WO2022199896A1 - Pharmaceutical composition comprising rivaroxaban and method of preparation thereof - Google Patents

Pharmaceutical composition comprising rivaroxaban and method of preparation thereof Download PDF

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Publication number
WO2022199896A1
WO2022199896A1 PCT/EP2022/025120 EP2022025120W WO2022199896A1 WO 2022199896 A1 WO2022199896 A1 WO 2022199896A1 EP 2022025120 W EP2022025120 W EP 2022025120W WO 2022199896 A1 WO2022199896 A1 WO 2022199896A1
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Prior art keywords
tablet
total weight
pharmaceutical composition
rivaroxaban
granules
Prior art date
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PCT/EP2022/025120
Other languages
French (fr)
Inventor
Evangelos Karavas
Efthymios Koutris
Vasiliki SAMARA
Ionna KOUTRI
Anastasia Kalaskani
Andreas KAKOURIS
Christina KIZIRIDI
Original Assignee
Pharmathen S.A.
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Publication date
Application filed by Pharmathen S.A. filed Critical Pharmathen S.A.
Publication of WO2022199896A1 publication Critical patent/WO2022199896A1/en

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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to a stable immediate release pharmaceutical formulation for oral administration containing a therapeutically effective quantity of an anticoagulant agent such as Rivaroxaban or a pharmaceutically acceptable salt thereof, and a method for the preparation thereof.
  • an anticoagulant agent such as Rivaroxaban or a pharmaceutically acceptable salt thereof
  • Blood coagulation also known as heamostasis is a protective mechanism of the human body which helps by sealing defects in the wall of the blood vessels quickly and reliably. Thus, loss of blood can be avoided or kept to a minimum.
  • the process of blood coagulation is affected mainly by the coagulation system in which an enzymatic cascade of complex reactions of plasma proteins is triggered. Numerous blood coagulation factors are involved in this process, each of which factors converts, on activation, the respectively next inactive precursor into its active form. At the end of this process comes the conversion of soluble fibrinogen into insoluble fibrin, resulting in the formation of a blood clot.
  • factor Xa which is formed from the proenzyme factor X, plays a key role, since it connects the two coagulation paths.
  • the activated serine protease Xa cleaves prothrombin to thrombin.
  • the resulting thrombin in turn, cleaves fibrinogen to fibrin, a fibrous/gelatinous coagulant.
  • thromboembolic disorders Maintenance of normal haemostasis-between bleeding and thrombosis-is subject to a complex regulatory mechanism. Uncontrolled activation of the coagulant system or defective inhibition of the activation processes may cause formation of local thrombi or embolisms in vessels or in heart cavities. This may lead to serious disorders, such as myocardial infarction, angina pectoris, reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusive disorders, pulmonary embolisms or deep venous thromboses which are collectively also referred to as thromboembolic disorders.
  • Rivaroxaban is a low molecular weight anticoagulant agent which has been administered for the prophylaxis and treatment of various thromboembolic diseases.
  • the molecular formula of Ribaroxaban is C19H18CIN3O5S and it corresponds to a molecular weight of 435.89. It is an odorless, non-hygroscopic, white to yellowish powder which is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and practically insoluble in water and aqueous media.
  • Ribaroxaban is a BCS Class II drug that poses challenging problems in pharmaceutical product development process because of its low solubility and dissolution rate.
  • BCS Class II drugs require enhancement in solubility and dissolution rate especially in solid pharmaceutical dosage forms.
  • the drug substance is micronized.
  • Rivaroxaban exhibits polymorphism and five polymorphs are reported in literature.
  • the polymorph used for the development of current pharmaceutical product described herein matches Form-I disclosed in WO-A-2007/039132.
  • EP-B-1689370 describes a pharmaceutical composition prepared by fluidized wet granulation wherein the granule comprises the active ingredient in hydrophilized form.
  • WO 2006/072367 describes a modified release pharmaceutical composition which uses the crystalline form I in the hydrophilized form.
  • the patent application also claims the use of amorphous API, which has been amorphized by melt extrusion.
  • WO-A-2007/039122 describes the manufacturing process of a composition comprising Rivaroxaban in an amorphous form or in thermodynamically metastable crystal modification.
  • the preferred manufacturing process used is melt extrusion. The use of these modifications significantly increases the solubility and the oral bioavailability.
  • the main object of the present invention is to provide a stable solid pharmaceutical composition containing Rivaroxaban or pharmaceutical acceptable salt thereof, as an active ingredient that not only matches the physical and chemical attributes of the reference product but also overcomes the disadvantages associated with the prior art compositions related to the low water solubility of the API.
  • Further object of the present invention is to provide an immediate release film-coated tablet comprising Rivaroxaban as an active ingredient, which is bioavailable and with sufficient self-life.
  • Said dosage form has predictable and reproducible drug release rates to achieve better treatment and patient compliance.
  • Another aspect of the present invention is to provide immediate release film-coated tablets comprising Rivaroxaban or a pharmaceutically acceptable salt thereof comprising appropriate amount of binders, fillers, disintegrants and surfactants. More specifically, the pharmaceutical composition of the present invention comprises Rivaroxaban or a pharmaceutically acceptable salt thereof as the active ingredient and an appropriate amount of microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, croscarmellose cellulose and sodium lauryl sulfate in the internal phase.
