WO2021019499A1

WO2021019499A1 - Solid oral multiple-unit immediate release compositions, methods and uses thereof

Info

Publication number: WO2021019499A1
Application number: PCT/IB2020/057224
Authority: WO
Inventors: Ricardo José CAMILO FERREIRA PEREIRA; João Pedro SILVA SERRA
Original assignee: TECNIMEDE - Sociedade Técnico-medicinal, SA
Priority date: 2019-07-31
Filing date: 2020-07-30
Publication date: 2021-02-04
Also published as: BR112022001783A2; CO2022000503A2

Abstract

The present disclosure relates to stable solid oral multiple-unit immediate release compositions comprising therapeutically effective doses of ezetimibe and rosuvastatin. It also relates to the process of obtaining said solid oral multiple-unit immediate release compositions as well as their use in the treatment of primary hypercholesterolemia.

Description

D E S C R I P T I O N

SOLI D ORAL MULTI PLE-U NIT I MM EDIATE RELEASE

COMPOSITIONS, M ETHODS AND USES TH EREOF

Technical Field

[0001] The present disclosure relates to stable solid oral multiple-unit immediate release compositions comprising therapeutically effective doses of ezetimibe and rosuvastatin. It also relates to the process of obtaining said solid oral multiple-unit immediate release compositions as well as their use in the treatment of primary hypercholesterolemia.

Background

[0002] Ezetimibe is the international non-proprietary name (INN) of chemical compound (3R,4S)-l-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4- (4-hydroxyphenyl)-2-azetidinone, also known by the code name SCH-58235. Its molecular formula is C24H21F2NO3 and its molecular weight is 409.425 g mol ¹. It has the following structural formula:

[0003] Ezetimibe is a cholesterol absorption inhibitor that blocks intestinal absorption (both dietary and biliary) and has confirmed lipid-lowering and antiatherosclerotic activity in clinical hypercholesterolaemia. Amongst other therapeutical indications, Ezetimibe is indicated in the treatment of primary hypercholesterolaemia either as an adjunct therapy to diet (when statin therapy is inappropriate or is not tolerated) or co-administered with a statin as an adjunct therapy to diet. [0004] Ezetimibe had its first regulatory approvals in Puerto Rico, Germany and USA in 2002 and has since been approved worldwide. It is also available as a generic drug. Ezetimibe is available in European markets in 10 mg tablet form.

[0005] Rosuvastatin is the international nonproprietary name (INN) of the chemical compound (3R,5S,6E)-7-{4-(4-Fluorophenyl)-6-isopropyl-2-

[methyl(methylsulfonyl)amino]-5-pyrimidinyl}-3,5-dihydroxy-6-heptenoic acid, also known by the code names ZD 4522 and S 4522. Its molecular formula is C H FN O S and its molecular weight is 481.538 g mol ¹. It has the following structural formula :

[0006] Rosuvastatin is a statin compound (also known as B-hydroxy-B-methyl- glutaryl-coenzyme A reductases or HMG-CoA reductases). Statin treatment for primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) is recommended in the guidelines currently published, for example, by the U.K. National Institute for Health and Care Excellence (NICE) and the American College of Cardiology/American Heart Association (ACC/AHA).

[0007] Rosuvastatin had its first regulatory approval in Canada in 2002 and has since been approved worldwide. It is also available as a generic drug. Rosuvastatin is available in European markets in 5 mg, 10 mg, 20 mg and 40 mg film coated tablet form. The most common salt form is hemicalcic rosuvastatin (usually referred to as simply rosuvastatin calcium).

[0008] As compared to the use of rosuvastatin alone, use of ezetimibe and rosuvastatin as a combination provided significantly superior efficacy in lowering LDL cholesterol, total cholesterol and triglyceride levels (Cardiovascular therapeutics 2016; 34: 371-382). Nowadays it is a common pharmacological treatment for many patients. The latest scientific findings (Drugs Context. 2018; 7: 212534) continue to support the therapeutic use of ezetimibe combined with statins as evidence shows that it leads to lowering of low-density lipoprotein cholesterol (LDL-C) and reduction of risk of ASCVD without raising significant safety concerns.

[0009] Ezetimibe is virtually insoluble in aqueous media (8.46 ng/L) and has a bioavailability of 35%. This reduced solubility conditions the options available in the planning of pharmaceutical compositions containing ezetimibe as active pharmaceutical ingredient (API).

