EP4580636A1 - Thérapie anticoagulante avec un régime posologique amélioré - Google Patents

Thérapie anticoagulante avec un régime posologique amélioré

Info

Publication number
EP4580636A1
EP4580636A1 EP23782423.0A EP23782423A EP4580636A1 EP 4580636 A1 EP4580636 A1 EP 4580636A1 EP 23782423 A EP23782423 A EP 23782423A EP 4580636 A1 EP4580636 A1 EP 4580636A1
Authority
EP
European Patent Office
Prior art keywords
component
pharmaceutical composition
tablet
rivaroxaban
acetylsalicylic acid
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
EP23782423.0A
Other languages
German (de)
English (en)
Inventor
Sylwia Berdzik-Kalarus
Malgorzata Owczarz-Rabiega
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.)
Adamed Pharma SA
Original Assignee
Adamed Pharma SA
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 Adamed Pharma SA filed Critical Adamed Pharma SA
Publication of EP4580636A1 publication Critical patent/EP4580636A1/fr
Pending legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the twice daily rivaroxaban dosage is foreseen in combination with an Acetylsalicylic acid dosage (selected form a list) administered twice daily.
  • the twice daily rivaroxaban dosage is in combination with Acetylsalicylic acid administered twice daily.
  • the dosages are to be selected from the respective lists.
  • the dosage regiment foreseen be the prior art is following: administration of 2.5 mg of rivaroxaban twice daily accompanied by Acetylsalicylic acid dosage form the range 75-100 mg taken at any time during the day, or administration of 2.5 mg of rivaroxaban once daily accompanied by Acetylsalicylic acid dosage form the range 75-100 mg taken at the same time.
  • the present invention solves to the above-mentioned problem by provision of a fixed-dose pharmaceutical composition for oral administration comprising component a) comprising 2.5 mg of rivaroxaban and component b) comprising 50 mg of Acetylsalicylic acid, and pharmaceutically acceptable excipients, wherein both component a) and component b) are in a form of immediate release.
  • the fixed-dose composition in all embodiments and variants thereof is understood as composition in a single dosage-form.
  • the dosage form is an immediate release form, i.e. both component a) and component b) are in a form of immediate release, so that the dosage-form containing component a) and component b) form disintegrates rapidly and get dissolved to release the Rivaroxaban and Acetylsalicylic acid without any modification. It isintended that excipients, diluents or carriers do not prolong or modify the rate of release and/or absorption of Rivaroxaban and Acetylsalicylic acid. Also, the coating(s) does/do not modify the disintegration and active substances release rates. The same applies to capsules bodies.
  • the fixed-dose pharmaceutical composition is intended for use in a method of treatment and prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers and/or for the prevention of atherothrombotic events in adult patients with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD) at high risk of ischaemic events, characterised in that the pharmaceutical composition is administered orally twice daily. Twice daily administration means that preferably the fixed dose dosage form is administered 11 to 13 hours apart, most preferably 12 hours apart.
  • the present invention relates to the following aspects:
  • a fixed-dose oral pharmaceutical composition comprising: component a) comprising 2.5 mg of rivaroxaban and one or more pharmaceutically acceptable excipients; and component b) comprising 50 mg of Acetylsalicylic acid and one or more pharmaceutically acceptable excipients, and one or more pharmaceutically acceptable excipients, wherein both component a) and component b) are in a form of immediate release.
  • composition according to (1) wherein the pharmaceutical composition is in the form of a tablet, in which the component a) forms a first layer, the component b) forms a second layer, and the first layer at least partially covers the surface of the second layer.
  • the tablet is a bilayer tablet.
  • composition according to (1) or (2) wherein the pharmaceutical composition is in the form of a tablet, in which the component a) forms a first layer, the component b) forms a second layer, and the first layer completely covers the surface of the second layer.
  • the component b) can form a first layer while the component a) forms a second layer.
  • composition according to (1) wherein the pharmaceutical composition is a single dosage form in the form of a mono-layer tablet in which the component a) is in a form of a granulate or powder, and component b) is in a form of a granulate, or powder, preferably both component a) and component b) are in form of a granulate, most preferably only component a) is in a form of a granulate.
  • the granulates/powders are further compressed to form a mono-layer tablet.
  • the tablet is uncoated or coated.
  • the tablet is uncoated.