  • a further approach of the present invention is to provide a tablet composition for oral administration comprising Rivaroxaban which is manufactured through fast, simple and cost- effective process.
  • Further object of the present invention is to provide a solid dosage form for oral administration containing Rivaroxaban or pharmaceutical acceptable salt thereof, which can be formulated into dosage forms of different strengths by proportionally adjusting the amounts of the pharmaceutically acceptable excipients, as well as the active compound Rivaroxaban.
  • the dosage forms of the present invention are characterized by pharmacotechnical linearity, without having any effect on the dissolution profile and bioavailability of said drug.
  • alternative processes for the preparation of a stable, solid pharmaceutical composition for oral administration, containing Rivaroxaban or pharmaceutical acceptable salt thereof as the active ingredient, and an effective amount of appropriate excipients in the internal phase are provided.
  • wet granulation process comprises the following steps:
  • a dry -granulation process comprising the following steps:
  • a pharmaceutical composition comprising an active ingredient is considered to be “stable” if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions.
  • the primary goal of the present invention is to develop an immediate release film-coated tablet formulation comprising Rivaroxaban or a pharmaceutical acceptable salt thereof as the single drug substance that is simple to manufacture, bioavailable, cost effective, stable and possesses good pharmacotechnical properties.
  • Rivaroxaban or a pharmaceutical acceptable salt thereof as the single drug substance that is simple to manufacture, bioavailable, cost effective, stable and possesses good pharmacotechnical properties.
  • One of the major challenges in the design of the present pharmaceutical composition lies with the drug’s poor aqueous solubility which is linked to the bioavailability of Rivaroxaban.
  • Solubility is one of the most important parameters to achieve desired concentration of a drug in systemic circulation. Poorly water-soluble drugs often require high doses in order to reach therapeutic plasma concentrations after oral administration. Any drug to be absorbed must be present in the form of an aqueous solution at the site of absorption. Most of the drugs are either weakly acidic or weakly basic having poor aqueous solubility.
  • Rivaroxaban is employed in crystalline form.
  • the preferred form is crystalline Form I as described in WO-A-2007/039132.
  • Rivaroxaban according to the present invention may be in an amount of from 4% to 20% w/w of the total weight of the tablet.
  • the tablet composition also contains one or more inert materials known as excipients.
  • the primary composition includes diluents, disintegrants, binders, glidants, lubricants and surfactants.
  • Other excipients which give physical characteristics to the finished tablet are coloring agents, and flavors in the case of chewable tablets.
  • excipients are selected to impart good flow and compression characteristics to the material being compressed. Excipients are also selected with the perspective to enhance dissolution, physicochemical characteristics, and stability of the drug substance in the final dosage form.
  • Dry granulation process for the preparation of solid dosage forms such as tablets is one of the most economical methods as only standard equipment is used and the tablets produced by this method are also characterized by satisfactory physical resistance with no need for special packaging.
  • the main advantages of said process are that less equipment and space is required. Further, said process eliminates the need for binder solution, heavy mixing equipment and the costly and time- consuming drying step required for wet granulation.
  • wet granulation using substantial amounts of wetting agent is the most common method used in pharmaceutical industry as it provides better prospects in terms of ease of processing and presumably less problems associated with physical characteristics of various ingredients in the formulation.
  • Direct compression is more economic over wet or dry granulation since it requires fewer unit operations. This means less equipment, lower power consumption, less space, less time and less labor leading to reduced production cost of tablets.
  • the tablets prepared by direct compression disintegrate into API particles instead of granules that directly come into contact with dissolution fluid and exhibits comparatively faster dissolution.
  • Both wet and dry granulation techniques specifically improve flow by creating granules with an increased particle size and improved cohesion during tablet compaction. More specifically wet granulation has further advantages such as improved tablet uniformity and API distribution and requires lower compression pressure during tableting and less environmental contamination.
  • the inventors of the present invention tested various techniques to overcome problems connected to low solubility of the API.
  • Lubricants are essential component of the tablet formulation. Some pharmaceutical scientists believe that the manner of which a lubricant is added to a formulation must be carefully controlled. Accordingly, lubricants are usually added to a granulation by gentle mixing. It is also believed that prolonged blending of a lubricant with a granulate can materially affect hardness and disintegration time for the resulting tablets. For these reasons, the tablet core is divided into two phases, an internal and an external phase. Lubricants are to be used in the external phase of the tablet core to avoid prolonged blending with the excipients used in the internal phase.
  • Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression and allow for removal of the compressed tablet from the die.
  • pharmaceutically acceptable lubricants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose.
  • the lubricant component may be hydrophobic or hydrophilic.
  • Magnesium stearate is the preferred lubricant in the present invention used in a concentration from 0.5% to 2 % w/w of the total weight of the tablet. It aids in the flow of the powder in the hopper and into the die. It is stable and does not polymerize within the tableting mix.