[0010] Rosuvastatin is an unstable molecule that has a tendency to react in acidic media (it easily converts into its anti isomer or degrades into its corresponding lactone) or through oxidation (forming its 5-keto analog).

[0011] As with all statin drugs, rosuvastatin is usually formulated with alkalinizing agents and/or buffers (for example NaOH, KOH, triethylamine, meglumine, L- Arginine, sodium phosphate buffers or sodium bicarbonate).

[0012] Document WO 199508532 is the first document which describes ezetimibe and its method of synthesis.

[0013] Documents JP 2648897 B2 and EP 0521471 B1 were the initial documents which describe rosuvastatin and its method of synthesis.

[0014] Document WO 2015044698 describes combinations of ezetimibe and rosuvastatin zinc. One of the defining characteristics of the compositions disclosed in this document is the fact that the immediate release of both ezetimibe and rosuvastatin is modulated to occur at different time points (there is a time lag between the releases of both APIs).

[0015] Document WO 2015102400 describes combinations of ezetimibe and rosuvastatin. Both APIs are contained in the same solid composite formulation for oral administration. The ezetimibe granules and rosuvastatin mixture present in the compositions are in direct and intimate contact (either blended or compressed together).

[0016] Document MX 2012014970 describes combinations of ezetimibe and rosuvastatin. It discloses tablets containing both APIs, both monolithic and bilayer. [0017] Document WO 2013166117 describes combinations of ezetimibe and rosuvastatin. It discloses tablets, particularly bilayer tablets comprising a combination of ezetimibe and rosuvastatin. Sodium stearyl fumarate is used as a lubricant, within the routine parameters known to the skilled person.

[0018] Document WO 2015199356 describes combinations of ezetimibe and rosuvastatin. It discloses tablets with improved content uniformity wherein ezetimibe granules are blended with a rosuvastatin mixture.

[0019] Document CN 107028906 describes combinations of ezetimibe and rosuvastatin in the form of a compound tablet. The disclosed compound tablet comprises ezetimibe and rosuvastatin granules.

[0020] Document IN2009CH01542 describes combinations of ezetimibe and HMG- CoA reductase inhibitors. It discloses a compound tablet comprising an ezetimibe core and an external coat comprising rosuvastatin.

[0021] Document EP 3243506 describes combinations of ezetimibe and rosuvastatin. The disclosed compositions are in the form of tablets comprising simultaneously ezetimibe and rosuvastatin granules.

[0022] Document KR 20150065323 describes combinations of ezetimibe and rosuvastatin. The disclosed compositions are tablets comprising simultaneously ezetimibe wet granulated with hydroxypropylcellulose and rosuvastatin.

[0023] Document KR 20160105044 describes combinations of amorphous ezetimibe and rosuvastatin. The disclosed compositions are tablets comprising simultaneously wet granulated ezetimibe and rosuvastatin.

[0024] Document WO 2013066279 describes ezetimibe compositions. It discloses bilayer tablets comprising ezetimibe and rosuvastatin.

[0025] Document CN 103585157 describes combinations of ezetimibe and rosuvastatin in the form of double layer tablets.

[0026] Document WO 2018101681 describes combinations of ezetimibe and rosuvastatin. The disclosed compositions are tablets comprising simultaneously ezetimibe wet granulated with povidone and rosuvastatin. [0027] Document WO 2018041281 describes combinations of ezetimibe and rosuvastatin. The disclosed compositions are circular two-layer tablets with specific dimensions.

[0028] Document WO 2018041282 describes combinations of ezetimibe and rosuvastatin. The disclosed compositions are circular two-layer tablets with specific ratios between the weights of the layers.

[0029] Document EP 3085364 describes combinations of cholesterol absorption inhibitors and HMG-CoA reductase inhibitors. It discloses tablets comprising ezetimibe and rosuvastatin.

[0030] Document WO 2006134604 describes combinations of ezetimibe and HMG- CoA reductase inhibitors. It discloses a tablet composition comprising ezetimibe and rosuvastatin.

[0031] Document WO 2009024889 describes combinations of ezetimibe and HMG- CoA reductase inhibitors. It discloses a tablet composition comprising ezetimibe and rosuvastatin granules.

