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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • 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
• • 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
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2813—Inorganic compounds

Definitions

• An object of the invention is a pharmaceutical composition
• a pharmaceutical composition comprising the active ingredients rosuvastatin of formula I, with the systematic name (3 ?,55,6E)-7-[4-(4-fluorophenyl)-2-(N- methylmethanesulfonamido)-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid or its pharmaceutically acceptable salts, and ezetimibe of formula II, with the systematic name (3 ?,45)-l-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3--hydroxypropyl]-4-(4- hydroxyphenyl)azetidin-2-one or its pharmaceutically acceptable salts, as well as a method for preparation of this pharmaceutical composition.
• Rosuvastatin or a pharmaceutically acceptable salt thereof is one of HMG-CoA reductase inhibitors that inhibit the synthesis of cholesterol to treatment dyslipidaemia.
• Crestor ® tablets rosuvastatin calcium salts developed by AstraZeneca
• rosuvastatin as a main ingredient
• research has been reporting on excellent effects of rosuvastatin in lowering LDL cholesterol levels in blood and increasing beneficial HDL cholesterol levels in the body, compared to the effects of atorvastatin or simvastatin, which is commercially available as a drug having the same mechanism as rosuvastatin. Accordingly, there is an increasing interest in rosuvastatin formulation.
• Ezetimibe ⁇ Ezetrof* tablets, Merck & Co. is a selective cholesterol absorption inhibitor.
• HMG-CoA reductase inhibitors are generally used in a combination with a therapeutic agent for dyslipidemia having a different mechanism from that of the HMG-CoA reductase inhibitors to enhance therapeutic effects.
• a therapeutic agent for dyslipidemia having a different mechanism from that of the HMG-CoA reductase inhibitors to enhance therapeutic effects.
• composite formulations of these two ingredients are actively being studied.
• Rosuzet ® composite pack containing both Ezetrol ® (ezetimibe) and MSD rosuvastatin tablets, was developed by Merck & Co. for the treatment of primary hypercholesterolemia.
• PLC EGIS Pharmaceuticals
• a dissolution pattern of the active ingredients of a solid formulation for oral administration is closely related to the bioavailability of the formulation, wherein high dissolution rate is premised on high bioavailability.
• WO2009024889 (Ranbaxy Laboratories) relates generally to combinations of HMG-CoA reductase inhibitors with ezetimibe and deals with the problem of degradation of ezetimibe in the presence of alkali metal salt additives. The issue is solved by addition of alkaline earth metal additives instead.
• WO2011019326 (Bilgic Mahmut) relates to a process for preparation of a pharmaceutical formulation comprising ezetimibe and rosuvastatin. The said process includes dissolution of ezetimibe and preparation of ezetimibe by wet granulation.
• the examples of such formulations include only monolayer compositions comprising a phosphate and microcrystalline cellulose among other excipients.
• WO2012064307 (Bilgic Mahmut) discloses rosuvastatin or its pharmaceutically acceptable salt formulations wherein the rosuvastatin particle size distribution d ( o.9o> is coarser than 100 ⁇ .
• the composition of the bilayer tablet is not disclosed sufficiently to be prepared by a person skilled in the art.
• WO2013066279 (Bilgic Mahmut) discloses examples of pharmaceutical formulations comprising ezetimibe and/or pharmaceutically acceptable salt thereof with a second active ingredient wherein the particle size of ezetimibe is between 10 to 50 ⁇ .
• WO2013166117 (Althera Life Sciences) discloses examples of solid dosage formulations comprising combinations of ezetimibe and rosuvastatin in one tablet that is expected to have the same area under curve (AUC) as the two active ingredients taken individually orally.
• AUC area under curve
• This patent application solves the issue of rosuvastatin degradation by addition of a basic milieu to the rosuvastatin layer; particularly the addition of dicalcium phosphate is mentioned.
