EP4188338A1 - Bilayer tablet comprising ezetimibe and atorvastatin - Google Patents

Bilayer tablet comprising ezetimibe and atorvastatin

Info

Publication number
EP4188338A1
EP4188338A1 EP21755380.9A EP21755380A EP4188338A1 EP 4188338 A1 EP4188338 A1 EP 4188338A1 EP 21755380 A EP21755380 A EP 21755380A EP 4188338 A1 EP4188338 A1 EP 4188338A1
Authority
EP
European Patent Office
Prior art keywords
layer
ezetimibe
dosage form
atorvastatin
form according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21755380.9A
Other languages
German (de)
French (fr)
Inventor
Danijel Videc
Polona Bukovec
Kristina DEBELJAK SIMONCIC
Grega Hudovornik
Klemen KORASA
Maja OMERZU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KRKA dd
Original Assignee
KRKA dd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by KRKA dd filed Critical KRKA dd
Publication of EP4188338A1 publication Critical patent/EP4188338A1/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • the invention relates to solid pharmaceutical dosage forms comprising Ezetimibe and Atorvas- tatin in separate layers, and to manufacturing methods for making the same.
  • the solid dosage forms are multilayer tablets, preferably bilayer tablets, suitable for oral administration.
  • Dyslipidemia is one of the most important risk factors for cardiovascular disease (Stehbens WE. Coronary heart disease, hypercholesterolemia, and atherosclerosis. II. Misrepresented data. Exp Mol Pathol. 2001;70: 120-139).
  • CHD coronary heart disease
  • LDL-C low-density lipoprotein cholesterol
  • Ezetimibe with chemical name l-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypro- pyl]4(S)-(4-hydroxyphenyl)-2-azetidinone is a potent cholesterol absorption inhibitor and is commer cially available in the form of tablet under the tradename Ezetrol ® . It is indicated as adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia in whom a statin is considered inappropriate or is not tolerated.
  • Ezetrol ® is indicated to reduce the risk of cardiovascular events in patients with coronary heart disease and a history of acute coronary syn drome when added to ongoing statin therapy or initiated concomitantly with a statin. Ezetrol ® is also indicated as adjunctive therapy to diet for use in patients with homozygous familial sitosterolaemia. The product contains lOmg Ezetimibe. Ezetimibe was first disclosed in EP0720599.
  • Atorvastatin with chemical name [R-(R*, R*)]-2-(4-fluorophenyl)-B, d, -dihydroxy-5 -(1-meth- ylethyl)-3 -phenyl-4 [(phenylamino) carbonyl] -lH-pyrrole-l-heptanoic acid is an inhibitor of the enzyme 3 -hydroxy-3 -methyl glutaryl coenzyme A reductase (HMG-CoA reductase) and is commercially avail able formulated as calcium salt trihydrate under the tradename Sortis ® .
  • the product contains 10 mg, 20 mg, 40 mg or 80 mg Atorvastatin.
  • Sortis ® is indicated to reduce total-C and LDL-C in adults with homozygous familial hypercholesterol aemia as an adjunct to other lipid-lowering treatments or if such treatments are unavailable. Additionally Sortis ® is also indicated for prevention of cardiovascular events in adult patients estimated to have a high risk for a first cardiovascular event, as an adjunct to correction of other risk factors. Atorvastatin was first disclosed in EP 0409 281.
  • US 2007 0014854 A1 and US 2007 0014864 A1 relate to a pharmaceutical composition in the form of a granulate, wherein the granulates comprises an active pharmaceutical ingredient (API) having a poor water solubility intimately associated with at least one pharmaceutically acceptable sugar, and optionally or preferably at least one pharmaceutically acceptable excipient other than the at least one pharmaceutically acceptable sugar, wherein the active pharmaceutically ingredient has a water solubility less than about 20 mg/ml.
  • API active pharmaceutical ingredient
  • US 2010 0209495 A1 relates to a granulate for use in a pharmaceutical composition and a phar maceutical composition manufacture using the granulate, where the granule comprises an active phar maceutical ingredient (API) having a poor water solubility (i.e., less than about 1 mg/mU) which is intimately associated with at least one pharmaceutically acceptable hydrophilic polymer.
  • API active phar maceutical ingredient
  • Combination compositions comprising a cholesterol absorption inhibitor in combination with a HMG-CoA reductase inhibitor are already known.
  • WO 2011 002422 relates to a pharmaceutical composition comprising Ezetimibe and Atorvas tatin or a pharmaceutically acceptable salts thereof wherein both active substances are pre-formulated in a series of manufacturing process steps to increase the solubility of Ezetimibe.
  • Ezetimibe and Atorvas tatin are not separated from one another in separate layers; bilayer tablets are not disclosed. Neither stability data nor dissolution data are provided for the final tablet.
  • a separate granulated composition comprising Ezetimibe (intermediate product) is said to exhibit a dissolution rate greater than 90% in the first 10 minutes.
  • Combination compositions comprising Ezetimibe and Atorvastatin is separate layers of bilayer tablets are also known.
  • a combination composition comprising Ezetimibe and Atorvastatin is commercially available as a fdm coated tablet under the tradename Atozet ® .
  • the product contains 10 mg Ezetimibe and 10 mg, 20 mg, 40 mg or 80 mg Atorvastatin calcium salt (2: 1) trihydrate.
  • Atozet ® is indicated for the reduction of elevated total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and non-high-density lipoprotein cholesterol, and to increase high-density lipoprotein cholesterol in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia.
  • Ato zet ® is also indicated for the reduction of elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments or if such treatments are unavailable.
  • WO 2013 166114 discloses a bilayer tablet comprising Ezetimibe and Atorvastatin or a phar maceutically acceptable salts thereof having similar dissolution profile to individual active substances and that is said to be stable regardless of incompatibilities of both active substances. Compared to ref erence product Ezetrol ® , however, dissolution according to WO 2013 166114 is delayed. While Ezetrol ® releases within 10 minutes 95% of the Ezetimibe that was originally contained in Ezetrol ® , the combi nation formulation according to WO 2013 166114 achieves a release of Ezetimibe of only 77% within 10 minutes (WO 2013 166114, Table 3).
  • EP 3 360 541 relates to a bilayer tablet comprising Atorvastatin calcium in a first layer and Ezetimibe in a second layer, wherein the weight ratio of the second layer to the first layer is between 0.05 and 8.0 and comprising at least one polymer. Neither stability data nor dissolution data are pro vided.
  • WO 2020 139237 relates to a bilayer tablet comprising Atorvastatin calcium in a first layer and Ezetimibe in a second layer, wherein the tablet comprises at least one binder in each layer. Neither stability data nor dissolution data are provided.
  • the dissolution profde of each active ingredient within the combination is similar to the dissolution profile of the two reference products that contain only one of the two active ingredients, and also to the dissolution profile of the reference combination product.
  • the reference product only containing Ezetimibe is Ezetrol ®
  • the reference product only containing Atorvastatin is Sortis ®
  • the reference combination product is Atozet ® .
  • a major challenge in achieving the desired dissolution profile of a new combination product is the large difference in tablet weights between the Ezetimibe reference product (Ezetrol ® ) and the refer ence combination product (Atozet ® ).
  • An Ezetrol ® tablet containing 10 mg Ezetimibe has a total weight of about 100 mg
  • Atorvastatin calcium salt (2: 1) trihydrate has a total weight of about 300 mg, 400 mg, 600 mg and 1000 mg, respectively.
  • the high dose strengths are particularly challenging (i.e. about 100 mg for Ezetrol ® vs. about 600 mg and 1000 mg for Atozet ® ).
  • a solid dosage form comprising a combination of Ezetimibe and Atorvastatin that can be manufactured by conventional manufacturing processes.
  • the solid dosage form should allow for preparing e.g. a dose strength of 10/10 mg and 10/80 mg from the same compression blend(s) merely by relatively ad justing the amount of the compression blend containing Atorvastatin.
  • Ezetimibe is classified in class II of the Biopharmaceutics Classification System (BCS) and dissolved quickly, which means that typically 55% of Ezetimibe are dissolved within 5 minutes, and 90% of Ezetimibe are dissolved within 10 minutes. It is generally known that tablets with higher weight have longer disintegration times and hence slower dissolution profiles at the initial stage of disintegra tion and dissolution.
  • BCS Biopharmaceutics Classification System
  • the weight ratio of the layers in bilayer tablet does not exceed 1 :2, there is a demand for bilayer tablets that tolerate layer weight ratios of from 1 : 1 to 1:4.
  • the invention aims at developing and preparing a solid dosage form comprising Ezetimibe and Atorvastatin, preferably in separate layers, that has a similar or even faster dissolution profile compared to Ezetrol ® , Sortis ® and Atozet ® and that successfully overcomes the drawbacks of the prior art.
  • the invention pertains to a solid dosage form comprising Ezetimibe and Atorvastatin in separate layers, which provides an improved dissolution profile, excellent physical stability, improved chemical stability, good bioavailability and long shelf-life.
  • the solid dosage form according to the invention can be prepared by a robust manufacturing process with good processibility on laboratory and industrial level.
  • solid dosage forms comprising at least two layers comprising Ezetimibe in a combination with Atorvastatin including its salts, solvates, hydrates, enantiomers and any polymorphs thereof wherein Ezetimibe and Atorvastatin are present in separate layers are provided.
  • a first aspect of the invention relates to a solid pharmaceutical dosage form comprising
  • an Ezetimibe layer comprising (i) Ezetimibe, a pharmaceutically acceptable salt and/or solvate thereof; (ii) a first diluent; (iii) optionally, a second diluent; and (iv) optionally, a first binder; preferably, wherein the Ezetimibe layer comprises an intragranular phase and optionally an extra- granular phase; and
  • Atorvastatin layer comprising Atorvastatin, a pharmaceutically acceptable salt and/or solvate thereof; preferably, wherein the Atorvastatin layer comprises an intragranular phase and optionally an extra- granular phase;
  • the first diluent of the Ezetimibe layer is a sugar alcohol; preferably, mannitol; and/or
  • the optionally first binder of the Ezetimibe layer is a polyvinylpyrrolidone.
  • the solid dosage forms according to the invention are im proved and are effective in the treatment of abnormal lipid levels. They combine pharmacologic efficacy with adequate physical stability as well as chemical stability of both Ezetimibe and Atorvastatin. Fur ther, they can be prepared by a reliable and robust method of manufacture.
  • the solid dosage forms according to the invention show at least a similar dissolution profile compared to that of reference products Ezetrol®, Sortis® and Atozet®.
  • the solid dosage forms according to the invention can be manufactured by conventional manufacturing processes.
  • they can be prepared from separate pharmaceutical formulations (compression blends) each containing one of the two active ingre prodes that are both interchangeably useful as compression blends either for first layer or for the second layer of a multilayer tablet, preferably of a bilayer tablet.
  • they can be provided in different dose strengths (e.g. 10/10 mg, 10/20 mg, 10/40 mg and 10/80 mg) without requiring significant modification of the composition, i.e. of the excipients and their individual weight content.
  • the solid dosage form allows for preparing e.g. a dose strength of 10/10 mg and 10/80 mg from the same compression blend(s) merely by relatively adjusting the amount of the compression blend containing Atorvastatin.
  • the solid dosage forms according to the invention may have a comparatively high total weight but nonetheless provide fast disintegration and quick release of Ezetimibe. In particular, they have a similar and even faster dissolution profde compared to reference product Ezetrol®.
  • the solid dosage forms according to the inven tion can be prepared by a robust manufacturing process with good processibility on laboratory and par ticularly on industrial scale.
  • Figure 1 describes a dissolution profde of Ezetimibe for fdm coated tablet of Example 3g.
  • Figure 2 describes a dissolution profde of Atorvastatin for fdm coated tablet of Example 3g.
  • the solid pharmaceutical dosage form according to the invention form comprises
  • Ezetimibe layer comprising Ezetimibe, a pharmaceutically acceptable salt and/or solvate thereof and a first diluent; preferably, wherein the Ezetimibe layer comprises an intragranular phase and optionally an extragranular phase;
  • Atorvastatin layer comprising Atorvastatin, a pharmaceutically acceptable salt and/or solvate thereof; preferably, wherein the Atorvastatin layer comprises an intragranular phase and optionally an extragranular phase.
  • the first diluent of the Ezetimibe layer is a sugar alcohol.
  • the solid pharmaceutical dosage form according to the invention comprises
  • an Ezetimibe layer comprising Ezetimibe, a pharmaceutically acceptable salt and/or solvate thereof; a first diluent; optionally, a second diluent; and optionally, a first binder; preferably, wherein the Ezetimibe layer comprises an intragranular phase and optionally an extragranular phase; and
  • Atorvastatin layer comprising Atorvastatin, a pharmaceutically acceptable salt and/or solvate thereof; preferably, wherein the Atorvastatin layer comprises an intragranular phase and optionally an extragranular phase; wherein the optionally first binder of the Ezetimibe layer is polyvinylpyrrolidone.
  • the solid pharmaceutical dosage form com prises - an Ezetimibe layer comprising Ezetimibe, a pharmaceutically acceptable salt and/or solvate thereof; a first diluent; a second diluent; and a first binder; preferably, wherein the Ezetimibe layer comprises an intragranular phase and optionally an extragranular phase; and
  • Atorvastatin layer comprising Atorvastatin, a pharmaceutically acceptable salt and/or solvate thereof; preferably, wherein the Atorvastatin layer comprises an intragranular phase and optionally an extragranular phase; wherein the first binder of the Ezetimibe layer is polyvinylpyrrolidone.
  • the solid dosage form according to the invention comprises at least two active substances, par ticularly cholesterol absorption inhibitor in a combination with one or more HMG-CoA reductase in hibitor wherein the active substances are present in separate layers. More particularly, the solid dosage form according to the invention comprises Ezetimibe in a combination with Atorvastatin including its salts, solvates, hydrates, enantiomers and any polymorphs thereof, wherein Ezetimibe and Atorvastatin are present in separate layers.
  • the solid dosage form according to the invention is a bilayer tablet, preferably a film-coated bilayer tablet, that comprises Ezetimibe in a combination with Atorvas tatin including its salts, solvates, hydrates, enantiomers and any polymorphs thereof, wherein Ezetimibe and Atorvastatin are present in separate layers.
  • all amount indications are provided on a weight basis or weight/weight basis, as appropriate. If the active pharmaceutical substance is used in the form of a pharmaceutically acceptable salt, the weight of the entire salt is to be considered, in cluding the weight component of the counter ion. If the active pharmaceutical substance is used in the form of a solvate or hydrate, the additional weight associated with solvent or water components in the substance is to be disregarded. That is, a theoretical weight of the anhydrous pure substance (or its pharmaceutically acceptable salt and/or hydrate or solvate, if appropriate) is to be calculated and con sidered in connection with the invention.
  • the term " essentially the total amount" means at least 95 wt.-%, preferably at least 98 wt.-%, more preferably at least 99 wt.-%.
  • the term "layer” as used herein designates a layer in a multilayer tablet wherein at least two active substances are not in intimate contact and that they are separated from each other (except at the interface of the layers) .
  • the term “layer” refers to a physical part of the solid dosage form comprising at least two layers, wherein the components of one layer are not intimately mixed with the components of another layer of the composition. In particular, the interaction between the components of one layer and the components of another layer is reduced.
  • a multilayer tablet according to the invention has at least 2 layers, for example, a bilayer tablet involves the compression of two formulations comprising an active substance into a single solid oral dosage form, while maintaining physical separation of the for mulations by layering one on top of the other.
  • the layer is preferably formed from a compression blend, which consists of at least one active substance and one or more pharmaceu tically acceptable excipients.
  • compression blend designates the mixture of at least one active sub stance and one or more pharmaceutically acceptable excipients.
  • the Ezetimibe layer comprises an intragranular phase and optionally an extragranular phase; and/or the Atorvastatin layer comprises an intragranular phase and optionally an extragranular phase.
  • the terms "intragranular phase " and “extragranular phase " are known to the skilled person and are used in the conventional meaning.
  • the Ezetimibe layer and/or the Atorvastatin layer is preferably prepared from a compression blend that contains a granulate, optionally mixed with one or more excip ients, the granulate and its constituents forms the intragranular phase, whereas the optionally present one or more excipients form the extragranular phase.
  • the Ezetimibe layer comprises an intragranular phase and an extra granular phase
  • the Atorvastatin layer comprises an intragranular phase but not an extragranular phase
  • the solid dosage form according to the invention comprises Ezetimibe and Atorvastatin as the active substances in separate layers and one or more pharmaceutically acceptable excipients such as one or more diluents, one or more lubricants, one or more glidants, one or more disintegrants, one or more binders, and the like.
  • excipient refers to any pharmaceutically acceptable substance that has no therapeutic activity as such. Pharmaceutically acceptable excipients may for ex ample be selected from diluents, lubricants, glidants, disintegrants and binders.
  • the solid dosage form according to the invention may further comprise any other pharmaceuti cally acceptable excipients that can be selected among any known state of the art for solid dosage forms, as described e.g. in Remington: The Science and Practice of Pharmacy, Edited by Loyd V. Allen, Jr, Pharmaceutical Press, 22 Edition, 2012.
  • Individual excipients may have polyfunctional properties in the solid dosage form according to the invention, e.g. may exert both disintegrating and binding properties or both lubricating and gliding properties or my exert filling, binding and disintegrating properties.
  • the excipients may be split into fractions, where a first fraction is contained in the Ezetimibe layer and a second fraction is contained in the Atorvastatin layer.
  • a first fraction is contained in the Ezetimibe layer and a second fraction is contained in the Atorvastatin layer.
  • said representatives are preferably numbered such as “first diluent”, “ second diluent”, “third diluent” and “fourth diluent”, “first binder” and “ second binder”, “first di sinte grant” , “ second disintegrant” and “third disintegrant”; “first wetting agent “ and “ second wetting agent” .
  • the first disintegrant and the third disintegrant according to the invention by both be sodium croscarmellose, the first disintegrant being contained in the Ezetimibe layer and the third disintegrant being contained in the Atorvastatin layer.
  • the second diluent and the fourth diluent according to the invention by both be microcrystalline cellulose optionally being silicified, the second diluent being contained in the Ezetimibe layer and the fourth diluent being contained in the Atorvastatin layer.
  • Ezetimibe designates Ezetimibe in its any known form or any poly morph form known from the state of the art.
  • Ezetimibe used in the solid dosage form according to the invention may be prepared according to any manufacturing process known from the state of the art.
  • the Ezetimibe, pharmaceutically acceptable salt and/or solvate thereof is present in the non-salt non-solvate form of Ezetimibe.
  • the weight content of the Ezetimibe, pharmaceuti cally acceptable salt and/or solvate thereof is
  • essentially the total amount of the Ezetimibe, phar maceutically acceptable salt and/or solvate thereof comprised in the dosage form is present in the Ezetimibe layer.
  • essentially the total amount of the Ezetimibe, phar maceutically acceptable salt and/or solvate thereof comprised in the Ezetimibe layer is present in the intragranular phase of the Ezetimibe layer.
  • Ezetimibe in accordance with the invention is characterized by particle size distribution (PSD) as determined by the laser diffraction method such as Malvern Master Sizer, preferably in accordance with USP ⁇ 429> " Laser Diffraction Measurement of Particle Size” .
  • PSD particle size distribution
  • Ezetimibe particles in the solid dosage form comprising at least two layers of the invention have a d(0.9) value of less than 50 pm, preferably less than 30 pm and more preferably less than 15 pm. In preferred embodiments, Ezetimibe particles in the solid dosage form comprising at least two layers of the invention have a d(0.5) value of less than 20 pm, preferably less than 15 pm and more preferably less than 10 pm. In preferred embodiments, Ezetimibe particles in the solid dosage form comprising at least two layers of the invention have a d(0.1) value of less than 15 pm, preferably less than 10 pm and more preferably less than 5 pm.
  • Ezetimibe is present in the solid dosage form comprising at least two layers in the amount from 0.1 to 12 wt.-%, preferably in the amount of 0.5 to 8 wt.-% and more prefer ably in the amount of 1 to 4 wt.-% of the final composition (i.e. solid dosage form).
  • Atorvastatin designates Atorvastatin in any of its pharmaceutically acceptable salts, solvates, hydrates, enantiomers and any mixture thereof in any pharmaceutically ac ceptable polymorphic form.
  • Atorvastatin is present in the form of Atorvastatin calcium (2: 1) trihydrate.
  • Atorvastatin used in the solid dosage form according to the invention may be prepared ac cording to any manufacturing process known from the state of the art.
  • the Atorvastatin, pharmaceutically acceptable salt and/or solvate thereof is present in the form of Atorvastatin calcium (2: 1); preferably Atorvastatin cal cium (2: 1) trihydrate.
  • the weight content of the Atorvastatin, pharmaceu tically acceptable salt and/or solvate thereof is
  • Atorvastatin within the range of 10 ⁇ 1.0 wt.-%, 11 ⁇ 2.0 wt.-%, 11 ⁇ 1.0 wt.-%, 12 ⁇ 2.0 wt.-%, 12 ⁇ 1.0 wt.-%, or 13 ⁇ 1.0 wt.-%; in each case expressed as the actual weight of the Atorvastatin, pharmaceutically acceptable salt and/or solvate thereof and relative to the total weight of the Atorvastatin layer.
  • Atorvastatin essentially the total amount of the Atorvastatin, pharmaceutically acceptable salt and/or solvate thereof comprised in the dosage form is present in the Atorvastatin layer.
  • Atorvastatin essentially the total amount of the Atorvastatin, pharmaceutically acceptable salt and/or solvate thereof comprised in the Atorvastatin layer is present in the intragranular phase of the Atorvastatin layer.
  • Atorvastatin in accordance with the invention is characterized by particle size distribution (PSD) as determined by the laser diffraction method such as Malvern Master Sizer, preferably in accordance with USP ⁇ 429> " Laser Diffraction Measurement of Particle Size” .
  • PSD particle size distribution
  • Atorvastatin particles in the solid dosage form comprising at least two layers of the invention have a d(0.9) value of less than 70 pm, preferably less than 50 pm and more preferably less than 30 pm. In preferred embodiments, Atorvastatin particles in the solid dosage form comprising at least two layers of the invention have a d(0.5) value of less than 40 pm, preferably less than 25 pm and more preferably less than 15 pm. In preferred embodiments, Atorvastatin particles in the solid dosage form comprising at least two layers of the invention have a d(0.1) value of less than 15 pm, preferably less than 10 pm and more preferably less than 5 pm.
  • Atorvastatin is present in the solid dosage form comprising at least two layers in the amount from 1 to 20 wt.-%, preferably in the amount of 2 to 15 wt.-% and more preferably in the amount of 3 to 12 wt.-% of the final composition (i.e. solid dosage form).
  • the Ezetimibe layer comprises a first diluent, optionally, a second diluent and optionally, a first binder.
  • the Ezetimibe layer may further comprise one or more pharmaceutically acceptable excipients that may be for example selected from diluents, lubricants, glidants, disintegrants, binders, wetting agents, colorants, and the like.
  • the pharmaceutically acceptable excipients of the solid dosage form according to the invention present in the Ezetimibe layer may be present in relative amounts as shown in the following table 1. Amount indications in the following tables may be understood as indications in parts by weight of the Ezetimibe layer.
  • Table 1 List of pharmaceutically acceptable ingredients present in Ezetimibe layer
  • the Atorvastatin layer may further comprise one or more pharmaceutically acceptable excipi ents that may be for example selected from diluents, lubricants, glidants, disintegrants, binders, basic alkaline or alkaline earth metal salts (stabilizing agents), wetting agents, colorants and the like.