  • one aspect of the invention includes a pharmaceutical formulation comprising Rivaroxaban and carefully selected excipients in the granules formulated in the internal phase during wet granulation and a lubricant dispensed at the external phase.
  • a suitable binder and disintegrant are enclosed in the formulation to regulate the drug release rate and disintegration of film coated tablets.
  • Binders are used in the formulation of solid oral dosage forms to hold the API (active pharmaceutical ingredient) and excipients (inactive ingredients) together and to promote cohesive compacts for directly compressed tablets.
  • Binders may be selected from acacia mucilage, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch and sucrose.
  • the preferred binder of the present invention is hydroxypropyl methylcellulose, also known as hypromellose, a water-miscible, “hydrophilic” polymer which modifies the drug release profile by forming a polymer gel layer in aqueous medium, effectively increasing the duration of release of a drug to prolong its therapeutic effect.
  • Hydroxypropyl methylcellulose is used as tablet binder at concentrations of 2-15 % w/w in granulation and direct compression tableting processes.
  • the preferred concentration of hydroxypropyl methylcellulose in the present invention is from 2% to 8,5% w/w of the total weight of the tablet, most preferably from 5% to 8,5% w/w of the total weight of the tablet.
  • Microcrystalline cellulose is available from several suppliers. Suitable microcrystalline cellulose includes Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH 105 and Avicel PH 200, manufactured by FMC Corporation. Anhydrous form of calcium phosphates is often used to overcome the problems related to dihydrate form.
  • diluents are cellulose, cellulose acetate, dextrates, dextrin, dextrose, fructose, l-0-a- D-Glucopyranosyl-D-mannitol, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, lactose mono-hydrate, maltitol, mannitol, maltodextrin, maltose, pregelatinized starch, sodium chloride, sorbitol, starches, sucrose, talc and xylitol or a mixture of one or more of said diluents.
  • the preferred diluent of the present invention is microcrystalline cellulose and the preferred concentration is from 20% to 60% w/w of the total weight of the tablet.
  • Another preferred diluent of the present invention is lactose monohydrate and the preferred concentration is from 10 to 50% w/w of the total weight of the tablet.
  • a combination of microcrystalline cellulose and lactose monohydrate showed the best results in a total concentration from 60 to 90% w/w of the total weight of the tablet.
  • Disintegrants are included to ensure that the tablet has an acceptable rate of disintegration.
  • examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone, cross-linked calcium carboxymethylcellulose and cross-linked sodium carboxymethylcellulose (croscarmellose sodium); soy polysaccharides; and guar gum, sodium starch glycolate.
  • Croscarmellose sodium is reported to aid disintegration by rapid swelling and wicking upon contact with water. Wicking is a “whipping” action where material-air or material-material interface is spontaneously replaced by material-water interface and thus helps in maintaining capillary flow.
  • Croscarmellose sodium is the preferred disintegrant used in the present invention in a concentration from 4% to 15% w/w of the total weight of the tablet.
  • Surfactants are materials that lower the surface tension between two liquids or between a liquid and a solid.
  • Surfactants can be selected from sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate, sulphosuccinates such as sodium dioctyl sulphosuccinate, partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, partial fatty acid esters of sorbitan such as sorbitan monolaurate, partial fatty acid esters of polyhydroxyethylenesorbitan such as polyethylene glycol sorbitan monolaurate, monostearate or monooleate, polyhydroxyethylene fatty alcohol ethers, polyhydroxyethylene fatty acid esters, ethylene oxide-propylene oxide block copolymers (Pluronic®) or ethoxylated triglycerides.
  • fatty alcohol sulphates such as sodium lauryl sulphate
  • sulphosuccinates such as sodium diocty
  • Sodium lauryl sulphate is the surfactant preferably used in the present invention in a concentration of 0.5% to 8% w/w of the total weight of the tablet, more preferably in a concentration of 0.5% to 6.5% w/w of the total weight of the tablet as it enhances the active ingredient’s poor solubility.
  • Pre compressed granules in dry granulation process are prepared after dry mixing the excipients of the internal phase and compressing in large punches (20mm) in order to improve cohesiveness of the granule.
  • the dried granules obtained after mixing the excipients of the internal phase & kneading with a wet solution of the surfactant when sieved so that more than 60% of the sieved granules have a size by weight that is higher than 160pm, resulted in immediate release tablets of Rivaroxaban with the desired physicochemical properties.
  • the scope of the present invention is the preparation of a stable pharmaceutical dosage form for oral administration comprising Rivaroxaban exhibiting an immediate drug release profile at aqueous medium.
  • the pharmaceutical composition shall be bioequivalent to reference product as per acceptance criteria indicated for generic products and be stable under different storage conditions.
  • the first step in formulation development was to produce compositions based on direct compression process (Table 1), which is the simplest manufacturing process, and study their impact on product’s characteristics.
  • Table 1 Composition of Trial 1
  • Table 2 Physical characteristics of composition of Trial 1
  • Table 3 Dissolution profile of Trial 1 in Acetate Buffer pH 4.5 (0.2% SLS), 900mL, Paddles, 50rpm
  • direct compression process provides poor flow properties (Carr’s Index out of target) as well as poor dissolution.