• the process for preparation of the ezetimibe layer is very complex and thus also cost-demanding: two steps out of the five require usage of solvents (organic solvents and water, respectively), each of them followed by energy demanding drying.
• solvents organic solvents and water, respectively
• WO2015044698 discloses examples of combined ezetimibe and rosuvastatin pharmaceutical composition wherein the interaction with the individual active ingredients is minimized.
• the solution to such a problem is a capsule containing a tablet comprising rosuvastatin zinc salt (2: 1) and a tablet comprising ezetimibe.
• WO2015102400 discloses examples of ezetimibe and rosuvastatin compositions in a form of a single-layered or a double-layered tablet or capsules.
• the only example of a double-layered tablet is a composition containing ezetimibe and rosuvastatin wherein the ezetimibe part of the composition includes magnesium stearate in the concentration of 1.3 wt.%.
• WO2015199356 (HANMI Pharm. Co.) relates to a composite formulation including ezetimibe and rosuvastatin having improved dissolution rate and velocity of active ingredients.
• the main invention is the critical content of organic solvent for the preparation of ezetimibe wet-granules.
• An object of the present invention is preparation of a stable two-layer tablet comprising as the active ingredients rosuvastatin or its pharmaceutically acceptable salts and ezetimibe or its pharmaceutically acceptable salts.
• the invention relates to a stable pharmaceutical composition
• a stable pharmaceutical composition comprising, as the active ingredients, rosuvastatin or its pharmaceutically acceptable salts, hydrates, solvates or esters, and ezetimibe or its pharmaceutically acceptable salts, hydrates, solvates or esters, the pharmaceutical composition according to the invention having the form of a two-layer tablet wherein each layer of the tablet only contains one of these active ingredients.
• the weight ratio of the rosuvastatin layer and the ezetimibe layer of the two-layer tablet is preferably 1:2 to 2: 1, including the limit values.
• the ezetimibe layer preferably contains 0.15 to 0.5 % by weight of a glidant, relative to the total weight of the ezetimibe layer, said glidant being preferably selected from stearic acid or its pharmaceutically acceptable salts.
• the ezetimibe layer is preferably free of cellulose and its derivatives, i.e., the ezetimibe layer comprises other pharmaceutically acceptable excipients than cellulose and its derivatives.
• the ezetimibe layer comprises cellulose and/or its derivatives (preferably microcrystalline cellulose) in an amount of up to 10.5 % by weight, incl. the limit values, relative to the total weight of the ezetimibe layer, whereas the cellulose and/or its derivatives are present in the extragranular phase only.
• the rosuvastatin layer is free of basic stabilizing excipients.
• Another object of the invention is a robust production method of such a composition. Detailed description of the Invention
• An object of the invention is a pharmaceutical composition
• rosuvastatin of formula I with the systematic name (3 ?,55,6E)-7-[4-(4-fluorophenyl)-2-(N- methylmethanesulfonamido)-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid or its pharmaceutically acceptable salts, hydrates, solvates or esters, and ezetimibe of formula II, with the systematic name (3 ?,45)-l-(4-fluorophenyl)-3-[(35)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one or its pharmaceutically acceptable salts, hydrates, solvates or esters, and pharmaceutically acceptable excipients, characterized in that it is in the form of a two-layer tablet with one layer comprising ezetimibe as the only active
• An advantage of the two-layer tablet is separation of individual ingredients, which prevents their interaction and also allows to independently adapt each tablet layer to the physicochemical characteristics of individual active ingredients. Thus, independent and free releasing of ezetimibe and rosuvastatin from individual layers of the tablet can be ensured.
• the two-layer tablets according to individual aspects of the present invention show further improved physico-chemical properties.
• ezetimibe refers to ezetimibe or its pharmaceutically acceptable inorganic or organic salt, ester, hydrate, solvate, enantiomer, racemate, polymorph, crystalline form and amorphous form and/or combination thereof.