  • pharmaceutically acceptable excipi ents may be for example selected from diluents, lubricants, glidants, disintegrants, binders, basic alkaline or alkaline earth metal salts (stabilizing agents), wetting agents, colorants and the like.
  • the pharmaceutically acceptable excipients of the solid dosage form according to the invention present in the Atorvastatin layer may be present in relative amounts as shown in the following table 2.
  • Amount indications in the following tables may be understood as indications in parts by weight of the Atorvastatin layer.
  • Table 2 List of preferred pharmaceutically acceptable ingredients present in Atorvastatin layer
  • the thickness of the Ezetimibe layer is between 1.0 to 4.6 mm, pref erably between 1.3 to 4.2 mm and more preferably between 1.6 to 3.8 mm.
  • the thickness of the Ezetimibe layer for Ezetimibe/Atorvastatin 10/10 mg film coated tablets is between 1.5 to 4.5 mm, preferably between 1.7 to 4.1 mm and more preferably between 1.9 to 2.7 mm.
  • the thickness of the Ezetimibe layer for Ezetimibe/Atorvastatin 10/20 mg film coated tablets is between 1.0 to 3.5 mm, preferably between 1.3 to 3.2 mm and more preferably between 1.6 to 2.9 mm.
  • the thickness of the Ezetimibe layer for Ezetimibe/Atorvastatin 10/40 mg film coated tablets is between 1.2 to 3.1 mm, preferably between 1.5 to 2.9 mm and more preferably between 1.8 to 2.6 mm.
  • the thickness of the Ezetimibe layer for Ezetimibe/Atorvastatin 10/80 mg film coated tablets is between 1.2 to 4.6 mm, preferably between 1.6 to 4.2 mm and more preferably between 2.0 to 3.8 mm.
  • the thickness of the layer is determined using any technique known from the state of the art, as for example an optical microscope (e.g. stereomicroscope) or any other similar techniques known in the art.
  • an optical microscope e.g. stereomicroscope
  • the thickness of the Atorvastatin layer is between 0.6 to 5.4 mm, preferably between 0.9 to 5.0 mm and more preferably between 1.2 to 4.6 mm.
  • the thickness of the Atorvastatin layer for Ezetimibe/Atorvastatin 10/10 mg film coated tablets is between 0.6 to 2.7 mm, preferably between 0.9 to 2.4 mm and more preferably between 1.2 to 2.1 mm.
  • the thickness of the Atorvastatin layer for Ezetimibe/Atorvastatin 10/20 mg film coated tablets is between 1.0 to 3.5 mm, preferably between 1.3 to 3.2 mm and more preferably between 1.6 to 2,9 mm.
  • the thickness of the Atorvastatin layer for Ezetimibe/Atorvastatin 10/40 mg film coated tablets is between 1.8 to 4.0 mm, preferably between 2.1 to 3.9 mm and more preferably between 2.4 to 3.4 mm.
  • the thickness of the Atorvastatin layer for Ezetimibe/Atorvastatin 10/80 mg film coated tablets is between 2.9 to 5.4 mm, preferably between 3.3 to 5.0 mm and more preferably between 3.7 to 4.6 mm.
  • the thickness of the layer is determined using any technique known from the state of the art, as for example an optical microscope (e.g. stereomicroscope) or any other similar techniques known in the art.
  • an optical microscope e.g. stereomicroscope
  • the weight ratio of the Ezetimibe layer and of the Atorvastatin layer is between 0.1 to 6, preferably between 0.15 to 4 and more preferably between 0.2 to 2.
  • the solid dosage form according to the invention may in addition to Ezetimibe and Atorvastatin further comprise one or more any other active substances suitable for the treatment of abnormal lipid levels and/or any other one or more active substances that show beneficial effect on said patient.
  • the solid dosage form according to the invention may in addition to Ezetimibe and Atorvastatin further comprise one or more any other active substances suitable for the treatment of abnormal lipid levels and/or any other one or more active substances that show beneficial effect on said patient, such as for example bempedoic acid, fibrates (e.g. Fenofibrate, Pemafibrate), bile acid sequestrants (e.g. Colestyramine, Colestipol, Colesevelam), nicotinic acid and its derivatives, omega-3 -triglycerides incl. other esters and acids (e.g.
  • eicosapentaenoic acid docosahexaenoic acid
  • acetylsalicylic acid antihypertensive agents (e.g. Perindopril, Enalapril, Ramipril, Lisinopril, Valsartan, Losartan, Telmisartan, Candesartan, Olmesartan, Amlodipine, Lercanidipine, Lacidipine, Hydrochloro thiazide, Indapamide, Chlortalidone, Spironolactone, Metoprolol, Bisoprolol, Nebivolol, Atenolol) or antidiabetic agents (e.g.
  • the solid dosage form according to the invention may in addition to Ezetimibe and Atorvastatin further comprise any one or more other active substances suitable to be incorporated into the same composition such as for example bempedoic acid, fibrates (e.g. Fenofibrate, Pemafibrate) bile acid sequestrants (e.g. Colestyramine, Colestipol, Colesevelam), nicotinic acid and its derivatives, omega-3 -triglycerides incl. other esters and acids (e.g.
  • eicosapentaenoic acid docosahex aenoic acid
  • acetylsalicylic acid antihypertensive agents
  • antihypertensive agents e.g. Perindopril, Enalapril, Ramipril, Lis inopril, Valsartan, Losartan, Telmisartan, Candesartan, Olmesartan, Amlodipine, Lercanidipine, Laci dipine, Hydrochlorothiazide, Indapamide, Chlortalidone, Spironolactone, Metoprolol, Bisoprolol, Nebivolol, Atenolol) or antidiabetic agents (e.g.
  • the solid dosage form according to the invention is used in for treat ment of hypercholesterolaemia (primary hypercholesterolaemia [heterozygous familial and non-famil- ial], mixed hyperlipidaemia or homozygous familial hypercholesterolaemia) or for reduction of cardio vascular event risk.
  • hypercholesterolaemia primary hypercholesterolaemia [heterozygous familial and non-famil- ial], mixed hyperlipidaemia or homozygous familial hypercholesterolaemia
  • the solid dosage form according to the invention does not con tain any other pharmaceutically active ingredients besides the Ezetimibe, pharmaceutically acceptable salt and/or solvate thereof and the Atorvastatin, pharmaceutically acceptable salt and/or solvate thereof.
  • the solid dosage form according to the invention is a solid dosage form comprising at least two layers.
  • Preferred solid dosage form is a tablet, coated or uncoated.
  • the solid dosage form according to the invention is a bilayer tablet, preferably a coated bilayer tablet.
  • the tablet is a coated tablet.
  • the coating is applied onto the solid pharmaceutical formulation, it is preferably composed of at least one film forming polymer for coating and at least one further pharmaceutically acceptable excipient, which can be selected from, but is not limited to, plasticizers, anti-tacking agents, pigments and coloring agents, pore formers and any mixture thereof.
  • Film forming polymers for coating are preferably selected from, but are not limited to, cellulose ethers such as low molecular weight hydroxypropylmethylcellulose and low molecular weight hydroxypropyl cellulose, polyvinyl alcohol, copolymers of vinyl alcohol and ethylene glycol such as Kollicoat ® IR and/or Kollicoat ® Protect manufactured by BASF.
  • ready to use products for fdm coating such as Opadry ® can be used.
  • the thickness of the coating can be in the range e.g. from 5 to 100 pm, preferably from 10 to 80 pm. and most preferably from 20 to 50 pm.
  • the solid dosage form according to the invention under in vitro con ditions in accordance with USP paddle method, optionally equipped with 7-coil helical sinker, at 75 rpm and 37 ⁇ 0.5°C in in 900 mL of phosphate buffer at pH 6.8 with 0.2% w/v Tween 80 has released after 5 minutes at least 50% of the content of Ezetimibe that was originally contained in the dosage form, pref erably at least 55%, more preferably at least 60%, still more preferably at least 65%, most preferably at least 70%, and in particular at least 75%.
  • the solid dosage form according to the invention under in vitro con ditions in accordance with USP paddle method, optionally equipped with 7-coil helical sinker, at 75 rpm and 37 ⁇ 0.5°C in in 900 mL of 0.005 M HC1 has released after 5 minutes at least 10% of the content of Atorvastatin that was originally contained in the dosage form, preferably at least 15%, more preferably at least 20%, still more preferably at least 25%, most preferably at least 30%.
  • the Ezetimibe layer is prepared by wet granulation; preferably aque ous wet granulation.
  • the Atorvastatin layer is prepared by wet granulation; preferably aqueous wet granulation.
  • the solid dosage form according to the invention may comprise one or more diluents (fillers).
  • Diluents are selected from, but not limited to, lactose (e.g. anhydrous or hydrate or amorphous (partially or completely)), polysaccharides (e.g. starches or celluloses), monosaccharides, disaccharides, oligosac charides, sugar alcohols, inorganic salts of phosphoric acid, inorganic salts and any mixture thereof.
  • Starch may be selected from partially or wholly pregelatinized starch, com starch, wheat starch, rice starch, tapioca starch, potato starch and any mixture thereof.
  • Cellulose may be selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, co-processed microcrystalline cellulose with other excipients such as lactose, starch, silicon dioxide, mannitol, etc. and any mixture thereof.
  • Monosaccharides, disaccharides, oligosaccharides and sugar alcohols may be selected from glu cose, fructose, sucrose, lactose monohydrate, anhydrous lactose, a-lactose, b-lactose, raffmose, isomalt ose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol, compressible sugars, and mixtures thereof.
  • Mannitol, microcrystalline cellulose that may optionally be silicified, and lactose are preferred diluents.
  • the Ezetimibe layer of the solid pharmaceutical dosage form according to the invention com prises a first diluent.
  • the first diluent is a sugar alcohol; preferably selected from the group consisting of mannitol, sorbitol, maltitol, xylitol, lactitol, and erythritol, and mixtures thereof; more preferably mannitol.
  • essentially the total amount of the first diluent is comprised in the intragranular phase of the Ezetimibe layer.
  • the weight content of the first diluent is - at least 7.5 wt.-%, preferably at least 10 wt.-%, more preferably at least 12.5 wt.-%, still more pref erably at least 15 wt.-%, yet more preferably at least 17.5 wt.-%, even more preferably at least 20 wt.-%, most preferably at least 22.5 wt.-%, and in particular at least 25 wt.-%;
  • the Ezetimibe layer of the solid pharmaceutical dosage form according to the invention option ally comprises a second diluent, wherein the second diluent differs from the first diluent.
  • the Ezetimibe layer of the solid pharmaceutical dosage form according to the invention comprises a second diluent that differs from the first diluent.
  • At least a fraction or essentially the total amount of the second diluent is comprised in the intragranular phase of the Ezetimibe layer.
  • essentially the total amount of the second diluent is com prised in the extragranular phase of the Ezetimibe layer.
  • the second diluent is selected from the group consisting of
  • lactose preferably anhydrous lactose, lactose hydrate, partially amorphous lactose, completely amor phous lactose;
  • starch or starch derivatives preferably partially or wholly pregelatinized starch, com starch, wheat starch, rice starch, tapioca starch, potato starch;
  • cellulose or cellulose derivatives preferably powdered cellulose, microcrystalline cellulose, silici- fied microcrystalline cellulose, co-processed microcrystalline cellulose with other excipients such as lactose, starch, silicon dioxide, and mannitol;
  • - monosaccharides, disaccharides, oligosaccharides and sugar alcohols preferably glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, a-lactose, b-lactose, raffmose, isomaltose, treha lose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol, or compressible sugars; and mixture thereof; preferably microcrystalline cellulose which may optionally be silicified, lactose monohydrate, and mix tures thereof; more preferably microcrystalline cellulose which may optionally be silicified.
  • the weight content of the second diluent is
  • the Ezetimibe layer comprises no lactose, i.e. neither lactose mono hydrate, nor lactose dihydrate, nor anhydrous lactose, nor spray-dried lactose, nor crystalline lactose, nor partially amorphous lactose, nor completely amorphous lactose.
  • the Atorvastatin layer comprises a third diluent; preferably lactose; more preferably lactose monohydrate.
  • Atorvastatin layer At least a fraction or essentially the total amount of the third diluent is comprised in the intragranular phase of the Atorvastatin layer.
  • the weight content of the third diluent is
  • the Atorvastatin layer comprises a fourth diluent; preferably micro crystalline cellulose which may optionally be silicified.
  • Atorvastatin layer At least a fraction or essentially the total amount of the fourth diluent is comprised in the intragranular phase of the Atorvastatin layer.
  • the weight content of the fourth diluent is
  • Atorvastatin layer within the range of 20.5 ⁇ 1.0 wt.-%, 21 ⁇ 2.0 wt.-%, 21 ⁇ 1.0 wt.-%, or 21.5 ⁇ 1.0 wt.-%; in each case relative to the total weight of the Atorvastatin layer.
  • the solid dosage form according to the invention may comprise one or more disintegrants.
  • Dis- integrants are selected from, but not limited to, crospovidone, starch, maize starch, pregelatinized starch, sodium starch gly collate, modified starch, hydroxypropyl starch, carboxymethyl starch, sodium and/or calcium salts of carboxymethyl cellulose, cross-linked carboxymethylcellulose (e.g.
  • croscarmellose so dium and/or croscarmellose calcium polacrilin potassium, alginic acid or alginates, sodium and/or cal cium alginate, polyacrylates, docusate sodium, methylcellulose, agar, guar gum, chitosan, gums and mixtures thereof.
  • Preferred disintegrants are croscarmellose sodium, crospovidone and mixtures thereof.
  • the Ezetimibe layer comprises a first disintegrant, preferably sodium croscarmellose; and optionally a second disintegrant; preferably crospovidone.
  • At least a fraction of the first disintegrant is comprised in the intra granular phase of the Ezetimibe layer.
  • the relative weight ratio of the fraction of the first disintegrant com prised in the intragranular phase of the Ezetimibe layer and of the fraction of the first disintegrant com prised in the extragranular phase of the Ezetimibe layer is within the range of from 0.1 to 0.9, preferably from 0.2 to 0.8, and more preferably from 0.3 to 0.7.
  • At least a fraction or essentially the total amount of the optionally present second disintegrant is comprised in the intragranular phase of the Ezetimibe layer.
  • the first disintegrant and the optionally second disintegrant are inde pendently of another selected from the group consisting of
  • - cellulose or cellulose derivatives preferably microcrystalline cellulose, methylcellulose, sodium salts of carboxymethyl cellulose, calcium salts of carboxymethyl cellulose, or cross-linked carbox- ymethylcellulose, e.g. croscarmellose sodium and/or croscarmellose calcium; preferably croscarmel- lose sodium;
  • starch or starch derivatives preferably starch, maize starch, pregelatinized starch, sodium starch gly- collate, modified starch, hydroxypropyl starch, or carboxymethyl starch;
  • cellulose ethers preferably low substituted hydroxypropylcellulose (L-HPC);
  • alginic acid or alginates e.g. sodium alginate or calcium alginate
  • agar, guar gum, or gums e.g., agar, guar gum, or gums
  • croscarmellose sodium crospovidone and mixtures thereof; more preferably croscarmellose sodium.
  • the total weight content of the first disintegrant and the optionally present second disintegrant is
  • the Atorvastatin layer comprises a third disintegrant, preferably so dium croscarmellose.
  • Atorvastatin layer At least a fraction or essentially the total amount of the third disinte grant is comprised in the intragranular phase of the Atorvastatin layer.
  • the weight content of the third disintegrant is
  • Atorvastatin layer within the range of 6.0 ⁇ 1.0 wt.-%, 7.0 ⁇ 2.0 wt.-%, 7.0 ⁇ 1.0 wt.-%, or 8.0 ⁇ 1.0 wt.-%; in each case relative to the total weight of the Atorvastatin layer.
  • the solid dosage form according to the invention may comprise one or more binders.
  • Binders are selected from, but not limited to, povidone (polyvinylpyrrolidone), copovidone (vinylpyrrolidone- vinyl acetate copolymer), powdered cellulose, crystalline cellulose, cellulose derivatives such as cellu lose esters or cellulose ethers (e.g. hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellu- lose, low substituted hydroxypropylcellulose and hydroxypropylmethylcellulose), polyvinyl alcohol, starch (e.g.
  • binders are polyvinylpyrrolidone and hydroxypropylcellulose .
  • the Ezetimibe layer of the solid pharmaceutical dosage form according to the invention option ally comprises a first binder.
  • the Ezetimibe layer of the solid pharmaceutical dosage form according to the invention comprises a first binder.
  • essentially the total amount of the first binder is comprised in the intragranular phase of the Ezetimibe layer.
  • the first binder is selected from the group consisting of
  • - cellulose preferably powdered cellulose, crystalline cellulose, microcrystalline cellulose, silicified microcrystalline cellulose;
  • cellulose derivatives cellulose esters or cellulose ethers; preferably hydroxymethylcellulose, hy- droxyethylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose or hydroxy- propylmethylcellulose;
  • starch or starch derivatives preferably com starch, potato starch, rice starch, a-starch, or pregelati nized starch;
  • povidone polyvinylpyrrolidone
  • copovidone vinylpyrrolidone-vinyl acetate copolymer
  • povidone polyvinylpyrrolidone
  • the weight content of the first binder is
  • the Atorvastatin layer comprises a second binder; preferably a cellu lose ether; more preferably hydroxypropylcellulose.
  • essentially the total amount of the second binder is comprised in the intragranular phase of the Atorvastatin layer.
  • the weight content of the second binder is
  • At least 0.8 wt.-% preferably at least 1.1 wt.-%, more preferably at least 1.4 wt.-%, still more pref erably at least 1.7 wt.-%, yet more preferably at least 2.0 wt.-%, even more preferably at least 2.3 wt.-%, most preferably at least 2.6 wt.-%, and in particular at least 2.9 wt.-%;
  • Atorvastatin layer within the range of 3.0 ⁇ 0.5 wt.-% or 3.5 ⁇ 0.5 wt.-%; in each case relative to the total weight of the Atorvastatin layer.
  • the solid dosage form according to the invention may comprise one or more wetting agents.
  • Wetting agents can be selected but are not limited to cationic, anionic, zwitterionic and non-ionic, pref erably anionic, such as carboxylates: alkyl carboxylates-fatty acid salts; carboxylate fluoro surfactants, sulfates: alkyl sulfates (e.g., sodium lauryl sulfate); alkyl ether sulfates (e.g., sodium laureth sulfate), sulfonates: docusates (e.g., dioctyl sodium sulfosuccinate); alkyl benzene sulfonates, phosphate esters: alkyl aryl ether phosphates; alkyl ether phosphates.
  • wetting agents are non ionic wetting agents, such as polyol esters, polyoxyethylene esters, poloxamers.
  • polyol esters includes glycol and glycerol esters and sorbitan derivatives (such as fatty acid esters of sorbitan (generally re ferred to as Spans) and their ethoxylated derivatives (generally referred to as Tweens).
  • Preferred wetting agents are polysorbate 80 and sodium lauryl sulfate.
  • the Ezetimibe layer comprises a first wetting agent.
  • essentially the total amount of the first wetting agent is comprised in the intragranular phase of the Ezetimibe layer.
  • the first wetting agent is selected from the group consisting of cationic surfactants, anionic surfactants, zwitterionic surfactants and non-ionic surfactants; preferably an anionic surfactant; more preferably sodium lauryl sulfate.
  • the weight content of the first wetting agent is
  • the Atorvastatin layer comprises a second wetting agent; preferably polysorbate (ethoxylated sorbitan fatty acid esters); more preferably polysorbate 80 (polyoxyeth- ylene(20)-sorbitan-monooleate).
  • a second wetting agent preferably polysorbate (ethoxylated sorbitan fatty acid esters); more preferably polysorbate 80 (polyoxyeth- ylene(20)-sorbitan-monooleate).
  • essentially the total amount of the second wetting agent is comprised in the intragranular phase of the Atorvastatin layer.
  • the weight content of the second wetting agent is
  • Atorvastatin layer within the range of 0.6 ⁇ 0.1 wt.-%; in each case relative to the total weight of the Atorvastatin layer.
  • the solid dosage form according to the invention may comprise one or more basic alkaline or alkaline earth metal salts (stabilizing agents), preferably selected from, but not limited to, alkaline com pounds, such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potas sium carbonate, magnesium carbonate and calcium carbonate; particularly preferably calcium car bonate.
  • stabilizing agents such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potas sium carbonate, magnesium carbonate and calcium carbonate; particularly preferably calcium car bonate.
  • the Atorvastatin layer comprises a basic alkaline or alkaline earth metal salt.
  • the basic alkaline or alkaline earth metal salt is selected from the group consisting of calcium carbonate, calcium hydroxide, sodium hydrogen carbonate, potassium hy drogen carbonate, sodium carbonate, potassium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, calcium acetate, calcium gluconate, calcium glycerol phosphate, magnesium carbonate, magnesium hydroxide, magnesium sulfate, magnesium acetate, magnesium silicate, magne sium aluminate or mixtures thereof; preferably calcium carbonate.
  • essentially the total amount of the basic alkaline or alkaline earth metal salt is comprised in the intragranular phase of the Atorvastatin layer.
  • the weight content of the basic alkaline or alkaline earth metal salt is
  • the solid dosage form according to the invention may comprise one or more lubricants.
  • Lubri cants are selected from, but not limited to, Lubricants are selected from, but not limited to, fatty acids (i.e. carboxylic acids with 12 to 20 carbon atoms); fatty acid esters including glyceride esters such as glyceryl monostearate, glyceryl tribehenate, or glyceryl dibehenate (e.g. Compritol® 888); metal salts of fatty acids, including magnesium, calcium, aluminum or zinc salts of fatty acids (e.g.
  • magnesium, calcium, aluminum or zinc stearate, magnesium palmitate, or magnesium oleate hydrogenated vegeta ble oil, hydrogenated castor oil; waxes (e.g. Sterotex® NL, Lubriwax® [hydrogenated vegetable oil type], meads wax or spermaceti); boric acid; sodium stearyl fumarate; polymers (e.g., PEG, macrogols); sugar esters such as sorbitan monostearate and sucrose monopalmitate and any mixtures thereof.
  • Pre ferred lubricants are magnesium stearate and sodium stearyl fumarate.
  • the Ezetimibe layer of the solid pharmaceutical dosage form accord ing to the invention comprises sodium stearyl fumarate, magnesium stearate, or mixtures thereof, pref erably sodium stearyl fumarate.
  • the weight content of lubricant in the Ezetimibe layer is within the range of 0.5 to 3.5 wt.-%, relative to the total weight of the Ezetimibe layer.
  • the Atorvastatin layer of the solid pharmaceutical dosage form ac cording to the invention comprises magnesium stearate.
  • the weight content of lubricant in the Atorvastatin layer is within the range of 0.3 to 1.5 wt.-%, relative to the total weight of the Atorvas tatin layer.
  • the solid dosage form according to the invention may comprise one or more glidants.
  • Glidants are selected from, but not limited to, colloidal silicon dioxide (colloidal silica), talc, magnesium trisili- cate, and mixtures thereof.
  • Preferred glidants are colloidal silica, talc and any mixtures thereof.
  • a pre ferred glidant is hydrophobic colloidal silica.
  • the Atorvastatin layer of the solid pharmaceutical dosage form ac cording to the invention comprises hydrophobic colloidal silica.
  • the weight content of glidant in the Atorvastatin layer is within the range of 0.3 to 1.0 wt.-%, relative to the total weight of the Atorvastatin layer.
  • the solid dosage form according to the invention may comprise one or more colorants.
