compatible with the ezetimibe reference product Ezetrol®.

[00120] In one aspect of the present disclosure, the oral fixed-dose combination pharmaceutical composition has a pharmacokinetic profile for Pitavastatin which gives rise to a 90% confidence interval (90% Cl) for the ratio of the geometric means of AUCo-t for test product (present disclosure) and Livazo’ (reference product), from 80.00 to 125.00%.

[00121] In another aspect of the disclosure, the oral fixed-dose combination pharmaceutical composition has a pharmacokinetic profile for Pitavastatin which gives rise to a 90% Cl for the ratio of the geometric means of Cmax for test product (present disclosure) and Livazo’ (reference product), from 80.00 to 125.00%.

[00122] In another aspect of the present disclosure, the oral fixed-dose combination pharmaceutical composition has a pharmacokinetic profile for total Ezetimibe which gives rise to a 90% Cl for the ratio of the geometric means of AUC for test product (present disclosure) and Ezetrol’ (reference product), from 80.00 to 125.00%.

[00123] In one further aspect of the present disclosure, the oral fixed-dose combination pharmaceutical composition has a pharmacokinetic profile for total Ezetimibe which gives rise to a 90% confidence interval (90% Cl) for the ratio of the geometric means of Cmax for test product (present disclosure) and Ezetrol’ (reference product).

[00124] In a further aspect, there is a bioequivalence between the blood concentration levels of pitavastatin and ezetimibe resulting from the administration of the oral fixed dose composition and the blood concentration levels resulting from the co-administration of the European reference products of Pitavastatin and the European reference product of Ezetimibe. Table 19 - Data related to the bioequivalence of Fixed-dose Composition XIV versus Livazo® 4 mg (Pitavastatin) and versus Ezetrol® 10 mg tablets (Ezetimibe) Active Pharmacokinetic Parameter 90% Confidence Intervals of Parametric Means Point Estimate [%] Lower Limit [%] Upper Limit [%] Pitavastatin c x) 102.00 87.33 119.14 4mg AUCo^< 96.61 88.06 105.98 Ezetimibe c 2> 86.97 80.00 94.55 lOmg AUCo^2’ 94.71 87.61 102.38 11 Reference: Livazo® 4 mg 2) Reference: Ezetrol® 10 mg tablets

[00125] Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and / or the understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. It is also to be understood that unless otherwise indicated or otherwise evident from the context and / or the understanding of one of ordinary skill in the art, values expressed as ranges can assume any subrange within the given range, wherein the endpoints of the subrange are expressed to the same degree of accuracy as the tenth of the unit of the lower limit of the range.

[00126] The term "comprising" whenever used in this document is intended to indicate the presence of stated features, integers, steps, components, but not to preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

[00127] The disclosure should not be seen in any way restricted to the embodiments described and a person with ordinary skill in the art will foresee many possibilities to modifications thereof. The abovedescribed embodiments are combinable.

[00128] The following dependent claims further set out particular embodiments of the disclosure.

Claims

1. Stable solid oral pharmaceutical composition comprising a therapeutically effective amount of pitavastatin or a pharmaceutically acceptable salt, an alkalizing agent and colloidal silicon dioxide and a therapeutically effective amount of Ezetimibe.

2. Composition according to the previous claim wherein the weight ratio between pitavastatin or a pharmaceutically acceptable salt: colloidal silicon dioxide ranges from 1:1 to 1:5.

3. Composition according to the previous claim, wherein at least around 80 % of the amount of each ezetimibe and pitavastatin are released in 15 min.

4. Composition according to the previous claim, wherein at least around 85% of the amount of each ezetimibe and pitavastatin are released in 15 min.

5. Composition according to any of the previous claims, wherein the alkalizing agent is selected from the list consisting of: sodium carbonate, dipotassium hydrogen orthophosphate, magnesium hydroxide or mixtures thereof.

6. Composition according to the previous claim, wherein the alkalizing agent is sodium carbonate.

7. Composition according to any of the previous claims, wherein the weight ratio between pitavastatin or a pharmaceutically acceptable salt: colloidal silicon dioxide ranges from 1:1 to 1:3.