  • the next step in formulation development was to produce compositions based on dry granulation process and study the physicochemical characteristics of tablets as well as their dissolution properties.
  • Two formulations were prepared (2.1 & 2.2) with different amount of SLS.
  • the pre-compressed granules were sieved appropriately to get 60% of the particles by weight with size higher than 160pm (formulations 2.1 A & 2.2A) & 60% of the particles by weight with size lower than 160pm (formulations 2. IB & 2.2B).
  • Table 4 Formulations based on the dry granulation process (Trial 2.1 & Trial 2.2).
  • step 1 Sieve the Rivaroxaban, MCC, Lactose monohydrate, HPMC, croscarmellose sodium and SLS and mix. 2. Pre-compress bulk of step 1, using 20mm round punch at low compression force to prepare granules.
  • Example 3
  • compositions based on wet granulation process were prepared (3.1, 3.2 & 3.3) with different amount of SLS.
  • the granules after drying were sieved appropriately to get 60% of the particles by weight with size higher than 160pm (formulations 3.1 A, 3.2A & 3.3A) & 60% of the particles by weight with size lower than 160pm (formulations 3. IB, 3.3B & 3.3B).
  • Table 7 Formulations based on wet granulation process (Trial 3, 3.1, 3.2, 3.3)
  • tablets of both dry and wet granulation were stored under normal and accelerated conditions for 6 months and were examined for their physical properties in terms of polymorphic form as well as chemical properties in terms of impurities in appropriate time points in order to study their stability. Based on the stability results, trial formulations of examples 2 and 3 remain stable after 6 months storage under normal and accelerated conditions with regards to polymorphic form and impurities.

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Abstract

The present invention relates to an immediate release stable pharmaceutical formulation for oral administration containing a therapeutically effective quantity of 5-chloro-N-({(5S)-2-oxo-3-[4-(3- oxo-4-morpholinyl)-phenyl]-l,3-oxazolidin-5-yl}-methyl)-2 -thiophenecarboxamide or a pharmaceutically acceptable salt thereof, and a method for the preparation thereof.

Description

PHARMACEUTICAL COMPOSITION COMPRISING RIVAROXABAN AND METHOD OF PREPARATION THEREOF
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a stable immediate release pharmaceutical formulation for oral administration containing a therapeutically effective quantity of an anticoagulant agent such as Rivaroxaban or a pharmaceutically acceptable salt thereof, and a method for the preparation thereof.
BACKROUND OF THE INVENTION
Blood coagulation also known as heamostasis is a protective mechanism of the human body which helps by sealing defects in the wall of the blood vessels quickly and reliably. Thus, loss of blood can be avoided or kept to a minimum. After injury of the blood vessels, the process of blood coagulation is affected mainly by the coagulation system in which an enzymatic cascade of complex reactions of plasma proteins is triggered. Numerous blood coagulation factors are involved in this process, each of which factors converts, on activation, the respectively next inactive precursor into its active form. At the end of this process comes the conversion of soluble fibrinogen into insoluble fibrin, resulting in the formation of a blood clot. In blood coagulation, traditionally the intrinsic and the extrinsic system, which end in a joint reaction path, are distinguished. Here factor Xa, which is formed from the proenzyme factor X, plays a key role, since it connects the two coagulation paths. The activated serine protease Xa cleaves prothrombin to thrombin. The resulting thrombin, in turn, cleaves fibrinogen to fibrin, a fibrous/gelatinous coagulant.
Maintenance of normal haemostasis-between bleeding and thrombosis-is subject to a complex regulatory mechanism. Uncontrolled activation of the coagulant system or defective inhibition of the activation processes may cause formation of local thrombi or embolisms in vessels or in heart cavities. This may lead to serious disorders, such as myocardial infarction, angina pectoris, reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusive disorders, pulmonary embolisms or deep venous thromboses which are collectively also referred to as thromboembolic disorders. 5 -chloro-N -( { (5 S)-2-oxo-3 - [4-(3 -oxo-4-morpholinyl)-phenyl] - 1 , 3 -oxazoli din-5 -yl } -methyl)-2- thiophenecarboxamide known as Rivaroxaban is a low molecular weight anticoagulant agent which has been administered for the prophylaxis and treatment of various thromboembolic diseases. The molecular formula of Ribaroxaban is C19H18CIN3O5S and it corresponds to a molecular weight of 435.89. It is an odorless, non-hygroscopic, white to yellowish powder which is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and practically insoluble in water and aqueous media.
Ribaroxaban is a BCS Class II drug that poses challenging problems in pharmaceutical product development process because of its low solubility and dissolution rate. BCS Class II drugs require enhancement in solubility and dissolution rate especially in solid pharmaceutical dosage forms. There are many ways to improve bioavailability, in the current invention the drug substance is micronized.
Rivaroxaban exhibits polymorphism and five polymorphs are reported in literature. The polymorph used for the development of current pharmaceutical product described herein matches Form-I disclosed in WO-A-2007/039132.
EP-B-1689370 describes a pharmaceutical composition prepared by fluidized wet granulation wherein the granule comprises the active ingredient in hydrophilized form.