  • Color ants can be selected but are not limited to iron oxides and/or titanium dioxide, e.g. ferric oxide yellow (E 172).
  • the Ezetimibe layer of the solid pharmaceutical dosage form accord ing to the invention comprises ferric oxide, preferably ferric oxide yellow.
  • the weight content of colorant in the Ezetimibe layer is within the range of 0.05 to 0.2 wt.-%, relative to the total weight of the Ezetimibe layer.
  • the Ezetimibe layer comprises
  • lubricant preferably sodium stearyl fumarate; preferably in the extragranular phase of the Ezetimibe layer; and/or
  • the Ezetimibe layer comprises
  • first disintegrant preferably sodium croscarmellose; preferably a fraction in the intragranular phase of the Ezetimibe layer and a fraction in the extragranular phase of the Ezetimibe layer; preferably wherein the relative weight ratio of the fraction comprised in the intragranular phase of the Ezetimibe layer and of the fraction comprised in the extragranular phase of the Ezetimibe layer is within the range of from 0.3 to 0.7; and/or
  • the Atorvastatin layer comprises at least 12 wt.-%, preferably at least 15 wt.-%, more preferably at least 18 wt.-%, still more preferably at least 21 wt.-%, yet more preferably at least 24 wt.-%, even more preferably at least 27 wt.-%, most preferably more than 30 wt.-%, and in particular at least 31 wt.-% of basic alkaline or alkaline earth metal salt; preferably calcium carbonate; preferably in the intragranular phase of the Atorvastatin layer; in each case relative to the total weight of the Atorvastatin layer.
  • the Atorvastatin layer comprises - 27 ⁇ 20 wt.-%, preferably 27 ⁇ 18 wt.-%, more preferably 27 ⁇ 16 wt.-%, still more preferably 27 ⁇ 14 wt.-%, yet more preferably 27 ⁇ 12 wt.-%, even more preferably 27 ⁇ 10 wt.-%, most preferably 27 ⁇ 8 wt.-%, and in particular 27 ⁇ 6 wt.-% of third diluent; preferably lactose; more preferably lactose monohydrate; preferably in the intragranular phase of the Atorvastatin layer; and/or
  • 6.0 ⁇ 5.5 wt.-% preferably 6.0 ⁇ 5.0 wt.-%, more preferably 6.0 ⁇ 4.5 wt.-%, still more preferably 6.0 ⁇ 4.0 wt.-%, yet more preferably 6.0 ⁇ 3.5 wt.-%, even more preferably 6.0 ⁇ 3.0 wt.-%, most pref erably 6.0 ⁇ 2.5 wt.-%, and in particular 6.0 ⁇ 2.0 wt.-% of third disintegrant; preferably sodium croscarmellose; preferably in the intragranular phase of the Atorvastatin layer; and/or
  • Another aspect of the invention relates to a process for the preparation of a solid dosage form according to the invention described above.
  • the process for the preparation of the solid dosage form according to the invention comprises the steps of
  • A) preparing an Ezetimibe compression blend comprising the sub-steps: a) dispersing a first binder in a suitable liquid thereby obtaining a dispersion; b) homogenizing Ezetimibe, a pharmaceutically acceptable salt and/or solvate thereof in the dis persion obtained in sub-step a) thereby obtaining a suspension; c) dispersing a first wetting agent in a suitable liquid thereby obtaining a dispersion; d) mixing the suspension obtained in sub-step b) and the dispersion obtained in sub-step c) thereby obtaining a granulation liquid; e) spraying the granulation liquid onto a mixture comprising a first diluent, at least a fraction of a first disintegrant and optionally, a second disintegrant thereby obtaining granules; f) drying and sieving the granules obtained in sub-step e) thereby obtaining a granulate; g) blending the granulate
  • Atorvastatin compression blend comprising the sub-steps: i) dispersing a second wetting agent and/or a second binder in a suitable liquid thereby obtaining a dispersion; j) homogenizing Atorvastatin, a pharmaceutically acceptable salt and/or solvate thereof with at least one pharmaceutically acceptable excipient, preferably by means of a homogenizer, thereby obtaining a homogenous mixture; k) spraying the dispersion obtained in sub-step step i) onto the homogenous mixture obtained in sub-step j) thereby obtaining granules; l) kneading the granules obtained in sub-step k) thereby obtaining densified agglomerated parti cles; m) drying the densified agglomerated particles obtained in sub-step 1) thereby obtaining dried densified agglomerated particles; n) sieving the dried densified agglomerated particles obtained in sub-step m)
  • sub-step a) involves dissolving the first binder in an organic solvent or in water.
  • sub-step c) involves dissolving the first wetting agent in an organic solvent or in water.
  • the at least one pharmaceutical excipient comprises a second diluent and at least a fraction of the first disintegrant.
  • sub-step i) involves dispersing the second wetting agent and/or the second binder in an organic liquid or water.
  • step C) involves the sub-steps of q) filling a tablet press with a predetermined amount of the Ezetimibe compression blend prepared in step A) or of the Atorvastatin compression blend prepared in step B); r) compressing the predetermined amount thereby obtaining the first layer of the layered tablet; s) filling the tablet press with a predetermined amount of the other of the two compression blends; t) compressing the first layer simultaneously with the predetermined amount thereby obtaining the layered tablet; and u) removing the layered tablet from the table press.
  • Another aspect of the invention relates to a solid dosage form that is obtainable by the process according to the invention as described above.
  • One embodiment of the invention is a process for the preparation of the solid dosage form com prising at least two layers comprising Ezetimibe and Atorvastatin in the form of its salts, solvates, hy drates, enantiomers and any polymorphs thereof wherein Ezetimibe and Atorvastatin are present in sep arate layers comprising the following steps: 1. Ezetimibe layer: a. dispersing binder to obtain dispersion; b. homogenization of Ezetimibe in the obtained dispersion to obtain suspension; c. dispersing wetting agent to obtain dispersion; d. mixing the suspension from step b and the dispersion from step c to obtain granulation liquid; e.
  • Atorvastatin layer a. dispersing wetting agent and/or binder to obtain dispersion; b. homogenization of Atorvastatin with at least one pharmaceutically acceptable excipient to obtain homogenous mixture; c. spraying the dispersion from step a on the obtained homogenous mixture; d.
  • step c kneading the obtained product from step c to obtain densified agglomerated particles; e. drying the ob tained densified agglomerated particles; f. sieving the dried densified agglomerated particles to obtain sieved agglomerated particles; g. drying the sieved agglomerated particles to obtain dry granulate; h. addition of one or more lubricant to obtain compression blend; 3. tablets compression; 4. optionally film-coating of the tablets.
  • Another embodiment of the invention is a process for the preparation of the solid dosage form comprising at least two layers comprising Ezetimibe and Atorvastatin in the form of its salts, solvates, hydrates, enantiomers and any polymorphs thereof wherein Ezetimibe and Atorvastatin are present in separate layers comprising the following steps: 1. Ezetimibe layer: a. dissolving binder in an organic solvent or in water to obtain solution; b. homogenization of Ezetimibe with homogenizer in the obtained solution to obtain suspension; c. dissolving wetting agent in organic solvent or in water to obtain solu tion; d. mixing the suspension from step b and the solution from step c to obtain granulation liquid; e.
  • Atorvastatin layer a. dissolving wetting agent and/or binder in organic liquid or water to obtain granulation liquid; b. homogenization of Atorvastatin with at least one pharmaceutically ac ceptable excipient to obtain homogenous mixture; c. spraying the granulation liquid from step a on the obtained homogenous mixture; d.
  • step c kneading the obtained product from step c to obtain densified agglom erated particles; e. drying the obtained densified agglomerated particles; f. sieving the dried densified agglomerated particles to obtain sieved densified agglomerated particles; g. drying the sieved densified agglomerated particles to obtain dry granulate; h. sieving the dry granulate; i. addition of one or more lubricant to the obtained granulate to obtain compression blend; 3. tablet compression: a. compression of the compression blend of the first layer selected from Ezetimibe layer and Atorvastatin layer; b.
  • Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein binder of step la is dissolved in an organic solvent such as for ex ample ethanol, isopropanol, acetone and any mixture thereof or in water, preferably in purified water.
  • organic solvent such as for ex ample ethanol, isopropanol, acetone and any mixture thereof or in water, preferably in purified water.
  • Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein homogenization of Ezetimibe in step lb is performed with homoge nizer such as for example high pressure homogenizer or rotor-stator homogenizer.
  • homoge nizer such as for example high pressure homogenizer or rotor-stator homogenizer.
  • Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein wetting agent of step lc is dissolved in an organic solvent such as for example ethanol, isopropanol, acetone and any mixture thereof or in water, preferably in purified water.
  • Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein mixing of diluent and disintegrant of step le is performed in the granulator using fluidized air.
  • Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein spraying of step le is performed with binary nozzle.
  • Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein sieving the granules of step If is performed through sieve with open ings between 0.6 and 1.4 mm, preferably between 0.5 and 1.1 mm, more preferably between 0.6 and 1.0 mm.
  • Ezetimibe granulate in accordance with the invention is characterized by particle size distribu tion (PSD) as determined by the dynamic image analysis such as Camsizer.
  • PSD particle size distribu tion
  • the size of the obtained granulate has value of d(0.5) between 100 and 420 pm, preferably between 150 and 370 pm and more preferably between 190 and 330 pm.
  • Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein the diluent used in lg is different than diluent used in step le and disintegrant used in lg is the same as disintegrant used in step le.
  • Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein Atorvastatin is present in the form of its any pharmaceutically ac ceptable salts, solvates, hydrates, enantiomers and any mixture thereof in any pharmaceutically accepta ble polymorphic form, preferably Atorvastatin is present in the form of Atorvastatin calcium (2: 1) tri hydrate.
  • Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein wetting agent and/or binder of step 2a are dispersed in an organic solvent such as for example ethanol, isopropanol, acetone and any mixture thereof or in water, preferably in purified water.
  • an organic solvent such as for example ethanol, isopropanol, acetone and any mixture thereof or in water, preferably in purified water.
  • purified water used in step 2a is pre-heated water at temperature between 30 and 90°C, preferably between 40 and 80°C and more preferably between 50 and 70°C.
  • Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein the pharmaceutical excipient used in step 2b is at least one disinte- grant and/or at least one basic alkaline or alkaline earth metal salt (stabilizing agent) and/or at least one diluent.
  • the pharmaceutical excipient used in step 2b is at least one disinte- grant and/or at least one basic alkaline or alkaline earth metal salt (stabilizing agent) and/or at least one diluent.
  • Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein homogenization of step 2c is performed in high shear mixer.
  • Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein spraying of step 2d is performed with nozzle.
  • Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein sieving the granules of step 2f is performed through sieve with open ings between 0.4 and 1.2mm, preferably between 0.5 and 1.1 mm, more preferably between 0.6 and 1.0 mm.
  • Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein sieving the granules of step 2h is performed through sieve with openings between 0.4 and 1.2mm, preferably between 0.5 and 1.1 mm, more preferably between 0.6 and 1.0 mm.
  • Atorvastatin granulate in accordance with the invention is characterized by particle size distri bution (PSD) as determined by the dynamic image analysis such as Camsizer.
  • PSD particle size distri bution
  • the size of the obtained granulate has value of d(0.5) between 50 and 320 pm, preferably between 90 and 280 pm and more preferably between 120 and 250 pm.
  • Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein each compression blend can be used for the compression of the first or for the compression of the second layer.
  • Table 3 A Compositions of Ezetimibe layer [mg]
  • Table 3B Compositions of Ezetimibe layer [wt.-%]
  • intragranular disintegrant sodium croscarmellose: Examples la, lb, lc, Id, lg, lh, li; cro- spovidone: Example le
  • two intragranular disintegrants sodium croscarmellose and cro- spovidone: Example If
  • microcrystalline cellulose examples la, lb, lc, If, lg, lh, li; silicified microcrystalline cellulose: Example Id) or two extragranular diluents (microcrystalline cellulose and silicified microcrystalline cellulose: Example le), and
  • Example 2 Preparation of Atorvastatin layer [0194]
  • Table 4A Compositions of Atorvastatin layer for Ezetimibe/Atorvastatin 10/80 mg film coated tablets [mg]
  • Table 4B Compositions of Atorvastatin layer for Ezetimibe/Atorvastatin 10/80 mg film coated tablets [wt.-%]
  • Table 5A Compositions of Atorvastatin layer for Ezetimibe/Atorvastatin 10/10 mg, 10/20 mg and 10/40 mg film coated tablets [mg] 1 active substance; 2 wetting agent; 3 binder; 4 diluent; 5 disintegrant; 6 glidant; 7 lubricant; 8 stabilizing agent
  • Table 5B Compositions of Atorvastatin layer for Ezetimibe/Atorvastatin 10/10 mg, 10/20 mg and 10/40 mg film coated tablets [wt.-%]
  • Table 6a Final bilayer solid dosage forms comprising at least two layers for Ezetimibe/Atorvas tatin 10/80 mg film coated tablets
  • Table 6b Final bilayer solid dosage forms comprising at least two layers for Ezetimibe/ Atorvas- tatin 10/80 mg film coated tablets
  • Table 7 Final bilayer solid dosage forms comprising at least two layers for Ezetimibe/ Atorvas tatin 10/10 mg, 10/20 mg, 10/40 mg and 10/80 mg film coated tablets
  • Example 4 Dissolution profile of Ezetimibe/ Atorvastatin film coated tablets
  • the dissolution profile of Ezetimibe released from the bilayer tablet of Example 3g according to the invention satisfies the similarity requirements compared to the dissolution profile of Ezetimibe released from Atozet ® 10/80 mg (B.No: S034177) and from Ezetrol ® 10 mg (B.No: S027811).
  • the bilayer tablet of Example 3g according to the invention even provides faster dissolution within the initial 5 minutes.
  • the bilayer tablets according to the invention provide an improved in vitro dissolution of Ezetimibe compared to reference product Ezetrol ® and reference combination product Atozet ® .
  • the dissolution profile of Atorvastatin released from the bilayer tablet of Example 3g according to the invention satisfies the similarity requirements compared to the dissolution profile of Atorvastatin released from Atozet ® 10/80 mg (B.No: S034177) and from Sortis ® 80 mg (B.No: CK1527).
  • Example 5 Chemical stability of Ezetimibe/ Atorvastatin film coated tablets
  • Table 8 Accelerated stability results of solid dosage forms comprising at least two layers of the inven tion, Atozet ® (10/80 mg (R019711)), Sortis ® (80 mg (W53718)) and Ezetrol ® (10 mg (N034153)): after n.d. n.d. n.d. n.d. 0.13 0.25
  • Ezetrol ® contains no Atorvastatin and Sortis ® ® contains no Ezetimibe.
  • the chemical stability of Ezetimibe and Atorvastatin in the bilayer table of Example 3c according to the invention satisfies the stability requirements.
  • the stability of Ezetimibe in the bilayer table of Example 3c according to the invention is even better than the stability of Ezetimibe in reference product Ezetrol ® (10 mg (N034153)) and reference combination product Atozet ® (10/80 mg (R019711)).
  • the stability of Atorvastatin in the bi layer table of Example 3c according to the invention is even better than the stability of Atorvastatin in reference product Sortis ® (80 mg (W53718)) and reference combination product Atozet ® (10/80 mg (R019711)).

Abstract

The invention relates to solid pharmaceutical dosage forms comprising Ezetimibe and Atorvastatin in separate layers, and to manufacturing methods for making the same. The solid dosage forms are multi- layer tablets, preferably bilayer tablets, suitable for oral administration.

Description

BILAYER TABLET COMPRISING EZETIMIBE AND ATORVASTATIN
[0001] Priority is claimed of Slovenian patent application no. P-202000126 filed on July 27, 2020.
[0002] The invention relates to solid pharmaceutical dosage forms comprising Ezetimibe and Atorvas- tatin in separate layers, and to manufacturing methods for making the same. The solid dosage forms are multilayer tablets, preferably bilayer tablets, suitable for oral administration.
[0003] Dyslipidemia is one of the most important risk factors for cardiovascular disease (Stehbens WE. Coronary heart disease, hypercholesterolemia, and atherosclerosis. II. Misrepresented data. Exp Mol Pathol. 2001;70: 120-139). In patients with high or very high risk of coronary heart disease (CHD) and similar critical conditions, low-density lipoprotein cholesterol (LDL-C) should be reduced by at least 30-50% in order to obtain a clinical benefit (Whayne TF., Jr. Assessment of low-density lipoprotein targets. Angiology. 2013;64:411-416). However, it is difficult to achieve these target levels with the administration of a statin alone (Weng TC, Yang YH, Lin SJ, Tai SH. A systematic review and meta analysis on the therapeutic equivalence of statins. J Clin Pharm Ther. 2010;35: 139-151). Clinical stud ies showed that the combination of statins with a cholesterol absorption inhibitor (Ezetimibe) signifi cantly decreased LDL-C levels in patients with hypercholesterolemia, and resulted in superior lipid- lowering efficacy compared to treatment with a statin alone (Toth PP, Foody JM, Tomassini JE, et al. Therapeutic practice patterns related to statin potency and Ezetimibe/simvastatin combination therapies in lowering LDL-C in patients with high-risk cardiovascular disease. J Clin Lipidol. 2014;8: 107-116 and Foody JM, Toth PP, Tomassini JE, et al. Changes in LDL-C levels and goal attainment associated with addition of ezetimibe to simvastatin, atorvastatin, or rosuvastatin compared with titrating statin monotherapy. Vase Health Risk Manag. 2013;9:719-727).
[0004] Ezetimibe with chemical name l-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypro- pyl]4(S)-(4-hydroxyphenyl)-2-azetidinone is a potent cholesterol absorption inhibitor and is commer cially available in the form of tablet under the tradename Ezetrol®. It is indicated as adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia in whom a statin is considered inappropriate or is not tolerated. Ezetrol® is indicated to reduce the risk of cardiovascular events in patients with coronary heart disease and a history of acute coronary syn drome when added to ongoing statin therapy or initiated concomitantly with a statin. Ezetrol® is also indicated as adjunctive therapy to diet for use in patients with homozygous familial sitosterolaemia. The product contains lOmg Ezetimibe. Ezetimibe was first disclosed in EP0720599. [0005] Atorvastatin with chemical name [R-(R*, R*)]-2-(4-fluorophenyl)-B, d, -dihydroxy-5 -(1-meth- ylethyl)-3 -phenyl-4 [(phenylamino) carbonyl] -lH-pyrrole-l-heptanoic acid is an inhibitor of the enzyme 3 -hydroxy-3 -methyl glutaryl coenzyme A reductase (HMG-CoA reductase) and is commercially avail able formulated as calcium salt trihydrate under the tradename Sortis®. The product contains 10 mg, 20 mg, 40 mg or 80 mg Atorvastatin. It is indicated for an adjunct to diet for reduction of elevated total cholesterol, LDL-cholesterol, apolipoprotein B, and triglycerides in adults, adolescents and children aged 10 years or older with primary hypercholesterolaemia including familial hypercholesterolaemia or combined hyperlipidaemia when response to diet and other nonpharmacological measures is inadequate. Sortis® is indicated to reduce total-C and LDL-C in adults with homozygous familial hypercholesterol aemia as an adjunct to other lipid-lowering treatments or if such treatments are unavailable. Additionally Sortis® is also indicated for prevention of cardiovascular events in adult patients estimated to have a high risk for a first cardiovascular event, as an adjunct to correction of other risk factors. Atorvastatin was first disclosed in EP 0409 281.
[0006] US 2007 0014854 A1 and US 2007 0014864 A1 relate to a pharmaceutical composition in the form of a granulate, wherein the granulates comprises an active pharmaceutical ingredient (API) having a poor water solubility intimately associated with at least one pharmaceutically acceptable sugar, and optionally or preferably at least one pharmaceutically acceptable excipient other than the at least one pharmaceutically acceptable sugar, wherein the active pharmaceutically ingredient has a water solubility less than about 20 mg/ml.
[0007] US 2010 0209495 A1 relates to a granulate for use in a pharmaceutical composition and a phar maceutical composition manufacture using the granulate, where the granule comprises an active phar maceutical ingredient (API) having a poor water solubility (i.e., less than about 1 mg/mU) which is intimately associated with at least one pharmaceutically acceptable hydrophilic polymer.
[0008] Combination compositions comprising a cholesterol absorption inhibitor in combination with a HMG-CoA reductase inhibitor are already known.
[0009] WO 2011 002422 relates to a pharmaceutical composition comprising Ezetimibe and Atorvas tatin or a pharmaceutically acceptable salts thereof wherein both active substances are pre-formulated in a series of manufacturing process steps to increase the solubility of Ezetimibe. Ezetimibe and Atorvas tatin are not separated from one another in separate layers; bilayer tablets are not disclosed. Neither stability data nor dissolution data are provided for the final tablet. A separate granulated composition comprising Ezetimibe (intermediate product) is said to exhibit a dissolution rate greater than 90% in the first 10 minutes. [0010] Combination compositions comprising Ezetimibe and Atorvastatin is separate layers of bilayer tablets are also known.
[0011] A combination composition comprising Ezetimibe and Atorvastatin is commercially available as a fdm coated tablet under the tradename Atozet®. The product contains 10 mg Ezetimibe and 10 mg, 20 mg, 40 mg or 80 mg Atorvastatin calcium salt (2: 1) trihydrate. Atozet® is indicated for the reduction of elevated total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and non-high-density lipoprotein cholesterol, and to increase high-density lipoprotein cholesterol in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia. Ato zet® is also indicated for the reduction of elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments or if such treatments are unavailable.
[0012] WO 2013 166114 discloses a bilayer tablet comprising Ezetimibe and Atorvastatin or a phar maceutically acceptable salts thereof having similar dissolution profile to individual active substances and that is said to be stable regardless of incompatibilities of both active substances. Compared to ref erence product Ezetrol®, however, dissolution according to WO 2013 166114 is delayed. While Ezetrol® releases within 10 minutes 95% of the Ezetimibe that was originally contained in Ezetrol®, the combi nation formulation according to WO 2013 166114 achieves a release of Ezetimibe of only 77% within 10 minutes (WO 2013 166114, Table 3).
[0013] EP 3 360 541 relates to a bilayer tablet comprising Atorvastatin calcium in a first layer and Ezetimibe in a second layer, wherein the weight ratio of the second layer to the first layer is between 0.05 and 8.0 and comprising at least one polymer. Neither stability data nor dissolution data are pro vided.
[0014] WO 2020 139237 relates to a bilayer tablet comprising Atorvastatin calcium in a first layer and Ezetimibe in a second layer, wherein the tablet comprises at least one binder in each layer. Neither stability data nor dissolution data are provided.
[0015] The properties of the known combination products of Ezetimibe and Atorvastatin are not satis factory in every respect. While Atorvastatin has been reported to be more stable in near neutral to alka line pH, such conditions are detrimental to the stability of Ezetimibe. There is a demand for improved oral dosage forms that comprise fixed doses of Ezetimibe and Atorvastatin and that are effective in the treatment of abnormal lipid levels. The dosage forms should combine pharmacologic efficacy with ad equate physical stability as well as chemical stability of both Ezetimibe and Atorvastatin. Further, there is a demand for a reliable and robust method for the manufacture of such dosage forms. [0016] When more than one active substance is formulated in a combination product, it is usually re quired for regulatory reasons, particularly with respect to bioequivalence, that the dissolution profde of each active ingredient within the combination is similar to the dissolution profile of the two reference products that contain only one of the two active ingredients, and also to the dissolution profile of the reference combination product. In the present case, the reference product only containing Ezetimibe is Ezetrol®, the reference product only containing Atorvastatin is Sortis®, and the reference combination product is Atozet®.