  • the tablet is coated, wherein the coating is not-functional, i.e., the coating doesn’t change the disintegration or release rate of any one of components a) or b), so that immediate release of the active ingredients is not affected.
  • composition according to (1) wherein the pharmaceutical composition is a single dosage form in the form of a coated tablet, in which the component b) forms a core of the tablet and component a) is in a form of a coat applied on this core.
  • composition according to (1) wherein the pharmaceutical composition is in the form of a hard capsule, in which the and component a) is in a form of a granulate or a pellet or a tablet, preferably a pellet or a tablet, most preferably a tablet and component b) is in a form of a granulate or a pellet or a tablet, preferably a pellet or a tablet, most preferably a tablet.
  • the component b) comprises, as the at least one excipient, at least one of a fdler, a disintegrant, a binder, a lubricant, a glidant and any combination thereof.
  • the component b) comprises a fdler, a disintegrant, a lubricant, and, optionally, a binder, and optionally a glidant. More preferably, the component b) contains no binder or the component b) contains no glidant.
  • the component a) and the component b) comprise a fdler.
  • the fdler is at least one independently selected from the group consisting of anhydrous or monohydrate lactose, sucrose, microcrystalline cellulose, starch such as maize starch, pregelatinized starch, microcrystalline cellulose coated with colloidal silica, mannitol, sorbitol and any combination thereof, preferably the fdler is at least one independently selected from the group consisting of anhydrous or monohydrate lactose, mannitol, microcrystalline cellulose, maize starch, saccharose and any combination thereof, and more preferably the fdler is at least one selected from the group consisting of lactose monohydrate, microcrystalline cellulose, or a combination thereof.
  • the component a) and/or the component b) comprise a binder.
  • the component a) comprises a binder.
  • the binder is at least one independently selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, hydroxycellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, copovidone, pregelatinized starch, gelatine and any combination thereof, preferably the binder is at least one independently selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone and any combination thereof, and more preferably the binder is Hypromellose, more specifically Hypromellose E 5 with viscosity: 4-6 mPa s.
  • component a) contains the disintegrant in an amount of 0.5 to 25 wt.%, preferably 2 to 16 wt.%, more preferably 5 wt.%, based on the weight of the component a), and/or wherein the component b) contains the disintegrant in an amount of 0.3 to 5 wt.%, preferably 2 to 5 wt.%, more preferably 3 wt.%, based on the weight of the component b).
  • composition according to any one of (1) to (21), wherein the component a) and/or the component b) comprise a lubricant.
  • the component a) and the component b) comprise a lubricant.
  • the lubricant is at least one independently selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, glycerol tristearate, palm oil derivatives such as palmitic acid or hydrogenated palm oil, hydrogenated vegetable oil, such as hydrogenated castor oil, and any combination thereof, preferably the lubricant is at least one independently selected from magnesium stearate and stearic acid.
  • glidant is at least one independently selected from the group consisting of fumed silica (colloidal silicon dioxide), such as colloidal anhydrous silica, starch, talc and any combination thereof.
  • fumed silica colloidal silicon dioxide
  • the glidant in aspects (1) to (3) and (5) to (24) is colloidal anhydrous silica, wherein Aspect (4) is preferably free of silica.
  • composition according to any one of (1) to (27), wherein the component a) comprises 5 to 90 wt.% of a fdler, 0.5 to 25 wt.% of a disintegrant, 0. 1 to 5.0 wt.% of a lubricant, 0.4 to 10 wt.% of a binder, and optionally 0.1 to 5.0 wt.% of a glidant based on the total weight of the component a).
  • composition according to any one of (1) to (29), wherein the component b) comprises 5 to 90 wt.% of a fdler, 0.5 to 5 wt.% of a disintegrant, 0.1 to 5.0 wt.% of a lubricant, 0.1 to 5.0 wt.% of a glidant, and optionally 0.4 to 5 wt.% of a binder, based on the total weight of the component b).
  • composition according to any one of (6) to (8), wherein the component a) comprises 3-8 wt.% of a standard coating system based on the total weight of the component a) wherein the rest constitutes rivaroxaban.
  • composition according to any one of (1) to (31), wherein the component b) comprises 5 to 90 wt.% of a fdler, 0.5 to 5 wt.% of a disintegrant, 0.1 to 3.0 wt.% of a lubricant, 0.1 to 1.0 wt.% of a glidant, and optionally 0.4 to 5 wt.% of a binder, based on the total weight of the component b).