• a two-layer tablet preferably contains the amount corresponding to 10 mg of free ezetimibe, i.e. ezetimibe that is not in the form of an inorganic or organic salt, ester, hydrate or solvate.
• rosuvastatin refers to rosuvastatin or its pharmaceutically acceptable inorganic or organic salt, ester, hydrate, solvate, enantiomer, racemate, crystalline form and amorphous form and/or combination thereof.
• inorganic salts e.g. calcium, magnesium, sodium, potassium, lithium, zinc, copper, manganese or cadmium salts are preferred.
• Calcium, magnesium, zinc and copper salts are especially preferred, with the calcium and magnesium salts being most preferred, especially the calcium salt.
• One two-layer tablet according to the invention preferably contains the amount corresponding to 2.5 - 40 mg of free rosuvastatin, i.e. rosuvastatin that is not in the form of an inorganic or organic salt, ester, hydrate or solvate.
• ezetimibe layer refers to one of the two layers of the two-layer tablet that contains the active substance ezetimibe as the only active substance in this layer, and pharmaceutically acceptable excipients.
• the ezetimibe layer comprises a glidant selected from the group consisting of stearic acid or its acceptable salts, which is used in the ezetimibe layer at a concentration of 0.15 to 0.5% by weight, relative to the total weight of this layer.
• the ezetimibe layer may contain at least one pharmaceutically acceptable excipient selected from:
• filler or a combination of fillers selected from the group of lactose, glucose, cellulose and its derivatives, calcium carbonate, calcium phosphate, starch, mannitol and other sugar alcohols, and other fillers known from the prior art,
• disintegrant or a combination of disintegrants selected from the group of the sodium salt of croscarmellose, sodium salt of carboxymethyl starch, crospovidone and alginates,
• binders selected from the groups of water-soluble polymers such as polyvinylpyrrolidone, preferably polyvinylpyrrolidone with the average molecular weight up to 1,500,000, preferably up to 60,000, water-soluble cellulose derivatives, preferably methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sugar alcohols, preferably mannitol, sorbitol,
• water-soluble polymers such as polyvinylpyrrolidone, preferably polyvinylpyrrolidone with the average molecular weight up to 1,500,000, preferably up to 60,000, water-soluble cellulose derivatives, preferably methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sugar alcohols, preferably mannitol, sorbitol,
• a surfactant or a combination of surfactants selected from the group of block copolymers of ethylene oxide and propylene oxide referred to as poloxamers, where the term “poloxamer” means a polymer of formula HO(C 2 H 4 ) a (C 3 H 6 0) 3 ⁇ 4 (C 2 H 4 0) a H, wherein "a” and “b” indicate the number of oxyethylene and oxypropylene units), alkyl sulphates, preferably sodium lauryl sulphate, sodium stearyl sulphate, sodium dioctyl sulfosuccinate, alkyl aryl sulfonates, preferably sodium dodecyl benzene sulfonate, polyethylene glycols and polysorbates.
• the ezetimibe layer comprises at least one first pharmaceutically acceptable excipient and at least one second pharmaceutically acceptable excipient.
• the ezetimibe layer comprises a granulate comprising ezetimibe and at least one first pharmaceutically acceptable excipient, and an extragranular phase comprising at least one second pharmaceutically acceptable excipient.
• the second pharmaceutically acceptable excipients include a glidant selected from the group consisting of stearic acid or its pharmaceutically acceptable salts, in an amount of 0.15 to 0.5 % by weight, relative to the total weight of the ezetimibe layer.
• the ezetimibe layer comprises a granulate and an extragranular phase, wherein the granulate is substantially free of cellulose and its derivatives.
• the extragranular phase may be free of cellulose and its derivaties, or may contain cellulose and/or its derivatives in an amount of up to 10.5% by weight, incl. the limit values, relative to the weight of the ezetimibe layer.