[0017] A major challenge in achieving the desired dissolution profile of a new combination product is the large difference in tablet weights between the Ezetimibe reference product (Ezetrol®) and the refer ence combination product (Atozet®). An Ezetrol® tablet containing 10 mg Ezetimibe has a total weight of about 100 mg, whereas an Atozet® tablet additionally containing 10 mg, 20 mg, 40 mg or 80 mg Atorvastatin calcium salt (2: 1) trihydrate has a total weight of about 300 mg, 400 mg, 600 mg and 1000 mg, respectively. The high dose strengths are particularly challenging (i.e. about 100 mg for Ezetrol® vs. about 600 mg and 1000 mg for Atozet®).
[0018] Therefore, it was an object of the invention to provide a solid dosage form comprising a combi nation of Ezetimibe and Atorvastatin that shows at least a similar dissolution profile compared to that of Ezetrol®, Sortis® and Atozet®.
[0019] The significant difference in tablet weights further presents a great challenge with respect to processability in the manufacturing process, especially when each active substance in contained in a separate layer. This represents a challenge particularly in a manufacturing process for bilayer tablets, wherein according to general knowledge it is preferred that the first layer has higher or same weight as the second layer.
[0020] Therefore, it was another object of the invention to provide a solid dosage form comprising a combination of Ezetimibe and Atorvastatin that can be manufactured by conventional manufacturing processes. In particular, it was another object of the invention to provide separate pharmaceutical for mulations each containing one of the two active ingredients that are both interchangeably useful as com pression blends either for first layer or for the second layer of a multilayer tablet, preferably of a bilayer tablet. Further, it was an object of the invention to provide a solid dosage form comprising a combination of Ezetimibe and Atorvastatin that can be provided in different dose strengths (e.g. 10/10 mg, 10/20 mg, 10/40 mg and 10/80 mg) without requiring significant modification of the composition, i.e. of the ex cipients and their individual weight content. The solid dosage form should allow for preparing e.g. a dose strength of 10/10 mg and 10/80 mg from the same compression blend(s) merely by relatively ad justing the amount of the compression blend containing Atorvastatin.
[0021] Ezetimibe is classified in class II of the Biopharmaceutics Classification System (BCS) and dissolved quickly, which means that typically 55% of Ezetimibe are dissolved within 5 minutes, and 90% of Ezetimibe are dissolved within 10 minutes. It is generally known that tablets with higher weight have longer disintegration times and hence slower dissolution profiles at the initial stage of disintegra tion and dissolution.
[0022] Therefore, it was a further object of the invention to provide dosage forms having a compara tively high total weight that provide fast disintegration and quick release of Ezetimibe. In particular, it was a further object of the invention to provide a solid dosage form comprising Ezetimibe and Atorvas tatin and that has a similar, preferably a faster dissolution profile compared to Ezetrol®.
[0023] While it is generally preferred that the weight ratio of the layers in bilayer tablet does not exceed 1 :2, there is a demand for bilayer tablets that tolerate layer weight ratios of from 1 : 1 to 1:4.
[0024] Therefore, it was another object of the invention to provide a solid dosage form comprising at least two layers comprising Ezetimibe and Atorvastatin in separate layers that allows robust manufac turing process with good processibility on laboratory and particularly on industrial scale.
[0025] Therefore, the invention aims at developing and preparing a solid dosage form comprising Ezetimibe and Atorvastatin, preferably in separate layers, that has a similar or even faster dissolution profile compared to Ezetrol®, Sortis® and Atozet® and that successfully overcomes the drawbacks of the prior art.
[0026] One or more of the above objects have been achieved by the subject-matter of the patent claims.
[0027] The invention pertains to a solid dosage form comprising Ezetimibe and Atorvastatin in separate layers, which provides an improved dissolution profile, excellent physical stability, improved chemical stability, good bioavailability and long shelf-life. The solid dosage form according to the invention can be prepared by a robust manufacturing process with good processibility on laboratory and industrial level.
[0028] In accordance with the invention solid dosage forms comprising at least two layers comprising Ezetimibe in a combination with Atorvastatin including its salts, solvates, hydrates, enantiomers and any polymorphs thereof wherein Ezetimibe and Atorvastatin are present in separate layers are provided. [0029] A first aspect of the invention relates to a solid pharmaceutical dosage form comprising
- an Ezetimibe layer comprising (i) Ezetimibe, a pharmaceutically acceptable salt and/or solvate thereof; (ii) a first diluent; (iii) optionally, a second diluent; and (iv) optionally, a first binder; preferably, wherein the Ezetimibe layer comprises an intragranular phase and optionally an extra- granular phase; and
- an Atorvastatin layer comprising Atorvastatin, a pharmaceutically acceptable salt and/or solvate thereof; preferably, wherein the Atorvastatin layer comprises an intragranular phase and optionally an extra- granular phase; wherein
- the first diluent of the Ezetimibe layer is a sugar alcohol; preferably, mannitol; and/or
- the optionally first binder of the Ezetimibe layer is a polyvinylpyrrolidone.
[0030] It has been surprisingly found that the solid dosage forms according to the invention are im proved and are effective in the treatment of abnormal lipid levels. They combine pharmacologic efficacy with adequate physical stability as well as chemical stability of both Ezetimibe and Atorvastatin. Fur ther, they can be prepared by a reliable and robust method of manufacture.
[0031] Further, it has been surprisingly found that the solid dosage forms according to the invention show at least a similar dissolution profile compared to that of reference products Ezetrol®, Sortis® and Atozet®.
[0032] Still further, it has been surprisingly found that the solid dosage forms according to the invention can be manufactured by conventional manufacturing processes. In particular, they can be prepared from separate pharmaceutical formulations (compression blends) each containing one of the two active ingre dients that are both interchangeably useful as compression blends either for first layer or for the second layer of a multilayer tablet, preferably of a bilayer tablet. Further, they can be provided in different dose strengths (e.g. 10/10 mg, 10/20 mg, 10/40 mg and 10/80 mg) without requiring significant modification of the composition, i.e. of the excipients and their individual weight content. The solid dosage form allows for preparing e.g. a dose strength of 10/10 mg and 10/80 mg from the same compression blend(s) merely by relatively adjusting the amount of the compression blend containing Atorvastatin.
[0033] Yet further, it has been surprisingly found that the solid dosage forms according to the invention may have a comparatively high total weight but nonetheless provide fast disintegration and quick release of Ezetimibe. In particular, they have a similar and even faster dissolution profde compared to reference product Ezetrol®.
[0034] Furthermore, it has been surprisingly found that the solid dosage forms according to the inven tion can be prepared by a robust manufacturing process with good processibility on laboratory and par ticularly on industrial scale.
[0035] Figure 1 describes a dissolution profde of Ezetimibe for fdm coated tablet of Example 3g.
[0036] Figure 2 describes a dissolution profde of Atorvastatin for fdm coated tablet of Example 3g.
[0037] In particularly preferred embodiments, the solid pharmaceutical dosage form according to the invention form comprises
- an Ezetimibe layer comprising Ezetimibe, a pharmaceutically acceptable salt and/or solvate thereof and a first diluent; preferably, wherein the Ezetimibe layer comprises an intragranular phase and optionally an extragranular phase; and
- an Atorvastatin layer comprising Atorvastatin, a pharmaceutically acceptable salt and/or solvate thereof; preferably, wherein the Atorvastatin layer comprises an intragranular phase and optionally an extragranular phase. wherein the first diluent of the Ezetimibe layer is a sugar alcohol.
[0038] In other particularly preferred embodiments, the solid pharmaceutical dosage form according to the invention comprises
- an Ezetimibe layer comprising Ezetimibe, a pharmaceutically acceptable salt and/or solvate thereof; a first diluent; optionally, a second diluent; and optionally, a first binder; preferably, wherein the Ezetimibe layer comprises an intragranular phase and optionally an extragranular phase; and
- an Atorvastatin layer comprising Atorvastatin, a pharmaceutically acceptable salt and/or solvate thereof; preferably, wherein the Atorvastatin layer comprises an intragranular phase and optionally an extragranular phase; wherein the optionally first binder of the Ezetimibe layer is polyvinylpyrrolidone.
[0039] In still other particularly preferred embodiments, the solid pharmaceutical dosage form com prises - an Ezetimibe layer comprising Ezetimibe, a pharmaceutically acceptable salt and/or solvate thereof; a first diluent; a second diluent; and a first binder; preferably, wherein the Ezetimibe layer comprises an intragranular phase and optionally an extragranular phase; and
- an Atorvastatin layer comprising Atorvastatin, a pharmaceutically acceptable salt and/or solvate thereof; preferably, wherein the Atorvastatin layer comprises an intragranular phase and optionally an extragranular phase; wherein the first binder of the Ezetimibe layer is polyvinylpyrrolidone.
[0040] The solid dosage form according to the invention comprises at least two active substances, par ticularly cholesterol absorption inhibitor in a combination with one or more HMG-CoA reductase in hibitor wherein the active substances are present in separate layers. More particularly, the solid dosage form according to the invention comprises Ezetimibe in a combination with Atorvastatin including its salts, solvates, hydrates, enantiomers and any polymorphs thereof, wherein Ezetimibe and Atorvastatin are present in separate layers. Preferably, the solid dosage form according to the invention is a bilayer tablet, preferably a film-coated bilayer tablet, that comprises Ezetimibe in a combination with Atorvas tatin including its salts, solvates, hydrates, enantiomers and any polymorphs thereof, wherein Ezetimibe and Atorvastatin are present in separate layers.
[0041] According to the invention and unless specified otherwise, all amount indications are provided on a weight basis or weight/weight basis, as appropriate. If the active pharmaceutical substance is used in the form of a pharmaceutically acceptable salt, the weight of the entire salt is to be considered, in cluding the weight component of the counter ion. If the active pharmaceutical substance is used in the form of a solvate or hydrate, the additional weight associated with solvent or water components in the substance is to be disregarded. That is, a theoretical weight of the anhydrous pure substance (or its pharmaceutically acceptable salt and/or hydrate or solvate, if appropriate) is to be calculated and con sidered in connection with the invention.
[0042] The term " essentially the total amount " means at least 95 wt.-%, preferably at least 98 wt.-%, more preferably at least 99 wt.-%.
[0043] The term "layer" as used herein designates a layer in a multilayer tablet wherein at least two active substances are not in intimate contact and that they are separated from each other (except at the interface of the layers) . The term "layer" refers to a physical part of the solid dosage form comprising at least two layers, wherein the components of one layer are not intimately mixed with the components of another layer of the composition. In particular, the interaction between the components of one layer and the components of another layer is reduced. A multilayer tablet according to the invention has at least 2 layers, for example, a bilayer tablet involves the compression of two formulations comprising an active substance into a single solid oral dosage form, while maintaining physical separation of the for mulations by layering one on top of the other. According to the invention the layer is preferably formed from a compression blend, which consists of at least one active substance and one or more pharmaceu tically acceptable excipients.
[0044] The term "compression blend " as used herein designates the mixture of at least one active sub stance and one or more pharmaceutically acceptable excipients.
[0045] Preferably, the Ezetimibe layer comprises an intragranular phase and optionally an extragranular phase; and/or the Atorvastatin layer comprises an intragranular phase and optionally an extragranular phase. The terms "intragranular phase " and "extragranular phase " are known to the skilled person and are used in the conventional meaning. As the Ezetimibe layer and/or the Atorvastatin layer is preferably prepared from a compression blend that contains a granulate, optionally mixed with one or more excip ients, the granulate and its constituents forms the intragranular phase, whereas the optionally present one or more excipients form the extragranular phase.
[0046] In preferred embodiments, the Ezetimibe layer comprises an intragranular phase and an extra granular phase, whereas the Atorvastatin layer comprises an intragranular phase but not an extragranular phase.
[0047] The solid dosage form according to the invention comprises Ezetimibe and Atorvastatin as the active substances in separate layers and one or more pharmaceutically acceptable excipients such as one or more diluents, one or more lubricants, one or more glidants, one or more disintegrants, one or more binders, and the like. The term "excipient" as used herein refers to any pharmaceutically acceptable substance that has no therapeutic activity as such. Pharmaceutically acceptable excipients may for ex ample be selected from diluents, lubricants, glidants, disintegrants and binders. In preferred embodi ments, the solid dosage form according to the invention may further comprise any other pharmaceuti cally acceptable excipients that can be selected among any known state of the art for solid dosage forms, as described e.g. in Remington: The Science and Practice of Pharmacy, Edited by Loyd V. Allen, Jr, Pharmaceutical Press, 22 Edition, 2012. Individual excipients may have polyfunctional properties in the solid dosage form according to the invention, e.g. may exert both disintegrating and binding properties or both lubricating and gliding properties or my exert filling, binding and disintegrating properties.
[0048] The excipients may be split into fractions, where a first fraction is contained in the Ezetimibe layer and a second fraction is contained in the Atorvastatin layer. For the purpose of the specification, when more than one representative of a particular excipient is contained in the solid pharmaceutical dosage forms, said representatives are preferably numbered such as "first diluent", " second diluent", "third diluent" and "fourth diluent", "first binder" and " second binder", "first di sinte grant" , " second disintegrant" and "third disintegrant"; "first wetting agent " and " second wetting agent" . When these excipients are contained in one and the same layer of the solid dosage form, they differ from one another. However, when these excipients are contained in different layers of the solid dosage form, they may differ from one another or may be the same. For example, the first disintegrant and the third disintegrant according to the invention by both be sodium croscarmellose, the first disintegrant being contained in the Ezetimibe layer and the third disintegrant being contained in the Atorvastatin layer. Likewise, for example, the second diluent and the fourth diluent according to the invention by both be microcrystalline cellulose optionally being silicified, the second diluent being contained in the Ezetimibe layer and the fourth diluent being contained in the Atorvastatin layer.
[0049] Unless expressly stated otherwise, all references to USP, Ph. Eur., ASTM, EN ISO and the like refer to the official version that is valid on July 1, 2021.
[0050] The term "Ezetimibe" as used herein designates Ezetimibe in its any known form or any poly morph form known from the state of the art. Ezetimibe used in the solid dosage form according to the invention may be prepared according to any manufacturing process known from the state of the art.
[0051] In preferred embodiments of the invention, the Ezetimibe, pharmaceutically acceptable salt and/or solvate thereof is present in the non-salt non-solvate form of Ezetimibe.
[0052] In preferred embodiments of the invention, the weight content of the Ezetimibe, pharmaceuti cally acceptable salt and/or solvate thereof is
- at least 1.0 wt.-%, preferably at least 1.5 wt.-%, more preferably at least 2.0 wt.-%, still more pref erably at least 2.5 wt.-%, yet more preferably at least 3.0 wt.-%, even more preferably at least 3.5 wt.-%, most preferably at least 4.0 wt.-%, and in particular at least 4.5 wt.-%;
- at most 9.5 wt.-%, preferably at most 9.0 wt.-%, more preferably at most 8.5 wt.-%, still more pref erably at most 8.0 wt.-%, yet more preferably at most 7.5 wt.-%, even more preferably at most 7.0 wt.-%, most preferably at most 6.5 wt.-%, and in particular at most 6.0 wt.-%; and/or
- within the range of 5.0±0.5 wt.-% or 5.5±0.5 wt.-%; in each case expressed as equivalent weight relative to the non-salt non-solvate form of Ezetimibe and relative to the total weight of the Ezetimibe layer.
[0053] In preferred embodiments of the invention, essentially the total amount of the Ezetimibe, phar maceutically acceptable salt and/or solvate thereof comprised in the dosage form is present in the Ezetimibe layer. [0054] In preferred embodiments of the invention, essentially the total amount of the Ezetimibe, phar maceutically acceptable salt and/or solvate thereof comprised in the Ezetimibe layer is present in the intragranular phase of the Ezetimibe layer.
[0055] Ezetimibe in accordance with the invention is characterized by particle size distribution (PSD) as determined by the laser diffraction method such as Malvern Master Sizer, preferably in accordance with USP <429> " Laser Diffraction Measurement of Particle Size" .
[0056] In preferred embodiments, Ezetimibe particles in the solid dosage form comprising at least two layers of the invention have a d(0.9) value of less than 50 pm, preferably less than 30 pm and more preferably less than 15 pm. In preferred embodiments, Ezetimibe particles in the solid dosage form comprising at least two layers of the invention have a d(0.5) value of less than 20 pm, preferably less than 15 pm and more preferably less than 10 pm. In preferred embodiments, Ezetimibe particles in the solid dosage form comprising at least two layers of the invention have a d(0.1) value of less than 15 pm, preferably less than 10 pm and more preferably less than 5 pm.
[0057] In preferred embodiments, Ezetimibe is present in the solid dosage form comprising at least two layers in the amount from 0.1 to 12 wt.-%, preferably in the amount of 0.5 to 8 wt.-% and more prefer ably in the amount of 1 to 4 wt.-% of the final composition (i.e. solid dosage form).
[0058] The term " Atorvastatin " as used herein designates Atorvastatin in any of its pharmaceutically acceptable salts, solvates, hydrates, enantiomers and any mixture thereof in any pharmaceutically ac ceptable polymorphic form. Preferably, Atorvastatin is present in the form of Atorvastatin calcium (2: 1) trihydrate. Atorvastatin used in the solid dosage form according to the invention may be prepared ac cording to any manufacturing process known from the state of the art.
[0059] In preferred embodiments of the invention, the Atorvastatin, pharmaceutically acceptable salt and/or solvate thereof is present in the form of Atorvastatin calcium (2: 1); preferably Atorvastatin cal cium (2: 1) trihydrate.
[0060] In preferred embodiments of the invention, the weight content of the Atorvastatin, pharmaceu tically acceptable salt and/or solvate thereof is
- at least 6.0 wt.-%, preferably at least 6.5 wt.-%, more preferably at least 7.0 wt.-%, still more pref erably at least 7.5 wt.-%, yet more preferably at least 8.0 wt.-%, even more preferably at least 8.5 wt.-%, most preferably at least 9.0 wt.-%, and in particular at least 9.5 wt.-%; - at most 17 wt.-%, preferably at most 16.5 wt.-%, more preferably at most 16 wt.-%, still more pref erably at most 15.5 wt.-%, yet more preferably at most 15 wt.-%, even more preferably at most 14.5 wt.-%, most preferably at most 14 wt.-%, and in particular at most 13.5 wt.-%; and/or
- within the range of 10±1.0 wt.-%, 11±2.0 wt.-%, 11±1.0 wt.-%, 12±2.0 wt.-%, 12±1.0 wt.-%, or 13±1.0 wt.-%; in each case expressed as the actual weight of the Atorvastatin, pharmaceutically acceptable salt and/or solvate thereof and relative to the total weight of the Atorvastatin layer.
[0061] In preferred embodiments of the invention, essentially the total amount of the Atorvastatin, pharmaceutically acceptable salt and/or solvate thereof comprised in the dosage form is present in the Atorvastatin layer.
[0062] In preferred embodiments of the invention, essentially the total amount of the Atorvastatin, pharmaceutically acceptable salt and/or solvate thereof comprised in the Atorvastatin layer is present in the intragranular phase of the Atorvastatin layer.
[0063] Atorvastatin in accordance with the invention is characterized by particle size distribution (PSD) as determined by the laser diffraction method such as Malvern Master Sizer, preferably in accordance with USP <429> " Laser Diffraction Measurement of Particle Size" .
[0064] In preferred embodiments, Atorvastatin particles in the solid dosage form comprising at least two layers of the invention have a d(0.9) value of less than 70 pm, preferably less than 50 pm and more preferably less than 30 pm. In preferred embodiments, Atorvastatin particles in the solid dosage form comprising at least two layers of the invention have a d(0.5) value of less than 40 pm, preferably less than 25 pm and more preferably less than 15 pm. In preferred embodiments, Atorvastatin particles in the solid dosage form comprising at least two layers of the invention have a d(0.1) value of less than 15 pm, preferably less than 10 pm and more preferably less than 5 pm.
[0065] In preferred embodiments, Atorvastatin is present in the solid dosage form comprising at least two layers in the amount from 1 to 20 wt.-%, preferably in the amount of 2 to 15 wt.-% and more preferably in the amount of 3 to 12 wt.-% of the final composition (i.e. solid dosage form).
[0066] The Ezetimibe layer comprises a first diluent, optionally, a second diluent and optionally, a first binder. The Ezetimibe layer may further comprise one or more pharmaceutically acceptable excipients that may be for example selected from diluents, lubricants, glidants, disintegrants, binders, wetting agents, colorants, and the like. [0067] The pharmaceutically acceptable excipients of the solid dosage form according to the invention present in the Ezetimibe layer may be present in relative amounts as shown in the following table 1. Amount indications in the following tables may be understood as indications in parts by weight of the Ezetimibe layer.
Table 1 : List of pharmaceutically acceptable ingredients present in Ezetimibe layer
[0068] The Atorvastatin layer may further comprise one or more pharmaceutically acceptable excipi ents that may be for example selected from diluents, lubricants, glidants, disintegrants, binders, basic alkaline or alkaline earth metal salts (stabilizing agents), wetting agents, colorants and the like.
[0069] The pharmaceutically acceptable excipients of the solid dosage form according to the invention present in the Atorvastatin layer may be present in relative amounts as shown in the following table 2. Amount indications in the following tables may be understood as indications in parts by weight of the Atorvastatin layer.
Table 2: List of preferred pharmaceutically acceptable ingredients present in Atorvastatin layer
[0070] In preferred embodiments, the thickness of the Ezetimibe layer is between 1.0 to 4.6 mm, pref erably between 1.3 to 4.2 mm and more preferably between 1.6 to 3.8 mm. [0071] In preferred embodiments, the thickness of the Ezetimibe layer for Ezetimibe/Atorvastatin 10/10 mg film coated tablets is between 1.5 to 4.5 mm, preferably between 1.7 to 4.1 mm and more preferably between 1.9 to 2.7 mm.
[0072] In preferred embodiments, the thickness of the Ezetimibe layer for Ezetimibe/Atorvastatin 10/20 mg film coated tablets is between 1.0 to 3.5 mm, preferably between 1.3 to 3.2 mm and more preferably between 1.6 to 2.9 mm.
[0073] In preferred embodiments, the thickness of the Ezetimibe layer for Ezetimibe/Atorvastatin 10/40 mg film coated tablets is between 1.2 to 3.1 mm, preferably between 1.5 to 2.9 mm and more preferably between 1.8 to 2.6 mm.
[0074] In preferred embodiments, the thickness of the Ezetimibe layer for Ezetimibe/Atorvastatin 10/80 mg film coated tablets is between 1.2 to 4.6 mm, preferably between 1.6 to 4.2 mm and more preferably between 2.0 to 3.8 mm.
[0075] The thickness of the layer is determined using any technique known from the state of the art, as for example an optical microscope (e.g. stereomicroscope) or any other similar techniques known in the art.
[0076] In preferred embodiments, the thickness of the Atorvastatin layer is between 0.6 to 5.4 mm, preferably between 0.9 to 5.0 mm and more preferably between 1.2 to 4.6 mm.
[0077] In preferred embodiments, the thickness of the Atorvastatin layer for Ezetimibe/Atorvastatin 10/10 mg film coated tablets is between 0.6 to 2.7 mm, preferably between 0.9 to 2.4 mm and more preferably between 1.2 to 2.1 mm.
[0078] In preferred embodiments, the thickness of the Atorvastatin layer for Ezetimibe/Atorvastatin 10/20 mg film coated tablets is between 1.0 to 3.5 mm, preferably between 1.3 to 3.2 mm and more preferably between 1.6 to 2,9 mm.