[0032] In the state of the art, the provision of a combined rosuvastatin and ezetimibe composition represents a formulation challenge as each active pharmaceutical ingredient (APIs) has specific requirements (pH and the need for solubility improving ingredients) that are not overlapping (i.e. the ideal conditions for rosuvastatin are substandard for ezetimibe and vice-versa). The interactions between the APIs are not only evident when the APIs are present in a common solid formulation, they can also be observed for example when commercial compositions of rosuvastatin and ezetimibe are administered together. The dissolution profiles of rosuvastatin and ezetimibe tablets, when dissolved simultaneously, are different from the dissolution profiles of rosuvastatin and ezetimibe tablets when each is evaluated separately.

[0033] Several alternative solutions were tested in the art to try to solve this problem (for example bilayer tablets and other complex compositions comprising more than one phase, sometimes including coatings separating the APIs, or the use of alternate salts of rosuvastatin) but from the point of view of pharmaceutical formulation or pharmaceutical regulatory matters, these alternative solutions always entail further hurdles. There is a need for rosuvastatin and ezetimibe combined compositions that are simple and industrially straightforward to produce.

[0034] These facts are disclosed in order to illustrate the technical problem addressed by the present disclosure.

General Description

[0035] The present disclosure relates to stable solid oral multiple-unit immediate release compositions comprising therapeutically effective doses of ezetimibe and rosuvastatin. It also relates to the process of obtaining said solid oral multiple-unit immediate release compositions as well as their use in the treatment of primary hypercholesterolemia.

[0036] In view of the current state of the art, there is a need for solid oral multiple- unit immediate release compositions that are stable, comprise therapeutically effective doses of rosuvastatin and ezetimibe for effective treatment of primary hypercholesterolemia, and can be obtained by simple, effective, and straightforward industrial processes.

[0037] The compositions of the present disclosure overcome the problems related to this specific pharmaceutical combination and thus allow efficient industrial preparation of fixed dose pharmaceutical combinations.

[0038] One advantage of the compositions disclosed is that the first and the second part of the multi-unit immediate release composition consistently present desired in vitro dissolution profiles. The in vitro dissolution profiles are equivalent regardless of whether the dissolution is evaluated together or separately. This means that the compressed compositions can also be used for monotherapy (i.e. each part of the solid oral multiple-unit immediate release pharmaceutical composition can also be administered by itself) and represents a great industrial advantage.

[0039] The solid oral multiple-unit immediate release compositions of the present disclosure comprise rosuvastatin calcium and ezetimibe as active pharmaceutical ingredients are characterized in that both the first part and the second part of the solid oral multiple-unit composition are immediate release compositions. The release of the APIs is fast for ezetimibe and rosuvastatin. Surprisingly, the compositions of the present disclosure allow that 15 minutes after the start of dissolution more than 85% of each API is in solution.

[0040] Surprisingly, the rosuvastatin calcium and ezetimibe in the solid oral multiple- unit composition of the present disclosure is also stable even when subjected to different conditions of temperature and humidity (25 °C/60% HR, 30 °C/75% HR and 40 °C/60% HR).

[0041] In an embodiment, the solubility behavior of the rosuvastatin calcium and ezetimibe in the solid oral multiple-unit immediate release composition is similar to the reference products for ezetimibe and rosuvastatin.

[0042] In an embodiment, the rosuvastatin part does not include alkalinizing excipients, acidifying excipients or buffers.

[0043] In the context of the present disclosure a solid dispersion is understood to be the dispersion of one API (ezetimibe in this specific case) in an inert carrier (hypromellose in this specific case) at solid state prepared by solvent evaporation method.

[0044] In the context of the present disclosure the solid dispersion of ethanol comprised in the first part of the solid oral multiple-unit immediate release composition was prepared using ethanol and comprises a residual amount of ethanol between 0.0001 and 5 mg.

[0045] In an embodiment, the compositions are in close physical proximity but constitute separate forms. This close proximity may be achieved by the combined loading of the first part of the solid oral multiple-unit immediate release pharmaceutical composition of the present disclosure and the second part of the solid oral multiple-unit immediate release pharmaceutical composition of the present disclosure in the same hard capsule, preferably a hard capsule of size 00, 0, 1 or 2. [0046] In an embodiment, the solid oral multiple-unit immediate release compositions optionally comprise one or more excipients selected from the following list: diluents, binders, disintegrants, wetting agents, lubricants, anti adherents, glidants, or coating agents.