WO 2006/072367 describes a modified release pharmaceutical composition which uses the crystalline form I in the hydrophilized form. However, the patent application also claims the use of amorphous API, which has been amorphized by melt extrusion.
WO-A-2007/039122 describes the manufacturing process of a composition comprising Rivaroxaban in an amorphous form or in thermodynamically metastable crystal modification. The preferred manufacturing process used is melt extrusion. The use of these modifications significantly increases the solubility and the oral bioavailability.
Although each of the patents above represents an attempt to overcome the active ingredient’s low water solubility resulting in poor oral bioavailability, there still remains the need in the art for alternative formulations with enhanced dissolution and adequate chemical and physical characteristics that overcome such problems. SUMMARY OF THE INVENTION
The main object of the present invention is to provide a stable solid pharmaceutical composition containing Rivaroxaban or pharmaceutical acceptable salt thereof, as an active ingredient that not only matches the physical and chemical attributes of the reference product but also overcomes the disadvantages associated with the prior art compositions related to the low water solubility of the API.
Further object of the present invention is to provide an immediate release film-coated tablet comprising Rivaroxaban as an active ingredient, which is bioavailable and with sufficient self-life.
It is an object of the present invention the selection of optimal combination of pharmaceutical acceptable excipients and method of preparation to achieve the appropriate dissolution profile and stability for the finished dosage form. Said dosage form has predictable and reproducible drug release rates to achieve better treatment and patient compliance.
Another aspect of the present invention is to provide immediate release film-coated tablets comprising Rivaroxaban or a pharmaceutically acceptable salt thereof comprising appropriate amount of binders, fillers, disintegrants and surfactants. More specifically, the pharmaceutical composition of the present invention comprises Rivaroxaban or a pharmaceutically acceptable salt thereof as the active ingredient and an appropriate amount of microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, croscarmellose cellulose and sodium lauryl sulfate in the internal phase.
A further approach of the present invention is to provide a tablet composition for oral administration comprising Rivaroxaban which is manufactured through fast, simple and cost- effective process.
Further object of the present invention is to provide a solid dosage form for oral administration containing Rivaroxaban or pharmaceutical acceptable salt thereof, which can be formulated into dosage forms of different strengths by proportionally adjusting the amounts of the pharmaceutically acceptable excipients, as well as the active compound Rivaroxaban. The dosage forms of the present invention are characterized by pharmacotechnical linearity, without having any effect on the dissolution profile and bioavailability of said drug. According to another embodiment of the present invention, alternative processes for the preparation of a stable, solid pharmaceutical composition for oral administration, containing Rivaroxaban or pharmaceutical acceptable salt thereof as the active ingredient, and an effective amount of appropriate excipients in the internal phase are provided.
More specifically, wet granulation process comprises the following steps:
- sieving and mixing the active ingredient and the excipients;
- preparing granulating solution by dissolving surfactant in water;
- wet granulation of the mixed ingredients in the granulation solution;
- drying and sieving the granules;
- adding lubricant to the granules;
-compressing into tablets;
-optionally film-coating of the tablets.
Alternatively, a dry -granulation process may be used comprising the following steps:
- sieving and mixing the active ingredient and the excipients of the internal phase; -pre-compressing bulk to prepare granules;
-sieving to produce the granules;
- adding lubricant to the granules;
- compressing into tablets;
-optionally film-coating of the tablets.
Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
For the purposes of the present invention, a pharmaceutical composition comprising an active ingredient is considered to be “stable” if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions.
The primary goal of the present invention is to develop an immediate release film-coated tablet formulation comprising Rivaroxaban or a pharmaceutical acceptable salt thereof as the single drug substance that is simple to manufacture, bioavailable, cost effective, stable and possesses good pharmacotechnical properties. One of the major challenges in the design of the present pharmaceutical composition lies with the drug’s poor aqueous solubility which is linked to the bioavailability of Rivaroxaban. Solubility is one of the most important parameters to achieve desired concentration of a drug in systemic circulation. Poorly water-soluble drugs often require high doses in order to reach therapeutic plasma concentrations after oral administration. Any drug to be absorbed must be present in the form of an aqueous solution at the site of absorption. Most of the drugs are either weakly acidic or weakly basic having poor aqueous solubility.
In a preferred embodiment of the present invention, Rivaroxaban is employed in crystalline form. In particularly, the preferred form is crystalline Form I as described in WO-A-2007/039132. Rivaroxaban according to the present invention may be in an amount of from 4% to 20% w/w of the total weight of the tablet.
In addition to the active ingredient, the tablet composition also contains one or more inert materials known as excipients. The primary composition includes diluents, disintegrants, binders, glidants, lubricants and surfactants. Other excipients which give physical characteristics to the finished tablet are coloring agents, and flavors in the case of chewable tablets. Typically, excipients are selected to impart good flow and compression characteristics to the material being compressed. Excipients are also selected with the perspective to enhance dissolution, physicochemical characteristics, and stability of the drug substance in the final dosage form.