[0079] In preferred embodiments, the thickness of the Atorvastatin layer for Ezetimibe/Atorvastatin 10/40 mg film coated tablets is between 1.8 to 4.0 mm, preferably between 2.1 to 3.9 mm and more preferably between 2.4 to 3.4 mm. [0080] In preferred embodiments, the thickness of the Atorvastatin layer for Ezetimibe/Atorvastatin 10/80 mg film coated tablets is between 2.9 to 5.4 mm, preferably between 3.3 to 5.0 mm and more preferably between 3.7 to 4.6 mm.
[0081] The thickness of the layer is determined using any technique known from the state of the art, as for example an optical microscope (e.g. stereomicroscope) or any other similar techniques known in the art.
[0082] In preferred embodiments, the weight ratio of the Ezetimibe layer and of the Atorvastatin layer is between 0.1 to 6, preferably between 0.15 to 4 and more preferably between 0.2 to 2.
[0083] In preferred embodiments, the solid dosage form according to the invention may in addition to Ezetimibe and Atorvastatin further comprise one or more any other active substances suitable for the treatment of abnormal lipid levels and/or any other one or more active substances that show beneficial effect on said patient.
[0084] In preferred embodiments, the solid dosage form according to the invention may in addition to Ezetimibe and Atorvastatin further comprise one or more any other active substances suitable for the treatment of abnormal lipid levels and/or any other one or more active substances that show beneficial effect on said patient, such as for example bempedoic acid, fibrates (e.g. Fenofibrate, Pemafibrate), bile acid sequestrants (e.g. Colestyramine, Colestipol, Colesevelam), nicotinic acid and its derivatives, omega-3 -triglycerides incl. other esters and acids (e.g. eicosapentaenoic acid, docosahexaenoic acid), acetylsalicylic acid, antihypertensive agents (e.g. Perindopril, Enalapril, Ramipril, Lisinopril, Valsartan, Losartan, Telmisartan, Candesartan, Olmesartan, Amlodipine, Lercanidipine, Lacidipine, Hydrochloro thiazide, Indapamide, Chlortalidone, Spironolactone, Metoprolol, Bisoprolol, Nebivolol, Atenolol) or antidiabetic agents (e.g. Metformin, Glimepiride, Glipizide, Gliclazide, Pioglitazone, Rosiglitazone, Sitagliptin, Vildagliptin, Gemigliptin, Saxagliptin, Linagliptin, Dapagliflozin, Empagliflozin, Canagli- flozin).
[0085] In preferred embodiments, the solid dosage form according to the invention may in addition to Ezetimibe and Atorvastatin further comprise any one or more other active substances suitable to be incorporated into the same composition such as for example bempedoic acid, fibrates (e.g. Fenofibrate, Pemafibrate) bile acid sequestrants (e.g. Colestyramine, Colestipol, Colesevelam), nicotinic acid and its derivatives, omega-3 -triglycerides incl. other esters and acids (e.g. eicosapentaenoic acid, docosahex aenoic acid), acetylsalicylic acid, antihypertensive agents (e.g. Perindopril, Enalapril, Ramipril, Lis inopril, Valsartan, Losartan, Telmisartan, Candesartan, Olmesartan, Amlodipine, Lercanidipine, Laci dipine, Hydrochlorothiazide, Indapamide, Chlortalidone, Spironolactone, Metoprolol, Bisoprolol, Nebivolol, Atenolol) or antidiabetic agents (e.g. Metformin, Glimepiride, Glipizide, Gliclazide, Pioglita- zone, Rosiglitazone, Sitagliptin, Vildagliptin, Gemigliptin, Saxagliptin, Linagliptin, Dapagliflozin, Em- pagliflozin, Canagliflozin).
[0086] In preferred embodiments, the solid dosage form according to the invention is used in for treat ment of hypercholesterolaemia (primary hypercholesterolaemia [heterozygous familial and non-famil- ial], mixed hyperlipidaemia or homozygous familial hypercholesterolaemia) or for reduction of cardio vascular event risk.
[0087] In other preferred embodiments, the solid dosage form according to the invention does not con tain any other pharmaceutically active ingredients besides the Ezetimibe, pharmaceutically acceptable salt and/or solvate thereof and the Atorvastatin, pharmaceutically acceptable salt and/or solvate thereof.
[0088] The solid dosage form according to the invention is a solid dosage form comprising at least two layers. Preferred solid dosage form is a tablet, coated or uncoated. Preferably, the solid dosage form according to the invention is a bilayer tablet, preferably a coated bilayer tablet.
[0089] In preferred embodiments, the tablet is a coated tablet. In case the coating is applied onto the solid pharmaceutical formulation, it is preferably composed of at least one film forming polymer for coating and at least one further pharmaceutically acceptable excipient, which can be selected from, but is not limited to, plasticizers, anti-tacking agents, pigments and coloring agents, pore formers and any mixture thereof. Film forming polymers for coating are preferably selected from, but are not limited to, cellulose ethers such as low molecular weight hydroxypropylmethylcellulose and low molecular weight hydroxypropyl cellulose, polyvinyl alcohol, copolymers of vinyl alcohol and ethylene glycol such as Kollicoat® IR and/or Kollicoat® Protect manufactured by BASF. In preferred embodiments, ready to use products for fdm coating such as Opadry® can be used.
[0090] The thickness of the coating can be in the range e.g. from 5 to 100 pm, preferably from 10 to 80 pm. and most preferably from 20 to 50 pm.
[0091] In preferred embodiments, the solid dosage form according to the invention under in vitro con ditions in accordance with USP paddle method, optionally equipped with 7-coil helical sinker, at 75 rpm and 37±0.5°C in in 900 mL of phosphate buffer at pH 6.8 with 0.2% w/v Tween 80 has released after 5 minutes at least 50% of the content of Ezetimibe that was originally contained in the dosage form, pref erably at least 55%, more preferably at least 60%, still more preferably at least 65%, most preferably at least 70%, and in particular at least 75%. [0092] In preferred embodiments, the solid dosage form according to the invention under in vitro con ditions in accordance with USP paddle method, optionally equipped with 7-coil helical sinker, at 75 rpm and 37±0.5°C in in 900 mL of 0.005 M HC1 has released after 5 minutes at least 10% of the content of Atorvastatin that was originally contained in the dosage form, preferably at least 15%, more preferably at least 20%, still more preferably at least 25%, most preferably at least 30%.
[0093] In preferred embodiments, the Ezetimibe layer is prepared by wet granulation; preferably aque ous wet granulation.
[0094] In preferred embodiments, the Atorvastatin layer is prepared by wet granulation; preferably aqueous wet granulation.
[0095] The solid dosage form according to the invention may comprise one or more diluents (fillers). Diluents are selected from, but not limited to, lactose (e.g. anhydrous or hydrate or amorphous (partially or completely)), polysaccharides (e.g. starches or celluloses), monosaccharides, disaccharides, oligosac charides, sugar alcohols, inorganic salts of phosphoric acid, inorganic salts and any mixture thereof. Starch may be selected from partially or wholly pregelatinized starch, com starch, wheat starch, rice starch, tapioca starch, potato starch and any mixture thereof. Cellulose may be selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, co-processed microcrystalline cellulose with other excipients such as lactose, starch, silicon dioxide, mannitol, etc. and any mixture thereof. Monosaccharides, disaccharides, oligosaccharides and sugar alcohols may be selected from glu cose, fructose, sucrose, lactose monohydrate, anhydrous lactose, a-lactose, b-lactose, raffmose, isomalt ose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol, compressible sugars, and mixtures thereof. Mannitol, microcrystalline cellulose that may optionally be silicified, and lactose are preferred diluents.
[0096] The Ezetimibe layer of the solid pharmaceutical dosage form according to the invention com prises a first diluent.
[0097] In preferred embodiments, the first diluent is a sugar alcohol; preferably selected from the group consisting of mannitol, sorbitol, maltitol, xylitol, lactitol, and erythritol, and mixtures thereof; more preferably mannitol.
[0098] In preferred embodiments, essentially the total amount of the first diluent is comprised in the intragranular phase of the Ezetimibe layer.
[0099] In preferred embodiments, the weight content of the first diluent is - at least 7.5 wt.-%, preferably at least 10 wt.-%, more preferably at least 12.5 wt.-%, still more pref erably at least 15 wt.-%, yet more preferably at least 17.5 wt.-%, even more preferably at least 20 wt.-%, most preferably at least 22.5 wt.-%, and in particular at least 25 wt.-%;
- at most 72.5 wt.-%, preferably at most 70 wt.-%, more preferably at most 67.5 wt.-%, still more preferably at most 65 wt.-%, yet more preferably at most 62.5 wt.-%, even more preferably at most 60 wt.-%, most preferably at most 57.5 wt.-%, and in particular at most 55 wt.-%; and/or
- within the range of 30±5.0 wt.-%, 35±10 wt.-%, 35±5.0 wt.-%, 40±10 wt.-%, 40±5.0 wt.-%, 45±10 wt.-%, 45±5.0 wt.-%, or 50±5.0 wt.-%; in each case relative to the total weight of the Ezetimibe layer.
[0100] The Ezetimibe layer of the solid pharmaceutical dosage form according to the invention option ally comprises a second diluent, wherein the second diluent differs from the first diluent.
[0101] In particularly preferred embodiments, the Ezetimibe layer of the solid pharmaceutical dosage form according to the invention comprises a second diluent that differs from the first diluent.
[0102] In preferred embodiments, at least a fraction or essentially the total amount of the second diluent is comprised in the intragranular phase of the Ezetimibe layer.
[0103] In particularly preferred embodiments, essentially the total amount of the second diluent is com prised in the extragranular phase of the Ezetimibe layer.
[0104] In preferred embodiments, the second diluent is selected from the group consisting of
- lactose; preferably anhydrous lactose, lactose hydrate, partially amorphous lactose, completely amor phous lactose;
- starch or starch derivatives; preferably partially or wholly pregelatinized starch, com starch, wheat starch, rice starch, tapioca starch, potato starch;
- cellulose or cellulose derivatives; preferably powdered cellulose, microcrystalline cellulose, silici- fied microcrystalline cellulose, co-processed microcrystalline cellulose with other excipients such as lactose, starch, silicon dioxide, and mannitol;
- monosaccharides, disaccharides, oligosaccharides and sugar alcohols; preferably glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, a-lactose, b-lactose, raffmose, isomaltose, treha lose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol, or compressible sugars; and mixture thereof; preferably microcrystalline cellulose which may optionally be silicified, lactose monohydrate, and mix tures thereof; more preferably microcrystalline cellulose which may optionally be silicified.
[0105] In preferred embodiments, the weight content of the second diluent is
- at least 8.0 wt.-%, preferably at least 10 wt.-%, more preferably at least 12 wt.-%, still more prefer ably at least 14 wt.-%, yet more preferably at least 16 wt.-%, even more preferably at least 18 wt- %, most preferably at least 20 wt.-%, and in particular at least 22 wt.-%;
- at most 71 wt.-%, preferably at most 69 wt.-%, more preferably at most 67 wt.-%, still more prefer ably at most 65 wt.-%, yet more preferably at most 63 wt.-%, even more preferably at most 61 wt.- %, most preferably at most 59 wt.-%, and in particular at most 57 wt.-%; and/or
- within the range of 25±5.0 wt.-%, 30±10 wt.-%, 30±5.0 wt.-%, 35±10 wt.-%, 35±5.0 wt.-%, 40±10 wt.-%, 40±5.0 wt.-%, 45±10 wt.-%, 45±5.0 wt.-%, or 50±5.0 wt.-%; in each case relative to the total weight of the Ezetimibe layer.
[0106] In preferred embodiments, the Ezetimibe layer comprises no lactose, i.e. neither lactose mono hydrate, nor lactose dihydrate, nor anhydrous lactose, nor spray-dried lactose, nor crystalline lactose, nor partially amorphous lactose, nor completely amorphous lactose.
[0107] In preferred embodiments, the Atorvastatin layer comprises a third diluent; preferably lactose; more preferably lactose monohydrate.
[0108] In preferred embodiments, at least a fraction or essentially the total amount of the third diluent is comprised in the intragranular phase of the Atorvastatin layer.
[0109] In preferred embodiments, the weight content of the third diluent is
- at least 5.0 wt.-%, preferably at least 7.0 wt.-%, more preferably at least 9.0 wt.-%, still more pref erably at least 11 wt.-%, yet more preferably at least 13 wt.-%, even more preferably at least 15 wt.- %, most preferably at least 17 wt.-%, and in particular at least 19 wt.-%;
- at most 42 wt.-%, preferably at most 40 wt.-%, more preferably at most 38 wt.-%, still more prefer ably at most 36 wt.-%, yet more preferably at most 34 wt.-%, even more preferably at most 32 wt.- %, most preferably at most 30 wt.-%, and in particular at most 28 wt.-%; and/or
- within the range of from 20±2.5 wt.-%, 22.5±2.5 wt.-%, or 25±2.5 wt.-%; in each case relative to the total weight of the Atorvastatin layer. [0110] In preferred embodiments, the Atorvastatin layer comprises a fourth diluent; preferably micro crystalline cellulose which may optionally be silicified.
[0111] In preferred embodiments, at least a fraction or essentially the total amount of the fourth diluent is comprised in the intragranular phase of the Atorvastatin layer.
[0112] In preferred embodiments, the weight content of the fourth diluent is
- at least 5.0 wt.-%, preferably at least 7.0 wt.-%, more preferably at least 9.0 wt.-%, still more pref erably at least 11 wt.-%, yet more preferably at least 13 wt.-%, even more preferably at least 15 wt.- %, most preferably at least 17 wt.-%, and in particular at least 19 wt.-%;
- at most 37 wt.-%, preferably at most 35 wt.-%, more preferably at most 33 wt.-%, still more prefer ably at most 31 wt.-%, yet more preferably at most 29 wt.-%, even more preferably at most 27 wt.- %, most preferably at most 25 wt.-%, and in particular at most 23 wt.-%; and/or
- within the range of 20.5±1.0 wt.-%, 21±2.0 wt.-%, 21±1.0 wt.-%, or 21.5±1.0 wt.-%; in each case relative to the total weight of the Atorvastatin layer.
[0113] The solid dosage form according to the invention may comprise one or more disintegrants. Dis- integrants are selected from, but not limited to, crospovidone, starch, maize starch, pregelatinized starch, sodium starch gly collate, modified starch, hydroxypropyl starch, carboxymethyl starch, sodium and/or calcium salts of carboxymethyl cellulose, cross-linked carboxymethylcellulose (e.g. croscarmellose so dium and/or croscarmellose calcium), polacrilin potassium, alginic acid or alginates, sodium and/or cal cium alginate, polyacrylates, docusate sodium, methylcellulose, agar, guar gum, chitosan, gums and mixtures thereof. Preferred disintegrants are croscarmellose sodium, crospovidone and mixtures thereof.
[0114] In preferred embodiments, the Ezetimibe layer comprises a first disintegrant, preferably sodium croscarmellose; and optionally a second disintegrant; preferably crospovidone.
[0115] In preferred embodiments, at least a fraction of the first disintegrant is comprised in the intra granular phase of the Ezetimibe layer.
[0116] In other preferred embodiments, at least a fraction of the first disintegrant is comprised in the extragranular phase of the Ezetimibe layer. [0117] In preferred embodiments, the relative weight ratio of the fraction of the first disintegrant com prised in the intragranular phase of the Ezetimibe layer and of the fraction of the first disintegrant com prised in the extragranular phase of the Ezetimibe layer is within the range of from 0.1 to 0.9, preferably from 0.2 to 0.8, and more preferably from 0.3 to 0.7.
[0118] In preferred embodiments, at least a fraction or essentially the total amount of the optionally present second disintegrant is comprised in the intragranular phase of the Ezetimibe layer.
[0119] In preferred embodiments, the first disintegrant and the optionally second disintegrant are inde pendently of another selected from the group consisting of
- cellulose or cellulose derivatives; preferably microcrystalline cellulose, methylcellulose, sodium salts of carboxymethyl cellulose, calcium salts of carboxymethyl cellulose, or cross-linked carbox- ymethylcellulose, e.g. croscarmellose sodium and/or croscarmellose calcium; preferably croscarmel- lose sodium;
- crospovidone;
- starch or starch derivatives; preferably starch, maize starch, pregelatinized starch, sodium starch gly- collate, modified starch, hydroxypropyl starch, or carboxymethyl starch;
- polacrilin potassium or docusate sodium;
- cellulose ethers; preferably low substituted hydroxypropylcellulose (L-HPC);
- heteroglycanes; preferably alginic acid or alginates, e.g. sodium alginate or calcium alginate; agar, guar gum, or gums;
- polyacrylates;
- glucosamines; preferably chitosan; and
- mixtures thereof; preferably croscarmellose sodium, crospovidone and mixtures thereof; more preferably croscarmellose sodium.
[0120] In preferred embodiments, the total weight content of the first disintegrant and the optionally present second disintegrant is
- at least 3.5 wt.-%, preferably at least 4.0 wt.-%, more preferably at least 4.5 wt.-%, still more pref erably at least 5.5 wt.-%, yet more preferably at least 6.0 wt.-%, even more preferably at least 6.5 wt.-%, most preferably at least 7.0 wt.-%, and in particular at least 7.5 wt.-%; - at most 16.5 wt.-%, preferably at most 16 wt.-%, more preferably at most 15.5 wt.-%, still more preferably at most 15 wt.-%, yet more preferably at most 14.5 wt.-%, even more preferably at most 14 wt.-%, most preferably at most 13.5 wt.-%, and in particular at most 13 wt.-%; and/or
- within the range of 9.0±1.0 wt.-%, 10±2.0 wt.-%, 10±1.0 wt.-%, ll±2.0 wt.-%, ll±1.0 wt.-%, 12±1.0 wt.-%; in each case relative to the total weight of the Ezetimibe layer.
[0121] In preferred embodiments, the Atorvastatin layer comprises a third disintegrant, preferably so dium croscarmellose.
[0122] In preferred embodiments, at least a fraction or essentially the total amount of the third disinte grant is comprised in the intragranular phase of the Atorvastatin layer.
[0123] In preferred embodiments, the weight content of the third disintegrant is
- at least 2.6 wt.-%, preferably at least 3.0 wt.-%, more preferably at least 3.4 wt.-%, still more pref erably at least 3.8 wt.-%, yet more preferably at least 4.2 wt.-%, even more preferably at least 4.6 wt.-%, most preferably at least 5.0 wt.-%, and in particular at least 5.4 wt.-%;
- at most 16 wt.-%, preferably at most 15 wt.-%, more preferably at most 14 wt.-%, still more prefer ably at most 13 wt.-%, yet more preferably at most 12 wt.-%, even more preferably at most 11 wt.- %, most preferably at most 10 wt.-%, and in particular at most 9.0 wt.-%; and/or
- within the range of 6.0±1.0 wt.-%, 7.0±2.0 wt.-%, 7.0±1.0 wt.-%, or 8.0±1.0 wt.-%; in each case relative to the total weight of the Atorvastatin layer.
[0124] The solid dosage form according to the invention may comprise one or more binders. Binders are selected from, but not limited to, povidone (polyvinylpyrrolidone), copovidone (vinylpyrrolidone- vinyl acetate copolymer), powdered cellulose, crystalline cellulose, cellulose derivatives such as cellu lose esters or cellulose ethers (e.g. hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellu- lose, low substituted hydroxypropylcellulose and hydroxypropylmethylcellulose), polyvinyl alcohol, starch (e.g. com starch, potato starch, or rice starch), a-starch, pregelatinized starch, dextrin, gum arabic, pullulan, poly(meth)acrylates and any mixture thereof. Preferred binders are polyvinylpyrrolidone and hydroxypropylcellulose .
[0125] The Ezetimibe layer of the solid pharmaceutical dosage form according to the invention option ally comprises a first binder. [0126] In particularly preferred embodiments, the Ezetimibe layer of the solid pharmaceutical dosage form according to the invention comprises a first binder.
[0127] In preferred embodiments, essentially the total amount of the first binder is comprised in the intragranular phase of the Ezetimibe layer.
[0128] In preferred embodiments, the first binder is selected from the group consisting of
- povidone (polyvinylpyrrolidone) or copovidone (vinylpyrrolidone-vinyl acetate copolymer);
- cellulose; preferably powdered cellulose, crystalline cellulose, microcrystalline cellulose, silicified microcrystalline cellulose;
- cellulose derivatives, cellulose esters or cellulose ethers; preferably hydroxymethylcellulose, hy- droxyethylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose or hydroxy- propylmethylcellulose;
- polyvinyl alcohol;
- starch or starch derivatives; preferably com starch, potato starch, rice starch, a-starch, or pregelati nized starch;
- mono- or polysaccharides; preferably dextrin, gum arabic, or pullulan;
- poly(meth)acrylates; and
- mixtures thereof; preferably povidone (polyvinylpyrrolidone) or copovidone (vinylpyrrolidone-vinyl acetate copolymer); more preferably povidone (polyvinylpyrrolidone).
[0129] In preferred embodiments, the weight content of the first binder is
- at least 0.1 wt.-%, preferably at least 0.3 wt.-%, more preferably at least 0.5 wt.-%, still more pref erably at least 0.7 wt.-%, yet more preferably at least 0.9 wt.-%, even more preferably at least 1.1 wt.-%, most preferably at least 1.3 wt.-%, and in particular at least 1.5 wt.-%;
- at most 5.9 wt.-%, preferably at most 5.7 wt.-%, more preferably at most 5.5 wt.-%, still more pref erably at most 5.3 wt.-%, yet more preferably at most 5.1 wt.-%, even more preferably at most 4.9 wt.-%, most preferably at most 4.7 wt.-%, and in particular at most 4.5 wt.-%; and/or
- within the range of 2.0±0.5 wt.-%, 2.5±1.0 wt.-%, 2.5±0.5 wt.-%, 3.0±1.0 wt.-%, 3.0±0.5 wt.-%, 3.5±1.0 wt.-%, 3.5±0.5 wt.-%, or 4.0±0.5 wt.-%; in each case relative to the total weight of the Ezetimibe layer. [0130] In preferred embodiments, the Atorvastatin layer comprises a second binder; preferably a cellu lose ether; more preferably hydroxypropylcellulose.
[0131] In preferred embodiments, essentially the total amount of the second binder is comprised in the intragranular phase of the Atorvastatin layer.
[0132] In preferred embodiments, the weight content of the second binder is
- at least 0.8 wt.-%, preferably at least 1.1 wt.-%, more preferably at least 1.4 wt.-%, still more pref erably at least 1.7 wt.-%, yet more preferably at least 2.0 wt.-%, even more preferably at least 2.3 wt.-%, most preferably at least 2.6 wt.-%, and in particular at least 2.9 wt.-%;
- at most 5.6 wt.-%, preferably at most 5.3 wt.-%, more preferably at most 5.0 wt.-%, still more pref erably at most 4.7 wt.-%, yet more preferably at most 4.4 wt.-%, even more preferably at most 4.1 wt.-%, most preferably at most 3.8 wt.-%, and in particular at most 3.5 wt.-%; and/or
- within the range of 3.0±0.5 wt.-% or 3.5±0.5 wt.-%; in each case relative to the total weight of the Atorvastatin layer.