[0047] In an embodiment, the solid oral multiple-unit immediate release composition optionally comprises one or more diluents selected from the following list: lactose (anhydrous or monohydrate) or microcrystalline cellulose.

[0048] In an embodiment, the solid oral multiple-unit immediate release compositions optionally comprise one or more binders selected from the following list: hypromellose or povidone.

[0049] In an embodiment, the solid oral multiple-unit immediate release composition optionally comprises one or more disintegrants selected from the following list: croscarmellose sodium, crospovidone or povidone.

[0050] In an embodiment, the solid oral multiple-unit immediate release composition optionally comprises sodium lauryl sulphate as a wetting agent

[0051] In an embodiment, the solid oral multiple-unit immediate release composition optionally comprises one or more lubricants selected from the following list: sodium stearyl fumarate or magnesium stearate

[0052] In an embodiment, the solid oral multiple-unit immediate release composition optionally comprises talc as an anti-adherent.

[0053] In an embodiment, the solid oral multiple-unit immediate release composition optionally comprises colloidal anhydrous silica as a glidant.

[0054] In an embodiment, the solid oral multiple-unit immediate release compositions are prepared using one or more solubilizing agents selected from the following list: purified water or ethanol.

[0055] An aspect of the present disclosure relates to a solid oral multiple-unit immediate release pharmaceutical composition comprising a first part and a second part that are physically separated, the first part comprising a plurality of units of a first compressed composition, wherein the first compressed composition comprises a solid dispersion of ezetimibe and from 0.0001 to 5 mg of a solubilizing agent; the second part comprising at least one unit of a second compressed composition, wherein the second compressed composition comprises amorphous rosuvastatin calcium; wherein the ezetimibe and the rosuvastatin are simultaneously released.

[0056] An aspect of the present disclosure relates to a solid oral multiple-unit immediate release pharmaceutical composition comprising a first part and a second part that are physically separated, the first part comprising a plurality of units of a first compressed composition, wherein the first compressed composition comprises a solid dispersion of ezetimibe and from 0.0001 to 5 mg of a solubilizing agent;

the second part comprising at least one unit of a second compressed composition, wherein the second compressed composition comprises amorphous rosuvastatin calcium.

wherein the ezetimibe and the rosuvastatin are simultaneously released, wherein at least around 48% of the amount of each ezetimibe and rosuvastatin are released in 5 min; i.e. at least around 48% of the amount of ezetimibe and at least around 48% of the amount of rosuvastatin.

[0057] In an embodiment, at least around 76% of the amount of each ezetimibe and rosuvastatin are released in 10 min, wherein the amount of ezetimibe released in 10 min is at least 80%.

[0058] In an embodiment, at least 85% of the amount of each ezetimibe and rosuvastatin are released in 15 min.

[0059] The composition of the present disclosure maintains its stability while surprisingly allowing simultaneous release of a considerable amount of each API within the first 5 min, preferably within the first 10 min, more preferably within the first 15 min. The combined effect is reinforced with the use of a small amount of solubilizing agent and hydrophilic agent, in particular with the combination of ethanol and hypromellose.

[0060] In an embodiment, the solubilizing agent of the first part of the solid oral multiple-unit immediate release pharmaceutical composition is ethanol. [0061] In an embodiment, the first part of the solid oral multiple-unit immediate release pharmaceutical composition further comprises a hydrophilic agent.

[0062] In an embodiment, the hydrophilic agent of the solid oral multiple-unit immediate release pharmaceutical composition is hypromellose.

[0063] In an embodiment, the second compressed composition of the solid oral multiple-unit immediate release pharmaceutical composition does not contain an alkalinizing excipient, an acidifying excipient or a buffer.

[0064] In an embodiment, the second part of the solid oral multiple-unit immediate release pharmaceutical composition further comprises an anti-adherent and/or a glidant.

[0065] In an embodiment, the anti-adherent is talc and the glidant is colloidal anhydrous silica.

[0066] In an embodiment, the anti-adherent and the glidant are in a proportion by weight from 4:1 to 8:1, more preferably from 5:1 to 7:1.