• the ezetimibe layer either comprises other pharmaceutically acceptable excipients than cellulose and its derivatives, or it comprises cellulose and/or its derivatives (preferably microcrystalline cellulose) at a concentration up to 10.5 % by weight, incl. the limit values, relative to the weight of the ezetimibe layer, in the extragranular phase only.
• rosuvastatin layer refers to one of the two layers of the two-layer tablet that contains the active substance rosuvastatin as the only active substance in this layer, preferably in an amount corresponding to 2.5-40 mg of rosuvastatin, and at least one pharmaceutically acceptable excipient.
• the rosuvastatin layer is preferably free of basic stabilizing excipients.
• the pharmaceutically acceptable non-basic excipients in the rosuvastatin layer may include: - a filler or a combination of fillers selected from the group of lactose, glucose, cellulose and its derivatives, starch, mannitol and other sugar alcohols, and other non-basic fillers known from the prior art,
• binders selected from the group of water-soluble polymers such as polyvinylpyrrolidone, preferably polyvinylpyrrolidone with the average molecular weight of up to 1,500,000, preferably up to 60,000, water-soluble cellulose derivatives, preferably methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sugar alcohols, preferably mannitol, sorbitol,
• water-soluble polymers such as polyvinylpyrrolidone, preferably polyvinylpyrrolidone with the average molecular weight of up to 1,500,000, preferably up to 60,000, water-soluble cellulose derivatives, preferably methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sugar alcohols, preferably mannitol, sorbitol,
• glidant or a combination of glidants such as colloidal silicon dioxide, maize starch, magnesium or calcium stearate, stearic acid, sodium stearyl fumarate, talc, polyethylene oxide and other glidants known from the prior art,
• Base stabilizing excipients are excipients which, after dispersing the pharmaceutical composition in an aqueous environment, increase the pH value above pH 9.
• Such substances include e.g. carbonates such as calcium carbonate, hydroxides of alkaline metals and alkaline earth metals such as calcium hydroxide, calcium phosphate, or calcium hydrogen phosphate, basic amino acids or meglumine.
• the claimed "two-layer tablet” consists of an ezetimibe layer and a rosuvastatin layer.
• This two- layer tablet can be preferably coated.
• the coating of the tablets then comprises film-forming substances such as hydroxypropyl methylcellulose, methylcellulose, polyvinyl alcohol, and optionally other excipients selected from the group of softeners such as e.g. triethyl citrate, dibutyl sebacate, or polyethylene glycol, surfactants such as e.g. sodium lauryl sulphate, colorants such as e.g. iron oxides and titanium dioxide, and additives preventing sticking of tablets, e.g. talc. If the text refers to a "tablet", it is to be understood as referring to the "two- layer tablet” according to the invention.
• stable formulation and/or “stable two-layer tablet” refers to such a formulation and/or tablet that, subjected to a stability test, contains
• particle size ⁇ 3 ⁇ 4" means that lOOx x % of the particle volume have a diameter that is smaller than, larger than or equal, respectively, to the said diameter value d, measured with the laser scattering method.
• d(o.9Q) of rosuvastatin is larger than 100 ⁇
• the particle size d ( o .9 o> is equal to or smaller than 15 ⁇ , it means that 90 % of the volume of particles of ezetimibe or its pharmaceutically acceptable salt are equal to or smaller than 15 ⁇ , measured with the laser scattering method.
• d(o. 9 o> of ezetimibe is smaller than or equal to 25 ⁇ , more preferably d(o. 9 o> is smaller than or equal to 20 ⁇ and most preferably d(o. 9 o> is smaller than or equal to 15 ⁇ , measured with the laser scattering method.
• d(o. 9 o> of rosuvastatin is in the range of 100-225 ⁇ , more preferably d(o. 9 o> is in the range of 130-200 ⁇ and most preferably d(o. 9 o> is in the range of 150-175 ⁇ , measured with the laser scattering method.