[0133] The solid dosage form according to the invention may comprise one or more wetting agents. Wetting agents can be selected but are not limited to cationic, anionic, zwitterionic and non-ionic, pref erably anionic, such as carboxylates: alkyl carboxylates-fatty acid salts; carboxylate fluoro surfactants, sulfates: alkyl sulfates (e.g., sodium lauryl sulfate); alkyl ether sulfates (e.g., sodium laureth sulfate), sulfonates: docusates (e.g., dioctyl sodium sulfosuccinate); alkyl benzene sulfonates, phosphate esters: alkyl aryl ether phosphates; alkyl ether phosphates. Other preferable type of wetting agents are non ionic wetting agents, such as polyol esters, polyoxyethylene esters, poloxamers. polyol esters includes glycol and glycerol esters and sorbitan derivatives (such as fatty acid esters of sorbitan (generally re ferred to as Spans) and their ethoxylated derivatives (generally referred to as Tweens). Preferred wetting agents are polysorbate 80 and sodium lauryl sulfate.
[0134] In preferred embodiments, the Ezetimibe layer comprises a first wetting agent.
[0135] In preferred embodiments, essentially the total amount of the first wetting agent is comprised in the intragranular phase of the Ezetimibe layer.
[0136] In preferred embodiments, the first wetting agent is selected from the group consisting of cati onic surfactants, anionic surfactants, zwitterionic surfactants and non-ionic surfactants; preferably an anionic surfactant; more preferably sodium lauryl sulfate. [0137] In preferred embodiments, the weight content of the first wetting agent is
- at least 0.3 wt.-%, preferably at least 0.4 wt.-%, more preferably at least 0.5 wt.-%, still more pref erably at least 0.6 wt.-%, yet more preferably at least 0.7 wt.-%, even more preferably at least 0.8 wt.-%, most preferably at least 0.9 wt.-%, and in particular at least 1.0 wt.-%;
- at most 7.5 wt.-%, preferably at most 7.0 wt.-%, more preferably at most 6.5 wt.-%, still more pref erably at most 6.0 wt.-%, yet more preferably at most 5.5 wt.-%, even more preferably at most 5.0 wt.-%, most preferably at most 4.5 wt.-%, and in particular at most 4.0 wt.-%; and/or
- within the range of 2.0± 1.0 wt.-% or 3.0± 1.0 wt.-%; in each case relative to the total weight of the Ezetimibe layer.
[0138] In preferred embodiments, the Atorvastatin layer comprises a second wetting agent; preferably polysorbate (ethoxylated sorbitan fatty acid esters); more preferably polysorbate 80 (polyoxyeth- ylene(20)-sorbitan-monooleate).
[0139] In preferred embodiments, essentially the total amount of the second wetting agent is comprised in the intragranular phase of the Atorvastatin layer.
[0140] In preferred embodiments, the weight content of the second wetting agent is
- at least 0.1 wt.-%, preferably at least 0.15 wt.-%, more preferably at least 0.2 wt.-%, still more pref erably at least 0.25 wt.-%, yet more preferably at least 0.3 wt.-%, even more preferably at least 0.35 wt.-%, most preferably at least 0.4 wt.-%, and in particular at least 0.45 wt.-%;
- at most 1.4 wt.-%, preferably at most 1.3 wt.-%, more preferably at most 1.2 wt.-%, still more pref erably at most 1.1 wt.-%, yet more preferably at most 1.0 wt.-%, even more preferably at most 0.9 wt.-%, most preferably at most 0.8 wt.-%, and in particular at most 0.7 wt.-%; and/or
- within the range of 0.6±0.1 wt.-%; in each case relative to the total weight of the Atorvastatin layer.
[0141] The solid dosage form according to the invention may comprise one or more basic alkaline or alkaline earth metal salts (stabilizing agents), preferably selected from, but not limited to, alkaline com pounds, such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potas sium carbonate, magnesium carbonate and calcium carbonate; particularly preferably calcium car bonate.
[0142] In preferred embodiments, the Atorvastatin layer comprises a basic alkaline or alkaline earth metal salt. [0143] In preferred embodiments, the basic alkaline or alkaline earth metal salt is selected from the group consisting of calcium carbonate, calcium hydroxide, sodium hydrogen carbonate, potassium hy drogen carbonate, sodium carbonate, potassium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, calcium acetate, calcium gluconate, calcium glycerol phosphate, magnesium carbonate, magnesium hydroxide, magnesium sulfate, magnesium acetate, magnesium silicate, magne sium aluminate or mixtures thereof; preferably calcium carbonate.
[0144] In preferred embodiments, essentially the total amount of the basic alkaline or alkaline earth metal salt is comprised in the intragranular phase of the Atorvastatin layer.
[0145] In preferred embodiments, the weight content of the basic alkaline or alkaline earth metal salt is
- at least 18 wt.-%, preferably at least 20 wt.-%, more preferably at least 22 wt.-%, still more preferably at least 24 wt.-%, yet more preferably at least 26 wt.-%, even more preferably at least 28 wt.-%, most preferably more than 30 wt.-%, and in particular at least 31 wt.-%;
- at most 47 wt.-%, preferably at most 46 wt.-%, more preferably at most 45 wt.-%, still more prefer ably at most 44 wt.-%, yet more preferably at most 43 wt.-%, even more preferably at most 42 wt.- %, most preferably at most 41 wt.-%, and in particular at most 40 wt.-%; and/or
- within the range of 32.5±5.0 wt.-%, 35±5.0 wt.-%, or 37.5±5 wt.-%; in each case relative to the total weight of the Ezetimibe layer.
[0146] The solid dosage form according to the invention may comprise one or more lubricants. Lubri cants are selected from, but not limited to, Lubricants are selected from, but not limited to, fatty acids (i.e. carboxylic acids with 12 to 20 carbon atoms); fatty acid esters including glyceride esters such as glyceryl monostearate, glyceryl tribehenate, or glyceryl dibehenate (e.g. Compritol® 888); metal salts of fatty acids, including magnesium, calcium, aluminum or zinc salts of fatty acids (e.g. magnesium, calcium, aluminum or zinc stearate, magnesium palmitate, or magnesium oleate); hydrogenated vegeta ble oil, hydrogenated castor oil; waxes (e.g. Sterotex® NL, Lubriwax® [hydrogenated vegetable oil type], meads wax or spermaceti); boric acid; sodium stearyl fumarate; polymers (e.g., PEG, macrogols); sugar esters such as sorbitan monostearate and sucrose monopalmitate and any mixtures thereof. Pre ferred lubricants are magnesium stearate and sodium stearyl fumarate.
[0147] In preferred embodiments, the Ezetimibe layer of the solid pharmaceutical dosage form accord ing to the invention comprises sodium stearyl fumarate, magnesium stearate, or mixtures thereof, pref erably sodium stearyl fumarate. Preferably, the weight content of lubricant in the Ezetimibe layer is within the range of 0.5 to 3.5 wt.-%, relative to the total weight of the Ezetimibe layer. [0148] In preferred embodiments, the Atorvastatin layer of the solid pharmaceutical dosage form ac cording to the invention comprises magnesium stearate. Preferably, the weight content of lubricant in the Atorvastatin layer is within the range of 0.3 to 1.5 wt.-%, relative to the total weight of the Atorvas tatin layer.
[0149] The solid dosage form according to the invention may comprise one or more glidants. Glidants are selected from, but not limited to, colloidal silicon dioxide (colloidal silica), talc, magnesium trisili- cate, and mixtures thereof. Preferred glidants are colloidal silica, talc and any mixtures thereof. A pre ferred glidant is hydrophobic colloidal silica.
[0150] In preferred embodiments, the Atorvastatin layer of the solid pharmaceutical dosage form ac cording to the invention comprises hydrophobic colloidal silica. Preferably, the weight content of glidant in the Atorvastatin layer is within the range of 0.3 to 1.0 wt.-%, relative to the total weight of the Atorvastatin layer.
[0151] The solid dosage form according to the invention may comprise one or more colorants. Color ants can be selected but are not limited to iron oxides and/or titanium dioxide, e.g. ferric oxide yellow (E 172).
[0152] In preferred embodiments, the Ezetimibe layer of the solid pharmaceutical dosage form accord ing to the invention comprises ferric oxide, preferably ferric oxide yellow. Preferably, the weight content of colorant in the Ezetimibe layer is within the range of 0.05 to 0.2 wt.-%, relative to the total weight of the Ezetimibe layer.
[0153] In preferred embodiments, the Ezetimibe layer comprises
- 53±40 wt.-%, preferably 53±35 wt.-%, more preferably 53±30 wt.-%, still more preferably 53±25 wt.-%, yet more preferably 53±20 wt.-%, even more preferably 53±15 wt.-%, most preferably 53±10 wt.-%, and in particular 53±5 wt.-% of first diluent; preferably sugar alcohol; more preferably man nitol; preferably in the intragranular phase of the Ezetimibe layer; and/or
- no lactose; and/or
- 1.5±1.4 wt.-%, preferably 1.5±1.2 wt.-%, more preferably 1.5±1.0 wt.-%, still more preferably 1.5±0.8 wt.-%, yet more preferably 1.5±0.6 wt.-%, even more preferably 1.5±0.4 wt.-%, most pref erably 1 5±0.2 wt.-% of lubricant; preferably sodium stearyl fumarate; preferably in the extragranular phase of the Ezetimibe layer; and/or
- no magnesium stearate; in each case relative to the total weight of the Ezetimibe layer.
[0154] In preferred embodiments, the Ezetimibe layer comprises
- 24±20 wt.-%, preferably 24±18 wt.-%, more preferably 24±16 wt.-%, still more preferably 24±14 wt.-%, yet more preferably 24±12 wt.-%, even more preferably 24±10 wt.-%, most preferably 24±8 wt.-%, and in particular 24±6 wt.-% of second diluent; preferably microcrystalline cellulose; prefer ably in the extragranular phase of the Ezetimibe layer; and/or
- 10±9 wt.-%, preferably 10±8 wt.-%, more preferably 10±7 wt.-%, still more preferably 10±6 wt.-%, yet more preferably 10±5 wt.-%, even more preferably 10±4 wt.-%, most preferably 10±3 wt.-%, and in particular 10±2 wt.-% of first disintegrant; preferably sodium croscarmellose; preferably a fraction in the intragranular phase of the Ezetimibe layer and a fraction in the extragranular phase of the Ezetimibe layer; preferably wherein the relative weight ratio of the fraction comprised in the intragranular phase of the Ezetimibe layer and of the fraction comprised in the extragranular phase of the Ezetimibe layer is within the range of from 0.3 to 0.7; and/or
- 5.0±4.5 wt.-%, preferably 5.0±4.0 wt.-%, more preferably 5.0±3.5 wt.-%, still more preferably 5.0±3.0 wt.-%, yet more preferably 5.0±2.5 wt.-%, even more preferably 5.0±2.0 wt.-%, most pref erably 5.0±1.5 wt.-%, and in particular 5.0±1.0 wt.-% of Ezetimibe in the non-solvate non-salt form; preferably in the intragranular phase of the Ezetimibe layer; and/or
- 3.0±2.7 wt.-%, preferably 3.0±2.4 wt.-%, more preferably 3.0±2.1 wt.-%, still more preferably 3.0±1.8 wt.-%, yet more preferably 3.0±1.5 wt.-%, even more preferably 3.0±1.2 wt.-%, most pref erably 3.0±0.9 wt.-%, and in particular 3.0±0.6 wt.-% of first binder; preferably polyvinylpyrroli done; preferably in the intragranular phase of the Ezetimibe layer; and/or
- 3.0±2.7 wt.-%, preferably 3.0±2.4 wt.-%, more preferably 3.0±2.1 wt.-%, still more preferably 3.0±1.8 wt.-%, yet more preferably 3.0±1.6 wt.-%, even more preferably 3.0±1.4 wt.-%, most pref erably 3.0±1.2 wt.-%, and in particular 3.0± 1.0 wt.-% of first wetting agent; preferably sodium lauryl sulfate; preferably in the intragranular phase of the Ezetimibe layer; in each case relative to the total weight of the Ezetimibe layer.
[0155] In preferred embodiments, the Atorvastatin layer comprises at least 12 wt.-%, preferably at least 15 wt.-%, more preferably at least 18 wt.-%, still more preferably at least 21 wt.-%, yet more preferably at least 24 wt.-%, even more preferably at least 27 wt.-%, most preferably more than 30 wt.-%, and in particular at least 31 wt.-% of basic alkaline or alkaline earth metal salt; preferably calcium carbonate; preferably in the intragranular phase of the Atorvastatin layer; in each case relative to the total weight of the Atorvastatin layer.
[0156] In preferred embodiments, the Atorvastatin layer comprises - 27±20 wt.-%, preferably 27±18 wt.-%, more preferably 27±16 wt.-%, still more preferably 27±14 wt.-%, yet more preferably 27±12 wt.-%, even more preferably 27±10 wt.-%, most preferably 27±8 wt.-%, and in particular 27±6 wt.-% of third diluent; preferably lactose; more preferably lactose monohydrate; preferably in the intragranular phase of the Atorvastatin layer; and/or
- 20±18 wt.-%, preferably 20±16 wt.-%, more preferably 20±14 wt.-%, still more preferably 20±12 wt.-%, yet more preferably 20±10 wt.-%, even more preferably 20±8 wt.-%, most preferably 20±6 wt.-%, and in particular 20±4 wt.-% of fourth diluent; preferably microcrystalline cellulose; prefer ably in the intragranular phase of the Atorvastatin layer; and/or
- 11±10 wt.-%, preferably 11±9 wt.-%, more preferably 11±8 wt.-%, still more preferably 11±7 wt- %, yet more preferably 11±6 wt.-%, even more preferably 11±5 wt.-%, most preferably 11±4 wt.-%, and in particular 11±3 wt.-% of Atorvastatin calcium trihydrate; preferably in the intragranular phase of the Atorvastatin layer; and/or
- 6.0±5.5 wt.-%, preferably 6.0±5.0 wt.-%, more preferably 6.0±4.5 wt.-%, still more preferably 6.0±4.0 wt.-%, yet more preferably 6.0±3.5 wt.-%, even more preferably 6.0±3.0 wt.-%, most pref erably 6.0±2.5 wt.-%, and in particular 6.0±2.0 wt.-% of third disintegrant; preferably sodium croscarmellose; preferably in the intragranular phase of the Atorvastatin layer; and/or
- 3.0±2.7 wt.-%, preferably 3.0±2.4 wt.-%, more preferably 3.0±2.1 wt.-%, still more preferably 3.0±1.8 wt.-%, yet more preferably 3. Oil.6 wt.-%, even more preferably 3.0il.4 wt.-%, most pref erably 3. Oil.2 wt.-%, and in particular 3.0il.0 wt.-% of second binder; preferably hydroxypropyl- cellulose; preferably in the intragranular phase of the Atorvastatin layer; and/or
- 0.6i0.5 wt.-%, preferably 0.6i0.4 wt.-%, more preferably 0.6i0.3 wt.-%, still more preferably 0.6i0.2 wt.-%, yet more preferably 0.6i0.1 wt.-% of second wetting agent; preferably polysorbate; more preferably polysorbate 80; preferably in the intragranular phase of the Atorvastatin layer; in each case relative to the total weight of the Atorvastatin layer.
[0157] Another aspect of the invention relates to a process for the preparation of a solid dosage form according to the invention described above.
[0158] The process for the preparation of the solid dosage form according to the invention comprises the steps of
A) preparing an Ezetimibe compression blend comprising the sub-steps: a) dispersing a first binder in a suitable liquid thereby obtaining a dispersion; b) homogenizing Ezetimibe, a pharmaceutically acceptable salt and/or solvate thereof in the dis persion obtained in sub-step a) thereby obtaining a suspension; c) dispersing a first wetting agent in a suitable liquid thereby obtaining a dispersion; d) mixing the suspension obtained in sub-step b) and the dispersion obtained in sub-step c) thereby obtaining a granulation liquid; e) spraying the granulation liquid onto a mixture comprising a first diluent, at least a fraction of a first disintegrant and optionally, a second disintegrant thereby obtaining granules; f) drying and sieving the granules obtained in sub-step e) thereby obtaining a granulate; g) blending the granulate obtained in sub-step f) with at least one pharmaceutical excipient thereby obtaining a homogenous blend; and h) adding a lubricant to the homogenous blend obtained in sub-step g) thereby obtaining the Ezetimibe compression blend;
B) preparing an Atorvastatin compression blend comprising the sub-steps: i) dispersing a second wetting agent and/or a second binder in a suitable liquid thereby obtaining a dispersion; j) homogenizing Atorvastatin, a pharmaceutically acceptable salt and/or solvate thereof with at least one pharmaceutically acceptable excipient, preferably by means of a homogenizer, thereby obtaining a homogenous mixture; k) spraying the dispersion obtained in sub-step step i) onto the homogenous mixture obtained in sub-step j) thereby obtaining granules; l) kneading the granules obtained in sub-step k) thereby obtaining densified agglomerated parti cles; m) drying the densified agglomerated particles obtained in sub-step 1) thereby obtaining dried densified agglomerated particles; n) sieving the dried densified agglomerated particles obtained in sub-step m) thereby obtaining sieved agglomerated particles; o) drying the sieved agglomerated particles obtained in sub-step n) thereby obtaining a dry gran ulate; p) adding a lubricant to the dry granulate obtained in sub-step o) thereby obtaining the Atorvas tatin compression blend;
C) compressing a layered tablet having a first layer made from the Ezetimibe compression blend pre pared in step A) or from the Atorvastatin compression blend prepared in step B); and a second layer made from the other of the two compression blends; and
D) optionally, film-coating the layered tablet obtained in step C). [0159] In preferred embodiments, sub-step a) involves dissolving the first binder in an organic solvent or in water.
[0160] In preferred embodiments, sub-step c) involves dissolving the first wetting agent in an organic solvent or in water.
[0161] In preferred embodiments, in sub-step g) the at least one pharmaceutical excipient comprises a second diluent and at least a fraction of the first disintegrant.
[0162] In preferred embodiments, sub-step i) involves dispersing the second wetting agent and/or the second binder in an organic liquid or water.
[0163] In preferred embodiments, step C) involves the sub-steps of q) filling a tablet press with a predetermined amount of the Ezetimibe compression blend prepared in step A) or of the Atorvastatin compression blend prepared in step B); r) compressing the predetermined amount thereby obtaining the first layer of the layered tablet; s) filling the tablet press with a predetermined amount of the other of the two compression blends; t) compressing the first layer simultaneously with the predetermined amount thereby obtaining the layered tablet; and u) removing the layered tablet from the table press.
[0164] Another aspect of the invention relates to a solid dosage form that is obtainable by the process according to the invention as described above.
[0165] One embodiment of the invention is a process for the preparation of the solid dosage form com prising at least two layers comprising Ezetimibe and Atorvastatin in the form of its salts, solvates, hy drates, enantiomers and any polymorphs thereof wherein Ezetimibe and Atorvastatin are present in sep arate layers comprising the following steps: 1. Ezetimibe layer: a. dispersing binder to obtain dispersion; b. homogenization of Ezetimibe in the obtained dispersion to obtain suspension; c. dispersing wetting agent to obtain dispersion; d. mixing the suspension from step b and the dispersion from step c to obtain granulation liquid; e. spraying the granulation liquid on the mixture of diluent and disintegrant; f. drying and sieving the obtained granules to obtain granulate; g. blending the obtained granulate with at least one pharmaceutical excipient to obtain homogenous blend; h. addition of one or more lubricant to obtain compression blend; 2. Atorvastatin layer: a. dispersing wetting agent and/or binder to obtain dispersion; b. homogenization of Atorvastatin with at least one pharmaceutically acceptable excipient to obtain homogenous mixture; c. spraying the dispersion from step a on the obtained homogenous mixture; d. kneading the obtained product from step c to obtain densified agglomerated particles; e. drying the ob tained densified agglomerated particles; f. sieving the dried densified agglomerated particles to obtain sieved agglomerated particles; g. drying the sieved agglomerated particles to obtain dry granulate; h. addition of one or more lubricant to obtain compression blend; 3. tablets compression; 4. optionally film-coating of the tablets.
[0166] Another embodiment of the invention is a process for the preparation of the solid dosage form comprising at least two layers comprising Ezetimibe and Atorvastatin in the form of its salts, solvates, hydrates, enantiomers and any polymorphs thereof wherein Ezetimibe and Atorvastatin are present in separate layers comprising the following steps: 1. Ezetimibe layer: a. dissolving binder in an organic solvent or in water to obtain solution; b. homogenization of Ezetimibe with homogenizer in the obtained solution to obtain suspension; c. dissolving wetting agent in organic solvent or in water to obtain solu tion; d. mixing the suspension from step b and the solution from step c to obtain granulation liquid; e. spraying the granulation liquid on the mixture of diluent and disintegrant; f. drying and sieving the obtained granules to obtain granulate; g. blending the obtained granulate with at least one diluent and at least one disintegrant to obtain homogenous blend; h. addition of one or more lubricant to obtain com pression blend; 2. Atorvastatin layer: a. dissolving wetting agent and/or binder in organic liquid or water to obtain granulation liquid; b. homogenization of Atorvastatin with at least one pharmaceutically ac ceptable excipient to obtain homogenous mixture; c. spraying the granulation liquid from step a on the obtained homogenous mixture; d. kneading the obtained product from step c to obtain densified agglom erated particles; e. drying the obtained densified agglomerated particles; f. sieving the dried densified agglomerated particles to obtain sieved densified agglomerated particles; g. drying the sieved densified agglomerated particles to obtain dry granulate; h. sieving the dry granulate; i. addition of one or more lubricant to the obtained granulate to obtain compression blend; 3. tablet compression: a. compression of the compression blend of the first layer selected from Ezetimibe layer and Atorvastatin layer; b. sim ultaneous compression of the first layer selected from Ezetimibe layer and Atorvastatin layer and com pression blend of the second layer selected from Ezetimibe layer and Atorvastatin layer; and 4. option ally film-coating of the tablets.
[0167] Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein binder of step la is dissolved in an organic solvent such as for ex ample ethanol, isopropanol, acetone and any mixture thereof or in water, preferably in purified water.
[0168] Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein homogenization of Ezetimibe in step lb is performed with homoge nizer such as for example high pressure homogenizer or rotor-stator homogenizer. [0169] Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein wetting agent of step lc is dissolved in an organic solvent such as for example ethanol, isopropanol, acetone and any mixture thereof or in water, preferably in purified water.
[0170] Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein mixing of diluent and disintegrant of step le is performed in the granulator using fluidized air.
[0171] Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein spraying of step le is performed with binary nozzle.
[0172] Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein sieving the granules of step If is performed through sieve with open ings between 0.6 and 1.4 mm, preferably between 0.5 and 1.1 mm, more preferably between 0.6 and 1.0 mm.
[0173] Ezetimibe granulate in accordance with the invention is characterized by particle size distribu tion (PSD) as determined by the dynamic image analysis such as Camsizer. The size of the obtained granulate has value of d(0.5) between 100 and 420 pm, preferably between 150 and 370 pm and more preferably between 190 and 330 pm.
[0174] Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein the diluent used in lg is different than diluent used in step le and disintegrant used in lg is the same as disintegrant used in step le.
[0175] Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein Atorvastatin is present in the form of its any pharmaceutically ac ceptable salts, solvates, hydrates, enantiomers and any mixture thereof in any pharmaceutically accepta ble polymorphic form, preferably Atorvastatin is present in the form of Atorvastatin calcium (2: 1) tri hydrate.
[0176] Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein wetting agent and/or binder of step 2a are dispersed in an organic solvent such as for example ethanol, isopropanol, acetone and any mixture thereof or in water, preferably in purified water. [0177] Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein purified water used in step 2a is pre-heated water at temperature between 30 and 90°C, preferably between 40 and 80°C and more preferably between 50 and 70°C.
[0178] Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein the pharmaceutical excipient used in step 2b is at least one disinte- grant and/or at least one basic alkaline or alkaline earth metal salt (stabilizing agent) and/or at least one diluent.