[0067] In an embodiment, the first compressed composition and the second compressed composition of the solid oral multiple-unit immediate release pharmaceutical composition are microtablets or tablets.

[0068] In an embodiment, the first part of the solid oral multiple-unit immediate release pharmaceutical composition comprises two to four units of a first compressed composition, preferably two units.

[0069] In an embodiment, the second part of the solid oral multiple-unit immediate release pharmaceutical composition comprises one to five units of the second compressed compositions, preferably one to four units.

[0070] In an embodiment, the first part of the solid oral multiple-unit immediate release pharmaceutical composition comprises two compressed compositions and the second part comprises one to four compressed compositions.

[0071] In an embodiment, the second compressed composition may be coated by a film, in particular an aqueous film, namely coating film for an oral solid-dosage form. In an embodiment, the coating film may be Opadry^® pink 30K34297 commercialized by Colorcon^® (containing lactose monohydrate, hypromellose, titanium dioxide, triacetin and iron oxide red).

[0072] Another aspect of the present disclosure relates to a solid oral multiple-unit immediate release pharmaceutical composition for use in the treatment of primary hypercholesterolemia.

[0073] Another aspect of the present disclosure relates to a capsule comprising the composition described.

BRI EF DESCRIPTION OF TH E DRAWI NGS

[0074] The following figures provide preferred embodiments for illustrating the disclosure and should not be seen as limiting the scope of invention.

[0075] Figure 1 illustrates the dissolution profile of compositions 1 and 2 as compared to the dissolution profile of comparative compositions 1 to 3 and ezetimibe reference product - Ezetrol^® tablets.

[0076] Figure 2 illustrates the dissolution profiles of comparative compositions 4 to 9 and uncoated composition 3 as compared to rosuvastatin reference product - Crestor^® tablets.

[0077] Figure 3 illustrates the dissolution profile of ezetimibe in comparative composition 10 as compared to ezetimibe reference product - Ezetrol^® tablets.

[0078] Figure 4 illustrates the dissolution profile of rosuvastatin in comparative composition 10 as compared to rosuvastatin reference product - Crestor^® tablets.

[0079] Figure 5 illustrates the ezetimibe dissolution profile of a hard capsule comprising a solid oral multiple-unit immediate release composition comprising compressed compositions (composition 1 and composition 3) as compared to ezetimibe reference product - Ezetrol^® tablets.

[0080] Figure 6 illustrates the rosuvastatin dissolution profile of a hard capsule comprising a solid oral multiple-unit immediate release composition comprising compressed composition according (composition 1 and composition 3) as compared to rosuvastatin reference product - Crestor^® tablets.

Detailed Description

[0081] The present disclosure relates to stable solid oral multiple-unit immediate release compositions comprising therapeutically effective doses of ezetimibe and rosuvastatin. It also relates to the process of obtaining said solid oral multiple-unit immediate release compositions as well as their use in the treatment of primary hypercholesterolemia.

[0082] In an embodiment, the method of preparing composition 1 and composition 2 comprises the following steps:

• Lactose monohydrate and croscarmellose sodium were mixed in a fluid bed granulator.

• An ethanolic suspension of ezetimibe and an aqueous solution of hypromellose were added to the Lactose monohydrate-croscarmellose sodium and the mixture was granulated.

• The ezetimibe solid dispersion granules obtained was dried and sieved.

• Sodium lauryl sulfate, croscarmellose sodium, microcrystalline cellulose and a lubricant (magnesium stearate or sodium stearyl fumarate) were added to the granules. The granules and powders were mixed and compressed into tablets.

[0083] Table 1 shows the breakdown of the quantity of each component forming compositions 1 and 2. Table 1 - Ezetimibe tablets (first compressed composition)

* Purified water and ethanol anhydrous were evaporated by drying and were not included in the composition calculations.

[0084] In an embodiment, the method of preparing composition 3 comprises the following steps:

• Colloidal anhydrous silica and talc powders were mixed. Rosuvastatin calcium, microcrystalline cellulose, anhydrous lactose and crospovidone powders were then added to the mixture. The combined powder mixture was lubricated with sodium stearyl fumarate and compressed into tablets.

• A film coating solution (Opadry^® pink 30K34297) was prepared and applied to the compressed tablets obtained.