  • composition according to any one of (1) to (33), wherein the component a) has a rivaroxaban content of 0.2 to 5 wt.%, preferably 0.35 to 2.5 wt.%, more preferably 0.5 to 1.5 wt.%, such as 0.55 wt.%, based on the total weight of the fdm-coated tablet and, the component b) has an acetylsalicylic acid content of 5 to 25 wt.%, preferably 10 to 20 wt.%, more preferably 11 to 15 wt.%, such as 11.2 wt.%, based on the total weight of the film -coated tablet.
  • the component b) has an acetylsalicylic acid content of 10 to 50 wt.%, preferably 15 to 35 wt.%, more preferably 20 to 25 wt.%, such as 22.7 wt.%, based on the total weight of the composition.
  • component a) contains 3.0 wt.% of rivaroxaban, 53.5 wt.% of microcrystalline cellulose, 5.0 wt.% of croscarmellose sodium, 30.0 wt.% of Lactose monohydrate, 2.0 wt.% of hypromellose, 2.0 wt.% of sodium lauryl sulphate and 1.0 wt.% of magnesium stearate, based on the total weight of the component a); and component b) contains 55.6 wt. % of acetylsalicylic acid, 28.3 wt. % of cellulose microcry stalline, 14.4 wt.
  • composition comprises 35.0-70 wt.%. preferably 37.9 wt. % of Acetylsalicylic acid, 1.5-3.5 wt. % , preferably 1.9 wt. % of rivaroxaban, 5.0-90.0 wt. % , preferably 18.9 wt. % of Lactose monohydrate, 5.0-90.0 wt. % , preferably 33.7 wt. % of cellulose microcrystalline, 0.5 - 25 wt. % , preferably 3.0 wt. % of croscarmellose sodium, 0.5 - 10 wt. % , preferably
  • composition according to any one of (1) to (36), wherein the component a) contains 0.5 wt. % of rivaroxaban and 9.6 wt.% of a coating system based on the total weight of the component a) and the component b) contains 11.2 wt. % of acetylsalicylic acid, 51.7 wt. % of cellulose microcrystalline, 25.6 wt. % of starch, maize, 0.9 wt. % of silica, colloidal anhydrous and 0.45 wt. % stearic acid based on the total weight of component b)
  • composition according to any one of (1) to (37), wherein the component a) contains 1.1 wt. % of rivaroxaban, 11.4 wt. % of lactose monohydrate, 0.2 wt. % of cellulose microcry stalline, 1.8 wt. % of croscarmellose sodium, 0.7 wt. % of hypromellose, 0.7 wt. % of sodium lauryl sulphate and 0.4 wt. % of magnesium stearate based on the total weight of the component a) and the component b) contains 22.7 wt. % of acetylsalicylic acid, 26.6 wt.
  • % of cellulose microcrystalline 13.4 wt. % of starch, maize, 0.6 wt. % of silica, colloidal anhydrous and 0.4 wt. % stearic acid based on the total weight of the component b).
  • the binder may be used in an amount equal to 0.4 to 10 wt.%, preferably 0.8 to 8 wt.%, more preferably 0.8 or 0.9 or 0.5 wt.%, based on the total mass of the composition.
  • the component a) may contain the binder in an amount of 0.4 to 5 wt.%, preferably 0.4 to 3 wt.%, more preferably 0.5 wt.%, based on the weight of the component a).
  • the component b) may contain the binder in an amount of 0 of 0.4 to 10 wt. % preferably 0.8 to 8 wt.%, also preferably 0.7 or 0.9 or 0.5 wt.% based on the weight of the component a).
  • a binder is not required if the respective component is produced by dry granulation or direct compacting. It is however preferred to use wet granulation in the preparation of the components, where a binder is commonly used as described in more detail below.
  • the component a) and/or, preferably the component b) comprise a lubricant.
  • a lubricant means at least one lubricant.
  • the lubricant may, for example, be at least one lubricant independently selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, glycerol tristearate, palm oil derivatives such as palmitic acid or hydrogenated palm oil, especially Softisan 154, hydrogenated vegetable oil, such as hydrogenated castor oil, and any combination thereof.
  • the lubricant is at least one independently selected from magnesium stearate and stearic acid.
  • the glidant is not present, particularly silica is not present.