[0179] Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein homogenization of step 2c is performed in high shear mixer.
[0180] Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein spraying of step 2d is performed with nozzle.
[0181] Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein sieving the granules of step 2f is performed through sieve with open ings between 0.4 and 1.2mm, preferably between 0.5 and 1.1 mm, more preferably between 0.6 and 1.0 mm.
[0182] Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein sieving the granules of step 2h is performed through sieve with openings between 0.4 and 1.2mm, preferably between 0.5 and 1.1 mm, more preferably between 0.6 and 1.0 mm.
[0183] Atorvastatin granulate in accordance with the invention is characterized by particle size distri bution (PSD) as determined by the dynamic image analysis such as Camsizer. The size of the obtained granulate has value of d(0.5) between 50 and 320 pm, preferably between 90 and 280 pm and more preferably between 120 and 250 pm.
[0184] Another embodiment of the invention is the process for the preparation of the solid dosage form according to the invention wherein each compression blend can be used for the compression of the first or for the compression of the second layer.
[0185] Pharmaceutically acceptable excipients used in the process for the preparation of the solid dos age form comprising at least two layers are the same as stated above. [0186] Preferred specific embodiments of the invention are described in the following examples. It is, however, to be understood that the invention is not limited to these examples.
Example 1 : Preparation of Ezetimibe layer
[0187] Table 3 A: Compositions of Ezetimibe layer [mg]
1 active substance; 2 wetting agent; 3 binder; 4 diluent; 5 disintegrant; 6 glidant; 7 lubricant; 8 colorant
[0188] Table 3B: Compositions of Ezetimibe layer [wt.-%]
1 active substance; 2 wetting agent; 3 binder; 4 diluent; 5 disintegrant; 6 glidant; 7 lubricant; 8 colorant [0189] Povidone (binder) was dissolved in purified water thereby obtaining an aqueous binder solution. Ezetimibe was homogenized in the aqueous binder solution with a rotor-stator homogenizer (Examples la-lf, lh) or with high pressure homogenizer (Example lg) thereby obtaining an aqueous suspension. Sodium lauryl sulfate (wetting agent) was dissolved in purified water thereby obtaining an aqueous solution. The aqueous suspension was mixed with the aqueous solution thereby obtaining a granulation liquid.
[0190] The granulation liquid was sprayed with binary nozzle onto a mixture of
- one intragranular diluent (mannitol: Examples lb, lc, Id, If, lg, lh, li; lactose monohydrate: Exam ples la, le) and
- one intragranular disintegrant (sodium croscarmellose: Examples la, lb, lc, Id, lg, lh, li; cro- spovidone: Example le) or two intragranular disintegrants (sodium croscarmellose and cro- spovidone: Example If).
[0191] The thus obtained granules were dried to loss on drying (LOD) of less than 0.8% and sieved through a sieve with openings of 1 mm thereby obtaining a sized granulate with the size of d(0.5) value between 200 and 260 pm (Examples la, lc, Id and lg).
[0192] The sized granulate was blended with
- ferric oxide yellow (colorant), (Examples la, lc, If, lg, lh, li)
- hydrophobic colloidal silica (glidant), (Examples lb, Id)
- one extragranular diluent (microcrystalline cellulose: Examples la, lb, lc, If, lg, lh, li; silicified microcrystalline cellulose: Example Id) or two extragranular diluents (microcrystalline cellulose and silicified microcrystalline cellulose: Example le), and
- one extragranular disintegrant (sodium croscarmellose: Examples la, lb, lc, Id, If, lg, lh, li) to obtain a homogenous blend.
[0193] Finally, one lubricant (sodium stearyl fumarate: Examples lc, Id, If, lg, lh, li; magnesium stearate: Examples lb, le) or two lubricants (sodium stearyl fumarate and magnesium stearate: Example la) were added thereby obtaining a compression blend.
Example 2: Preparation of Atorvastatin layer [0194] Table 4A: Compositions of Atorvastatin layer for Ezetimibe/Atorvastatin 10/80 mg film coated tablets [mg]
1 active substance; 2 wetting agent; 3 binder; 5 disintegrant; 6 glidant; 7 lubricant; 8 stabilizing agent
[0195] Table 4B: Compositions of Atorvastatin layer for Ezetimibe/Atorvastatin 10/80 mg film coated tablets [wt.-%]
1 active substance; 2 wetting agent; 3 binder; 4 diluent; 5 disintegrant; 6 glidant; 7 lubricant; 8 stabilizing agent
[0196] Table 5A: Compositions of Atorvastatin layer for Ezetimibe/Atorvastatin 10/10 mg, 10/20 mg and 10/40 mg film coated tablets [mg] 1 active substance; 2 wetting agent; 3 binder; 4 diluent; 5 disintegrant; 6 glidant; 7 lubricant; 8 stabilizing agent
[0197] Table 5B: Compositions of Atorvastatin layer for Ezetimibe/Atorvastatin 10/10 mg, 10/20 mg and 10/40 mg film coated tablets [wt.-%]
1 active substance; 2 wetting agent; 3 binder; 4 diluent; 5 disintegrant; 6 glidant; 7 lubricant; 8 stabilizing agent
[0198] Polysorbate 80 (wetting agent) and hydroxypropylcellulose (binder) were added to preheated purified water at 55-65°C. The thus obtained dispersion was cooled to below 40°C thereby obtaining a granulation liquid. Atorvastatin was homogenized in a high shear mixer with microcrystalline cellulose and lactose monohydrate (diluents), sodium croscarmellose (disintegrant) and calcium carbonate (basic alkaline or alkaline earth metal salt, stabilizing agent) thereby obtaining a homogenous mixture. The granulation liquid was sprayed with a nozzle onto the homogenous mixture.
[0199] After kneading, densified agglomerated particles were obtained that were afterwards dried and sieved through a sieve with openings 0.8 mm. The thus obtained sieved densified agglomerated particles were dried to loss on drying (LOD) of less than 1.8% and sieved through a sieve with openings of 0.8 mm thereby obtaining a sized granulate with the size of d(0.5) value between 70 and 240 pm (Examples 2c, 2d, 2f, 2g, 2h and 2i). Magnesium stearate (lubricant) and hydrophobic colloidal silica (glidant, Examples 2h, 2i) were added thereby obtaining a compression blend.
Example 3 : Preparation of Ezetimibe/Atorvastatin film coated tablets
[0200] Table 6a: Final bilayer solid dosage forms comprising at least two layers for Ezetimibe/Atorvas tatin 10/80 mg film coated tablets
[0201] Table 6b: Final bilayer solid dosage forms comprising at least two layers for Ezetimibe/ Atorvas- tatin 10/80 mg film coated tablets
[0202] Table 7: Final bilayer solid dosage forms comprising at least two layers for Ezetimibe/ Atorvas tatin 10/10 mg, 10/20 mg, 10/40 mg and 10/80 mg film coated tablets
[0203] In the manufacture of the bilayer tablets of Examples 3a-3g, 3h-3j, and 3k-3p, the compression blend of Examples 2a-2g, 2h-2i, and 2j-2o, respectively, was compressed to form the first layer. After wards, the compression blend of Examples la-li, respectively, was added and compressed with the first layer to form the bilayer tablet.
[0204] In the manufacture of the bilayer tablets of Examples 3k and 31, the compression blend of Ex amples la and lb, respectively, was compressed to form the first layer. Afterwards, the compression blend of Examples 2j and 2k, respectively, was added and compressed with the first layer to form the bilayer tablet.
[0205] All obtained bilayer tablets were subsequently film-coated with Opadry® coating.
Example 4: Dissolution profile of Ezetimibe/ Atorvastatin film coated tablets
[0206] The in vitro dissolution profile for Ezetimibe released from the bilayer tablet of Example 3g (10/80 mg, lg + 2g) was measured in phosphate buffer, pH 6.8 with 0.2% w/v Tween 80 at 75rpm (the recommended dissolution method according to Food and Drug Administration (FDA)). The in vitro dissolution profile for Ezetimibe is shown in Figure 1.
[0207] As demonstrated by Figure 1, the dissolution profile of Ezetimibe released from the bilayer tablet of Example 3g according to the invention satisfies the similarity requirements compared to the dissolution profile of Ezetimibe released from Atozet® 10/80 mg (B.No: S034177) and from Ezetrol® 10 mg (B.No: S027811). In particular, the bilayer tablet of Example 3g according to the invention even provides faster dissolution within the initial 5 minutes. Thus, as demonstrated by Figure 1, the bilayer tablets according to the invention provide an improved in vitro dissolution of Ezetimibe compared to reference product Ezetrol® and reference combination product Atozet®.
[0208] The in vitro dissolution profile for Atorvastatin released from the bilayer tablet of Example 3g (10/80 mg, lg + 2g) was measured in 0.005 M HC1. The in vitro dissolution profile for Atorvastatin is shown in Figure 2.
[0209] As demonstrated by Figure 2, the dissolution profile of Atorvastatin released from the bilayer tablet of Example 3g according to the invention satisfies the similarity requirements compared to the dissolution profile of Atorvastatin released from Atozet® 10/80 mg (B.No: S034177) and from Sortis® 80 mg (B.No: CK1527).
Example 5 : Chemical stability of Ezetimibe/ Atorvastatin film coated tablets
[0210] Chemical stability of solid dosage forms comprising at least two layers of the invention pack aged in Alu/alu blister packaging (flushed with nitrogen) is comparable to Atozet®, Ezetrol® and Sortis® (Table 8). The chemical stability of samples was tested under accelerated storage conditions (i.e. 40°C/ 75% r.h.) for three months.
Table 8: Accelerated stability results of solid dosage forms comprising at least two layers of the inven tion, Atozet® (10/80 mg (R019711)), Sortis® (80 mg (W53718)) and Ezetrol® (10 mg (N034153)): after n.d. n.d. n.d. n.d. n.d. 0.13 0.25
* as defined by Ph. Eur.; b.l.r. - below the limit of reporting (< 0.10%); Atorvastatin impurities were not analyzed for Ezetrol® and Ezetimibe impurities were not determined (n.d.) for Sortis®, since
Ezetrol® contains no Atorvastatin and Sortis ®® contains no Ezetimibe.
[0211] As demonstrated by the data in Table 8, the chemical stability of Ezetimibe and Atorvastatin in the bilayer table of Example 3c according to the invention satisfies the stability requirements. In partic ular, the stability of Ezetimibe in the bilayer table of Example 3c according to the invention is even better than the stability of Ezetimibe in reference product Ezetrol® (10 mg (N034153)) and reference combination product Atozet® (10/80 mg (R019711)). Likewise, the stability of Atorvastatin in the bi layer table of Example 3c according to the invention is even better than the stability of Atorvastatin in reference product Sortis® (80 mg (W53718)) and reference combination product Atozet® (10/80 mg (R019711)).

Claims

Patent claims:
1. A solid pharmaceutical dosage form comprising
- an Ezetimibe layer comprising Ezetimibe, a pharmaceutically acceptable salt and/or solvate thereof; a first diluent; optionally, a second diluent; and optionally, a first binder; preferably, wherein the Ezetimibe layer comprises an intragranular phase and optionally an extragranular phase; and
- an Atorvastatin layer comprising Atorvastatin, a pharmaceutically acceptable salt and/or solv ate thereof; preferably, wherein the Atorvastatin layer comprises an intragranular phase and optionally an extragranular phase; wherein
- the first diluent of the Ezetimibe layer is a sugar alcohol; preferably, mannitol; and/or
- the optionally first binder of the Ezetimibe layer is a polyvinylpyrrolidone.
2. The dosage form according to claim 1, wherein the first diluent is a sugar alcohol; preferably selected from the group consisting of mannitol, sorbitol, maltitol, xylitol, lactitol, and erythritol, and mixtures thereof; more preferably mannitol.
3. The dosage form according to claim 1 or 2, wherein essentially the total amount of the first diluent is comprised in the intragranular phase of the Ezetimibe layer.
4. The dosage form according to any of the preceding claims, wherein the weight content of the first diluent is
- at least 7.5 wt.-%, preferably at least 10 wt.-%, more preferably at least 12.5 wt.-%, still more preferably at least 15 wt.-%, yet more preferably at least 17.5 wt.-%, even more preferably at least 20 wt.-%, most preferably at least 22.5 wt.-%, and in particular at least 25 wt.-%;
- at most 72.5 wt.-%, preferably at most 70 wt.-%, more preferably at most 67.5 wt.-%, still more preferably at most 65 wt.-%, yet more preferably at most 62.5 wt.-%, even more prefer ably at most 60 wt.-%, most preferably at most 57.5 wt.-%, and in particular at most 55 wt- %; and/or
- within the range of 30±5.0 wt.-%, 35±10 wt.-%, 35±5.0 wt.-%, 40±10 wt.-%, 40±5.0 wt.-%, 45±10 wt.-%, 45±5.0 wt.-%, or 50±5.0 wt.-%; in each case relative to the total weight of the Ezetimibe layer.
5. The dosage form according to any of the preceding claims, wherein essentially the total amount of the first binder is comprised in the intragranular phase of the Ezetimibe layer.
6. The dosage form according to any of the preceding claims, wherein the first binder is selected from the group consisting of
- povidone (polyvinylpyrrolidone) or copovidone (vinylpyrrolidone-vinyl acetate copolymer);
- cellulose; preferably powdered cellulose, crystalline cellulose, microcrystalline cellulose, si- licified microcrystalline cellulose;
- cellulose derivatives, cellulose esters or cellulose ethers; preferably hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose or hydroxypropylmethylcellulose;
- polyvinyl alcohol;
- starch or starch derivatives; preferably com starch, potato starch, rice starch, a-starch, or pre gelatinized starch;
- mono- or polysaccharides; preferably dextrin, gum arabic, or pullulan;
- poly(meth)acrylates; and
- mixtures thereof; preferably povidone (polyvinylpyrrolidone) or copovidone (vinylpyrrolidone-vinyl acetate copol ymer); more preferably povidone (polyvinylpyrrolidone).
7. The dosage form according to any of the preceding claims, wherein the weight content of the first binder is
- at least 0.1 wt.-%, preferably at least 0.3 wt.-%, more preferably at least 0.5 wt.-%, still more preferably at least 0.7 wt.-%, yet more preferably at least 0.9 wt.-%, even more preferably at least 1.1 wt.-%, most preferably at least 1.3 wt.-%, and in particular at least 1.5 wt.-%;
- at most 5.9 wt.-%, preferably at most 5.7 wt.-%, more preferably at most 5.5 wt.-%, still more preferably at most 5.3 wt.-%, yet more preferably at most 5.1 wt.-%, even more preferably at most 4.9 wt.-%, most preferably at most 4.7 wt.-%, and in particular at most 4.5 wt.-%; and/or
- within the range of2.0±0.5 wt.-%, 2.5±1.0 wt.-%, 2.5±0.5 wt.-%, 3.0±1.0 wt.-%, 3.0±0.5 wt.- %, 3.5±1.0 wt.-%, 3.5±0.5 wt.-%, or 4.0±0.5 wt.-%; in each case relative to the total weight of the Ezetimibe layer.
8. The dosage form according to any of the preceding claims, wherein at least a fraction or essen tially the total amount of the second diluent is comprised in the intragranular phase of the Ezetimibe layer.
9. The dosage form according to any of the preceding claims, wherein essentially the total amount of the second diluent is comprised in the extragranular phase of the Ezetimibe layer.
10. The dosage form according to any of the preceding claims, wherein the second diluent is selected from the group consisting of
- lactose; preferably anhydrous lactose, lactose hydrate, partially amorphous lactose, completely amorphous lactose;
- starch or starch derivatives; preferably partially or wholly pregelatinized starch, com starch, wheat starch, rice starch, tapioca starch, potato starch;
- cellulose or cellulose derivatives; preferably powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, co-processed microcrystalline cellulose with other excip ients such as lactose, starch, silicon dioxide, and mannitol;
- monosaccharides, disaccharides, oligosaccharides and sugar alcohols; preferably glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, a-lactose, b-lactose, raffmose, iso maltose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol, or com pressible sugars; and
- mixture thereof; preferably microcrystalline cellulose which may optionally be silicified, lactose monohydrate, and mixtures thereof; more preferably microcrystalline cellulose which may optionally be silici fied.
11. The dosage form according to any of the preceding claims, wherein the weight content of the second diluent is
- at least 8.0 wt.-%, preferably at least 10 wt.-%, more preferably at least 12 wt.-%, still more preferably at least 14 wt.-%, yet more preferably at least 16 wt.-%, even more preferably at least 18 wt.-%, most preferably at least 20 wt.-%, and in particular at least 22 wt.-%;
- at most 71 wt.-%, preferably at most 69 wt.-%, more preferably at most 67 wt.-%, still more preferably at most 65 wt.-%, yet more preferably at most 63 wt.-%, even more preferably at most 61 wt.-%, most preferably at most 59 wt.-%, and in particular at most 57 wt.-%; and/or within the range of 25±5.0 wt.-%, 30±10 wt.-%, 30±5.0 wt.-%, 35±10 wt.-%, 35±5.0 wt.-%, 40±10 wt.-%, 40±5.0 wt.-%, 45±10 wt.-%, 45±5.0 wt.-%, or 50±5.0 wt.-%; in each case relative to the total weight of the Ezetimibe layer.
12. The dosage form according to any of the preceding claims, wherein the Ezetimibe layer comprises no lactose, i.e. neither lactose monohydrate, nor lactose dihydrate, nor anhydrous lactose, nor spray-dried lactose, nor crystalline lactose, nor partially amorphous lactose, nor completely amor phous lactose.
13. The dosage form according to any of the preceding claims, wherein the Ezetimibe, pharmaceuti cally acceptable salt and/or solvate thereof is present in the non-salt non-solvate form of Ezetimibe.
14. The dosage form according to any of the preceding claims, wherein the weight content of the Ezetimibe, pharmaceutically acceptable salt and/or solvate thereof is
- at least 1.0 wt.-%, preferably at least 1.5 wt.-%, more preferably at least 2.0 wt.-%, still more preferably at least 2.5 wt.-%, yet more preferably at least 3.0 wt.-%, even more preferably at least 3.5 wt.-%, most preferably at least 4.0 wt.-%, and in particular at least 4.5 wt.-%;
- at most 9.5 wt.-%, preferably at most 9.0 wt.-%, more preferably at most 8.5 wt.-%, still more preferably at most 8.0 wt.-%, yet more preferably at most 7.5 wt.-%, even more preferably at most 7.0 wt.-%, most preferably at most 6.5 wt.-%, and in particular at most 6.0 wt.-%; and/or
- within the range of 5.0±0.5 wt.-% or 5.5±0.5 wt.-%; in each case expressed as equivalent weight relative to the non-salt non-solvate form of Ezetimibe and relative to the total weight of the Ezetimibe layer.
15. The dosage form according to any of the preceding claims, wherein essentially the total amount of the Ezetimibe, pharmaceutically acceptable salt and/or solvate thereof comprised in the dosage form is present in the Ezetimibe layer.
16. The dosage form according to any of the preceding claims, wherein essentially the total amount of the Ezetimibe, pharmaceutically acceptable salt and/or solvate thereof comprised in the Ezetimibe layer is present in the intragranular phase of the Ezetimibe layer.
17. The dosage form according to any of the preceding claims, wherein the Ezetimibe layer comprises a first disintegrant, preferably sodium croscarmellose; and optionally a second disintegrant; pref erably crospovidone.
18. The dosage form according to claim 17, wherein at least a fraction of the first disintegrant is comprised in the intragranular phase of the Ezetimibe layer.
19. The dosage form according to claim 17 or 18, wherein at least a fraction of the first disintegrant is comprised in the extragranular phase of the Ezetimibe layer.
20. The dosage form according to claim 19, wherein the relative weight ratio of the fraction of the first disintegrant comprised in the intragranular phase of the Ezetimibe layer and of the fraction of the first disintegrant comprised in the extragranular phase of the Ezetimibe layer is within the range of from 0.1 to 0.9, preferably from 0.2 to 0.8, and more preferably from 0.3 to 0.7.
21. The dosage form according to any of claims 17 to 20, wherein at least a fraction or essentially the total amount of the optionally present second disintegrant is comprised in the intragranular phase of the Ezetimibe layer.
22. The dosage form according to any of claims 17 to 21, wherein the first disintegrant and the op tionally second disintegrant are independently of another selected from the group consisting of
- cellulose or cellulose derivatives; preferably microcrystalline cellulose, methylcellulose, so dium salts of carboxymethyl cellulose, calcium salts of carboxymethyl cellulose, or cross- linked carboxymethylcellulose, e.g. croscarmellose sodium and/or croscarmellose calcium; preferably croscarmellose sodium;
- crospovidone;
- starch or starch derivatives; preferably starch, maize starch, pregelatinized starch, sodium starch glycollate, modified starch, hydroxypropyl starch, or carboxymethyl starch;
- polacrilin potassium or docusate sodium;
- cellulose ethers; preferably low substituted hydroxypropylcellulose (L-HPC);
- heteroglycanes; preferably alginic acid or alginates, e.g. sodium alginate or calcium alginate; agar, guar gum, or gums;
- polyacrylates;
- glucosamines; preferably chitosan; and
- mixtures thereof; preferably croscarmellose sodium, crospovidone and mixtures thereof; more preferably croscar mellose sodium.
23. The dosage form according to any of claims 17 to 22, wherein the total weight content of the first disintegrant and the optionally present second disintegrant is
- at least 3.5 wt.-%, preferably at least 4.0 wt.-%, more preferably at least 4.5 wt.-%, still more preferably at least 5.5 wt.-%, yet more preferably at least 6.0 wt.-%, even more preferably at least 6.5 wt.-%, most preferably at least 7.0 wt.-%, and in particular at least 7.5 wt.-%;
- at most 16.5 wt.-%, preferably at most 16 wt.-%, more preferably at most 15.5 wt.-%, still more preferably at most 15 wt.-%, yet more preferably at most 14.5 wt.-%, even more prefer ably at most 14 wt.-%, most preferably at most 13.5 wt.-%, and in particular at most 13 wt- %; and/or
- within the range of 9.0±1.0 wt.-%, 10±2.0 wt.-%, 10±1.0 wt.-%, ll±2.0 wt.-%, l l±1.0 wt.-%, 12±1.0 wt.-%; in each case relative to the total weight of the Ezetimibe layer.
24. The dosage form according to any of the preceding claims, wherein the Ezetimibe layer comprises a first wetting agent.
25. The dosage form according to claim 24, wherein essentially the total amount of the first wetting agent is comprised in the intragranular phase of the Ezetimibe layer.
26. The dosage form according to claim 24 or 25, wherein the first wetting agent is selected from the group consisting of cationic surfactants, anionic surfactants, zwitterionic surfactants and non ionic surfactants; preferably an anionic surfactant; more preferably sodium lauryl sulfate.
27. The dosage form according to any of claims 24 to 26, wherein the weight content of the first wetting agent is
- at least 0.3 wt.-%, preferably at least 0.4 wt.-%, more preferably at least 0.5 wt.-%, still more preferably at least 0.6 wt.-%, yet more preferably at least 0.7 wt.-%, even more preferably at least 0.8 wt.-%, most preferably at least 0.9 wt.-%, and in particular at least 1.0 wt.-%;
- at most 7.5 wt.-%, preferably at most 7.0 wt.-%, more preferably at most 6.5 wt.-%, still more preferably at most 6.0 wt.-%, yet more preferably at most 5.5 wt.-%, even more preferably at most 5.0 wt.-%, most preferably at most 4.5 wt.-%, and in particular at most 4.0 wt.-%; and/or
- within the range of 2.0±1.0 wt.-% or 3.0±1.0 wt.-%; in each case relative to the total weight of the Ezetimibe layer.