[0085] Table 2 shows the breakdown of the quantity of each component forming composition 3. Table 2 - Rosuvastatin film-coated tablets (second compressed composition)

* Purified water was evaporated by drying and was not included in the composition calculations.

[0086] A compatibility test was performed to assess the APIs^' compatibility. API's compatibility is an important part of understanding the role of active ingredients interaction in product quality. Drug substance-drug substance compatibility for rosuvastatin and ezetimibe were assessed through HPLC analysis of pure solid ezetimibe, pure solid rosuvastatin calcium and binary mixtures of both at 1:1 ratio. Samples were analyzed at the initial time and after 6 days of storage at 60 °C.

[0087] Table 3 shows the results of the API compatibility test. The compatibility test results show that there is an increase in the percentage of degradation of the compositions immediately after preparation of the binary mixture and that the percentage of degradation increases after 7 days at 60 °C. Table 3 - Ezetimibe and Rosuvastatin compatibility test

[0088] Comparative examples of ezetimibe compressed composition were prepared.

[0089] Comparative compositions 1 to 3 are alternative ezetimibe compressed compositions wherein the API is not in solid dispersion form.

[0090] Comparative composition 1 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 and povidone. The granulate that was formed was dried, lubricated with magnesium stearate and compressed.

[0091] Comparative composition 2 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 and povidone. The granules that were formed were dried, lubricated with magnesium stearate and compressed.

[0092] Comparative composition 3 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.

[0093] Table 4 shows the breakdown of the quantity of each component forming comparative compositions 1, 2 and 3. Table 4 - Ezetimibe compressed compositions (comparative examples)

* Purified water or ethanol anhydrous were evaporated by drying and were not included in the composition calculations.

[0094] Comparative examples of rosuvastatin calcium compressed composition were prepared.

[0095] Comparative compositions 4 to 9 are alternative rosuvastatin calcium compressed compositions.

[0096] Comparative composition 4 was prepared by mixing rosuvastatin calcium, lactose, microcrystalline cellulose, calcium phosphate and crospovidone powders. The powder mixture was lubricated with magnesium stearate and compressed.

[0097] Comparative compositions 5 and 6 were prepared by mixing rosuvastatin calcium, lactose, microcrystalline cellulose, sodium bicarbonate, crospovidone, talc and silica colloidal anhydrous powders. The powder mixtures were lubricated with magnesium stearate and compressed. [0098] Comparative composition 7 was prepared by mixing silica colloidal anhydrous and talc powders. Rosuvastatin calcium, lactose, microcrystalline cellulose, calcium phosphate tribasic and crospovidone were then added to the mixture. The combined powder mixture was lubricated with magnesium stearate and compressed into tablets.

[0099] Comparative compositions 8 and 9 were prepared by mixing silica colloidal anhydrous and talc powders. Rosuvastatin calcium, lactose, microcrystalline cellulose, calcium phosphate tribasic and crospovidone were then added to the previous mixtures. The combined powder mixtures were lubricated with magnesium stearate and compressed into tablets.

[00100] Table 5 and 6 show the breakdown of the quantity of each component forming comparative compositions 4 - 9.

Table 5 - Comparative compositions of Rosuvastatin

Table 6 - Comparative compositions of Rosuvastatin

[00101] The method of prepa ring comparative composition 10 (fixed combination tablet) comprises the following steps:

• Lactose monohydrate and croscarmel lose sodium were mixed in a fluid bed granulator.

• An ethanolic suspension of ezetimibe and an aqueous solution of hypromellose were added and the mixture was granulated.

• The ezetimibe solid dispersion granules obtained were dried and sieved.

• Talc and colloidal anhydrous silica were mixed. To the previous mixture rosuvastatin calcium, the previously formed ezetimibe solid dispersion granules, microcrystalline cellulose, lactose anhydrous, crospovidone, croscarmellose sodium and sodium lauryl sulphate were added. After mixing the mixture was lubrified with sodium stearyl fumarate and compressed.

[00102] Table 7 shows the breakdown of the quantity of each component forming comparative composition 10.

Table 7 - Ezetimibe and Rosuvastatin fixed combination tablets (comparative example)

* Purified water and ethanol anhydrous were evaporated by drying and were not included in the composition calculations. [00103] In an embodiment, the dissolution profiles of ezetimibe compressed compositions (compositions 1-2 and comparative compositions 1-3) were analyzed.