  • the component a) component a) has a rivaroxaban content of 1 to 5 wt.%, preferably 1.5 to 4.5 wt.%, more preferably 2.6 to 3.1 wt.%, such as 3 wt.%, based on the total weight of the component a); furthermore, the component b) has an acetylsalicylic acid content of 20 to 80 wt.%, preferably 35 to 75 wt.%, more preferably 33 to 72 wt.%, such as 55.6 wt.%, based on the total weight of the component b).
  • the component a) has a rivaroxaban content of 0.5 to 5 wt.%, preferably 0.8 to 2.5 wt.%, more preferably 1 to 1.5 wt.%, such as 1.1 wt.%, based on the total weight of the bilayer tablet furthermore the component b) has an acetylsalicylic acid content of 10 to 50 wt.%, preferably 15 to 35 wt.%, more preferably 20 to 25 wt.%, such as 22.7 wt.%, based on the total weight of the bilayer tablet.
  • the method enables the production of the pharmaceutical composition using conventional tools and well-known pharmaceutical technologies, while significantly simplifying the manufacturing process, and reducing its costs comparing to manufacturing standards known in the art.
  • the pharmaceutical composition in particular in the form of a bilayer tablet, can be prepared by a method comprising direct compression, dry granulation or wet granulation for making the immediate-release component and the component b).
  • a method of manufacturing the immediate-release pharmaceutical composition comprises (a) a step of preparing the component a); (b) a step of preparing the component b); (c) a step of combining the component a) and the component (b) to form a mono-layer tablet, in which the component a) and component (b) are compressed together; and, optionally, (d) a step of forming a coating around the mono-layer tablet obtained in step (c).
  • no coating is formed, that is, step (d) is preferably not carried out.
  • step (a) and step (b) the component a) and component b) may be independently prepared using a dry or wet technology such as dry or wet granulation.
  • a dry-granulated component a) or component b) can be obtained using direct dry granulation of a powder mixture comprising active ingredient or a pharmaceutically acceptable salt thereof, suitable excipients as described above. Other excipients can be also included, if needed. Suitable excipients, used in pharmacy, can be found in theticianHandbook of Pharmaceutical Excipients" edited by R. C. Rowe, P. J. Sheskey, and S. Owen, Pharmaceutical Press, edition VII.
  • the dry granulation method used to obtain the component (step (a)) or the component (step (b)) can be selected from roller compaction and slugging. Methods known to the skilled person and are described, for example, in the “Pharmaceutical Manufacturing Handbook” edited by Shayne Cox Gad, published by John Wiley & Sons, Inc., Hoboken, New Jersey.
  • a wet-granulated component a) or component b) can be obtained using a suitable granulation method known in the art using powder mixtures comprising rivaroxaban or acetylsalicylic acid, suitable excipients as described above.
  • the wet granulation is performed in water as a processing medium.
  • the wet granulation method used to obtain the component a) (step (a)) or the component b) (step (b)) can be selected from low shear, high shear, and fluid bed granulation.
  • the component a) and the component b) are obtained by wet granulation (steps (a) and (b)).
  • Blending operations can be performed in a suitable blender, preferably in a container blender.
  • the component a) and/or the component b) are prepared using dry granulation (steps (a) and (b)).
  • the method preferably comprises the following steps: (I) blending Acetylsalicylic acid or a pharmaceutically acceptable salt thereof with all excipients except lubricant and, to homogeneity; II) adding a part of the lubricant and subsequent blending; III) dry granulation by roller-compaction or slugging; IV) breaking down the resulting slugs or sheets using a milling technique to produce granules; V) adding the remaining part of lubricant and subsequent blending.
  • the primary powder blend particles are aggregated under high pressure using one of two main dry granulation processes: either roller-compaction or slugging.
  • the intermediate products, slugs or sheets are broken down using a suitable milling technique to produce granular material, which can be additionally sieved to separate the desired size fraction.
  • Such a way of processing the active ingredients powder blend is very advantageous for several reasons. It allows for the elimination of water, which may affect active ingredients stability, and obtaining a granulate having grain sizes that are optimal for further processing (combination with the second component and optional extragranular phase component without the effect of physical segregation). Additionally, a broad ratio (wt.%) of active ingredient can be blended into the dry granulate intermediate, which is not possible in other dry pharmaceutical processes (e.g. direct compression).
  • the component a) and/or the component b) are prepared using wet granulation (steps (a) and (b)).