8. Composition according to any of the previous claims, wherein the weight ratio between pitavastatin or a pharmaceutically acceptable salt: colloidal silicon dioxide ranges from 1:2.2 to 1:2.4.

9. Composition according to any of the previous claims, wherein the weight ratio between pitavastatin or a pharmaceutically acceptable salt: colloidal silicon dioxide is 1:2.3.

10. Composition according to any of the claims, wherein the amount of colloidal silicon dioxide ranges from 1.2 tO 5% w / w (w colloidal silicon dioxide / w total).

11. Composition according to the previous claim, wherein the amount of colloidal silicon dioxide ranges from 1.2 tO 3 % w / w (w colloidal silicon dioxide / w total).

12. Composition according to any of the previous claims, wherein the amount of alkalizing agent ranges from 0.5 to 6.6 %w / w (w alkalizing agent / w total).

13. Composition according to the previous claim, wherein the amount of alkalizing agent ranges from 0.8 to 2 % (w alkalizing agent / w total); preferably from 0.9 to 1.9 % (w alkalizing agent / w total)-14. Composition according to any of the previous claims, wherein the pitavastatin pharmaceutically acceptable salt is pitavastatin calcium.

15. Composition according to any of the previous claims, further comprising at least: a binder; a wetting agent; a filler; a disintegrant; and / or a lubricant.

16. Composition according to the previous claim, wherein the binder is selected from the list consisting of hypromellose and povidone, microcrystalline cellulose, hydroxypropylcellulose, hypromellose or polyvinylpyrrolidone, or mixtures thereof.

17. Composition according to any of the previous claims 15-16, wherein the wetting agent is sodium lauryl sulfate.

18. Composition according to any of the previous claim 15-17, wherein the lubricant is selected from the list consisting of: sodium stearyl fumarate, magnesium stearate, stearic acid, talc, or mixtures thereof; preferably sodium stearyl fumarate and / or magnesium stearate.

19. Composition according to any of the previous claims 15-18 wherein the disintegrant is selected from the list consisting of sodium starch glycolate, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, croscarmellose sodium, crospovidone, or mixtures thereof; preferably sodium starch glycolate and / or croscarmellose sodium.

20. Composition according to any of the previous claims 15-19 wherein the filler is selected from the list consisting of microcrystalline cellulose, calcium phosphate, lactose monohydrate, mannitol, starch, sorbitol, or mixtures thereof; preferably microcrystalline cellulose and / or lactose monohydrate.

21. Composition according to any of the previous claims wherein the composition is a compressed composition.

22. Composition according to any of the previous claims wherein the therapeutically effective amount of pitavastatin is in a form of a tablet of pitavastatin.

23. Composition according to any of the previous claims wherein the therapeutically effective amount of Ezetimibe is in a form of solid dispersion granules of Ezetimibe.

24. Composition according to any of the previous claims wherein the amount pf Ezetimibe ranges from 5 to 10 mg.

25. Composition according to the previous claim 23, wherein the solid dispersion granules of Ezetimibe comprise hypromellose, lactose monohydrate and croscarmellose sodium.

26. Composition according to any of the previous claims wherein the therapeutically effective amount of Ezetimibe is in a form of a compressed composition.

27. Composition according to any of the previous claims wherein the therapeutically effective amount of pitavastatin or a pharmaceutically acceptable salt is in a form of a compressed composition.

28. A fixed-dose composition comprising at least one pitavastatin compressed composition according to the previous claim 27 and at least an ezetimibe compressed composition according to claim 26, preferably the fixed-dose composition is a capsule dosage form.

29. Composition according to any of the previous claims for use in the prevention or treatment of hypercholesterolemia.

30. The use of the composition according to any of the previous claims for the manufacture of a medicament for the treatment of hypercholesterolemia.

31. A method for treating or preventing hypercholesterolemia in a subject, the method comprising administering the composition according to any of the previous claims to the subject.

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