[00104] The dissolution test was performed comparing the ezetimibe compressed compositions 1-2 and the comparative compositions 1 to 3. 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 (f2 ) 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 8 and presented in Figure 1.

Table 8 - Data related to the dissolution profiles of disclosed compositions 1 and 2 (table 1), comparative compositions 1 to 3 (table 4) and Ezetrol^® tablets

[00105] Comparative compositions 1 to 3 do not constitute compositions with dissolution behavior similar to the ezetimibe reference product Ezetrol^® whereas compositions 1 and 2 (according to example 1) do. [00106] In an embodiment, the dissolution profiles of rosuvastatin compressed compositions (compositions 3 and comparative compositions 4-9) were analyzed.

[00107] The dissolution test was performed comparing the rosuvastatin compressed compositions 3 and the comparative compositions 4 to 9. 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, 20, 30, 45 and 60 minutes from test initiation and analyzed for dissolved rosuvastatin using a suitable HPLC method at 240 nm. 0.1N HCI was used as dissolution medium, with adequate discrimination ability. The reported dissolution results are the average values of six tablets. The similarity factor (f2) 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 9 and presented in Figure 2.

Table 9 - Data related to the dissolution profiles of disclosed compositions 3

(uncoated), comparative compositions 4 to 9 (tables 5 and 6) and Crestor^® tablets

[00108] Comparative compositions 5 to 9 do not constitute compositions with dissolution behavior similar to the rosuvastatin reference product Crestor^® whereas uncoated composition 3 (according to example 2) does.

[00109] The dissolution profiles of ezetimibe and rosuvastatin reference products (Ezetrol^® and Crestor^® respectively) and comparative composition 10 were analyzed.

[00110] The dissolution test was performed comparing the comparative composition 10 and the ezetimibe and rosuvastatin reference products Ezetrol^® and Crestor^®. 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 (and also after 20 min in the case of rosuvastatin) from test initiation and analyzed for dissolved ezetimibe or rosuvastatin using a suitable HPLC method at 240 nm. 0.1N HCI + 0.15% SDS was used as dissolution medium for ezetimibe and 0.1N HCI was used as dissolution medium for rosuvastatin, with adequate discrimination ability. The reported dissolution results are the average values of six tablets. The similarity factor (f2) 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 10 and presented in Figures 3 and 4.

Table 10 - Data related to the dissolution profiles of comparative composition 10 (table 7) vs Ezetrol^® and Crestor^® tablets

[00111] The comparative composition 10 (table 7) does not constitute a composition with dissolution behavior simultaneously similar to the ezetimibe reference product Ezetrol^® and the rosuvastatin reference product Crestor^®. Ezetimibe is particularly sensible to the surrounding conditions.

[00112] In an embodiment, the dissolution profiles of compositions 1 and 3 were analyzed.

[00113] The dissolution test was performed comparing a hard capsule (size 00) comprising two units of compressed compositions 1 and four units of compressed composition 3 and the ezetimibe and rosuvastatin reference products Ezetrol^® and Crestor^®. The dissolution test was performed in 1000 mL of dissolution medium at 37 °C ± 0.5 °C, using USP Apparatus 1 (basket) method at a rotation speed of 100 rpm (ezetimibe) and 75 rpm (rosuvastatin). Samples are removed after 5, 10, 15, 30, 45 and 60 minutes (and also after 20 min in the case of rosuvastatin) from test initiation and analyzed for dissolved ezetimibe or rosuvastatin using a suitable HPLC method at 240 nm. 0.1N HCI + 0.15% SDS was used as dissolution medium for ezetimibe and 0.1N HCI was used as dissolution medium for rosuvastatin, with adequate discrimination ability. The reported dissolution results are the average values of six tablets. The similarity factor (f2 ) 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. Two immediate release compositions are considered similar (and calculation of /2 is not required) if more than 85% of the API is dissolved after 15 minutes. The results are summarized in table 11 and presented in Figures 5 and 6.