• Another problem that needed to be solved within the framework of the development of the two-layer tablet of ezetimibe and rosuvastatin consisted in achieving a sufficient release rate of ezetimibe from the tablet.
• Ezetimibe is almost insoluble in water, which reduces the dissolution rate in an aqueous environment, e.g. also in the digestive juices. This may result in low biological availability of ezetimibe, i.e. its insufficient efficiency. Therefore, developing a formulation providing high biological availability of ezetimibe and a high release rate of ezetimibe from the tablet is highly desirable for the pharmaceutical industry.
• Glidants such as stearic acid and its salts have a negative impact on release rate of active ingredients from pharmaceutical formulations. Glidants repel water, reducing the rate of dissolution of active ingredients from the formulation.
• Reference literature indicates that stearic acid or its pharmaceutically acceptable salts, preferably magnesium stearate and aluminum stearate, can be used in pharmaceutical formulations in a quantity of 0.2 to 2% by weight.
• stearic acid or its pharmaceutically acceptable salt preferably magnesium stearate, calcium stearate and/or aluminum stearate, for a pharmaceutical technological process, is approx. 1% by weight or higher for the tablets to be preparable at all. If an insufficient amount of glidants is used, technological problems can be expected during the production of tablets, such as sticking of the material to the punch or in the mold.
• a sufficient amount of stearic acid or its pharmaceutically acceptable salt, preferably magnesium stearate, calcium stearate and/or aluminum stearate, in the ezetimibe layer for the production of two-layer tablets in accordance with the invention is from 0.15 to 0.5 % by weight (including the limit values, relative to the total weight of the ezetimibe layer).
• a low content of stearic acid or its pharmaceutically acceptable salts, preferably magnesium stearate, calcium stearate and/or aluminum stearate, is advantageous for faster dissolution and release of ezetimibe from the tablet.
• this invention of a two-layer tablet brings the above-described advantages of a low content of a glidant, which is stearic acid or its acceptable salt, preferably magnesium stearate, calcium stearate and/or aluminum stearate, in the ezetimibe layer for the releasing of ezetimibe, and at the same time, these tablets are easy to prepare in spite of the low content of the glidant.
• a glidant which is stearic acid or its acceptable salt, preferably magnesium stearate, calcium stearate and/or aluminum stearate
• Testing of many varieties has shown that the presence of cellulose and its derivatives, especially microcrystalline cellulose, in the intragranular phase of the ezetimibe layer decelerates releasing of ezetimibe from the tablet.
• Cellulose and its derivatives can be used in the extragranular phase, but only at a concentration of up to 10.5 % by weight, including the limit values, relative to the weight of the ezetimibe layer, an extreme and advantageous embodiment being represented by a two-layer tablet whose ezetimibe layer does not comprise any cellulose or cellulose derivatives.
• the two-layer oral tablet according to the invention is thus characterized in that the ezetimibe layer comprises other pharmaceutically acceptable excipients than cellulose and its derivatives.
• the ezetimibe layer may comprise cellulose and its derivatives, preferably microcrystalline cellulose, at a concentration of up to 10.5% by weight, incl. the limit values, relative to the weight of the ezetimibe layer, in the extragranular phase only.
• More than 85 % by weight of the declared content of ezetimibe are released from the two- layer tablets according to the invention during 30 min in dissolution tests. In a preferred embodiment, more than 90 % by weight of the declared content of ezetimibe, and in an especially preferred embodiment, more than 95 % of the declared content of ezetimibe is released during 30 min in dissolution tests.
• More than 75 % by weight of the declared content of ezetimibe are released from the two- layer tablets according to the invention during 20 min in dissolution tests. In a preferred embodiment, more than 80 % by weight of the declared content of ezetimibe and in an especially preferred embodiment, more than 86 % of the declared content of ezetimibe is released during 20 min in dissolution tests.
• the third aspect of the present invention is the absence of basic excipients in the rosuvastatin layer. It is well-known from reference sources that rosuvastatin and its salts are unstable in an acidic environment.