Dry granulation process for the preparation of solid dosage forms such as tablets is one of the most economical methods as only standard equipment is used and the tablets produced by this method are also characterized by satisfactory physical resistance with no need for special packaging. The main advantages of said process are that less equipment and space is required. Further, said process eliminates the need for binder solution, heavy mixing equipment and the costly and time- consuming drying step required for wet granulation.
Wet granulation using substantial amounts of wetting agent is the most common method used in pharmaceutical industry as it provides better prospects in terms of ease of processing and presumably less problems associated with physical characteristics of various ingredients in the formulation. Direct compression is more economic over wet or dry granulation since it requires fewer unit operations. This means less equipment, lower power consumption, less space, less time and less labor leading to reduced production cost of tablets. The tablets prepared by direct compression disintegrate into API particles instead of granules that directly come into contact with dissolution fluid and exhibits comparatively faster dissolution.
Both wet and dry granulation techniques specifically improve flow by creating granules with an increased particle size and improved cohesion during tablet compaction. More specifically wet granulation has further advantages such as improved tablet uniformity and API distribution and requires lower compression pressure during tableting and less environmental contamination. The inventors of the present invention tested various techniques to overcome problems connected to low solubility of the API.
Lubricants are essential component of the tablet formulation. Some pharmaceutical scientists believe that the manner of which a lubricant is added to a formulation must be carefully controlled. Accordingly, lubricants are usually added to a granulation by gentle mixing. It is also believed that prolonged blending of a lubricant with a granulate can materially affect hardness and disintegration time for the resulting tablets. For these reasons, the tablet core is divided into two phases, an internal and an external phase. Lubricants are to be used in the external phase of the tablet core to avoid prolonged blending with the excipients used in the internal phase.
Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression and allow for removal of the compressed tablet from the die. Examples of pharmaceutically acceptable lubricants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose. The lubricant component may be hydrophobic or hydrophilic. Magnesium stearate is the preferred lubricant in the present invention used in a concentration from 0.5% to 2 % w/w of the total weight of the tablet. It aids in the flow of the powder in the hopper and into the die. It is stable and does not polymerize within the tableting mix.
More particularly, one aspect of the invention includes a pharmaceutical formulation comprising Rivaroxaban and carefully selected excipients in the granules formulated in the internal phase during wet granulation and a lubricant dispensed at the external phase. A suitable binder and disintegrant are enclosed in the formulation to regulate the drug release rate and disintegration of film coated tablets.
Binders are used in the formulation of solid oral dosage forms to hold the API (active pharmaceutical ingredient) and excipients (inactive ingredients) together and to promote cohesive compacts for directly compressed tablets. Binders may be selected from acacia mucilage, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch and sucrose.
The preferred binder of the present invention is hydroxypropyl methylcellulose, also known as hypromellose, a water-miscible, “hydrophilic” polymer which modifies the drug release profile by forming a polymer gel layer in aqueous medium, effectively increasing the duration of release of a drug to prolong its therapeutic effect. Hydroxypropyl methylcellulose is used as tablet binder at concentrations of 2-15 % w/w in granulation and direct compression tableting processes. The preferred concentration of hydroxypropyl methylcellulose in the present invention is from 2% to 8,5% w/w of the total weight of the tablet, most preferably from 5% to 8,5% w/w of the total weight of the tablet.
Diluents are added to solid pharmaceutical dosage forms to make the product large enough for swallowing and handling, and more stable. Microcrystalline cellulose is available from several suppliers. Suitable microcrystalline cellulose includes Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH 105 and Avicel PH 200, manufactured by FMC Corporation. Anhydrous form of calcium phosphates is often used to overcome the problems related to dihydrate form. Other example of diluents are cellulose, cellulose acetate, dextrates, dextrin, dextrose, fructose, l-0-a- D-Glucopyranosyl-D-mannitol, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, lactose mono-hydrate, maltitol, mannitol, maltodextrin, maltose, pregelatinized starch, sodium chloride, sorbitol, starches, sucrose, talc and xylitol or a mixture of one or more of said diluents.
The preferred diluent of the present invention is microcrystalline cellulose and the preferred concentration is from 20% to 60% w/w of the total weight of the tablet. Another preferred diluent of the present invention is lactose monohydrate and the preferred concentration is from 10 to 50% w/w of the total weight of the tablet.
Different combinations of diluents were also tested in the present invention. A combination of microcrystalline cellulose and lactose monohydrate showed the best results in a total concentration from 60 to 90% w/w of the total weight of the tablet.
Disintegrants are included to ensure that the tablet has an acceptable rate of disintegration. Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone, cross-linked calcium carboxymethylcellulose and cross-linked sodium carboxymethylcellulose (croscarmellose sodium); soy polysaccharides; and guar gum, sodium starch glycolate. Croscarmellose sodium is reported to aid disintegration by rapid swelling and wicking upon contact with water. Wicking is a “whipping” action where material-air or material-material interface is spontaneously replaced by material-water interface and thus helps in maintaining capillary flow. Croscarmellose sodium is the preferred disintegrant used in the present invention in a concentration from 4% to 15% w/w of the total weight of the tablet.