Table 11 - Data related to the dissolution profiles of hard capsule comprising compositions 1 and 3 (tables 1 and 2) vs Ezetrol^® and Crestor^® tablets

[00114] The above data shows that for composition of the present disclosure:

• at least around 48% of the amount of each ezetimibe and rosuvastatin are released in 5 min;

• at least around 76% of the amount of each ezetimibe and rosuvastatin are released in 10 min, wherein the amount of ezetimibe released in 10 min is at least 80%;

• at least 85% of the amount of each ezetimibe and rosuvastatin are released in 15 min.

[00115] In an embodiment, the stability of the solid oral multiple-unit immediate release composition was tested.

[00116] In an embodiment, compositions 1 and 3 were combined in hard capsules (size 00). Different proportions of compositions 1 and 3 were combined in order to mimic the most commonly used therapeutically dosages (two units of composition 1 combined with one, two or four units of composition 3). The hard capsules were packaged and subjected to different conditions (25 °C/60% HR, 30 °C/75% HR and 40 °C/60% HR) in order to study the product behavior and degradation profile. The capsules were tested after 3 months of exposition. Each composition was analyzed using a High-Performance Liquid Chromatography system with a UV detector at 260 nm. For the samples analysis a validated method was used, and the quantification was performed using characterized working standards.

[00117] The results of the stability test are summarized in tables 12- 14.

Table 12 - Stability data of hard capsule comprising two units of compressed composition 1 and one unit of compressed composition 3 (tables 1 and 2)

bql -Below quantification level; nd - Not detected

Table 13 - Stability data of hard capsule comprising two units of compressed composition 1 and two units of compressed composition 3 (tables 1 and 2)

bql -Below quantification level; nd - Not detected Table 14 - Stability data of hard capsule comprising two units of compressed composition 1 and four units of compressed composition 3 (tables 1 and 2)

bql -Below quantification level; nd - Not detected

[00118] After being subject to different conditions of temperature and humidity for 3 months, compositions of batches 1 to 9 are stable and the total level of impurities is well beyond the specification levels that ensure a high quality pharmaceutical effective product.

[00119] 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. [00120] 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.

[00121] The above described embodiments are combinable.

[00122] 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.

Claims

C L A I M S

1. Solid oral multiple-unit immediate release pharmaceutical composition comprising a first part and a second part that are physically separated, the first part comprising a plurality of units of a first compressed composition, wherein the first compressed composition comprises a solid dispersion of ezetimibe and from 0.0001 to 5 mg of a solubilizing agent;

the second part comprising at least one unit of a second compressed composition, wherein the second compressed composition comprises amorphous rosuvastatin calcium;

wherein the ezetimibe and the rosuvastatin are simultaneously released, wherein at least around 48% of the amount of each ezetimibe and rosuvastatin are released in 5 min.

2. Composition according to the previous claim wherein at least around 76% of the amount of each ezetimibe and rosuvastatin are released in 10 min, wherein the amount of ezetimibe released in 10 min is at least 80%.

3. Composition according to any of the previous claims wherein at least 85% of the amount of each ezetimibe and rosuvastatin are released in 15 min.

4. Composition according to the previous claim wherein the solubilizing agent of the first part is ethanol.

5. Composition according to any of the previous claims wherein the first part further comprises a hydrophilic agent.

6. Composition according to claim 3 wherein the hydrophilic agent is hypromellose.

7. Composition according to any of the previous claims wherein the second compressed composition does not contain an alkalinizing excipient, an acidifying excipient or a buffer.

8. Composition according to any of the previous claims wherein the second part further comprises an anti-adherent and/or a glidant.

9. Composition according to claim 6 wherein the anti-adherent is talc and the glidant is colloidal anhydrous silica.

10. Composition according to any of the claims 6 or 7 wherein the anti-adherent and the glidant are in a proportion by weight from 4:1 to 8:1, more preferably from 5:1 to 7:1.

11. Composition according to any of the previous claims wherein the first compressed composition and the second compressed composition are microtablets or tablets.

12. Composition according to any of the previous claims wherein the first part comprises two to four units of a first compressed composition, preferably two units.

13. Composition according to any of the previous claims wherein the second part comprises one to five units of the second compressed compositions, preferably one to four units.

14. Composition according to claims 10 or 11 wherein the first part comprises two compressed compositions and the second part comprises one to four compressed compositions.

15. Composition according to any of the previous claims for use in the treatment of primary hypercholesterolemia.

16. Capsule comprising the composition described in any of the previous claims.