• reference sources recommend the use of basic stabilizing substances such as calcium carbonate, calcium hydroxide, or phosphates, especially calcium hydrogen phosphate, which is contained in the commercial preparation of rosuvastatin Crestor ® .
• dissolution of a formulation containing basic stabilizing excipients can unnaturally increase the normal acidic pH in the stomach, which has an unfavorable impact on the mucous membrane of the stomach. This impact is especially negative for patients suffering from diseases of the stomach and stomach wall, special caution being necessary in patients with long-term rosuvastatin therapy.
• the presence of basic substances in the formulation can also have a negative influence on stability and dissolution of ezetimibe from a common formulation of ezetimibe and rosuvastatin.
• the two-layer tablet comprises, in the ezetimibe layer, a granulate of ezetimibe with lactose, sodium salt of croscarmellose and/or sodium salt of carboxymethyl starch, sodium lauryl sulfate and/or sodium lauryl stearate, and hydroxypropyl methylcellulose and/or polyvinylpyrrolidone with a molecular weight of less than 60,000.
• the two-layer tablet contains, in the ezetimibe layer, an extragranular phase with 0.15 to 0.5 % by weight of magnesium stearate or calcium stearate or aluminum stearate (relative to the weight of the ezetimibe layer), sodium salt of croscarmellose and/or sodium salt of carboxymethyl starch, and optionally microcrystalline cellulose at a concentration of up to 10.5 % by weight (relative to the weight of the ezetimibe layer).
• the two-layer tablet comprises, in the rosuvastatin layer: rosuvastatin, lactose, microcrystalline cellulose, sodium salt of croscarmellose and/or sodium salt of carboxymethyl starch, colloidal silicon dioxide, and magnesium stearate and/or calcium stearate and/or aluminum stearate.
• the two-layer tablet contains, in the ezetimibe layer, granulate of ezetimibe with lactose, sodium salt of croscarmellose, sodium lauryl sulphate and polyvinylpyrrolidone with a molecular weight of less than 35,000, and an extragranular phase comprising 0.15 to 0.5 % by weight of magnesium stearate (related to the weight of the ezetimibe layer), sodium salt of croscarmellose, and optionally microcrystalline cellulose at a concentration of up to 10.5 % by weight (relative to the weight of the ezetimibe layer).
• the two-layer tablet comprises, in the rosuvastatin layer: rosuvastatin, lactose, microcrystalline cellulose, sodium salt of croscarmellose, colloidal silicon dioxide and magnesium stearate.
• the tablet in accordance with the present invention can be produced with the use of methods that are known to a skilled person.
• the tableting blend for the production of the ezetimibe layer is preferably prepared using known granulation methods, wet granulation being preferred.
• the tableting blend for the production of the rosuvastatin method can be preferably prepared using dry methods, direct mixing and direct compression being preferred.
• a preferred production process is the combination of wet granulation for the ezetimibe layer and direct mixing and compression for the rosuvastatin layer.
• the composition of the rosuvastatin layer according to the invention which enables the use of direct mixing and compression, is very advantageous from the point of view of time and economy.
• the ratio of pressures for compression of the tableting blends into the two-layer tablet is preferably 1:2 to 1: 10, the first value relating to the pressure for compression of the first layer (typically the layer with a higher thickness) and the second value relating to the pressure for compression of the second layer and the whole tablet.
• the disintegration time of the two-layer tablets according to the invention is less than 15 min, preferably less than 8 min, most preferably less than 5 min, measured with the method according to the European Pharmacopoeia.
• the strength of the two-layer tablets according to the invention is at least 60 N, preferably more than 110 N and most preferably more than 140 N, measured with the method according to the European Pharmacopoeia.