Surfactants are materials that lower the surface tension between two liquids or between a liquid and a solid. Surfactants can be selected from sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate, sulphosuccinates such as sodium dioctyl sulphosuccinate, partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, partial fatty acid esters of sorbitan such as sorbitan monolaurate, partial fatty acid esters of polyhydroxyethylenesorbitan such as polyethylene glycol sorbitan monolaurate, monostearate or monooleate, polyhydroxyethylene fatty alcohol ethers, polyhydroxyethylene fatty acid esters, ethylene oxide-propylene oxide block copolymers (Pluronic®) or ethoxylated triglycerides. Sodium lauryl sulphate is the surfactant preferably used in the present invention in a concentration of 0.5% to 8% w/w of the total weight of the tablet, more preferably in a concentration of 0.5% to 6.5% w/w of the total weight of the tablet as it enhances the active ingredient’s poor solubility.
Surprisingly, there was a significant improvement in the physicochemical characteristics of the tablet when the pre-compressed granules prepared in dry granulation process, were sieved so that more than 60% of the sieved granules have a size by weight that is higher than 160pm. Pre compressed granules in dry granulation process are prepared after dry mixing the excipients of the internal phase and compressing in large punches (20mm) in order to improve cohesiveness of the granule.
Similarly, in a simple wet granulation process, the dried granules obtained after mixing the excipients of the internal phase & kneading with a wet solution of the surfactant, when sieved so that more than 60% of the sieved granules have a size by weight that is higher than 160pm, resulted in immediate release tablets of Rivaroxaban with the desired physicochemical properties.
EXAMPLES
The scope of the present invention is the preparation of a stable pharmaceutical dosage form for oral administration comprising Rivaroxaban exhibiting an immediate drug release profile at aqueous medium. Also, the pharmaceutical composition shall be bioequivalent to reference product as per acceptance criteria indicated for generic products and be stable under different storage conditions.
The target characteristics for the tablets are the following:
Figure imgf000010_0001
The formulations were tested for their physical characteristics as well as their dissolution properties. The examples below present the results when a lower amount of Rivaroxaban was included in the formulation trials, however similar results were obtained for amount of Rivaroxaban up to 20% by weight (keeping the amount of excipients on the same levels).
Example 1:
The first step in formulation development was to produce compositions based on direct compression process (Table 1), which is the simplest manufacturing process, and study their impact on product’s characteristics. Table 1: Composition of Trial 1
Figure imgf000011_0001
Manufacturing process (Direct Compression)
1. Sieve the Rivaroxaban and SLS and mix. 2. Sieve Lactose monohydrate, MCC, HPMC, croscarmellose sodium through and mix.
3. Combine granule of step 1 & 2 and mix.
4. Sieve Magnesium stearate, add to the blend and continue mixing.
5. Compression to tablets.
6. Film-Coating of tablets.
The physical characteristics as well as the dissolution profile of composition of Trial 1 are presented in tables 2 and 3 below:
Table 2: Physical characteristics of composition of Trial 1
Figure imgf000011_0002
Table 3: Dissolution profile of Trial 1 in Acetate Buffer pH 4.5 (0.2% SLS), 900mL, Paddles, 50rpm
Figure imgf000012_0001
According to the results presented above, direct compression process provides poor flow properties (Carr’s Index out of target) as well as poor dissolution.
Example 2:
The next step in formulation development was to produce compositions based on dry granulation process and study the physicochemical characteristics of tablets as well as their dissolution properties. Two formulations were prepared (2.1 & 2.2) with different amount of SLS. For each formulation the pre-compressed granules were sieved appropriately to get 60% of the particles by weight with size higher than 160pm (formulations 2.1 A & 2.2A) & 60% of the particles by weight with size lower than 160pm (formulations 2. IB & 2.2B).
Table 4: Formulations based on the dry granulation process (Trial 2.1 & Trial 2.2).
Figure imgf000012_0002
Manufacturing process (Dry granulation)
1. Sieve the Rivaroxaban, MCC, Lactose monohydrate, HPMC, croscarmellose sodium and SLS and mix. 2. Pre-compress bulk of step 1, using 20mm round punch at low compression force to prepare granules.
3. Pass through appropriate sieves to produce granules that have 60% of the particles by weight with size higher than 160pm (formulations 2.1 A & 2.2A) or 60% of the particles by weight with size lower than 160pm (formulations 2. IB & 2.2B).
4. Sieve Magnesium Stearate, add it to the granules of step 3 and mix.
5. Compression to tablets.
6. Film-Coating of tablets. Table 5: Carr’s index and particle size
Figure imgf000013_0001
Table 6: Dissolution profiles Acetate Buffer pH 4.5 (0.2% SLS), 900mL, Paddles, 50rpm
Figure imgf000013_0002
Trials 2. IB & 2.2B presented a slow dissolution profile. Also, Trial 2.2A is in the acceptable range. Example 3 :
The next step in formulation development was to produce compositions based on wet granulation process in order to study their impact on product’s characteristics. Three formulations were prepared (3.1, 3.2 & 3.3) with different amount of SLS. For each formulation the granules after drying were sieved appropriately to get 60% of the particles by weight with size higher than 160pm (formulations 3.1 A, 3.2A & 3.3A) & 60% of the particles by weight with size lower than 160pm (formulations 3. IB, 3.3B & 3.3B). Table 7: Formulations based on wet granulation process (Trial 3, 3.1, 3.2, 3.3)
Figure imgf000014_0001
Manufacturing process (Wet granulation)
1. Sieve Rivaroxaban, MCC, Lactose monohydrate, HPMC, croscarmellose sodium through and mix. 2. Dissolve SLS in the appropriate quantity of water and knead mixture of step 1 with SLS solution.