28. The dosage form according to any of the preceding claims, wherein the Atorvastatin, pharmaceu tically acceptable salt and/or solvate thereof is present in the form of Atorvastatin calcium (2: 1); preferably Atorvastatin calcium (2:1) trihydrate.
29. The dosage form according to any of the preceding claims, wherein the weight content of the Atorvastatin, pharmaceutically acceptable salt and/or solvate thereof is
- at least 6.0 wt.-%, preferably at least 6.5 wt.-%, more preferably at least 7.0 wt.-%, still more preferably at least 7.5 wt.-%, yet more preferably at least 8.0 wt.-%, even more preferably at least 8.5 wt.-%, most preferably at least 9.0 wt.-%, and in particular at least 9.5 wt.-%;
- at most 17 wt.-%, preferably at most 16.5 wt.-%, more preferably at most 16 wt.-%, still more preferably at most 15.5 wt.-%, yet more preferably at most 15 wt.-%, even more preferably at most 14.5 wt.-%, most preferably at most 14 wt.-%, and in particular at most 13.5 wt.-%; and/or
- within the range of 10± 1.0 wt.-%, l l±2.0 wt.-%, l l±1.0 wt.-%, 12±2.0 wt.-%, 12±1.0 wt.-%, or 13±1.0 wt.-%; in each case expressed as the actual weight of the Atorvastatin, pharmaceutically acceptable salt and/or solvate thereof and relative to the total weight of the Atorvastatin layer.
30. The dosage form according to any of the preceding claims, wherein essentially the total amount of the Atorvastatin, pharmaceutically acceptable salt and/or solvate thereof comprised in the dos age form is present in the Atorvastatin layer.
31. The dosage form according to any of the preceding claims, wherein essentially the total amount of the Atorvastatin, pharmaceutically acceptable salt and/or solvate thereof comprised in the Atorvastatin layer is present in the intragranular phase of the Atorvastatin layer.
32. The dosage form according to any of the preceding claims, wherein the Atorvastatin layer com prises a basic alkaline or alkaline earth metal salt.
33. The dosage form according to claim 32, wherein the basic alkaline or alkaline earth metal salt is selected from the group consisting of calcium carbonate, calcium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, dibasic cal cium phosphate, tribasic calcium phosphate, calcium sulfate, calcium acetate, calcium gluconate, calcium glycerol phosphate, magnesium carbonate, magnesium hydroxide, magnesium sulfate, magnesium acetate, magnesium silicate, magnesium aluminate or mixtures thereof; preferably calcium carbonate.
34. The dosage form according to claim 32 or 33, wherein essentially the total amount of the basic alkaline or alkaline earth metal salt is comprised in the intragranular phase of the Atorvastatin layer.
35. The dosage form according to any of claims 32 to 34, wherein the weight content of the basic alkaline or alkaline earth metal salt is
- at least 18 wt.-%, preferably at least 20 wt.-%, more preferably at least 22 wt.-%, still more preferably at least 24 wt.-%, yet more preferably at least 26 wt.-%, even more preferably at least 28 wt.-%, most preferably more than 30 wt.-%, and in particular at least 31 wt.-%;
- at most 47 wt.-%, preferably at most 46 wt.-%, more preferably at most 45 wt.-%, still more preferably at most 44 wt.-%, yet more preferably at most 43 wt.-%, even more preferably at most 42 wt.-%, most preferably at most 41 wt.-%, and in particular at most 40 wt.-%; and/or
- within the range of 32.5±5.0 wt.-%, 35±5.0 wt.-%, or 37.5±5 wt.-%; in each case relative to the total weight of the Ezetimibe layer.
36. The dosage form according to any of the preceding claims, wherein the Atorvastatin layer com prises a third diluent; preferably lactose; more preferably lactose monohydrate.
37. The dosage form according to claim 36, wherein at least a fraction or essentially the total amount of the third diluent is comprised in the intragranular phase of the Atorvastatin layer.
38. The dosage form according to claim 36 or 37, wherein the weight content of the third diluent is
- at least 5.0 wt.-%, preferably at least 7.0 wt.-%, more preferably at least 9.0 wt.-%, still more preferably at least 11 wt.-%, yet more preferably at least 13 wt.-%, even more preferably at least 15 wt.-%, most preferably at least 17 wt.-%, and in particular at least 19 wt.-%;
- at most 42 wt.-%, preferably at most 40 wt.-%, more preferably at most 38 wt.-%, still more preferably at most 36 wt.-%, yet more preferably at most 34 wt.-%, even more preferably at most 32 wt.-%, most preferably at most 30 wt.-%, and in particular at most 28 wt.-%; and/or
- within the range of from 20±2.5 wt.-%, 22.5±2.5 wt.-%, or 25±2.5 wt.-%; in each case relative to the total weight of the Atorvastatin layer.
39. The dosage form according to any of the preceding claims, wherein the Atorvastatin layer com prises a fourth diluent; preferably microcrystalline cellulose which may optionally be silicified.
40. The dosage form according to claim 39, wherein at least a fraction or essentially the total amount of the fourth diluent is comprised in the intragranular phase of the Atorvastatin layer.
41. The dosage form according to claim 39 or 40, wherein the weight content of the fourth diluent is
- at least 5.0 wt.-%, preferably at least 7.0 wt.-%, more preferably at least 9.0 wt.-%, still more preferably at least 11 wt.-%, yet more preferably at least 13 wt.-%, even more preferably at least 15 wt.-%, most preferably at least 17 wt.-%, and in particular at least 19 wt.-%;
- at most 37 wt.-%, preferably at most 35 wt.-%, more preferably at most 33 wt.-%, still more preferably at most 31 wt.-%, yet more preferably at most 29 wt.-%, even more preferably at most 27 wt.-%, most preferably at most 25 wt.-%, and in particular at most 23 wt.-%; and/or
- within the range of 20.5±1.0 wt.-%, 21±2.0 wt.-%, 21±1.0 wt.-%, or 21.5±1.0 wt.-%; in each case relative to the total weight of the Atorvastatin layer.
42. The dosage form according to any of the preceding claims, wherein the Atorvastatin layer com prises a second binder; preferably a cellulose ether; more preferably hydroxypropylcellulose.
43. The dosage form according to claim 42, wherein essentially the total amount of the second binder is comprised in the intragranular phase of the Atorvastatin layer.
44. The dosage form according to claim 42 or 43, wherein the weight content of the second binder is
- at least 0.8 wt.-%, preferably at least 1.1 wt.-%, more preferably at least 1.4 wt.-%, still more preferably at least 1.7 wt.-%, yet more preferably at least 2.0 wt.-%, even more preferably at least 2.3 wt.-%, most preferably at least 2.6 wt.-%, and in particular at least 2.9 wt.-%;
- at most 5.6 wt.-%, preferably at most 5.3 wt.-%, more preferably at most 5.0 wt.-%, still more preferably at most 4.7 wt.-%, yet more preferably at most 4.4 wt.-%, even more preferably at most 4.1 wt.-%, most preferably at most 3.8 wt.-%, and in particular at most 3.5 wt.-%; and/or
- within the range of 3.0±0.5 wt.-% or 3.5±0.5 wt.-%; in each case relative to the total weight of the Atorvastatin layer.
45. The dosage form according to any of the preceding claims, wherein the Atorvastatin layer com prises a third disintegrant, preferably sodium croscarmellose.
46. The dosage form according to claim 45, wherein at least a fraction or essentially the total amount of the third disintegrant is comprised in the intragranular phase of the Atorvastatin layer.
47. The dosage form according to claim 45 or 46, wherein the weight content of the third disintegrant is
- at least 2.6 wt.-%, preferably at least 3.0 wt.-%, more preferably at least 3.4 wt.-%, still more preferably at least 3.8 wt.-%, yet more preferably at least 4.2 wt.-%, even more preferably at least 4.6 wt.-%, most preferably at least 5.0 wt.-%, and in particular at least 5.4 wt.-%;
- at most 16 wt.-%, preferably at most 15 wt.-%, more preferably at most 14 wt.-%, still more preferably at most 13 wt.-%, yet more preferably at most 12 wt.-%, even more preferably at most 11 wt.-%, most preferably at most 10 wt.-%, and in particular at most 9.0 wt.-%; and/or
- within the range of 6.0±1.0 wt.-%, 7.0±2.0 wt.-%, 7.0±1.0 wt.-%, or 8.0±1.0 wt.-%; in each case relative to the total weight of the Atorvastatin layer.
48. The dosage form according to any of the preceding claims, wherein the Atorvastatin layer com prises a second wetting agent; preferably polysorbate (ethoxylated sorbitan fatty acid esters); more preferably polysorbate 80 (polyoxyethylene(20)-sorbitan-monooleate).
49. The dosage form according to claim 48, wherein essentially the total amount of the second wetting agent is comprised in the intragranular phase of the Atorvastatin layer.
50. The dosage form according to claim 48 or 49, wherein the weight content of the second wetting agent is
- at least 0.1 wt.-%, preferably at least 0.15 wt.-%, more preferably at least 0.2 wt.-%, still more preferably at least 0.25 wt.-%, yet more preferably at least 0.3 wt.-%, even more preferably at least 0.35 wt.-%, most preferably at least 0.4 wt.-%, and in particular at least 0.45 wt.-%;
- at most 1.4 wt.-%, preferably at most 1.3 wt.-%, more preferably at most 1.2 wt.-%, still more preferably at most 1.1 wt.-%, yet more preferably at most 1.0 wt.-%, even more preferably at most 0.9 wt.-%, most preferably at most 0.8 wt.-%, and in particular at most 0.7 wt.-%; and/or
- within the range of 0.6±0.1 wt.-%; in each case relative to the total weight of the Atorvastatin layer.
51. The dosage form according to any of the preceding claims, wherein the weight ratio of the Ezetimibe layer to the Atorvastatin layer is within the range of from 0.1 to 6, preferably from 0.15 to 4, and more preferably from 0.2 to 2.
52. The dosage form according to any of the preceding claims, wherein the dosage form does not contain any other pharmaceutically active ingredients besides the Ezetimibe, pharmaceutically acceptable salt and/or solvate thereof and the Atorvastatin, pharmaceutically acceptable salt and/or solvate thereof.
53. The dosage form according to any of the preceding claims, which is a bilayer tablet; preferably a fdm-coated bilayer tablet.
54. The dosage form according to any of the preceding claims, which under in vitro conditions in accordance with USP paddle method, optionally equipped with 7-coil helical sinker, at 75 rpm and 37±0.5°C in in 900 mL of phosphate buffer at pH 6.8 with 0.2% w/v Tween 80 has released after 5 minutes at least 50% of the content of Ezetimibe that was originally contained in the dosage form, preferably at least 55%, more preferably at least 60%, still more preferably at least 65%, most preferably at least 70%, and in particular at least 75%.
55. The dosage form according to any of the preceding claims, wherein the Ezetimibe layer comprises
- 53±40 wt.-%, preferably 53±35 wt.-%, more preferably 53±30 wt.-%, still more preferably 53±25 wt.-%, yet more preferably 53±20 wt.-%, even more preferably 53±15 wt.-%, most preferably 53±10 wt.-%, and in particular 53±5 wt.-% of first diluent; preferably sugar alcohol; more preferably mannitol; preferably in the intragranular phase of the Ezetimibe layer; and/or
- no lactose; and/or
- 1.5±1.4 wt.-%, preferably 1.5±1.2 wt.-%, more preferably 1.5±1.0 wt.-%, still more preferably 1.5±0.8 wt.-%, yet more preferably 1.5±0.6 wt.-%, even more preferably 1.5±0.4 wt.-%, most preferably 1.5±0.2 wt.-% of lubricant; preferably sodium stearyl fumarate; preferably in the extragranular phase of the Ezetimibe layer; and/or
- no magnesium stearate; in each case relative to the total weight of the Ezetimibe layer.
56. The dosage form according to any of the preceding claims, wherein the Ezetimibe layer comprises
- 24±20 wt.-%, preferably 24±18 wt.-%, more preferably 24±16 wt.-%, still more preferably 24±14 wt.-%, yet more preferably 24±12 wt.-%, even more preferably 24±10 wt.-%, most preferably 24±8 wt.-%, and in particular 24±6 wt.-% of second diluent; preferably microcrys- talline cellulose; preferably in the extragranular phase of the Ezetimibe layer; and/or
- 10±9 wt.-%, preferably 10±8 wt.-%, more preferably 10±7 wt.-%, still more preferably 10±6 wt.-%, yet more preferably 10±5 wt.-%, even more preferably 10±4 wt.-%, most preferably 10±3 wt.-%, and in particular 10±2 wt.-% of first disintegrant; preferably sodium croscarmel- lose; preferably a fraction in the intragranular phase of the Ezetimibe layer and a fraction in the extragranular phase of the Ezetimibe layer; preferably wherein the relative weight ratio of the fraction comprised in the intragranular phase of the Ezetimibe layer and of the fraction comprised in the extragranular phase of the Ezetimibe layer is within the range of from 0.3 to 0.7; and/or
- 5.0±4.5 wt.-%, preferably 5.0±4.0 wt.-%, more preferably 5.0±3.5 wt.-%, still more preferably 5.0±3.0 wt.-%, yet more preferably 5.0±2.5 wt.-%, even more preferably 5.0±2.0 wt.-%, most preferably 5.0±1.5 wt.-%, and in particular 5.0± 1.0 wt.-% of Ezetimibe in the non-solvate non salt form; preferably in the intragranular phase of the Ezetimibe layer; and/or
- 3.0±2.7 wt.-%, preferably 3.0±2.4 wt.-%, more preferably 3.0±2.1 wt.-%, still more preferably 3.0±1.8 wt.-%, yet more preferably 3.0±1.5 wt.-%, even more preferably 3.0±1.2 wt.-%, most preferably 3.0±0.9 wt.-%, and in particular 3.0±0.6 wt.-% of first binder; preferably polyvi nylpyrrolidone; preferably in the intragranular phase of the Ezetimibe layer; and/or
- 3 0±2.7 wt.-%, preferably 3 0±2.4 wt.-%, more preferably 3 0±2.1 wt.-%, still more preferably 3.0±1.8 wt.-%, yet more preferably 3.0±1.6 wt.-%, even more preferably 3.0±1.4 wt.-%, most preferably 3.0±1.2 wt.-%, and in particular 3.0±1.0 wt.-% of first wetting agent; preferably sodium lauryl sulfate; preferably in the intragranular phase of the Ezetimibe layer; in each case relative to the total weight of the Ezetimibe layer.
57. The dosage form according to any of the preceding claims, wherein the Atorvastatin layer com prises at least 12 wt.-%, preferably at least 15 wt.-%, more preferably at least 18 wt.-%, still more preferably at least 21 wt.-%, yet more preferably at least 24 wt.-%, even more preferably at least 27 wt.-%, most preferably more than 30 wt.-%, and in particular at least 31 wt.-% of basic alkaline or alkaline earth metal salt; preferably calcium carbonate; preferably in the intragranular phase of the Atorvastatin layer; in each case relative to the total weight of the Atorvastatin layer.
58. The dosage form according to any of the preceding claims, wherein the Atorvastatin layer com prises
- 27±20 wt.-%, preferably 27±18 wt.-%, more preferably 27±16 wt.-%, still more preferably 27±14 wt.-%, yet more preferably 27±12 wt.-%, even more preferably 27±10 wt.-%, most preferably 27±8 wt.-%, and in particular 27±6 wt.-% of third diluent; preferably lactose; more preferably lactose monohydrate; preferably in the intragranular phase of the Atorvastatin layer; and/or
- 20±18 wt.-%, preferably 20±16 wt.-%, more preferably 20±14 wt.-%, still more preferably 20±12 wt.-%, yet more preferably 20±10 wt.-%, even more preferably 20±8 wt.-%, most pref erably 20±6 wt.-%, and in particular 20±4 wt.-% of fourth diluent; preferably microcrystalline cellulose; preferably in the intragranular phase of the Atorvastatin layer; and/or - 11±10 wt.-%, preferably 11±9 wt.-%, more preferably 11±8 wt.-%, still more preferably 11±7 wt.-%, yet more preferably 11±6 wt.-%, even more preferably 11±5 wt.-%, most preferably 11±4 wt.-%, and in particular 11±3 wt.-% of Atorvastatin calcium trihydrate; preferably in the intragranular phase of the Atorvastatin layer; and/or
- 6.0±5.5 wt.-%, preferably 6.0±5.0 wt.-%, more preferably 6.0±4.5 wt.-%, still more preferably 6.0±4.0 wt.-%, yet more preferably 6.0±3.5 wt.-%, even more preferably 6.0±3.0 wt.-%, most preferably 6.0±2.5 wt.-%, and in particular 6.0±2.0 wt.-% of third disintegrant; preferably so dium croscarmellose; preferably in the intragranular phase of the Atorvastatin layer; and/or
- 3.0±2.7 wt.-%, preferably 3.0±2.4 wt.-%, more preferably 3.0±2.1 wt.-%, still more preferably 3.0±1.8 wt.-%, yet more preferably 3. Oil.6 wt.-%, even more preferably 3.0il.4 wt.-%, most preferably 3. Oil.2 wt.-%, and in particular 3.0il.0 wt.-% of second binder; preferably hy- droxypropylcellulose; preferably in the intragranular phase of the Atorvastatin layer; and/or
- 0.6i0.5 wt.-%, preferably 0.6i0.4 wt.-%, more preferably 0.6i0.3 wt.-%, still more preferably 0.6i0.2 wt.-%, yet more preferably 0.6i0.1 wt.-% of second wetting agent; preferably poly- sorbate; more preferably polysorbate 80; preferably in the intragranular phase of the Atorvas tatin layer; in each case relative to the total weight of the Atorvastatin layer.
59. The dosage form according to any of the preceding claims, wherein the Ezetimibe layer is pre pared by wet granulation; preferably aqueous wet granulation.
60. The dosage form according to any of the preceding claims, wherein the Atorvastatin layer is pre pared by wet granulation; preferably aqueous wet granulation.
61. A process for the preparation of the solid dosage form according to any of the preceding claims comprising the steps of
A) preparing an Ezetimibe compression blend comprising the sub-steps: a) dispersing a first binder in a suitable liquid thereby obtaining a dispersion; b) homogenizing Ezetimibe, a pharmaceutically acceptable salt and/or solvate thereof in the dispersion obtained in sub-step a) thereby obtaining a suspension; c) dispersing a first wetting agent in a suitable liquid thereby obtaining a dispersion; d) mixing the suspension obtained in sub-step b) and the dispersion obtained in sub-step c) thereby obtaining a granulation liquid; e) spraying the granulation liquid onto a mixture comprising a first diluent, at least a fraction of a first disintegrant and optionally, a second disintegrant thereby obtaining granules; f) drying and sieving the granules obtained in sub-step e) thereby obtaining a granulate; g) blending the granulate obtained in sub-step f) with at least one pharmaceutical excip ient thereby obtaining a homogenous blend; and h) adding a lubricant to the homogenous blend obtained in sub-step g) thereby obtaining the Ezetimibe compression blend;
B) preparing an Atorvastatin compression blend comprising the sub-steps: i) dispersing a second wetting agent and/or a second binder in a suitable liquid thereby obtaining a dispersion; j) homogenizing Atorvastatin, a pharmaceutically acceptable salt and/or solvate thereof with at least one pharmaceutically acceptable excipient, preferably by means of a ho- mogenizer, thereby obtaining a homogenous mixture; k) spraying the dispersion obtained in sub-step step i) onto the homogenous mixture ob tained in sub-step j) thereby obtaining granules; l) kneading the granules obtained in sub-step k) thereby obtaining densified agglomer ated particles; m) drying the densified agglomerated particles obtained in sub-step 1) thereby obtaining dried densified agglomerated particles; n) sieving the dried densified agglomerated particles obtained in sub-step m) thereby ob taining sieved agglomerated particles; o) drying the sieved agglomerated particles obtained in sub-step n) thereby obtaining a dry granulate; p) adding a lubricant to the dry granulate obtained in sub-step o) thereby obtaining the Atorvastatin compression blend;
C) compressing a layered tablet having a first layer made from the Ezetimibe compression blend prepared in step A) or from the Atorvastatin compression blend prepared in step B); and a second layer made from the other of the two compression blends; and
D) optionally, film-coating the layered tablet obtained in step C).
62. The process according to claim 61, wherein sub-step a) involves dissolving the first binder in an organic solvent or in water.
63. The process according to claim 61 or 62, wherein sub-step c) involves dissolving the first wetting agent in an organic solvent or in water.
64. The process according to any of claims 61 to 63, wherein in sub-step g) the at least one pharma ceutical excipient comprises a second diluent and at least a fraction of the first disintegrant.
65. The process according to any of claims 61 to 64, wherein sub-step i) involves dispersing the sec ond wetting agent and/or the second binder in an organic liquid or water.
66. The process according to any of claims 61 to 65, wherein step C) involves the sub-steps of q) filling a tablet press with a predetermined amount of the Ezetimibe compression blend pre pared in step A) or of the Atorvastatin compression blend prepared in step B); r) compressing the predetermined amount thereby obtaining the first layer of the layered tablet; s) filling the tablet press with a predetermined amount of the other of the two compression blends; t) compressing the first layer simultaneously with the predetermined amount thereby obtaining the layered tablet; and u) removing the layered tablet from the table press.
67. A solid dosage form obtainable by a process according to any of claims 61 to 66.
EP21755380.9A 2020-07-27 2021-07-23 Bilayer tablet comprising ezetimibe and atorvastatin Pending EP4188338A1 (en)

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PCT/EP2021/070680 WO2022023206A1 (en) 2020-07-27 2021-07-23 Bilayer tablet comprising ezetimibe and atorvastatin

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FI94339C (en) 1989-07-21 1995-08-25 Warner Lambert Co Process for the preparation of pharmaceutically acceptable [R- (R *, R *)] - 2- (4-fluorophenyl) -, - dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H- for the preparation of pyrrole-1-heptanoic acid and its pharmaceutically acceptable salts
US5631365A (en) 1993-09-21 1997-05-20 Schering Corporation Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
EP1741427A1 (en) * 2005-07-06 2007-01-10 KRKA, D.D., Novo Mesto Pharmaceutical composition comprising simvastatin and ezetimibe
US20070014854A1 (en) 2005-07-15 2007-01-18 Ilan Zalit Novel granulation process
US20070014864A1 (en) 2005-07-15 2007-01-18 Teva Pharmaceutical Industries, Ltd. Novel pharmaceutical granulate
NZ592194A (en) 2008-09-17 2013-04-26 Mylan Inc Reversed wet granulation process for preparing granulates and pharmaceutical products containing them
EP2448564A2 (en) 2009-07-02 2012-05-09 Bilgic Mahmut Solubility enhancing pharmaceutical formulation
WO2013166114A1 (en) 2012-05-01 2013-11-07 Althera Life Sciences, Llc Oral tablet formulation consisting of fixed combination of atorvastatin and ezetimibe
CZ2016539A3 (en) * 2016-09-05 2018-03-14 Zentiva, K.S. A pharmaceutical composition comprising two different active substances and a method of its preparation
TR201702101A2 (en) 2017-02-13 2018-08-27 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi ATORVASTATIN CALCIUM AND EZETIMIBIN PHARMACEUTICAL TWO-LAYER TABLET COMPOSITION
TR201820324A2 (en) 2018-12-25 2020-07-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi ATORVASTATIN CALCIUM AND EZETİMİBİN PHARMACEUTICAL DOUBLE LAYER TABLET FORMULATION

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