• the tablet in accordance with the present invention can be prepared by means of a production process comprising the following steps:
• a) ezetimibe or its pharmaceutically acceptable salt, together with at least one first pharmaceutically acceptable excipient, is granulated, preferably with the use of a wetting agent,
• rosuvastatin or its pharmaceutically acceptable salt is mixed together with at least one pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient(s) are non-basic,
• e) coating is optionally applied onto the obtained two-layer tablets.
• a preferred embodiment comprises a preparation method wherein a mixture of ezetimibe with at least one first pharmaceutically acceptable excipient in step a) is wetted with the use of water and the obtained mixture is processed into granulate by means of fluid granulation.
• the at least one first pharmaceutically acceptable excipient in step a) is selected from a group comprising a filler, a binder, a disintegrant, a surfactant or any combinations thereof, as described above.
• the at least one second excipient in step b) is a glidant selected from the group consisting of stearic acid or its acceptable salts, which is used in the ezetimibe layer at a concentration of 0.15 to 0.5 % by weight, relative to the total weight of this layer, and optionally further excipients, such as a filler, a binder or a disintegrant or a combination of these substances, as described above.
• the at least one second excipient in step b) can include microcrystalline cellulose at a concentration of up to 10.5% by weight (relative to the weight of the ezetimibe layer).
• the rosuvastatin layer can comprise at least one pharmaceutically acceptable non-basic excipient as defined in the above-described "rosuvastatin layer”.
• the first pharmaceutically acceptable excipient and the second pharmaceutically acceptable excipients are as defined in the above-described "ezetimibe layer".
• a two-layer tablet comprising, as the active ingredients, rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, wherein each tablet layer only contains one of these active substances and the weight ratio of the individual layers is 1:2 to 2: 1 (including the limit values). 2.
• a two-layer tablet comprising, as the active ingredients, rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, wherein the ezetimibe layer comprises 0.15 to 0.5 % by weight of a glidant, which is stearic acid or its acceptable salts. 3.
• a two-layer tablet comprising, as the active ingredients, rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, wherein the ezetimibe layer is substantially free of cellulose and its derivatives, or wherein the ezetimibe layer comprises cellulose and its derivatives in the extragranular phase only (preferably microcrystalline cellulose) at a concentration of up to 10.5 % by weight, incl. the limit values, relative to the weight of the ezetimibe layer.
• a two-layer tablet comprising as the active ingredients rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, wherein the rosuvastatin layer is substantially free of basic stabilizing excipients. 5.
• a two-layer tablet comprising, as the active ingredients, rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, wherein each tablet layer only contains one of these active substances and the weight ratio of the individual layers is 1:2 to 2: 1 (including the limit values), and wherein the ezetimibe layer comprises a glidant, which is stearic acid or its acceptable salts, at a concentration of 0.15 to 0.5 % by weight, relative to the weight of the ezetimibe layer.
• a two-layer tablet comprising, as the active ingredients, rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, wherein each tablet layer only comprises one of these active substances and the weight ratio of the individual layers is 1:2 to 2: 1 (including the limit values), and wherein the ezetimibe layer is substantially free of cellulose and its derivatives, or wherein the ezetimibe layer comprises cellulose and its derivatives in the extragranular phase only (preferably microcrystalline cellulose) at a concentration of up to 10.5 % by weight, incl. the limit values, relative to the weight of the ezetimibe layer.
• a two-layer tablet comprising, as the active ingredients, rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, wherein each tablet layer only contains one of these active substances and the weight ratio of the individual layers is 1:2 to 2: 1 (including the limit values), and wherein the rosuvastatin layer is substantially free of basic stabilizing excipients.
• a two-layer tablet comprising, as the active ingredients, rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, wherein each tablet layer only contains one of these active substances and the weight ratio of the individual layers is 1:2 to 2: 1 (including the limit values), and wherein the ezetimibe layer comprises a glidant, which is stearic acid or its acceptable salts, at a concentration of 0.15 to 0.5 % by weight, relative to the weight of the ezetimibe layer, and wherein the ezetimibe layer is substantially free of cellulose and its derivatives, or wherein the ezetimibe layer comprises cellulose and its derivatives in the extragranular phase only (preferably microcrystalline cellulose) at a concentration of up to 10.5 % by weight, inch the limit values, relative to the weight of the ezetimibe layer.