3. Dry at 40°C and then pass the granules through appropriate sieves to get 60% of the particles by weight with size higher than 160pm (formulations 3.1A, 3.2A & 3.3A) & 60% of the particles by weight with size lower than 160pm (formulations 3. IB, 3.3B & 3.3B. 4. Sieve Magnesium Stearate, add to the granules of step 3 and mix.
5. Compression to tablets.
6. Film-Coating of tablets. Table 8: Carr’s index and particle size
Figure imgf000015_0001
Table 9: Dissolution profiles Acetate Buffer pH 4.5 (0.2% SLS, Trial 3.2 & 0.4% SLS Trial 4),
900mL, Paddles, 50rpm
Figure imgf000015_0002
According to the results wet granulation process Trials 3. IB, 3.2B & 3.3B presented a slow dissolution profile..
In addition, tablets of both dry and wet granulation were stored under normal and accelerated conditions for 6 months and were examined for their physical properties in terms of polymorphic form as well as chemical properties in terms of impurities in appropriate time points in order to study their stability. Based on the stability results, trial formulations of examples 2 and 3 remain stable after 6 months storage under normal and accelerated conditions with regards to polymorphic form and impurities.

Claims

1. An immediate release solid pharmaceutical composition for oral administration comprising Rivaroxaban or a pharmaceutically acceptable salt thereof in an amount of from 4% to 20% w/w of the total weight of the tablet and sodium lauryl sulphate from 0,5% to 8,0% w/w of the total weight of the tablet.
2. The pharmaceutical composition according to claim 1, wherein the amount of sodium lauryl sulphate is from 0,5% to 6,5% w/w of the total weight of the tablet.
3. The pharmaceutical composition according to any preceding claim, wherein it further comprises a binder, a diluent and a disintegrant in the internal phase and a lubricant in the external phase.
4. The pharmaceutical composition according to claim 3, wherein the binder is hydroxypropyl methylcellulose.
5. The pharmaceutical composition according to claim 4, wherein the amount of hydroxypropyl methylcellulose is from 2% to 8,5% w/w of the total weight of the tablet, most preferably from 5 to 8,5% w/w of the total weight of the tablet.
6. The pharmaceutical composition according to claim 3, wherein the diluent is microcrystalline cellulose, lactose monohydrate or a combination thereof.
7. The pharmaceutical composition according to claim 3, wherein the disintegrant is croscarmellose sodium.
8. The pharmaceutical composition according to claim 7, wherein the amount of croscarmellose sodium is from 4% to 15% w/w of the total weight of the tablet.
9. Granules manufactured by dry or wet granulation appropriately sieved so that more than 60% of the particles by weight have size higher than 160pm, wherein said granules comprise Rivaroxaban or a pharmaceutically acceptable salt thereof in an amount of from 4% to 20% w/w of the total weight of the tablet and sodium lauryl sulphate from 0,5% to 8,0% w/w of the total weight of the tablet.
10. A process for the preparation of a stable, solid dosage form for oral administration, comprising Rivaroxaban or pharmaceutical acceptable salt thereof as an active ingredient in an amount of from 4% to 20% w/w of the total weight of the tablet and sodium lauryl sulphate from 0,5% to 8,0% w/w of the total weight of the tablet, which comprises:
- sieving and mixing the active ingredient and the excipients of the internal phase;
- preparing granulating solution by dissolving sodium lauryl sulphate in water;
- wet granulation of the mixed ingredients in the granulation solution;
- drying the granules & appropriately sieving so that more than 60% of the particles by weight have size higher than 160pm;
- adding lubricant to the sieved granules & mixing;
-compressing into tablets;
-optionally film-coating of the tablets.
11. A process for the preparation of a stable, solid dosage form for oral administration, containing an anticoagulant agent, and in particular Rivaroxaban or pharmaceutical acceptable salt thereof as an active ingredient in an amount of from 4% to 20% w/w of the total weight of the tablet and sodium lauryl sulphate from 0,5% to 8,0% w/w of the total weight of the tablet, which comprises:
- sieving and mixing the active ingredient, sodium lauryl sulfate and the excipients of the internal phase ;
-pre-compressing the mixture
- appropriately sieving the pre-compressed granules so that more than 60% of the particles by weight have size higher than 160pm;;
- adding lubricant to the sieved granules;
- compressing into tablets;
-optionally film-coating of the tablets.
PCT/EP2022/025120 2021-03-24 2022-03-24 Pharmaceutical composition comprising rivaroxaban and method of preparation thereof WO2022199896A1 (en)

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