  • the method preferably comprises the following steps: I) mixing of active ingredient or a pharmaceutically acceptable salt thereof with at least one filler, at least one disintegrant, optionally further excipients, in a high shear granulator to homogeneity; II) granulating the mixture of step I) by addition of a binder solution in water or another processing agent, such as an alcohol, e.g.
  • Active ingredient may be also subjected to a process of wet granulation (e.g., low shear, high shear or in a fluidized bed), to improve its solubility.
  • wet granulation facilitates obtaining the desired in vitro and in vivo release profiles.
  • the resulting wet granulate is dried and, for example, screened to obtain a proper distribution of the particles, allowing a durable combination with the other component and additional excipients.
  • the component a) is prepared by using wet granulation (step (a)) in water, and the component b) is prepared using dry granulation or is in a form of a simple blend (step (b)). It is also preferred to prepare the component a) (step (a) and the component b) (step (b)) by wet granulation. Most preferably component a) is prepared by wet granulation in water and component b) is prepared by blending the active ingredient with excipients.
  • step (c) of the method the resulting components a) and b) are combined together, and depending on the desired final form, for example, compressed into mono-layer tablets, separate layers in a tablet, or separate tablets or pellets to be packed together into a hard capsule; optionally followed by forming a coating in step (d), resulting in a single unit dosage form.
  • the fixed-dose pharmaceutical composition is prepared by using a bilayer tableting technology in step (c) or even more preferably by simple direct compression.
  • mono-layer tablet is prepared in a process in which component a) is prepared by wet granulation of rivaroxaban with excipients (step (a)) in water, and the component b) is prepared blending acetylsalicylic acid with excipients (step (b)).
  • step (c) of the method the resulting components a) and b) are compressed into a form of a mono-layer tablet.
  • the inventors have found that a more uniform release of both active substances can be achieved by the use of fixed combination of IR 2.5 mg of rivaroxaban component and IR 50 mg component of Acetylsalicylic acid.
  • the present invention provides a method of reducing the risk of myocardial infarction, stroke or cardiovascular death in a human patient with coronary artery disease and/or peripheral artery disease using a pharmaceutical composition as described herein above.
  • the present invention provides a pharmaceutical composition as described herein above for use in a method of prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers or for the prevention of atherothrombotic events in adult patients with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD).
  • the pharmaceutical composition is a single dosage form, such as a bilayer tablet or a capsule comprising 2 tablets or pellets of the respective active ingredients, which is administered orally twice daily, preferably 11 to 13 hours apart, more preferably 12 hours apart.
  • the pharmaceutical composition is administered for 1 day, preferably for 5 consecutive days and the therapy is continued up to 1 year, 2 years or 3 years or longer.
  • This regimen has the advantage of better patients’ compliance and improved quality of life during therapy in comparison to the prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers or for the prevention of atherothrombotic events in adult patients with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD) using a prior art active ingredient composition.
  • ACS acute coronary syndrome
  • CAD coronary artery disease
  • PAD symptomatic peripheral artery disease
  • the high dosages of rivaroxaban and acetylsalicylic acid requires usage of two separate dosage forms, with the necessity of taking 3 tablets during a day, instead of 2.
  • the pharmaceutical composition is administered with or without food. In combination with food means that the pharmaceutical composition is taken shortly before, together with or after the meal. It is thus preferred that the pharmaceutical composition is a single dosage form, which is administered orally within an interval of from 30 min or longer before a meal and 30 min or longer after a meal.
  • the pharmaceutical composition is administered between at a meal and 30 min after a meal, and more preferably, right after the meal, that is, within 5 min after a meal or irrespective of the meal.
  • the method of treatment according to the present invention thus provides favourable Rivaroxaban and acetylsalicylic acid pharmacokinetics, which are not obtained by prior art dosage regimens and dosages of the both actives.
  • oral administration of one single dosage form of the pharmaceutical composition provides after oral administration, a maximum plasma concentration of rivaroxaban (Cmax) of 77.69 ⁇ 28.2 ng/mL after median tmax of 2 hours after administration, and an area under the plasma concentration time curve from time zero to infinity of 481.26 ⁇ 22.3 ng h/mL, as determined by human PK studies described below.