• a two-layer tablet comprising, as the active ingredients, rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, wherein each tablet layer only contains one of these active substances and the weight ratio of the individual layers is 1:2 to 2: 1 (including the limit values), and wherein the ezetimibe layer comprises a glidant, which is stearic acid or its acceptable salts, at a concentration of 0.15 to 0.5 % by weight, relative to the weight of the ezetimibe layer, and wherein the rosuvastatin layer is substantially free of basic stabilizing excipients.
• a two-layer tablet comprising, as the active ingredients, rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, wherein each tablet layer only comprises one of these active substances and the mutual weight ratio of the individual layers is 1:2 to 2: 1 (including the limit values) and wherein the ezetimibe layer is substantially free of cellulose and its derivatives, or wherein the ezetimibe layer comprises cellulose and its derivatives in the extragranular phase only (preferably microcrystalline cellulose) at a concentration of up to 10.5 % by weight, incl.
• a two-layer tablet comprising, as the active ingredients, rosuvastatin or its pharmaceutically acceptable salts, esters, hydrates or solvates, and ezetimibe or its pharmaceutically acceptable salts, esters, hydrates or solvates, wherein each tablet layer only contains one of these active substances and the weight ratio of the individual layers is 1:2 to 2: 1 (including the limit values), and wherein the ezetimibe layer comprises a glidant, which is stearic acid or its acceptable salts, at a concentration of 0.15 to 0.5 % by weight, relative to the weight of the ezetimibe layer, and wherein the ezetimibe layer is substantially free of cellulose and its derivatives, or wherein the ezetimibe layer comprises cellulose and its derivatives in the extragranular phase only (preferably microcrystalline cellulose) at a concentration of up to 10.5
• Fig. 2 The dissolution profile of releasing of ezetimibe from a two-layer tablet according to the invention (example 13) as compared to the tablet of Comparative Example C Examples
• Example 1 the tableting blend for the ezetimibe layer was prepared by wet granulation with water as the granulating wetting agent.
• the tableting blend for the rosuvastatin layer was prepared by direct mixing.
• Lactose monohydrate filler binder 244.0
• Abrasion determined using the method according to the European Pharmacopoeia, was less than 0.2% for Examples 13- 15.
• Polyethylene glycol 60C 0 1.50 1 0.75
• Titanium dioxide 1.20 0.8 0.6
• Abrasion determined using the method according to the European Pharmacopoeia, was less than 0.2% for Examples 16- 18.
• Polyethylene glycol 6000 1.50 1 0.75
• Titanium dioxide 1.20 0.8 0.6 Talc 1.80 1.2 0.9
• Abrasion determined using the method according to the European Pharmacopoeia, was less than 0.2% for Examples 19-21.
• the tableting blend for the ezetimibe layer was prepared in the same way as in Examples 1 to 6, i.e. by means of wet granulation with water as the granulation wetting agent, and the tableting blend for the rosuvastatin layer was prepared in the same way as in Examples 7 to 12, i.e. by means of direct mixing. After the compression, coating was applied onto the two-layer tablets in the same way as in Example 13. Comparative Example A - magnesium stearate contents 1% by weight and 1.5% by weight
• Abrasion determined using the method according to the European Pharmacopoeia, was 4% for composition B l and 6% for composition B2.
• the dissolution profile of releasing of ezetimibe was measured and compared to the dissolution profile of the tablet in accordance with Example 13 and 21.
• the dissolution profile of the tablet in accordance with Comparative Example C and the tablet in accordance with Example 13 and 21 are shown in Figure 2.
• Titanium dioxide 1.20

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