  • Cmax maximum plasma concentration of rivaroxaban
  • the pharmaceutical composition according to any one of (1) to (38), wherein the pharmaceutical composition provides, after oral administration of a single dosage form of the pharmaceutical composition twice a day and preferably 12 hours apart, a maximum plasma concentration in steady state (Cmax) of Acetylsalicylic acid of 328.25 ⁇ 5.69 ng/mL after median tmax of 0.83 h and an area under the plasma concentration-time curve from time zero to infinity in steady state (AUC) of 531.75 ⁇ 2.80 ng h/mL, as determined by human PK studies described below.
  • Cmax maximum plasma concentration in steady state
  • AUC area under the plasma concentration-time curve from time zero to infinity in steady state
  • Table 1.1 Table 1.2 Purified water is processing agent using in granulation process and essentially removed during the manufacturing process.
  • Both tablets are coated: ASA, film-coated tablet & RIVA, film-coated tablet
  • Drug product excipients are sieving and mixing. Active substance is sieving.
  • the drug product components (API + excipients except of lubricant) are placed in suitable container and blend until homogenous mixture is obtained.
  • Lubricant is sieved into the mixture and blend to obtain tableting mass.
  • the tableting mass is compressed using a tablet press to obtain tablets with the desired strength.
  • the tablets with ASA may be film -coated.
  • Coating system is based on PVA (polyvinyl alcohol) orHPMC (Hypromellose) or HPS (hydroxypropyl pea starch).
  • l Purified water is processing agent using in granulation process and essentially removed during the manufacturing process.
  • the specified amounts of active substance (rivaroxaban) and intra-granular excipients are mixed with the aid of high-shear granulator to obtain the powder blend.
  • the binder solution is sprayed on the powder blend during mixing in high-shear granulator. Then the main granulation phase is performed.
  • the wet mass is transferred into the fluid bed dryer and the drying process is performed.
  • the dried mass is passed through a screen into a suitable container.
  • the specified amount of active substance acetylsalicylic acid
  • rivaroxaban are mixed with the aid of blender to obtain the powder blend.
  • Lubricant is sieved into the mixture and blend to obtain tableting mass.
  • the tableting mass with RIVA and ASA is compressed using a tablet press to obtain the tablets with the desired strengths.
  • the tablets may be film-coated.
  • RIVA can be granulated together with ASA and further compressed to a mono-layer tablet.
  • direct compression of all components results in stable mono-layer tablet with required dissolution profile and API %-content.
  • This study is designed as a single-dose, open-label, laboratory-blind, randomized, two-period, two- treatment, two-sequence, crossover bioequivalence study under fasting conditions, with blood sampling period of 24 hours after dosing and with at least 7 days of washout between IMP administrations in Study Period 1 and 2.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique orale à libération immédiate à dose fixe de 2,5 mg de rivaroxaban et 50 mg d'acide acétylsalicylique destinée à être utilisée dans la prévention d'événements athérothrombotiques chez des patients adultes après un syndrome coronarien aigu (SCA) avec biomarqueurs cardiaques élevés ou pour la prévention d'événements athérothrombotiques chez des patients adultes atteints d'une coronaropathie (CAD) et/ou d'une maladie artérielle périphérique (MAP) symptomatique à risque élevé d'événements ischémiques.
EP23782423.0A 2022-08-31 2023-08-31 Thérapie anticoagulante avec un régime posologique amélioré Pending EP4580636A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22193333.6A EP4331586A1 (fr) 2022-08-31 2022-08-31 Traitement anticoagulant avec un schéma posologique amélioré
PCT/EP2023/073979 WO2024047208A1 (fr) 2022-08-31 2023-08-31 Thérapie anticoagulante avec un régime posologique amélioré

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EP4580636A1 true EP4580636A1 (fr) 2025-07-09

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EP22193333.6A Pending EP4331586A1 (fr) 2022-08-31 2022-08-31 Traitement anticoagulant avec un schéma posologique amélioré
EP23782423.0A Pending EP4580636A1 (fr) 2022-08-31 2023-08-31 Thérapie anticoagulante avec un régime posologique amélioré

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ2013783A3 (cs) * 2013-10-08 2015-04-15 Zentiva, K. S Stabilní farmaceutická kompozice obsahující amlodipin a valsartan
US10828310B2 (en) * 2018-02-02 2020-11-10 Bayer Pharma Aktiengesellschaft Reducing the risk of cardiovascular events
CN112451531B (zh) * 2020-12-09 2022-01-07 乐普药业股份有限公司 一种阿司匹林和利伐沙班复方制剂及其制备方法

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WO2024047208A1 (fr) 2024-03-07

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